Ambrose S. Kibos Bradley P. Knight Vidal Essebag Steven B. Fishberger Mark Slevin Ion C. Țintoiu Editors
Cardiac Arrhythmias From Basic Mechanism to State-of-the-Art Management
123
Cardiac Arrhythmias
Ambrose S. Kibos • Bradley P. Knight Vidal Essebag • Steven B. Fishberger Mark Slevin • Ion C. T¸intoiu Editors
Cardiac Arrhythmias From Basic Mechanism to State-of-the-Art Management
Editors Ambrose S. Kibos, MD, PhD Department of Cardiology Center Hospitalier Coutances Coutances France Bradley P. Knight, MD, FACC, FHRS Division of Cardiology Department of Internal Medicine Northwestern University Feinberg School of Medicine Chicago, Illinois USA Vidal Essebag, MD, PhD, FRCPC, FACC Division of Cardiology McGill University Health Center Montreal Québec Canada
Steven B. Fishberger, MD Department of Cardiology Miami Children’s Hospital Miami, Florida USA Mark Slevin, PhD, FRCPath School of Healthcare Science Manchester Metropolitan University Manchester United Kingdom Ion C. T¸intoiu, MD, PhD, FESC “Acad. Vasile Candea” Emergency Clinical Center for Cardiovascular Diseases, “Carol Davila” University of Medicine and Pharmacy, “Titu Maiorescu” University Faculty of Medicine Bucharest Romania
ISBN 978-1-4471-5315-3 ISBN 978-1-4471-5316-0 DOI 10.1007/978-1-4471-5316-0 Springer London Heidelberg New York Dordrecht
(eBook)
Library of Congress Control Number: 2013956936 © Springer-Verlag London 2014 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. Exempted from this legal reservation are brief excerpts in connection with reviews or scholarly analysis or material supplied specifically for the purpose of being entered and executed on a computer system, for exclusive use by the purchaser of the work. Duplication of this publication or parts thereof is permitted only under the provisions of the Copyright Law of the Publisher's location, in its current version, and permission for use must always be obtained from Springer. Permissions for use may be obtained through RightsLink at the Copyright Clearance Center. Violations are liable to prosecution under the respective Copyright Law. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. While the advice and information in this book are believed to be true and accurate at the date of publication, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com)
This book is dedicated to my family, Gabriela, David, Victoria, and Peter, for their love and support; to all the current and future professionals of arrhythmias for whom this book was written; Additional thanks to Dr. Lucian Gheorghe, Dr. Vasile Murgu, Dr. Ionel Droc, Dr. Mocanu Iancu, Dr. Vasile Greere, Dr. Daniel Nita, Dr. Adela Cirstea, Dr. Gabriel Cristian. Special thanks are owed to Dr. Blanca Calinescu, Dr. Chantal Trudeau, Dr Jenica Roates, Associate Professor Liviu Chiriac, Professors Alexandru Campeanu, Tiberiu Nanea, and Ion C. T¸intoiu, for their guardianship, friendship and support through the good and bad times. I am eternally grateful to all Editors of this book who actively participated with me to realize this Edition. Ambrose S. Kibos, MD, PhD
Foreword
The field of cardiac arrhythmias has had a remarkable and light-speed progress in the past two decades. From being the Cinderella of Cardiology and practiced in dark damp basements in many institutions around the world, this field is now at the forefront of every cardiology division. Similarly the progress in understanding the mechanisms, anatomy, diagnosis, and treatment of all different forms of cardiac arrhythmias has been overwhelming in the past decade. The twenty-first-century cardiac electrophysiologist has to a possess a large bulk of knowledge in this field and is confronted with the challenge of staying updated at the millisecond pace in which new developments occur, a fate rarely seen in other subspecialties. For this reason this first edition of Cardiac Arrhythmias: From Basic Mechanism to State-of-the-Art Management encompasses one of the most comprehensive updated textbooks available to date. In its four sections this multiauthored international compilation brightly reviews the anatomy of arrhythmias, diagnostic methods, and diseases associated with arrhythmias and treatment of all forms of cardiac arrhythmias with lavishly illustrated and ample discussions on the most modern ablation and mapping techniques available to date. Similarly the field of devices in the management of cardiac arrhythmias is superbly reviewed. This new textbook adds to the field of cardiac arrhythmias a new and fresh perspective and should be useful not only for the trainee and new upcoming electrophysiologist but also for the seasoned one. This book should be on the shelves of all cardiac arrhythmia units around the globe as it is authored by a significant number of the most influential electrophysiologists in the field and presents a comprehensive and practical approach to cardiac arrhythmias. Carlos A. Morillo, MD, FRCPC, FACC, FHRS, FESC
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Preface
The past 50 years have witnessed the growth and evolution of clinical electrophysiology from a field whose initial goals were the understanding of arrhythmia mechanisms to one of significant therapeutic impact. The development and refinement of implantable devices and catheter ablation have made non-pharmacological therapy a treatment of choice for most arrhythmias encountered in clinical practice. The purpose of this book is to provide the “caring electrophysiologist” with an electrophysiologic approach to arrhythmias, which is predicted on the hypothesis that a better understanding of the mechanisms of arrhythmias will lead to more successful and rationally chosen therapy. As such, the techniques suggested to address these issues and specific therapeutic interventions employed represent a personal view on intuition, based on experiences of world renowned scientists. These include among others, Steve Fishberger, Vidal Essebag, Bradley Knight, G André Ng, Mauricio Scanavacca, Cheuk-Man Yu, Ion T¸intoiu and Mark Slevin. Ambrose S. Kibos, MD, PhD
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Letter from the Editors
Cardiac Arrhythmias: From Basic Mechanism to State-of-the-Art Management The editors of this book had three primary objectives. The first objective was to develop an outline for a comprehensive, modern-era textbook on heart rhythm disorders that properly covered each of the major topics in the field – from basic mechanisms to state-of-the-art clinical management. Careful organization of the chapters and precise wording of each chapter title were important to ensure that critical issues were all addressed and presented in a logical fashion. The second goal was to appropriately select the best possible authors for each chapter. The ideal author for a book chapter is not just an expert in the field with recognized experience and authority, but is also someone who is able to effectively communicate the key teaching points for the topic, has excellent writing skills, and can reliably meet submission deadlines. It was critical that these two objectives were accomplished very early in the planning stages of the book to lay the groundwork for the contributors. The third objective of the editors was to ensure that the finished product was of the best possible quality. Each chapter was thoroughly reviewed by at least one editor for both content and presentation. This can be a challenging task when the chapters are each written by different authors selected from all over the world, where English may not be the primary language and where books may have variable writing styles and formats. In addition, most of the chapters themselves were a product of collaboration among multiple authors who had to choreograph their work. Fortunately, we had the luxury of reviewing work from an outstanding international group of authors. This made our task enjoyable and educational. Any multiauthored book that ventures to cover as many topics as are covered in this book will inevitably contain some redundancy. We felt that it was more important to allow each author to fully present his or her topic in a chapter that could stand alone, rather than to try and eliminate all redundant content. We would like to thank each and every author for their effort and contribution and hope that you enjoy reading this book as much as each of the editors did when putting this collection together. Chicago, IL, USA
Bradley P. Knight, MD, FACC, FHRS
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Contents
1
2
3
4
Anatomy and Physiology of the Atrioventricular Node: Basic Concepts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ambrose S. Kibos and Blanca F. Calinescu
1
Anatomy and Physiology of the Atrioventricular Node: What Do We Know Today? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hidekazu Miyazaki
5
Molecular Basis of Arrhythmias Associated with the Cardiac Conduction System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sunil Jit R.J. Logantha, Andrew J. Atkinson, Mark R. Boyett, and Halina Dobrzynski Functional Anatomy in Arrhythmias and Vascular Support of the Conduction System. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cristian Stătescu, Radu A. Sascău, and Cătălina Arsenescu Georgescu
19
35
5
Autonomic Control of Cardiac Arrhythmia . . . . . . . . . . . . . . . . . . . . . . . . . . . . Kieran E. Brack and G. André Ng
43
6
Neural Mechanisms of Arrhythmia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hyung-Wook Park and Jeong-Gwan Cho
61
7
Understanding the Genetic Basis of Atrial Fibrillation: Towards a Pharmacogenetic Approach for Arrhythmia Treatment . . . . . . . . . . . . . . . . Jason D. Roberts and Michael H. Gollob
65
8
Importance of Isthmus Structure in the Right Atrium . . . . . . . . . . . . . . . . . . . Jiunn-Lee Lin, Ling-Ping Lai, Liang-Yu Lin, Chia-Ti Tsai, and Chih-Chieh Yu
77
9
Channelopathies and Heart Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Bogdan Amuzescu, Bogdan Istrate, and Sorin Musat
95
10
Late Open Artery Hypothesis and Cardiac Electrical Stability . . . . . . . . . . . . Craig Steven McLachlan, Brett Hambly, and Mark McGuire
131
11
The Clinical Utility of 12-Lead Resting ECG in the Era of Ablation Strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Jang-Ho Bae, Taek-Geun Kwon, and Ki-Hong Kim
145
12
Long-Term ECG (Holter) Monitoring and Head-Up Tilt Test . . . . . . . . . . . . . Santosh Kumar Dora
157
13
Echocardiography in Arrhythmias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ioan Tiberiu Nanea
165
14
Electrophysiologic Testing and Cardiac Mapping . . . . . . . . . . . . . . . . . . . . . . . Mitsunori Maruyama and Teppei Yamamoto
187
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xiv
15
16
17
18
Contents
How to Differentiate Between AVRT, AT, AVNRT, and Junctional Tachycardia Using the Baseline ECG and Intracardiac Tracings . . . . . . . . . . Sharon Shen and Bradley P. Knight
199
Recognizing the Origin of Ventricular Premature Depolarization During Sinus Rhythm and During Non-sustained Tachycardia . . . . . . . . . . . . Seow Swee-Chong
209
Detection and Management of Atrial Fibrillation in Patients with Stroke or TIA in Clinical Practice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Jerzy Krupinski, Jorge de Francisco, and Sonia Huertas
221
Ventricular Arrhythmias During Acute Myocardial Ischemia/ Infarction: Mechanisms and Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Theofilos M. Kolettis
237
19
Arrhythmias and Hypertrophic Cardiomyopathy . . . . . . . . . . . . . . . . . . . . . . . Krishnakumar Nair, Douglas Cameron, Gil Moravsky, and Jagdish Butany
253
20
Lai Tai, the Mysterious Death of Young Thai Men . . . . . . . . . . . . . . . . . . . . . . Gumpanart Veerakul, Lertlak Chaothawee, Kriengkrai Jirasirirojanakorn, and Koonlawee Nademanee
265
21
Cardiac Arrest Arrhythmias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Riccardo Proietti, Jacqueline Joza, Florea Costea, Mihai Toma, Dan Mănăstireanu, and Vidal Essebag
279
22
Electrical Storm: Recent Advances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mitsunori Maruyama and Teppei Yamamoto
285
23
Electrical Storm: Clinical Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sofia Metaxa, Spyridon Koulouris, and Antonis S. Manolis
293
24
Cellular Pharmacology of Cardiac Automaticity and Conduction: Implications in Antiarrhythmic Drug Assessment . . . . . . . . . . . . . . . . . . . . . . Gary Aistrup
305
25
Biophysical and Molecular Targets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mark Slevin, Michael Carroll, Chris Murgatroyd, and Garry McDowell
335
26
Proarrhythmia (Secondary) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Debabrata Dash
345
27
Connexin-43 Expression: A Therapeutic Target for the Treatment of Ventricular Tachycardia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Craig Steven McLachlan, Zakaria Ali Moh Almsherqi, Brett Hambly, and Mark McGuire
351
28
Biophysics of Modern Ablation Techniques and Their Limitations . . . . . . . . Erik Wissner and Andreas Metzner
361
29
Cardiac Imaging to Assist Complex Ablation Procedures . . . . . . . . . . . . . . . . Alejandro Jimenez Restrepo and Timm M. Dickfeld
369
30
AVNRT Ablation: Significance of Anatomic Findings and Nodal Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Félix Ayala-Paredes, Jean-Francois Roux, and Mariano Badra Verdu
31
Mechanisms of Atrial Fibrillation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Rishi Arora and Hemantha K. Koduri
387 401
Contents
xv
32
Importance of Left Atrial Imaging in Catheter Ablation of Atrial Fibrillation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Seil Oh, Youngjin Cho, and Eue-Keun Choi
413
33
Atrial Fibrillation Ablation: From Guidelines to Clinical Reality . . . . . . . . . . Joseph M. Lee and Steven M. Markowitz
419
34
Atrial Fibrillation: Should Cardiac Surgeons Be Consulted? . . . . . . . . . . . . . Max Baghai, Randolph H.L. Wong, Innes Y.P. Wan, and Malcolm John Underwood
439
35
Atrial Arrhythmias After AF Ablation: Challenge for the Next Decade?. . . . Tamás Tahin and Gábor Széplaki
451
36
Cavotricuspid Isthmus Anatomy Particularities in Atrial Flutter Ablation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Liviu Chiriac, Gabriel Cristian, Romi Bolohan, and Ion C. T¸intoiu
37
Location of Accessory Pathways in WPW: What and How Should We Ablate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Bieito Campos, Xavier Viñolas, José M. Guerra, Concepción Alonso, and Enrique Rodríguez
463
469
38
VT Ablation Importance of Linear Lesions and Late Potentials . . . . . . . . . . . Cristiano Pisani, Sissy Lara Melo, Carina Hardy, and Mauricio Scanavacca
489
39
Programmed Stimulation During Mapping and Ablation of VT . . . . . . . . . . . Yaariv Khaykin
497
40
Catheter Ablation in Pediatric and Congenital Heart Disease . . . . . . . . . . . . . Steven B. Fishberger
509
41
Interventional Electrophysiology in Patients with Congenital Heart Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sissy Lara Melo, Cristiano Pisani, Eduardo Sosa, and Mauricio Scanavacca
517
42
Epicardial Mapping and Ablation of Cardiac Arrhythmias . . . . . . . . . . . . . . Robert Lemery
525
43
Robotic Ablation in Electrophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ferdi Akca, Lara Dabiri, and Tamas Szili-Torok
533
44
Strategies for Restoring Cardiac Synchrony by Cardiac Pacing . . . . . . . . . . . Gabriel Cristian, Ecaterina Bontas, Liviu Chiriac, Silviu Ionel Dumitrescu, and Ion C. T¸intoiu
543
45
Device Therapy for Bradycardias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Chung-Wah Siu and Hung-Fat Tse
591
46
Pacemaker Dependence After Atrioventricular Node Ablation . . . . . . . . . . . . Joseph Yat-Sun Chan and Cheuk-Man Yu
597
47
Pacing Site: From Theory to Practice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cristian Stătescu and Cătălina Arsenescu Georgescu
605
48
Implantable Cardioverter Defibrillators in the Pediatric and Congenital Heart Population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Steven B. Fishberger
613
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Contents
49
Sensing Issues in CRT Devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Giuseppe Stabile, Assunta Iuliano, and Roberto Ospizio
50
Cardiac Resynchronization Therapy: Do Benefits Justify the Costs and Are They Sustained Over the Long Term? . . . . . . . . . . . . . . . . . . . . . . . . . Chin-Pang Chan and Cheuk-Man Yu
619
629
51
Complications of Cardiac Implantable Electronic Devices (CIED) . . . . . . . . . Sorin Pescariu and Raluca Sosdean
639
52
Peri-device Implantation Anticoagulation Management: Evidence and Clinical Implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Alexander Omelchenko, Martin Bernier, David Birnie, and Vidal Essebag
653
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
665
List of Contributors
Gary Aistrup, PhD Feinberg Cardiovascular Research Institute, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA Ferdi Akca Department of Clinical Electrophysiology, Thoraxcenter, Erasmus MC, Rotterdam, The Netherlands Zakaria Ali Moh Almsherqi, MD, PhD Department of Physiology, National University of Singapore, Singapore, Singapore Concepción Alonso, MD Electrophysiology and Arrhythmia Unit, Department of Cardiology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain Bogdan Amuzescu, MD, PhD Department of Biophysics and Physiology, Faculty of Biology, University of Bucharest, Bucharest, Romania Rishi Arora, MD Division of Cardiology, Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL, USA Andrew J. Atkinson Institute of Cardiovascular Sciences, School of BioMedicine, University of Manchester, Manchester, UK Félix Ayala-Paredes, MD, PhD Cardiology Service, CHUS, Sherbrooke University Hospitals, Sherbrooke, QC, Canada Jang-Ho Bae, MD, PhD, FACC Department of Internal Medicine, Heart Center, Konyang University Hospital, Daejeon, South Korea Max Baghai, MBBS, PhD, FRCS(CTh) Division of Cardiothoracic Surgery, Chinese University of Hong Kong, Prince of Wales Hospital, Sha Tin, Hong Kong Martin Bernier, MD Division of Cardiology, McGill University Health Center, Montreal, QC, Canada David Birnie, MB, ChB, MD Division of Cardiology, University of Ottawa, Heart Institute, Ottawa, ON, Canada Romi Bolohan, PhD Department of Cardiology, Army’s Clinical Center for Cardiovascular Disease, Bucharest, Romania Ecaterina Bontas, MD “Prof. Dr. C.C. Iliescu” Institute for Cardiovascular Diseases, Bucharest, Romania Mark R. Boyett, PhD Institute of Cardiovascular Sciences, School of BioMedicine, University of Manchester, Manchester, UK Kieran E. Brack, BSc, PhD Department of Cardiovascular Sciences, University of Leicester, Leicester, UK Jagdish Butany, MBBS, MS, FRCPC Division of Pathology, Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada xvii
xviii
Blanca F. Calinescu, MD Cardiovascular Surgery Department, Army’s Clinic Center for Cardiovascular Diseases, Bucharest, Romania Douglas Cameron Division of Cardiology, Department of Medicine, University of Toronto, Toronto, ON, Canada Bieito Campos, MD Electrophysiology and Arrhythmia Unit, Department of Cardiology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain Michael Carroll, PhD School of Healthcare Science, Manchester Metropolitan University, Manchester, UK Chin-Pang Chan, MRCP Division of Cardiology, Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR Joseph Yat-Sun Chan, FRCP Division of Cardiology, Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong Lertlak Chaothawee, MD, MSc Division of Cardiac Imaging, Bangkok Heart Hospital, Pacific Rim Electrophysiology Research Institute at Bangkok Hospital, Bangkok, Thailand Cardiac Imaging Unit, Bangkok Heart Hospital, Bangkok, Thailand Liviu Chiriac, MD, PhD, FESC Titu Maiorescu University of Medicine, Bucharest, Romania Department of Cardiology, Army’s Clinical Center for Cardiovascular Diseases, Bucharest, Romania Jeong-Gwan Cho, MD, PhD Department of Cardiovascular Medicine, Chonnam National University Hospital, Donggu, Gwangju, South Korea Youngjin Cho, MD Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea Eue-Keun Choi, MD, PhD Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea Florea Costea, MD, PhD Student Faculty of Medicine, Titu Maiorescu University, Bucharest, Romania Emergency Department Central Universitary Emergency Military Hospital “Dr. Carol Davila”, Bucharest, Romania Gabriel Cristian, MD, PhD, FESC Titu Maiorescu University of Medicine, Bucharest, Romania Department of Cardiology, Army’s Clinical Center for Cardiovascular Disease, Bucharest, Romania Lara Dabiri, MD Department of Clinical Electrophysiology, Thoraxcenter, Erasmus MC, Rotterdam, The Netherlands Debabrata Dash, MD, DM, FICC, FCCP, FSCAI, FAPSC Department of Cardiology, S.L. Raheja (a Fortis Associate) Hospital, Mumbai, MH, India Jorge de Francisco, MD Cerebrovascular Diseases Unit, Department of Neurology, Hospital Universitari Mútua Terrassa, Terrassa, Barcelona, Spain Timm M. Dickfeld, MD, PhD Division of Cardiology, University of Maryland Medical Center, Baltimore, MD, USA Halina Dobrzynski, PhD Institute of Cardiovascular Sciences, School of BioMedicine, University of Manchester, Manchester, UK
List of Contributors
List of Contributors
xix
Santosh Kumar Dora, MD, DM Cardiac Electrophysiology and Pacing, Asian Heart Institute and Research Center, Mumbai, MH, India Silviu Ionel Dumitrescu, MD, PhD “Acad. Vasile Candea” Emergency Clinical Center for Cardiovascular Diseases, “Titu Maiorescu” University, Faculty of Medicine, Calea Plevnei 134, Bucharest, Romania Vidal Essebag, MD, PhD, FRCPC, FACC Division of Cardiology, McGill University Health Center, Montreal, QC, Canada Steven B. Fishberger, MD Department of Cardiology, Miami Children’s Hospital, Miami, FL, USA Cătălina Arsenescu Georgescu, MD, PhD, FESC Cardiology and Internal Medicine, “Gr.T. Popa” University of Medicine and Pharmacy, Iaşi, Romania Cardiology Department, “George I.M. Georgescu” Cardiovascular Diseases Institute, Iaşi, Romania Michael H. Gollob, MD Inherited Arrhythmia Clinic and Research Laboratory, University of Ottawa Heart Institute, Ottawa, ON, Canada José M. Guerra, MD, PhD Electrophysiology and Arrhythmia Unit, Cardiology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain Brett Hambly, MBBS, PhD, DipAnt Department of Pathology, University of Sydney, Darlington, NSW, Australia Carina Hardy, MD Arrhythmia Clinical Unit, Heart Institute of the University of São Paulo Medical School, São Paulo, Brazil Sonia Huertas, MD Cerebrovascular Diseases Unit, Department of Neurology, Hospital Universitari Mútua Terrassa, Terrassa, Barcelona, Spain Bogdan Istrate, PhD Department of Biophysics and Physiology, Faculty of Biology, University of Bucharest, Bucharest, Romania Assunta Iuliano, MD Laboratorio di Elettrofisiologia – Clinica Mediterranea, Naples, Italy Kriengkrai Jirasirirojanakorn, MD Division of Cardiology, Department of Medicine, Cardiovascular Research and Prevention Center, Bhumibol Adulyadej Hospital, Bangkok, Thailand Yaariv Khaykin, MD, FRCPC, FACC, FHRS Division of Cardiology, Department of Medicine, Southlake Regional Health Center, Newmarket, Toronto, ON, Canada Faculty of Medicine, University of Toronto, Toronto, ON, Canada Heart Rhythm Program, Southlake Regional Health Centre, Newmarket, Toronto, ON, Canada Ambrose S. Kibos, MD Department of Cardiology, Center Hospitalier Coutances, Coutances, France Ki-Hong Kim, MD Department of Internal Medicine, Heart Center, Konyang University Hospital, Daejeon, South Korea Bradley P. Knight, MD, FACC, FHRS Division of Cardiology, Department of Internal Medicine, Bluhm Cardiovascular Institute, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA Hemantha K. Koduri, MD Division of Cardiology, Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL, USA Theofilos M. Kolettis, MD, PhD, FESC Department of Cardiology, University of Ioannina, Ioannina, Greece
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Spyridon Koulouris, MD Department of Cardiology, Evagelismos General Hospital of Athens, Athens, Greece Jerzy Krupinski, MD, PhD, DsC Cerebrovascular Diseases Unit, Department of Neurology, Hospital Universitari Mútua Terrassa, Terrassa, Barcelona, Spain Taek-Geun Kwon, MD, PhD Department of Internal Medicine, Heart Center, Konyang University Hospital, Daejeon, South Korea Ling-Ping Lai, MD, PhD Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan ROC Joseph M. Lee, MD, MSc Division of Cardiology, Department of Medicine, Weill Cornell Medical College, New York, NY, USA Division of Cardiac Electrophysiology Laboratory, New York Presbyterian Hospital, New York, NY, USA Robert Lemery, MD Division of Cardiology, University of Ottawa Heart Institute, Ottawa, ON, Canada Jiunn-Lee Lin, MD, PhD Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan ROC Liang-Yu Lin, MD, PhD Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan ROC Sunil Jit R.J. Logantha, PhD Cardiovascular Research Group, School of BioMedicine, University of Manchester, Manchester, UK Dan Mănăstireanu, MD, PhD Faculty of Medicine, Titu Maiorescu University, Bucharest, Romania Department of Surgical Specialities, Discipline Disaster Medicine, Bucharest, Romania Antonis S. Manolis, MD Department of Cardiology, Evagelismos General Hospital of Athens, Athens, Greece Steven M. Markowitz, MD Division of Cardiology, Department of Medicine, Weill Cornell Medical College, New York, NY, USA Division of Cardiac Electrophysiology Laboratory, New York Presbyterian Hospital, New York, NY, USA Mitsunori Maruyama, MD, PhD Cardiovascular Center, Chiba-Hokuso Hospital, Nippon Medical School, Inzai, Chiba, Japan Garry McDowell, PhD, FRCPath Health and Biomedical Science, University of Edgehill, Ormskirk, Liverpool, UK Mark McGuire, MBBS, PhD, FRACP Department of Cardiology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia Craig Steven McLachlan, PhD Rural Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia Sissy Lara Melo, MD, PhD Arrhythmia Clinical Unit, Heart Institute of the University of São Paulo Medical School, São Paulo, SP, Brazil Sofia Metaxa, MD Department of Cardiology, Evagelismos General Hospital of Athens, Athens, Greece
List of Contributors
List of Contributors
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Andreas Metzner, MD Department of Cardiology, Asklepios Klinik St. Georg, Hamburg, Germany Hidekazu Miyazaki, MD, PhD, CCDS Division of Cardiology, Department of Medicine, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan Department of Cardiology, Kawasaki Municipal Tama Hospital, Kawasaki, Kanagawa, Japan Gil Moravsky Division of Cardiology, Department of Medicine, University of Toronto, Toronto, ON, Canada Chris Murgatroyd, PhD School of Healthcare Science, Manchester Metropolitan University, Manchester, UK Sorin Musat, MD, PhD Department of Biophysics and Physiology, Faculty of Biology, University of Bucharest, Bucharest, Romania Koonlawee Nademanee, MD, FACC, FAHA Division of Electrophysiology, Pacific Rim Arrhythmia Research Institute at Bangkok Heart Hospital, Bangkok, Thailand Krishnakumar Nair Division of Cardiology, Department of Medicine, University of Toronto, Toronto, ON, Canada Ioan Tiberiu Nanea, MD, PhD, FESC Department of Cardiology, Prof Dr Th. Burghele University Hospital, University of Medicine and Pharmacy Carol Davila, Bucharest, Romania G. André Ng, MBChB, PhD, FRCP(Glasg), FRCP, FESC Department of Cardiovascular Sciences, University of Leicester, Leicester, UK Department of Cardiology, Glenfield Hospital, University Hospitals of Leicester NHS Trust, Leicester, UK Leicester Cardiovascular Biomedical Research Unit, National Institute for Health Research, Leicester, UK Seil Oh, MD, PhD, FHRS Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea Alexander Omelchenko, MD Division of Cardiology, McGill University Health Center, Montreal, QC, Canada Roberto Ospizio, BS Cardiac Rhythm Management, Boston Scientific, Naples, Italy Hyung-Wook Park, MD, PhD Department of Cardiovascular Medicine, Chonnam National University Hospital, Donggu, Gwangju, South Korea Sorin Pescariu, MD, PhD Department of Cardiology, “Victor Babeş” University of Medicine and Pharmacy, Timişoara, Romania Cristiano Pisani, MD Arrhythmia Clinical Unit, Heart Institute of the University of São Paulo Medical School, São Paulo, SP, Brazil Alejandro Jimenez Restrepo, MD Cardiology Department, Wellington Regional Hospital, Wellington, New Zealand International Arrhythmia Center, Fundacion Cardioinfantil, Bogota, Colombia Jason D. Roberts, MD Inherited Arrhythmia Clinic and Research Laboratory, University of Ottawa Heart Institute, Ottawa, ON, Canada Enrique Rodríguez, MD Electrophysiology and Arrhythmia Unit, Cardiology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
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Jean-Francois Roux, MD Cardiology Service, CHUS, Sherbrooke University Hospitals, Sherbrooke, QC, Canada Radu A. Sascău, MD, PhD Cardiology and Internal Medicine, “Gr.T. Popa” University of Medicine and Pharmacy, Iaşi, Romania Echocardiography Department “George I.M. Georgescu” Cardiovascular Diseases Institute, Iaşi, Romania Mauricio Scanavacca, MD, PhD Arrhythmia Clinical Unit, Heart Institute of the University of São Paulo Medical School, São Paulo, SP, Brazil Sharon Shen, MD Division of Cardiology, Department of Internal Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA Chung-Wah Siu, MD Cardiology Division, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong Mark Slevin, PhD, FRCPath SBCHS, Manchester Metropolitan University, Manchester, UK School of Healthcare Science, Manchester Metropolitan University, Manchester, UK Eduardo Sosa, MD, PhD Arrhythmia Clinical Unit, Heart Institute of the University of São Paulo Medical School, São Paulo, SP, Brazil Raluca Sosdean, MD Department of Cardiology, “Victor Babeş” University of Medicine and Pharmacy, Timişoara, Romania Giuseppe Stabile, MD Laboratorio di Elettrofisiologia – Clinica Mediterranea, Naples, Italy Cristian Stătescu, MD, PhD Department of Cardiology and Internal Medicine, “Gr.T. Popa” University of Medicine and Pharmacy, Iaşi, Romania Electrophysiology and Pacing Department, “George I.M. Georgescu” Cardiovascular Diseases Institute, Iaşi, Romania Seow Swee-Chong, MBBS, MRCP Department of Cardiology, National University Heart Centre, Singapore, Singapore Gábor Széplaki, MD, PhD Department of Cardiology, Semmelweis University Heart Center, Budapest, Hungary Tamas Szili-Torok, MD, PhD Department of Clinical Electrophysiology, Thoraxcenter, Erasmus MC, Rotterdam, The Netherlands Tamás Tahin, MD Department of Cardiology, Semmelweis University Heart Center, Budapest, Hungary Ion C. T¸intoiu, MD, PhD, FESC “Acad. Vasile Candea” Emergency Clinical Center for Cardiovascular Diseases, “Carol Davila” University of Medicine and Pharmacy, “Titu Maiorescu” University, Bucharest, Romania Mihai Toma, MD, PhD Faculty of Medicine, Titu Maiorescu University, Bucharest, Romania Emergency Department, Central Universitary Emergency Military Hospital “Dr. Carol Davila”, Bucharest, Romania Chia-Ti Tsai, MD, PhD Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan ROC Hung-Fat Tse, MD, PhD Cardiology Division, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong
List of Contributors
List of Contributors
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Malcolm John Underwood, MD, FRCS Division of Cardiothoracic Surgery, Chinese University of Hong Kong, Prince of Wales Hospital, Sha Tin, Hong Kong Gumpanart Veerakul, MD, FSCAI Pacific Rim Electrophysiology Research Institute at Bangkok Hospital, Bangkok, Thailand Division of Cardiology, Department of Medicine, Cardiovascular Research and Prevention Center, Bhumibol Adulyadej Hospital, Bangkok, Thailand Mariano Badra Verdu, MD Cardiology Service, CHUS, Sherbrooke University Hospitals, Sherbrooke, QC, Canada Xavier Viñolas, MD Electrophysiology and Arrhythmia Unit, Cardiology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain Innes Y.P. Wan, MB, ChB, FCSHK, FAMHK Division of Cardiothoracic Surgery, Chinese University of Hong Kong, Prince of Wales Hospital, Sha Tin, Hong Kong Erik Wissner, MD Department of Cardiology, Asklepios Klinik St. Georg, Hamburg, Germany Randolph H.L. Wong, MB, ChB, FCSHK, FAMHK Division of Cardiothoracic Surgery, Chinese University of Hong Kong, Prince of Wales Hospital, Sha Tin, Hong Kong Teppei Yamamoto, MD Cardiovascular Center, Chiba-Hokuso Hospital, Nippon Medical School, Inzai, Chiba, Japan Cheuk-Man Yu, MD, MBChB, FRCP, FRACP, FACC Division of Cardiology, Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR Chih-Chieh Yu, MD Department of Integrated Diagnostics and Therapeutics, National Taiwan University Hospital, Taipei, Taiwan ROC
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Anatomy and Physiology of the Atrioventricular Node: Basic Concepts Ambrose S. Kibos and Blanca F. Calinescu
Abstract
To appreciate the arrangement of the muscular connections between the atrial walls and the compact atrioventricular node, it is necessary to understand their anatomic relationships. Koch described the landmarks to the atrioventricular node that many subsequent investigators have illustrated the conduction axis running horizontally rather than vertically. The cardiac electrical physics is the “soul” of the heart, and hence, understanding of anatomy and physics is critical to unlocking the understanding of electrical workings and facilitates ablation procedures. Keywords
Dual atrioventricular • Triangle of Koch • Electrocardiographic • Atrial fibrillation • Wave fronts
Introduction Conduction within and through the critical architecture of the cardiac conduction system long fascinated scholars, beginning with the manifestation of initial electrocardiographic (ECG) recordings of cardiac electrical activity [1]. In 1963, the first published case report involving supraventricular tachycardia in canine was done by Moe et al. [2]. Later, in the following decade, Mendez and Moe [3] demonstrated the same findings in isolated rabbit AV nodal preparations using advanced microelectrode recordings. They demonstrated reentry as well as the collision of impulses from two surgically separated atrial sites, called alpha and beta pathways (later on named fast and slow pathways, respectively), that they could only explain by separate AV nodal inputs meeting in a common pathway. In the later years of the twentieth
A.S. Kibos, MD (*) Department of Cardiology, Center Hospitalier Coutances, Coutances, France e-mail:
[email protected] B.F. Calinescu, MD Cardiovascular Surgery Department, Army’s Clinic Center for Cardiovascular Diseases, Bucharest, Romania A.S. Kibos et al. (eds.), Cardiac Arrhythmias, DOI 10.1007/978-1-4471-5316-0_1, © Springer-Verlag London 2014
century, Janse et al. [4], through pivotal studies they conducted, helped to map out the complex electrophysiology of the AV node, correlating it with anatomy. Finally, a critical investigation by de Paes Carvalho and de Almeida [5] established the atrionodal (AN), nodal (N), and nodo-His (NH) regions of AV nodal conduction, with the calcium dependency of the upstroke for the cells in the N region being demonstrated a short time later.
Dual AV Nodal Physiology Moe et al. [6] first demonstrated that pacing could initiate and terminate supraventricular tachycardias (SVTs) drawing proper conclusions from existing evidence that the electrophysiologic features could only be explained by two or more pathways that are well distinct [7, 8]. For the first time, it was shown that during SVT [9] a ventricular impulse could reach the atrium retrograde without necessarily colliding with the anterograde impulse of the SVT and thus obtaining two ventricular responses from one atrial impulse. During atrial pacing stimulus [10], these two findings occur if two AV nodal pathways are present. Later research in patients after RF catheter ablation [11, 12] showed that elimination of conduction is one of the approaches to the AV node with abolition 1
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A.S. Kibos and B.F. Calinescu
of AVNRT also offered convincing proof of existence of two pathways. It is important to understand why there is duality [13], what is responsible, and why it has developed as a part of many. What about the slow pathway? Sparse distribution of gap junctions resulting in cellular uncoupling [14], uneven allocation of ion channels and autonomic innervation [15], anisotropic conduction leading to tortuous pathways, and Ca2+ dependency of the depolarization upstroke of cells in the N region but a probable Na+ contribution in the AN and NH regions all contribute [16–18]. The AV junction is a large area; therefore, the function may not be able to be deduced from structural changes in the AV node and its approaches, since presently it is not known how much of any structure is needed for its proper function. Any disease that may affect the heart has the potential to affect the AV junction including the AV node and its approaches, thereby having the potential for development of arrhythmias [19].
AV Conduction During Atrial Fibrillation We have learned from anatomists since the early work of Tawara [20] that the histologically specialized tissues of the AV node lie deep within the atrial walls and are overlain with atrial myocardium showing anatomic features favoring anisotropic conduction. RF procedures [21] have been used to tease out different pathways and their electrophysiologic features. It is still clear that the two pathways communicate with each other so that abolition of slow pathway by RF automatically shortens the refractory period of the fast pathway [22]. AV nodal modification, which generally involves slow pathway ablation [23], results in slowing of ventricular rate during atrial tachycardia and atrial fibrillation. Conduction during atrial fibrillation [24], critically important in the overall ablation strategy management, is also crucial to understand mechanistically [25], with collision of impulsion producing summation that regulates AV conduction during atrial fibrillation [26]. Conclusions
Dual pathway electrophysiology is based on separate wave fronts that propagate in functionally, rather than electrically, isolated domains [27]. The envelope of the transitional cells and brief trespass through compact nodal region in the anterior margin of the triangle of Koch constitutes the fast wave-front domain. The deeper inferior/posterior extensions and the compact cell region are the proposed domain of the slow wave front [28]. These domains are not exclusive, so that interaction of the wave fronts can be observed and can produce a variety of complex conduction phenomena. The reciprocating echo beat and AVNRT are just one manifestation of this interaction [29]. Finally, the specialized part
of the conduction system is a part of the entire heart, and therefore, any discussion of the conduction system should include the entire heart and vice versa [30]. This is a brief discussion of the AV nodal history, physiology, and connections, and therefore, the interested reader is encouraged to read the original works described in detail elsewhere in this book.
References 1. Fisch C. Electrocardiographic manifestation of dual AV nodal conduction during sinus rhythm. In: Mazgalev TN, Tchou PJ, editors. Atrial-AV nodal electrophysiology: a view from the millennium. Armonk: Futura Publishing Co., Inc; 2000. 2. Moe GK, Cohen W, Vick RL. Experimentally induced paroxysmal A-V nodal tachycardia in the dog. Am Heart J. 1963;65:87–92. 3. Mendez C, Moe GK. Demonstration of a dual AV nodal conduction system in the isolated rabbit heart. Circ Res. 1966;19:378–93. 4. Janse MJ, Loh P, de Bakker JMT. Is the atrium involved in AV nodal reentry? In: Mazgalev TN, Tchou PJ, editors. Atrial-AV nodal electrophysiology: a view from the millennium. Armonk: Futura Publishing Co., Inc; 2000. 5. de Paes Carvalho A, de Almeida DF. Spread of activity through the atrioventricular node. Circ Res. 1960;8:808–9. 6. Moe GK, Preston JB, Burlington H. Physiologic evidence for a dual A-V transmission system. Circ Res. 1956;4:357. 7. Zipes DP. Voltage dependency in rabbit atrioventricular nodal fibers. Circ Res. 1973;33:123–30. 8. Rosen KM, Denes P, Wu D, Dhingra RC. Electrophysiological diagnosis and manifestation of dual A-V nodal pathways. In: Wellens HJJ, Lie KI, Janse MJ, editors. The conduction system of the heart. Leiden: HE Stenfert Kroese BV; 1976. p. 453–66. 9. Zipes DP, Mendez C, Moe GK. Evidence for summation and voltage dependency in rabbit atrioventricular nodal fibers. Circ Res. 1973;32:170–7. 10. Langberg JJ, Leon A, Borganelli M, et al. A randomized, prospective comparison of anterior and posterior approaches to radiofrequency catheter ablation of atrioventricular nodal reentry tachycardia. Circulation. 1993;87:1551–6. 11. Fishberger SB. Radiofrequency ablation of probable atrioventricular nodal reentrant tachycardia in children with documented supraventricular tachycardia without inducible tachycardia. Pacing Clin Electrophysiol. 2003;26(8):1679–83. 12. Jackman WM, Beckman KJ, McClelland JH, et al. Treatment of supraventricular tachycardia due to atrioventricular nodal reentry, by radiofrequency catheter ablation of slow-pathway conduction. N Engl J Med. 1992;327:313–8. 13. Lee PC, Hwang B, Tai CT, Chen SA. Electrophysiological characteristics in patients with ventricular stimulation inducible fast-slow form atrioventricular nodal reentrant tachycardia. Pacing Clin Electrophysiol. 2006;29:1105–11. 14. Knight BP, Ebinger M, Oral H. Diagnostic value of tachycardia features and pacing maneuvers during paroxysmal supraventricular tachycardia. J Am Coll Cardiol. 2000;36(2):574–82. 15. Neyton J, Trautmann A. Physiological modulation of gap junction permeability. J Exp Biol. 1986;124:93–114. 16. Bennett MVL, Goodenough DM. Gap junctions, electrotonic coupling and intercellular communication. Neurosci Res Program Bull. 1978;16:373–486. 17. Caspar DLD, Goodenough DA, Makowski L, Phillips WC. Gap junction structures. I. Correlated electron microscopy and X-ray diffraction. J Cell Biol. 1977;74:605–28.
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Anatomy and Physiology of the Atrioventricular Node: Basic Concepts
18. Caveney S. Intercellular communication in insect development is hormonally controlled. Science. 1978;119:192–5. 19. Dahl G, Isenberg G. Decoupling of heart muscle cells: correlation with increased cytoplasmic calcium activity and with changes of nexus ultrastructure. J Membr Biol. 1980;53:63–75. 20. Tawara S. The conduction system of the mammalian heart. Translated by Kozo Suma and Munehiro Shimada. London: Imperial College Press, 2000. 21. Waller BF, Gering LE, Branyas NA, Slack JD. Anatomy, histology, and pathology of the cardiac conduction system: part I. Clin Cardiol. 1993;16:249–52. 22. Geller JC, Biblio LA, Carlson MD. New evidence that the AV node slow pathway conduction directly influences fast pathway conduction. J Cardiovasc Electrophysiol. 1998;9:1026–35. 23. Lee S, Tai CT, Lee PC, Chiang CE, Cheng JJ, Ueng KC, Chen YJ, Chen SA. Electrophysiological characteristics of functional rhythm during ablation of slow pathway in different types of atrioventricular nodal reentrant tachycardia. Pacing Clin Electrophysiol. 2005; 28:11–118. 24. Meijler FL, Jalife J. AV node functions during atrial fibrillation. In: Mazgalev TN, Tchou PJ, editors. Atrial – AV nodal electro-
25.
26.
27. 28.
29.
30.
3 physiology: a view from the millennium. Armonk: Futura Publishing Co., Inc; 2000. Lin YK, Ms L, Chen YC, Chen CC, Huang JH, Chen SA. Hypoxia and reoxygenation modulate the arrhythmogenic activity of the pulmonary vein and atrium. Clin Sci (Lond). 2012;122:122–32. Rudy Y. Principles of slow conduction in cardiac tissue; mathematical modeling. In: Mazgalev TN, Tchou PJ, editors. Atrial – AV nodal electrophysiology: a view from the millennium. Armonk: Futura Publishing Co., Inc.; 2000. Mazgalev T, Tchou P. Atrioventricular nodal conduction gap and dual pathway electrophysiology. Circulation. 1995;92(9):2705–14. Billette J, Janse MJ, van Capelle FJL, Anderson RH, Touboul P, Durrer D. Cycle-length dependent properties of AV nodal activation in rabbit hearts. Am J Physiol. 1976;231:1129–39. Schuilenburg RM, Durrer D. Atrial echo beats in the human heart elicited by induced atrial premature beats. Circulation. 1968; 37:680–93. Fishberger SB, Whalen R, Zahn EM, Welch EM, Rossi A. Radiofrequency ablation of pediatric AV nodal reentrant tachycardia during the ice age: a single center experience in the cryoablation era. Pacing Clin Electrophysiol. 2010;33(1):6–10.
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Anatomy and Physiology of the Atrioventricular Node: What Do We Know Today? Hidekazu Miyazaki
Abstract
Atrioventricular (AV) node consists of a part of the sole pathway of impulse conduction from the atria to the ventricles. It becomes the base of occurrence and maintenance of various arrhythmias involving this region by special electrophysiological characters as follows: The conduction across the node is quite slow, it functions as two separated conductors with property of fast or slow conduction, and it has the automaticity. AV junctional area including the node itself potentially works as the ectopic center of a subsidiary pacemaker when the sinus node as the primary pacemaker fails to control the cardiac rhythm. Muscular bundles consisting of dual AV pathways are not anatomically distinguished but can be functionally differentiated by the difference of conduction property and refractoriness. A fast pathway connects with the center of the node from anterior part of interatrial septum, and a slow pathway does from posteroinferior area to the tricuspid valve. In cells of slow pathway, the occurrence of automaticity is determined and the expression of ion channels is similar to ones in the center of the node. These facts suggest that the dual-pathway physiology of the AV node is not only formed by special electrophysiological property of cells but based on the morphology. Keywords
Atrioventricular node • Fast pathway • Slow pathway • Dual-pathway physiology • Nodal cell • Automaticity
Abbreviations AN AP AV AVNRT CS Cx DAVNP
Atrio-nodal Action potential Atrioventricular Atrioventricular nodal reentrant tachycardia Coronary sinus Connexin Dual atrioventricular nodal pathway
H. Miyazaki, MD, PhD, CCDS Division of Cardiology, Department of Medicine, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan Department of Cardiology, Kawasaki Municipal Tama Hospital, 1-30-37, Syukugawara, Tama-ward, Kawasaki, Kanagawa 214-8525, Japan e-mail:
[email protected],
[email protected] A.S. Kibos et al. (eds.), Cardiac Arrhythmias, DOI 10.1007/978-1-4471-5316-0_2, © Springer-Verlag London 2014
FP ICa,L ICa,T IK1 IVC MV NH PNE RA RV SP TV
Fast pathway L-type calcium channel current T-type calcium channel current Inward rectifier potassium current Inferior vena cava Mitral valve Nodo-His Posterior nodal extension Right atrium Right ventricle Slow pathway Tricuspid valve
Atrioventricular (AV) node is a part of the only normal electrical connection between the atria and the ventricles and plays a role to coordinate heart rate. Since the discovery of the AV node by Tawara [1], it still fascinates many 5
6
investigators in this field and has been enthusiastically studied by pioneers in anatomy, physiology, and cardiology. Highly intense debates have been exchanged on several major themes reflecting duality of the electrophysiological character of the AV node, which is known to be both a conductor of impulses and an oscillator. Characteristics of the AV node with slow conduction and long refractory period cause a delay of electrical impulse transmission from the atria to the ventricles, which promotes the blood repletion to the ventricles but prevents the ventricles from working excessively fast in atrial tachyarrhythmia. The AV node can become the subsidiary center of the pacemaker activity of the heart when the primary pacemaker in the sinus node fails to control the cardiac rhythm as the result of either a depressed automaticity or an impaired conduction. By showing the peculiar properties aforementioned, the AV node plays an extremely important role in pathophysiology which affects the occurrence of various arrhythmias. The ion currents, the channels, and the molecular mechanisms affecting its electrophysiological characteristics have been clarified through the development of molecular biology which involves in many investigations from recording an action potential (AP) of a cell with microelectrodes to an application of the patch-clamps technique to an isolated nodal cell. The elucidation of the structure of the AV node, the peculiarity of the AV conduction at histological and clinical levels, and the mechanism of the occurrence of arrhythmia has made tremendous progress since the introduction of the clinical electrophysiological study including a record of the His bundle electrocardiogram and the catheter ablation. But unsolved problems still remain. A profound complexity of the AV nodal area has presented a significant challenge to anatomists. Many scientists have disagreed on several major definitions of the components of the AV node, and the lack of a common terminology for the tissues at AV node was recently acknowledged [2]. Due to the lack of consensus on such fundamental issues of anatomy of the AV node, electrophysiologists have to choose between two distinctly different “anatomic” and “potential” approaches during clinical evaluation of AV conduction and therapy of AV nodal reentrant tachycardia (AVNRT) [3]. The “anatomic” approach is based on targeting the anatomic landmarks of a slow pathway (SP), such as the isthmus between the orifice of the coronary sinus (CS) and the tricuspid valve (TV). The “potential” approach is based on targeting a characteristic lowfrequency potential being as the signature of a SP [4, 5].
Structure of the AV Node The AV node, a.k.a Tawara’s node, was first discovered and reported by Dr. Tawara in 1906 [1]. His excellent works are not only the morphologic discovery of the nodal tissue but also a suggestion of its functional role as part of “the impulse conduction axis of the heart” through which the atria and the
H. Miyazaki
Fig. 2.1 The disposition of the atrioventricular conduction axis. Conduction pathway from the atrioventricular node (k) to the bundle of His, the right bundle (rs), and then to the right ventricular muscles in a human heart (Reproduced from Tawara [1])
Eustachian valve
Oval fossa
Coronary sinus
Tendon of Todaro
Triangle of Koch
Tricuspid valve
Fig. 2.2 Magnified view of the important posterior wall of the right atrium. Note the location of the triangle of Koch, delimited by the site of the tendon of Todaro, the attachment of the septal leaflet of the tricuspid valve, and the orifice of the coronary sinus. The small bracket shows the site of the septal isthmus, whereas the large bracket shows the inferior, or cavo-tricuspid, isthmus (Reproduced from Anderson and Cook [13], with permission)
His-Purkinje system are connected (Fig. 2.1). His report was published a few years after Einthoven recorded an electrocardiogram for the first time. The AV nodal tissue is a flat and fan-shaped mass located in the fibrous triangle at the bottom of the right atrium (RA) and in the upper part of the triangular area first illustrated by Koch [6] (Fig. 2.2). In human its size is roughly 6 mm in
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Anatomy and Physiology of the Atrioventricular Node: What Do We Know Today?
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length and 3 mm in width. It connects with atrial muscle bundles through the transitional cells and with the His bundle through the nodal infrastructure. Thus, the node per se is not isolated from surrounding tissues, which is also described in the first report of Tawara. The nodal cells which consist of the midsection of the AV nodal area have a small spindle-like shape and form cell bundles, which is similar to sinus nodal cells. But the points slightly different from them are that a bunch of muscle cells runs along the long axis of the AV node and makes a complex network structure by divergence and anastomosis. And it is clearly distinguished from other cardiac muscle tissues (e.g., atrial and ventricular muscles, Purkinje fibers). In fine structure of nodal cells, a transverse tubule does not exist, the connection between cells is simple, and the surface of the gap junction is smaller [7, 8]. The anatomic definition of the AV node has been debated. On the purely morphologic grounds, Anderson’s group insists that the term AV node can be applied only to morphologically nodal tissue outside of a fibrous collar [9]. Conversely, other investigators suggest the existence of an anterior enclosed and a posterior open part of the node [10] and that the AV node includes all structures contributing to atrial-His interval and being associated with rate-dependent and dual-pathway properties [11]. Billette’s definition is most acceptable and we will adhere to his definition of the AV node as a heterogeneous structure, consisting of the compact AV node as well as nodal extensions and approaches, comprising tissues of the triangle of Koch.
Location of the AV Node As described by Tawara [1], the AV conduction axis is a continuous system of histologically discrete cells which originates from the atrial myocardium and inserts in the ventricular Purkinje cells. The atrial components of this axis constitute the AV node, or the “Tawara’s node” (Fig. 2.1). The node, along with its surrounding zones of transitional cells, is positioned at the base of the atrial septum, occupying the upper part of the triangle of Koch (Fig. 2.2). The apex of the triangle is the AV component of the membranous septum (Fig. 2.3) [12, 13]. This fibrous structure is continuous on its left side with the thickened rightward end of the region of fibrous continuity between the leaflets of the aortic and mitral valves (Fig. 2.4). This fibrous thickening, a.k.a. the right fibrous trigone, together with the membranous septum, forms the so-called central fibrous body. When seen from the right side, the structures forming the sides of Koch’s triangle insert directly to the membranous septum (Fig. 2.3). The more posterior border is the fibrous strand continuation of the valve of the inferior vena cava (IVC), a.k.a. the tendon of Todaro. The anterior border of the triangle is the line of attachment of the septal leaflet of the TV. This structure crosses the right ventricular (RV) aspect of the membranous septum in most hearts, dividing it into AV
Fig. 2.3 Dissection of the human heart showing the medial wall of the right atrium removed its endocardial lining. This demonstrates the anisotropic orientation of the muscle fibers within the major muscular bundles delineated by the holes in the atrial wall (Reproduced from Anderson et al. [12], with permission)
and interventricular components. The muscular triangle delimited by these two borders separates the hinge of the TV in the RV from that of the mitral valve in the left ventricle and seems to be a septum. In the strictest sense, however, the area is not truly a septum, since a fibroadipose continuation of the inferior AV groove separates the atrial wall forming the floor of the triangle from the underlying ventricular musculature (Fig. 2.4). The artery supplying the AV node traverses this tissue plane, extending superiorly to the point where the node penetrates the plane of AV insulation to become the bundle of His. The base of the triangle is positioned inferiorly and is occupied by the CS. Adjacent to the orifice of the CS, which is guarded by the Thebesian valve, there is an important isthmus, a.k.a. the septal isthmus. This is bounded by the CS itself posteriorly and the hinge of the TV anteriorly. The musculature of the septal isthmus then continues inferiorly as the vestibule of the TV, while the musculature around the CS orifice itself continues
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H. Miyazaki
Fig. 2.4 Aortic root of the human heart viewed from the anterior aspect opened through the left coronary leaflet of the aortic valve. Note the fibrous continuity between the aortic and mitral valvular leaflets and the semilunar attachments of the aortic leaflets. The dotted lines demarcate the inter-leaflet triangle between the right and noncoronary leaflets of the aortic valve. The base of the triangle is occupied by the membranous septum. The entire triangle is an integral part of the left ventricular outflow tract, as are the triangles between the other leaflets (Reproduced from Anderson et al. [12], with permission)
Fig. 2.5 Section from a human heart showing the region of the atrioventricular node. The cells of the compact node are joined to the atrial myocardial cells through short regions of transitional cells. The node itself is part of the atrial wall, with no fibrous sheath interposed between the histologically specialized tissues and the working atrial myocardium. Trichrome stain (Reproduced from Anderson et al. [12], with permission)
inferiorly into another isthmus. This second isthmus is also known as the inferior isthmus or cavo-tricuspid isthmus, confined between the orifice of the IVC and the leaflets of the TV. This has trabecular, membranous, and vestibular components (Fig. 2.3). The membranous part is often expanded to form a prominent diverticulum. And the sinus, usually known as the sub-Eustachian sinus, is seen to be sub-Thebesian, lying directly beneath the CS orifice (Fig. 2.2). Two other muscular areas are important in the context of the relations of the triangle of Koch and the approaches to the AV node. The first is the muscular ridge between the CS orifice and the oval fossa, a.k.a. the Eustachian ridge. The second area is the atrial wall between the CS orifices and the IVC. Frequently described as the
“sinus septum,” this second area is no more than the fold between the two venous walls at their insertion into the musculature of the RA.
AV Node Relative to Koch’s Triangle The histologically specialized tissues making up the AV node occupy a relative small area within the triangle of Koch. The AV node itself is a half-oval of cells forming the base of the atrial wall and sets against the fibrofatty tissue of the AV junction (Fig. 2.5). When traced inferiorly, the half-oval breaks up into two extensions, which run toward the attachments of the mitral valve and TV. This dense knot of cells is
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Anatomy and Physiology of the Atrioventricular Node: What Do We Know Today?
the compact node. The artery supplying the node usually enters this compact nodal tissue between the two inferior extensions. The strand of compact nodal cells running toward the TV is the more prominent of these extensions. Its extent inferiorly, however, varies from heart to heart [14]. The compact node itself is then usually surrounded by an additional half-oval of transitional cells intermediate in their morphology between the nodal cells and the ordinary atrial myocytes. Of necessity, the transitional cells are not insulated by fibrous tissue from the remainder of the atrial myocardia. Because of this they do not qualify for consideration as conducting tracts, but they can be recognized as being histologically specialized since they can be traced from section to section. Additional transitional cells are found interposing between the atrial myocardium and the inferior nodal extensions, while still further areas of transitional cells interpose between the left edge of the compact node and the left atrial aspect of the septum. Thus, on all sides the compact node has transitional cells interposed between it and the ordinary atrial myocardium. The ordinary atrial myocardium then forms a further discrete overlay at the apex of Koch’s triangle. This layer extends anteriorly to insert into the vestibule of the TV. These overlay cells originate from the atrial wall in front of the oval fossa, which corresponds with the area targeted as the so-called fast pathway (FP) into the AV node (Fig. 2.3). It is composed of ordinary atrial myocardium. A SP into the AV node is located within the septal isthmus (Fig. 2.3), albeit its anatomic nature remains to be clarified. In cases with this pathway ablated to cure the AVNRT, the lesion placed to ablate the pathway was located in ordinary atrial myocardium and was distant from the compact AV node, its inferior extensions, and the areas of histologically discrete transitional cells [15]. Others argue, nonetheless, that the inferior extension from the compact node might itself form a SP [14]. In this respect, even in those cases where the inferior extension is not identified histologically, it is certain that cells with an initially nodal phenotype are present in this area. This is because the AV node and bundle are derived from a ring of cells which initially surrounds the embryonic interventricular foramen [16]. With subsequent development, part of this ring becomes incorporated into the vestibule of the TV, but loses its histologically discrete phenotype. Remnants of this ring almost certainly form the nodal structures which are mistakenly believed to provide multiple muscular AV connections in the normal heart. It is also the case in which this ring initially traversed the area ablated as a SP to cure the AVNRT, even if, in the postnatal heart, the cells are no longer recognized as being histologically specialized. Otherwise, we occasionally experienced the cases with an atrial reentrant tachycardia which was successfully ablated at the vicinity of the CS orifice or along the tricuspid or mitral annulus [17, 18]. In those cases it ceases after administration of relatively small amount of adenosine triphosphate (usually 1–3 mg) or verapamil
9
(ranging from 1.25 to 2.5 mg), which is much less compared to the dose required for termination of the AVNRT. In histological examination of a case with such atrial tachycardia successfully treated, a few distinct nodal structures were identified around the region of the ablation applied along the tricuspid or mitral annulus [19]. There are, however, still other morphologic possibilities that might account for the existence of a SP. In particular, there is marked variation in the alignment of the myofibrils in the septal isthmus from heart to heart (Fig. 2.3). It is now well established that this alignment of the myofibrils is responsible for nonuniform anisotropy, which could well produce a preferential route of conduction into the node through histologically ordinary atrial myocardium. The coupling of the myocardial cells by connexins (Cxs) may also differ in this area. The anatomic substrate for a SP has, therefore, still to be established. At the apex of the triangle of Koch, the compact AV node is set against the central fibrous body. Study of serial sections shows that as the axis of specialized musculature extends superiorly, it becomes engulfed by fibrous tissue, thus insulating it from the adjacent atrial myocardium. According to Tawara, it is at the point at which the conduction axis becomes surrounded by fibrous tissues that the compact AV node becomes the bundle of His. As noted by him, there is very little histological difference in human between cells of the axis still in contact with atrial myocardium (Fig. 2.5) as opposed to that part which is insulated within the central fibrous body. The anatomic difference between these two parts, nonetheless, is unequivocal and clear-cut. When traced superiorly, this penetrating part of the bundle turns slightly leftward and emerges from the fibrous tissue on the crest of the muscular ventricular septum. In human, this penetrating part of the axis is remarkably short. Having reached the crest of the muscular septum, and still contained within a fibrous sheath, the bundle runs a variable non-branching course before beginning to give off the fascicles of the left bundle branch. Having run forward along the septal crest and having given rise to the left bundle branch, the axis gives rise to the cord-like right bundle branch. This turns back through the substance of the muscular ventricular septum, emerging in the RV in relation to the medial papillary muscle. The bundle branches themselves extend in insulated fashion down the two sides of the ventricular septum, with the left bundle branch having a trifascicular form. Only at the apex the cells in the conduction axis lose their fibrous sheath, becoming the ventricular Purkinje cells.
Morphologic and Electrophysiological Heterogeneity of AV Junction With the spread of electrocardiogram recording, investigators’ attention has been drawn to the relationship of a delay of electrical signal transmission between the atria and the
10
ventricles to the role of the AV node. By recording the membrane potential with microelectrodes, the characteristics of the AP of nodal cells were clarified. These cells are characterized by a “low” (less negative) resting membrane potential and AP amplitude, slow rates of depolarization and repolarization, fewer intercellular connections such as gap junctions, and reduced excitability compared to surrounding cells [20–22]. Sano’s group demonstrated that cells showing a notch on the AP were present in the midsection of the nodal area from the results of experiment with AV junctional specimens by a correlation between staining data with ordinary dye and histological examination [23]. From a histological point of view, the AV node consists of three layers: (1) superficial or subendocardial, (2) intermediate or mid-part, and (3) deep innermost. This three-layered structure has been associated with three different electrophysiological responses observed in the AV junction [24]. The waveform of APs recorded with microelectrodes varies from area to area of the cells in the AV node [25]. Based on this finding, the following three distinct parts of the AV node have been identified [20, 26]: (1) the atrio-nodal (AN), (2) true nodal or compact nodal (N), and (3) nodo-His (NH). Nodal response was characterized by a relatively slow rate of rise during upstroke and small amplitude of the AP. The AP in the AN and NH parts showed an intermediate waveform between the N part and atrial muscle (AN) and between the N part and His bundle (NH), respectively. There are also morphologically “typical” nodal cells and the electrophysiologically typical nodal cells (N cells). Yet, a convincing proof of this association is still lacking. The automaticity (slow diastolic depolarization or the fourth phase depolarization) arises from the cells at the boundary, i.e., in the AN and NH parts, but does not in the N part [25]. It has been controversial, however, that the N part is incapable of becoming the subsidiary center of the impulse formation because the N cells lack to generate an impulse (albeit shown in some animal species by some reports). It has been also discussed which of AN and NH parts mainly behaves as a subsidiary pacemaker [25, 27]. As the function varies at the different part of the AV node and there are no clear boundaries by the atrium at the top and the His bundle at the bottom, the word of “AV junction” has been chiefly used [28], and the name of “Tawara’s node” instead has not been used. There are currently no established theories on the morphology, the borders, the definition, the functions and the role of the AV node per se, the entrance from the atrium, the transitional zone, the midsection, and the exit to the nodal infrastructure, but each of the researchers gives their own opinion in the current status. With the most comprehensive microelectrode mapping of the AV nodal area, six different cell types were identified as based on the waveform of the AP, excitability, and refractoriness [29]. Most importantly, there are cells of physiological types throughout almost the entire AV junctional area,
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well beyond the compact AV node. Recently presented morphologic [14] and electrophysiological [30, 31] evidence of the posterior nodal extensions (PNEs), which in some cases can reach the CS and perhaps connect directly to the crista terminalis, could conceivably explain the presence of the nodal and transitional cells at a significant anatomic distance from the compact AV node. Yet, purely morphologic analysis of the AV junction clearly has failed to explain the complex electrophysiological behavior of the AV node. Recent progress in molecular and cellular biology research provides highly promising insights, which could 1 day explain normal and pathologic AV conduction.
Molecular Basis of Electrophysiological Heterogeneity of AV Junction The heterogeneous electrophysiological characteristics of the AV nodal cells were revealed after the application of the patchclump method to isolated cardiac myocytes. Sodium channel density is lower in the midsection of the AV junction than that in the transitional area and the nodal infrastructure [32]. An inward current over L-type calcium channel (ICa,L) is the basis of the upstroke of the AP of N cell [21, 22, 33, 34]. The waveform of the AP is not identical among cells from different parts of the AV junction. The AP of the nodal cells shows a relatively gentle slope during depolarization (Fig. 2.6), ranging from 5 to 30 V/s. The maximum diastolic potential is at around −70 mV in all the parts. AN and NH cells and transitional atrial fibers have “higher” (high negative) resting potentials that are intermediate between those of N cells and of either atrial or His bundle cells, respectively. The upstroke of the AP in these cells depends mainly on a sodium inward current. As the sodium current is larger and has more rapid kinetics than the calcium channel current of N cells, conduction is faster through AN and NH regions than that through the compact AV node. Almost all the cells in the AV junction have the automaticity, but the frequency of its firing is different in each cell (Fig. 2.7) [34–36]. T-type Ca current (ICa,T), sodium current, and ICa,L are observed in some myocytes as an ion current and a channel current. Delayed outward potassium current (IK) and hyperpolarization-activated inward current (If) are also confirmed. These currents are observed not only at the level of the membrane current but also at the levels of singlechannel current, channel protein, and messenger RNA [22, 34, 37, 38]. The reason that the value of the diastolic potential of nodal cells are lower compared to the resting potential of other myocardial cells is thought that the nodal cells are short of the inward rectifier potassium current (IK1) [39]. As to the existence of sodium current, which varies from area to area of cells, it is hardly recorded from cells at the midsection of the AV junction but easily in the transitional area and the nodal infrastructure. This is consistent with the
Anatomy and Physiology of the Atrioventricular Node: What Do We Know Today?
ς 3
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Fig. 2.6 Action potentials and membrane currents of isolated atrioventricular nodal cells. (I) Action potential with automaticity. In upstroke phase, a slow component of inward current is observed. (II) Membrane current and current-voltage curve. A slow inward current and a delayed outward current are recorded after depolarization (a). An activated inward current was recorded after hyperpolarization. (b). From each current-voltage curve, they are equivalent to calcium current, delayed outward potassium current, and If current, respectively. (III) An inward current activated by depolarization is inhibited by a depressant of L-type calcium current (Reproduced from Noma et al. [33], with permission)
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results of experiments using immunostain with SCN5A (sodium channel gene) antibody and by the analysis of sites showing sodium channel expression [32, 40]. It is thought by these findings that sodium current involves a fast component of conduction at the entrance and exit parts of the AV junction, namely, the conduction over the transitional zone to the compact node and the nodal infrastructure to the bundle of His, respectively. As the ICa,L is observed on nearly all the cells
Fig. 2.7 Waveform of action potentials recorded from the atrioventricular junction. (I) Photograph shows the intact AV node specimen including the coronary sinus region of the rabbit heart. AV node region was divided into five strands, I to V perpendicularly to the AV ring and into three portions, A, B, and C, parallel to the ring by the grid. CS indicates orifice of coronary sinus, RV right ventricle, FO fossa ovalis, TV tricuspid valve, His bundle of His, RA, right atrium. (II) Action potentials recorded in the intact AV node specimen. I, III, and V correspond to the portions of I-B, III-B, and V-B as illustrated in upper panel. Action potential parameters are as follows: I: amplitude 92.6 mV, rate of rise of depolarization 28.6 V/s, and duration of action potential 61.4 ms. III: amplitude 93.6 mV, rate of rise 11.8 V/s, and duration 68.9 ms. V: amplitude 105.2 mV, rate of rise 21.8 V/s, and duration 95.6 ms (Reproduced from Kokubun et al. [35])
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throughout the AV junction, the function of calcium channel is clear in electrical activity. Regarding the ICa,T, however, the significance of its function is unclear, though its existence is confirmed by recording the membrane potential of the AV nodal cells [41]. According to a recent experiment with genetically modified animals in which CaV1.3 coding ICa,T knocked out, the ICa,T is unable to be recorded from the AV nodal cells and the prolongation of PR interval was found on an electrocardiogram in a living animal [42]. This channel could also affect a fast component of conduction across the AV node. The slow conduction along the AV junction, being its electrical characteristic, is related to not only the specificity of the distribution of ion channel expression forming the distinct AP but also the difference of gap junctions functioning the electrical coupling between myocytes. A gap junction consists of gap junction channels called as connexins. There are three types of connexins, e.g., Cx40, Cx43, and Cx45 in the heart, and a single gap junction channel is formed by single or mixed tetramer formation. Cx43 mostly present in the heart is mainly expressed in the atrial and the ventricular muscle and participates in a fast conduction. Cx40 is smaller than Cx43 in conductance and is mainly expressed at the sinoatrial and the AV nodes and in the conduction axis of the ventricle. The distribution of Cx45 is almost the same as that of Cx40. In the AV junction, the development of gap junction is far less compared to the atrium and the ventricle, and the type of connexins consisting of gap junctions varies among animal species and in developmental stages. In small animals Cx43 can be seen, but Cx40 and Cx45 are distributed in large animals including human, which have been thought to contribute that electrical signals slowly conduct across the AV junction [43, 44]. Recently Cx30.2 with smaller conductance compared to Cx40 is determined in the vascular endothelium, brain, and testis. And it was reported that the same type of Cx30.2 is expressed in the sinus node and the midsection of the AV junction [45]. The specificity of the distribution of connexins is thought to participate in a slow conduction along the AV junction.
Conduction Property of AV Junction and Dual-Pathway Physiology Conduction delay across the AV junction is described by the following characteristics: (1) There is the specific morphologic features that the nodal cells are small in diameter and diverge, and an array of them is thin. (2) The AP during upstroke does not depend on the sodium current but mainly the ICa,L. Sodium current is an inactivated small current because a diastolic potential is low. (3) There are fewer intercellular connections such as gap junctions which are composed of connexins with low function (Cx40, Cx45, and Cx30.2). 4) The nodal cells have a long refractory period because the signal transmission is dependent on the ICa,L and
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some nonactivated sodium current. These features play an important role for inhibition of rapid ventricular activation by blocking a part of the conduction across the AV junction while a fast supraventricular tachyarrhythmia, e.g., atrial fibrillation, occurs. The facts that impulses from the atrium incompletely reach and leave the refractory at the various levels of the AV junction result in the conduction block of the following impulses and give occasion to a different conductivity ratio in atrial fibrillation. The phenomenon that the refractory left by the preceding impulse variously modifies the following propagation is called as “concealed conduction” [46]. This is also a part of the functional features of the AV junction. Concealed conduction can be described as the characteristics of the AV nodal cells with the distinct AP, the slow conduction property, and the long refractory period. It is thought that the signal input at an atrial side from the midsection of the junction and transitional cells at the borders get involved in the concealed conduction because the AV junction has the complex structures and consists of groups of cells with various functions in the heart. In the early research, it was revealed that the conduction was not blocked in the midsection of the AV junction but mainly in the AN part in atrial fibrillation [47]. But they do not confirm yet the site of the conduction block in the human heart and the site which the concealed conduction occurs at. Another feature of the conduction across the AV junction is the property of dual AV nodal pathways (DAVNP) which the AVNRT is likely to occur with. In a rabbit heart with DAVNP, it was confirmed that a premature contraction given resulted in a functional vertical dissociation and two pathways with different characteristics appeared; one was a FP with fast conduction velocity and long refractory period and another a SP with slow conduction velocity and short refractory period [48, 49]. The presence of the “jump-up phenomenon” on AV conduction curve proves the existence of the two pathways with different refractory period and conduction velocity; the sudden extension of AV conduction time appears by 50 ms or longer at some point following the AV conduction curve gradually extends while the coupling interval of premature stimulation is gradually shortened. When a premature stimulation is given at the appropriate timing, an impulse is blocked in a FP during refractory period but goes down through a SP. After reaching at the bottom of the AV junction, it goes back through a FP to the atrium, which forms a reentry circuit. By this type of activation pattern sustaining, a tachycardia is maintained and lasts. Since the introduction of His bundle electrogram recording, this type of tachycardia is clarified to be equivalent to clinical AVNRT in humans [50]. In some cases, the jump-up phenomenon is present twice, suggesting the presence of one more pathway with the intermediate conduction velocity, or the AVNRT is induced despite continuous conduction curve. Through these researches, it is known that the conduction system below the bundle of His does not participate within the reentry circuit
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Anatomy and Physiology of the Atrioventricular Node: What Do We Know Today?
and impulses turn around toward the atrium at the bottom of the AV junction. But it has been unclear that the atrial muscle is involved in the upper part of the circuit. On a premature contraction and an echo beat in the AV junction, the impulse propagates nonuniformly in the AV junction [51], and the direction of its propagation and its blocking site are highly complex and does not show a certain pattern [52]. In functional-morphologic analyses, cell groups and bundles equivalent to a SP and a FP are not confirmed. Thus, the DAVNP has been thought to be formed by “functional vertical dissociation” which is functionally created [52–54]. In human with AVNRT, it was suggested that a typical AVNRT (going down over a SP and up over a FP) and an atypical AVNRT (the impulse going through at the opposite direction) are shown [55]. Some cases have one more circuit with property in between a SP and a FP. Some atrial muscle participates in the part of the circuit. However, there is no morphologic evidence that indicates the existence of these two routes and the essential remains unknown. Furthermore, the problem leaves unclear whether a SP exists in not only cases with AVNRT but also normal people. In the 1990s they reported the cases in whom the AVNRT was successfully treated by cryosurgery of atrial tissue posterior and inferior to the AV node and around the CS orifice [56]. Since then the catheter ablation method was introduced, it was reported that the SP potential was recorded in the area of Koch’s triangle, which was between the CS orifice and the TV, and was in inferior and posterior part of the RA (Figs. 2.2, 2.3,
13
and 2.4) [4, 5]. They also reported that the application of the radiofrequency energy where the SP potential was recorded easily eliminated the AVNRT. At the same time, it was ascertained that a FP was a route at the atrial septal side incoming from the anterior and superior site to the AV node, and the exit of the retrograde conduction from the ventricle during AVNRT did not always match the entry part of a FP and was confirmed at the site close to a SP (equivalent to the intermediate conduction pathway) in some cases [54]. It became clear by clinical case studies and animal experiments that the DAVNP was simply resulted from functional dissociation of the cells but primarily formed on the extent of structural basis. Zipes’s group examined the mechanisms of DAVNP in AVNRT with AV junctional specimens from the canine heart using voltage-sensitive dye [57]. As a result, the following things became clear: (1) Many entries of the impulse to the AV junction were present in the normal heart (SP, FP, and intermediate pathway). (2) The atrial muscle was involved in the upper part of the reentry circuit. (3) The unidirectional block occurred at the site between the midsection of the AV junction and the entry from the atrium. (4) Since the presence of a SP and a FP became unclear when an intermediate pathway existed, the continuous AV conduction curve was drawn without jump-up phenomenon observed. The correlation of these findings with the detailed cellular structure, however, has not been disclosed yet. The membrane potential-sensitive dye method has a disadvantage that the signals dealt with this method are pretty weak.
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Fig. 2.8 Correspondence between the stack-plot of the optical potential derivatives at the triangle of Koch during premature stimulation and reentry and Cx43 immunolabeling. The right panel shows a threedimensional spatial-temporal visualization of conduction in the AV nodal area during premature stimulation and reentry (stack-plot of first derivative of the optical potential signal is shown). The histological
10 mm
section on the left shows that Cx43-labeled bundles correspond to the optically detected activation pathways. AV indicates atrioventricular, RA and LA right and left atria, RV and LV right and left ventricles, SP and FP slow- and fast-pathway bundles, VS ventricular septum (Reproduced from Nikolski et al. [59], with permission)
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Then, a SP has been suggested at least equivalent to that of the posterior extension or the PNE from the AV junction (Fig. 2.8) [20, 30, 32, 58]. The results of the immunohistochemical studies have already provided a vast amount of information, which shaped our understanding of AV conduction and junctional rhythm, based on significant heterogeneity of expression of various proteins, including ion channels, receptors, gap junctions, and signaling molecules. In particular, they have recently demonstrated that their previous findings of bifurcation in the functional reentry pathway have a molecular basis [32, 59]. Using immunolabeling of Cx43, they found Cx43positive bundles approaching AV junction from the CS orifice, surrounded by Cx43-negative tissue. By correlation with fluorescent data, these Cx43-positive bundles are suggested to be the substrate for dual pathways and for reentry. In some preparations, they observed bifurcation of a SP in the middle of the triangle of Koch. Immunolabeling showed that this functionally defined bifurcating conduction pathway correlates with bifurcating Cx43-positive bundles. Figure 2.8 (right panel) shows an example of such bifurcating conduction pathway as a stack-plot visualizing the reentry circuit in the AV junction area during the premature stimulation beat and the reentry beat. Cx43 immunolabeling (see Fig. 2.8, left panel) shows that the Cx43-positive bundles spatially correlate with the optically detected activation pathways, corresponding to a FP (top) and a SP (bottom) bundles. The red arrows show the position of the immunostained section (see Fig. 2.8). These AV nodal data agree with the previously observed Cx43-postive bundles in the SA junction [60–62], which were earlier suggested as a mechanism of enhanced safety of the conduction from the small SA nodal area, which has to drive large atrium against unfavorable source-sink relation. Further investigation of other connexin isoforms is underway to determine their contribution in the AV junctional conduction and pacemaking.
AV Nodal Reentry There is a clear and elegant report of the AV nodal reentry published roughly a century ago, describing that the longitudinal dissociation precedes the onset of reentry and leads to its initiation [53]. Later on, it was presented that the AV nodal reentry was induced by premature stimulation in humans [54] and in rabbit preparation [52]. Despite numerous attempts, nobody has been able to reproduce the results by the enormously difficult study conducted by Janse’s group, mapping transmembrane potential during AV nodal reentry [52]. Microelectrode recordings, while remaining the golden standard of cellular electrophysiology, preset a sig-
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nificant challenge to those in search of spatially resolved electrical mapping of the heart. Nikolski’s group presented a detailed map of AV nodal reentry using fluorescent mapping of AV nodal AP [59]. Similar documentation of reentry was produced in their experiments with retrograde stimulation. During the basic beat, an impulse entered the AV junction from the bundle of His and split into two wavelets. One propagated toward the tendon Todaro (first-pathways exit), while the other propagated along the PNE. Conduction via a FP reached the breakthrough point of the AN layer earlier and rapidly activated the atrium and a SP, thereby annihilating a SP retrograde impulse. During a premature beat applied at a certain coupling interval, a FP was still refractory, resulting in conduction only through a SP, followed by rapid activation of the atrium. Reduced amplitude of the FP bipolar electrogram during a premature beat relative to the basic beat is consistent with the idea of decremental conduction, which provided reduced and insufficient driving force to activate the AV layer of cells as seen from the conduction failure. During slow propagation along a SP, a previously blocked FP was able to fully recover. Therefore, after breakthrough from a SP exit and activation of the entire atrial surface AN layer, the excitation reentered the AV junction through a FP. Then it split into separate wavelets. One wavelet went through the compact AV node and left the field of view toward the bundle of His. The optical signature of His activation was synchronous with a bipolar response. At the same time, the other wavelet spread retrogradely via a SP, reaching the breakthrough point of a SP at the isthmus below the CS again. Following the rapid activation of the atrium, the wave again reentered antegradely a FP and split into two wavelets. Once again, one wavelet crossed the AV junction and exited the field of view toward the bundle of His synchronously with the bipolar waveform. The other wavelet reentered a SP and vanished soon. Therefore, the reentry was self-terminated. Unlike human hearts, the rabbit heart rarely supports sustained AVNRT. If the reentry could be inducible, a single reentrant beat was observed in response to both retrograde and antegrade premature stimulation.
AV Junctional Automaticity It has been clinically well known that the AV junction behaves as a subsidiary pacemaker of the heart when the primary pacemaker in the sinus node fails to control the cardiac rhythm, as the result of either a depressed automaticity or an impaired conduction. Based on the relationship between P wave and QRS complex, names of “upper nodal rhythm,” “central nodal rhythm,” and “lower nodal rhythm”
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Anatomy and Physiology of the Atrioventricular Node: What Do We Know Today?
are used. As their relationship is altered by the position of pacemaker and the conduction property in forward or reverse direction, those names are not necessarily correct [63]. The site in the AV junction which ectopic impulses arise from has been unclear for a long time. Based on the recording of intracellular potentials, it has been controversial on the following subjects [25, 28]: (1) Does the impulse formation locate at the boundary with the atrium (AN) and with the infranodal tissue (NH), but not at the compact node (N)? (2) If so, what part of those is predominant? (3) Does the automaticity not really originate from the N part? The automaticity was confirmed in all AN, N, and NH parts by
a
15
recording the AP and the membrane current with isolated cells, although the waveform of the AP is slightly different among the parts. This matter is similar to an analysis with a tissue preparation at each part. All the parts of the AV junction can become the secondary center of pacemaker activity [33, 34]. It is explained that the reason why the automaticity cannot be recorded in the tissue specimens of the N part is because the depolarization of membrane potential is suppressed by electrical contact between cells. And because the automatic firing arisen from the N cells is caused by a tiny diastolic potential, which is affected by the deep diastolic potentials from atrial and ventricular myocytes [64]. In
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Fig. 2.9 NF160 and Cx43 expression at the junctional pacemaker site (PNE posterior nodal extension). (a) Masson’s trichrome–stained section cut in the plane. (b) Low-magnification montage of adjacent section labeled for NF160. (c) Low-magnification view of adjacent section labeled for Cx43. (d) High-magnification view of NF160 labeling
at the junctional pacemaker site (PNE, from region shown in (b)). (e) High-magnification view showing absence of Cx43 labeling at the junctional pacemaker site (PNE, from region shown in (c)). Scale bar for (b) is shown in (c). Scale bar for (d) is shown in (e) (Reproduced from Dobrzynski et al. [38], with permission)
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Fig. 2.9 (continued)
other words, the occurrence of the automaticity has a high possibility by the source-sink relationship of cell-to-cell electrical interference. These can describe that the automaticity is not observed in the N part. But it has been left behind a question still unanswered: what part of the AV junction the automaticity originate from in a tissue specimen or a real heart? The reasons why it is hard to identify the site which the impulse arises from in the AV junction in tissue specimens or in the heart are the following: (1) The structure of this site is not separated by clear boundaries, but there is a complex structure that consists of various groups of cells and bundles. (2) It is not located on the surface of endocardium side but inside a little deep. It is difficult to understand properly the direction of propagation of impulses because of weak electrical signals detected and is not easy to record the extracellular potential in detail. (3) It is also difficult to record simultaneously the intracellular potential with multiple cells. Recently, the method to record the electrical activity on multichannels simultaneously using membrane potential-sensitive dyes was developed [59]. This method provides a unique opportunity for an analysis of the complex activation sequence in the AV junction and a task of locating the site of origin of the heartbeat. According to the experiment, attempting to identify the site of impulse formation in the AV junction by a combination of the membrane potential-sensitive stain method with an immunostain
method with antibodies against channels, connexin proteins, and neurofilaments labeling the nodal tissue, the most highfrequency automaticity was shown on the so-called PNE (similar to the posterior extension in literature 14) [41], equivalent to the slow component of the DAVNP or a SP. In addition, in a histological study, they identified a muscle bundle that consists of the cells similar to small nodal cells which extended from the midsection of the AV junction to the tricuspid annulus with posteroinferior direction (posterior extension) [14]. At this site the same expression of nodal tissue-specific channel proteins of HCN4, connexins, and neurofilaments as that in the AV junction is confirmed (Fig. 2.9). By the fact that the initiation of pacemaker current is determined and the state of distribution of connexins, the tissue structure at this site configures the slow component of the DAVNP and can work as the center of an ectopic automaticity [31, 39, 61]. With the record using membrane potential-sensitive dye, the signal is relatively weak and it is difficult to determine the specific groups of cells associated with impulse formation, although the initiation site can be limited to the certain range. Thus the true center of automaticity was not identified in this experiment. As the center of automaticity was sought in sinus bradycardia, sinus arrest, or sinoatrial block, the site of impulse formation is not certain to be the same as the site which the tachycardia by accelerated ectopic automaticity arises from in clinical settings.
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Anatomy and Physiology of the Atrioventricular Node: What Do We Know Today?
Conclusion
The AV junction is composed of groups of cells which are different from atrial and ventricular myocytes in electrophysiological characteristics and structure but similar to the cells at the sinoatrial node in morphology and function. Thus its function is specific. It forms the complex structure because there are the cells with different electrophysiological property, e.g., transitional cells from the atrial muscle, nodal cells, and cells of the nodal infrastructure to the bundle of His, laid at a variety of levels. The array of different types of cells and the specific structure conduct the delay or block of conduction, concealed conduction and the dual-pathway physiology, the ectopic automaticity, and so on, and also contribute to the occurrence of a reentrant tachyarrhythmia.
References 1. Tawara S. Eine Anatomische-Histologishe Studie Uber Das Atrioventrikularbundel Und Die Purkinjeschen. In: Tawara S, editor. Das Reizleitungssystem Des Saugetierherzens. Faden. Jena/ Deutschland: Verlag Von Gustav Fisher; 1906. 2. Janse MJ, Loh P, de Bakker JM. Is the atrium involved in AV nodal reentry? In: Mazgalev TN, Tchou PJ, editors. Atrial-AV nodal electrophysiology: a view from the millennium. Armonk: Futura; 2000. 3. Shah D, Haissaguerre M, Gaita F. Slow pathway ablation for atrioventricular nodal reentry. J Cardiovasc Electrophysiol. 2002;13:1054–5. 4. Haissaguerre M, Gaita F, Fisher B, Commenges D, Montserrat P, d’Ivernois C, et al. Elimination of atrioventricular nodal reentrant tachycardia using discrete slow potentials to guide application of radiofrequency energy. Circulation. 1992;85:2162–75. 5. Jackman WM, Beckman KJ, McClelland JH, Wang X, Friday KJ, Roman CA, et al. Treatment of supraventricular tachycardia due to atrioventricular nodal reentry by radiofrequency catheter ablation of slow-pathway conduction. N Engl J Med. 1992;327:313–8. 6. Koch W. Weitere Mitteilungen Uber Den Sinusknoten Des Hertzens. Verh Dtsch Ges Pathol. 1989;13:85–92. 7. DeFelice LJ, Challice CE. Anatomic and ultrastructural study of the electrophysiological atrioventricular node of the rabbit. Circ Res. 1969;24:457–74. 8. Becker AE, Anderson RH. Morphology of the human atrioventricular junctional area. In: Wellens HJJ, Lie KI, Janse MJ, Stenfert HE, Kroese BV, editors. The conduction system of the heart. Leiden: Stenfert Kroese; 1976. p. 263–86. 9. Anderson RH, Janse MJ, van Capelle FJ, Billette J, Becker AE, Durrer D. A combined morphological and electrophysiological study of the atrioventricular junction of the rabbit heart. Circ Res. 1974;35:909–29. 10. Petrecca K, Shrier A. Spatial distribution of ion channels, receptors and innervation in the AV junction. In: Mazgalev TN, Tchou PJ, editors. Atrial-AV nodal electrophysiology: a view from the millennium. Armonk: Futura; 2000. 11. Billette J. What is the atrioventricular junction? Some clues in sorting out its structure-function relationship. J Cardiovasc Electrophysiol. 2002;13:515–8. 12. Anderson RH, Ho SY, Becker AE. Anatomy of human AV junction revisited. Anat Rec. 2000;260:81–91. 13. Anderson RH, Cook AC. The structure and components of the atrial chambers. Europace. 2007;9:vi3–9.
17
14. Inoue S, Becker AE. Posterior extensions of the human compact atrioventricular junction. A neglected anatomic feature of potential clinical significance. Circulation. 1998;97:188–93. 15. Sanchez-Quintana D, Davies DW, Ho SY, Oslizlok P, Anderson RH. Architecture of the atrial musculature in and around the triangle of Koch: its potential relevance to atrioventricular nodal reentry. J Cardiovasc Electrophysiol. 1997;8:1396–407. 16. Lamers WH, Wessels A, Verbeek FJ, Moorman AF, Viragh S, Wenink AC, et al. New findings concerning ventricular septation in the human heart. Implications for maldevelopment. Circulation. 1992;86:1194–205. 17. Miyazaki H, Abe K, Yamane T, Date T, Tsurusaki T, Honda Y, et al. Adenosine-sensitive atrial reentrant tachycardia originating near tricuspid annulus: electrophysiological characteristics, pharmacological response and effects of radiofrequency ablation. Circ J. 2002;66 Suppl 1:246. 18. Yamabe H, Tanaka Y, Okumura K, Morikami Y, Kimura Y, Hokamura Y, et al. Electrophysiologic characteristics of verapamilsensitive atrial tachycardia originating from the atrioventricular annulus. Am J Cardiol. 2005;95:1425–30. 19. Matsuyama T, Inoue S, Tanno K, Makino M, Ogawa G, Sakai T, et al. Ectopic nodal structures in a patient with atrial tachycardia originating from the mitral valve annulus. Europace. 2006;8:977–9. 20. Hoffmann BF, de Paes Carvalho A, de Mello WC. Trans-membrane potentials of single fibers of the atrioventricular junction. Nature. 1958;181:66–7. 21. Meijler FL, Janse MJ. Morphology and electrophysiology of the mammalian atrioventricular junction. Physiol Rev. 1988;68:608–47. 22. Munk AA, Adjemian RA, Zhao J, Ogbaghebriel A, Shrier A. Electrophysiological properties of morphologically distinct cells isolated from the rabbit atrio-ventricular junction. J Physiol. 1996;493:801–19. 23. Sano T, Tasaki M, Shimamoto T. Histological examination of the origin of the action potential characteristically obtained from the region bordering the atrioventricular junction. Circ Res. 1958;7:700–4. 24. Bharati S. Anatomic-morphologic relations between AV nodal structure and function in the normal and diseased heart. In: Mazgalev TN, Tchou PJ, editors. Atrial-AV nodal electrophysiology: a view from the millennium. Armonk: Futura; 2000. 25. de Paes Carvalho A, de Mello WC, Hoffman BF, editors. The specialized tissues of the heart. Amsterdam: Elsevier; 1961. 26. de Paes Carvalho A, de Almeida DF. Spread of activity through the atrioventricular node. Circ Res. 1960;8:801–9. 27. Watanabe Y, Dreifus LS. Site of impulse formation within the atrioventricular junction using optical coherence tomography. Circ Res. 1968;22:717–27. 28. Hoffman BF, Cranefield PF. Electrophysiology of the heart. New York: McGraw-Hill Book Co Inc; 1960. 29. Billette J. Atrioventricular nodal activation during periodic premature stimulation of the atrium. Am J Physiol. 1987;252:H163–77. 30. Medkour D, Becker AE, Khalife K, Billette J. Anatomic and functional characteristics of a slow posterior AV nodal pathway: role in dual-pathway physiology and reentry. Circulation. 1998;98: 164–74. 31. Nikolski V, Efimov I. Fluorescent imaging of a dual-pathway atrioventricular-nodal conduction system. Circ Res. 2001;88: E23–30. 32. Petrecca K, Amellal F, Laird DW, Cohen SA, Shrier A. Sodium channel distribution within the rabbit atrio-ventricular junction as analyzed by confocal microscopy. J Physiol. 1997;501:263–74. 33. Noma A, Irisawa H, Kokubun S, Hotake H, Nishimura M, Watanabe Y. Slow current systems in the A-V junction of the rabbit heart. Nature. 1980;285:228–9. 34. Hancox JC, Levi AJ, Lee CO, Heap PA. A method for isolating rabbit atrioventricular junction myocytes which retain normal morphology and function. Am J Physiol. 1993;265:H755–66.
18 35. Kokubun S, Nishimura M, Noma A, Irisawa H. The spontaneous action potential of rabbit atrioventricular junction cells. Jpn J Physiol. 1980;30:529–40. 36. Taniguchi J, Kokubun S, Noma A, Irisawa H. Spontaneously active cells isolated from the sino-atrial and atrio-ventricular junctions of rabbit heart. Jpn J Physiol. 1981;31:547–58. 37. Kokubun S, Nishimura M, Noma A, Irisawa H. Membrane currents in the rabbit atrio-ventricular junction cell. Pflugers Arch. 1982;393:15–22. 38. Dobrzynski H, Nikolski VP, Sambelashvili AT, Greener ID, Yamamoto M, Boyett MR, et al. Site of origin and molecular substrate of atrioventricular junctional rhythm in the rabbit heart. Circ Res. 2003;93:1102–10. 39. Noma A, Nakyana T, Kurachi Y, Irisawa H. Resting K conductance in pacemaker and non-pacemaker cells of the rabbit. Jpn J Physiol. 1984;34:245–54. 40. Yoo S, Dobrzynski H, Fedrov VV, Xu SZ, Yamanushi TT, Jones SA, et al. Localization of Na+ channel isoform at the atrioventricular junction and atrioventricular junction in the rat. Circulation. 2006;14:1360–71. 41. Efimov IR, Nikolski VP, Rothenberg F, Greener ID, Li J, Dobrzynski H, et al. Structure-function relationship in the A-V junction. Ant Rec A Discov Mol Cell Evol Biol. 2004;280:952–65. 42. Mangoni ME, Traboulsie A, Leoni A-L, Couette B, Marger L, Quang KL, et al. Bradycardia and slowing the atrioventricular conduction in mice lacking CaV3.1./α1G T-type calcium channels. Circ Res. 2006;98:1422–30. 43. Gros DB, Jongsma HJ. Connexins in mammalian heart function. Bioessays. 1996;18:719–30. 44. Spray DC, Suadicani SO, Vink MJ, Srinivas M. Gap junction channels and healing-over of injury. In: Sperelakis N, Kurachi Y, Terzic A, Cohen MV, editors. Heart physiology and pathophysiology. New York: Academic; 2000. p. 149–74. 45. Kreuzberg MM, Sohl G, Kim J-S, Verselis VK, Willecke K, Bukauskas FF. Functional properties of mouse connexin 30.2 expressed in the conduction system of the heart. Circ Res. 2005;96:1169–77. 46. Langendorf R. Concealed A-V conduction: the effect of blocked impulses on the formation and conduction of subsequent impulses. Am Heart J. 1948;35:542. 47. Yamada K, Okajima M, Hori K, Fujino T, Muraki H, Hishida H, et al. On the genesis of the absolute ventricular arrhythmia associated with atrial fibrillation. Circ Res. 1968;12:707–15. 48. Moe G, Preston JB, Burlington H. Physiological evidence for a dual A-V transmission system. Circ Res. 1956;4:357–75. 49. Mendenz C, Moe G. Demonstration of a dual A-V nodal conduction system in the isolated rabbit heart. Circ Res. 1966;19:378–93.
H. Miyazaki 50. Denes P, Wu D, Dhinga R, Amat-y-Leon F, Wyndham C, Rosen KM. Dual atrioventricular nodal pathways: a common electrophysiologic response. Br Heart J. 1975;37:1069–76. 51. Watanabe Y, Dreifus LS. Inhomogeneous conduction in the A-V junction: a model for reentry. Am Heart J. 1965;70:505–14. 52. Janse MJ, van Capelle FJL, Freud GE, Durrer D. Circus movement within the AV junction as a basis for supraventricular tachycardia as shown by multiple microelectrode recording in the isolated rabbit heart. Circ Res. 1971;28:403–14. 53. Mines GR. On dynamic equilibrium in the heart. J Physiol. 1913;46:349–83. 54. Coumel P, Carbol C, Fabiato A, Gourgon R, Slama R. Tachycardie Permanente Par Rhthme Reciproque. Arch Mal Coeur Vaiss. 1967;60:1830–64. 55. Heidbuchel H, Jackman WM. Characterization of sub-forms of AV nodal reentrant tachycardia. Europace. 2004;6:316–29. 56. Cox JL, Ferguson Jr TB, Lindsay BD, Cain ME. Perinodal surgery for AV nodal reentrant tachycardia in 23 patients. J Thoracic Cardiovasc Surg. 1990;99:440–50. 57. Wu JW, Olgin J, Miller JM, Zipes DP. Mechanisms underlying the reentrant circuit of atrioventricular nodal reentrant tachycardia in isolated canine atrioventricular nodal reparation using optical mapping. Circ Res. 2001;88:1180–95. 58. Zipes DP, Mendez C. Action of manganese ions and tetrodotoxin on atrioventricular nodal transmembrane potentials in isolated rabbit hearts. Circ Res. 1973;32:447–54. 59. Nikolski VP, Jones SA, Lancaster MK, Boyett MR, Efimov IR. Cx43 and dual-pathway electrophysiology of the atrioventricular node and atrioventricular nodal reentry. Circ Res. 2003;92: 469–75. 60. Kwong KF, Schuessler RB, Green KG, Laing JG, Beyer EC, Boineau JP, et al. Differential expression of gap junction proteins in the canine sinus node. Circ Res. 1998;82:604–12. 61. Joyner RW, van Capelle FJ. Propagation through electrically coupled cells: how a small SA node drives a large atrium. Biophys J. 1986;50:1157–64. 62. Coppen SR, Kodama I, Boyett MR, Dobrzynski H, Takagishi Y, Honjo H, et al. Connexin 45, a major connexin of the rabbit sinoatrial node, is co-expressed with connexin 43 in a restricted zone at the nodal-crista terminalis border. J Histochem Cytochem. 1999;47:907–18. 63. Scherf D, Cohen J, editors. The atrioventricular node and selected cardiac arrhythmias. New York: Grune & Stratton; 1964. 64. Spitzer KW, Sato N, Tanaka H, Firek L, Zani-boni M, Giles WR. Electrotonic modulation of electrical activity in rabbit atrioventricular node myocytes. Am J Physiol. 1997;273:H767–76.
3
Molecular Basis of Arrhythmias Associated with the Cardiac Conduction System Sunil Jit R.J. Logantha, Andrew J. Atkinson, Mark R. Boyett, and Halina Dobrzynski
Abstract
The cardiac conduction system is responsible for the initiation and coordination of the heartbeat. It consists of three central components: the sinus node, the atrioventricular node, and the His-Purkinje system. Since the discovery of the sinus node in 1907, the cardiac conduction system has been a topic of immense interest to basic science and clinical researchers investigating the function/dysfunction of the heart. In the last 10 years, our understanding of the system has been immensely enriched. We now know that the system has specialized (different from that in the working myocardium) expression profile of ion channels, intracellular Ca2+-handling proteins, and gap junction channels that are appropriate for its functioning, although there is continued debate concerning the ionic mechanisms underlying pacemaking. We are beginning to understand the mechanisms responsible for cardiac conduction system dysfunction in disease and appreciate how naturally occurring ion channel mutations cause congenital cardiac conduction system dysfunction. In this chapter we present the molecular basis of arrhythmias associated with the cardiac conduction system, with particular emphasis on recent developments in the field. Keywords
Cardiac conduction system • Sinus node • Atrioventricular node • His bundle • Purkinje network • Ion channels • Gap junctions • Ca2+-handling proteins • Arrhythmias • Channelopathies
Introduction
S.J.R.J. Logantha, PhD Cardiovascular Research Group, School of BioMedicine, University of Manchester, Manchester, UK A.J. Atkinson • M.R. Boyett, PhD • H. Dobrzynski, PhD (*) Institute of Cardiovascular Sciences, School of BioMedicine, University of Manchester, CTF Building, 46 Grafton Street, Manchester, M13 9NT, UK e-mail:
[email protected];
[email protected]
A.S. Kibos et al. (eds.), Cardiac Arrhythmias, DOI 10.1007/978-1-4471-5316-0_3, © Springer-Verlag London 2014
The three core components of the cardiac conduction system (CCS) are the sinus (or sinuatrial or sinoatrial) node (SN), the atrioventricular (AV) node, and the His-Purkinje network (Fig. 3.1). They have unique anatomical, molecular, and functional characteristics that enable them to work collectively as the electrical system of the heart. The specialized cardiac myocytes of this system have been the subject of extensive studies since the elucidation of the SN in 1907 by Keith and Flack [1]. With technological advancements in the last decade, our understanding of this specialized system has enhanced immensely, particularly,
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SVC
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Fig. 3.1 Cardiac conduction system. Schematic representation of the mammalian heart highlighting the location of the sinus node (SN), atrioventricular conduction axis (AVCA), His bundle (His), left bundle branch (LBB), right bundle branch (RBB), and Purkinje fibers (PF). The right atrium (RA), left atrium (LA), right ventricle (RV), left ventricle (LV), superior vena cava (SVC), inferior vena cava (IVC), coronary sinus (CS), tricuspid valve (TV), and mitral valve (MV) are labelled
the molecular determinants of its dysfunction (e.g., arrhythmogenic activity). In this chapter, we aim to describe our current understanding of the CCS focussing on the molecular changes that underlie arrhythmogenesis in these tissues.
Cardiac Conduction System Sinus Node In health, the heartbeat is initiated within the SN. Since the identification of this specialized tissue in 1907 [1], research in the field has provided a wealth of information regarding the molecular mechanisms underlying the initiation of the heartbeat (pacemaker activity). In the following paragraphs, we provide an overview of the functional anatomy of the SN and the molecular basis of its pacemaker activity and highlight the pathologies affecting its function.
Anatomy In humans, the SN is usually a banana-shaped structure embedded in the subepicardial intercaval region of the heart at the junction of the superior vena cava and the right atrium, with the tail extending along the crista terminalis also known as terminal crest (Fig. 3.1) [2–4]. Blood supply to the SN is provided by the SN artery, and nodal myocytes are embedded in a network of connective tissue (Fig. 3.2a). At the center of the SN, there are characteristic P cells (P for pacemaker), which are believed to generate pacemaker activity [5–7]. The P cells are small (less than half the size of atrial cells in the same species) and have fewer and poorly organized contractile myofilaments. They contain a large nucleus, fewer and randomly distributed mitochondria and little sarcoplasmic reticulum and are rich in glycogen granules [5, 7–10]. Within the SN, the P cells are surrounded by relatively larger transitional cells, whose appearance range between P cells and those of working atrial myocytes [5, 9]. Moving from the center to the periphery of the SN, there occurs a gradual transition in action potential characteristics from true nodal type to peripheral nodal type (Fig. 3.2c). The peripheral nodal-type action potentials share some characteristics with the surrounding working atrial myocytes [9, 11]. In the human heart, close to the periphery of the SN, a further histologically distinct area of loosely packed myocytes, the paranodal area, has been recently identified (Fig. 3.2a, b) [12]. The paranodal area occupies an area larger than the SN and runs parallel to this tissue along the length of the terminal crest. The myocytes in the paranodal area are loosely packed, and their extracellular matrix is composed of fatty tissue and not connective tissue, which is the case in the SN. The area is heterogeneous in that it consists of atrial-like myocytes that express the connexin 43 (Cx43), connexin 40 (Cx40) (gap junction channels responsible for electrical coupling between myocytes), and atrial natriuretic peptide (ANP) as well as SN-like myocytes (not expressing Cx43, Cx40, and ANP) [4]. The functional significance of this tissue is yet to be ascertained, although it has been suggested that the paranodal myocytes might facilitate the exit of the action potential from the SN into the atrial myocardium [4]. At its periphery, the SN interdigitates with the surrounding atrial myocardium [13, 14], and it has been suggested that such interdigitations assist the exit of the action potential from the SN into the atrial myocardium [15]. However, it has also been argued that action potentials exit from the SN at specific superior and inferior exit sites, and in all other directions, exit of the action potential is blocked by fibrous tissue and blood vessels [16–18]. This appearance of distinct superior and inferior exit sites, we believe, might be a result of the preferential supero-inferior myocyte orientation within the SN [4, 9] and the resultant preferential supero-inferior action potential propagation.
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Molecular Basis of Arrhythmias Associated with the Cardiac Conduction System
Fig. 3.2 Histological and a electrophysiological properties of the sinus node. (a) Masson’s trichrome-stained section through human sinus node showing the adjacent paranodal area [12]. (b) 3D anatomical model of the human sinus node showing endocardial side and epicardial views [4]. (c) Typical action potential traces from right atrial, sinus node (SN) periphery, and SN center (Modified form Tellez et al. [11]). The maximum diastolic potential (MDP), diastolic depolarization (phase 4), upstroke (phase 0), rapid repolarization b phase (phase 1), plateau (phase 2), and repolarization (phase 3) are shown. Note the absence of prominent phase 1 in the SN center
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Terminal crest Paranodal area
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Function The SN has unique electrical properties and is the primary source of electrical activity in the heart [2, 9, 19, 20]. The maximum diastolic potential (MDP, peak negative potential preceding the initiation of the action potential) in SN myocytes is less negative than that found in the working myocardium. This is due to smaller inward rectifier K+ current (IK,1), the chief determinant of the MDP [21] and poor expression level of the Kir2.1 channel that is primarily
responsible for IK,1 [12, 19]. Throughout diastole, the membrane potential slowly depolarizes giving rise to the characteristic pacemaker potential of the SN (Fig. 3.2c). Although precise knowledge of the sequence of events underlying the pacemaker potential remains unclear, the spontaneous depolarization is thought to be a net result of a complex synergistic interaction between two oscillators: the “membrane voltage-clock” and the “subcellular Ca2+-clock” [22–25].
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The voltage-clock mechanism involves a group of plasma membrane-bound voltage-dependent ion channels and activation/inactivation of their corresponding ionic currents. The earliest proposal was based on clues from microelectrode recordings of membrane response to changes in extracellular [K+] and [Na+] which suggested a role for voltage-dependent decay of K+ conductance in generating the diastolic depolarization [26]. With the advent of the patch clamp technique [27] and the successful isolation of spontaneously active single SN cells [28], several ionic components of the diastolic depolarization have been identified: hyperpolarizationactivated inward current popularly known as the funny current (If) [29, 30], sustained inward current (Ist) [31], and voltage-dependent L-type and T-type Ca2+ currents (ICa,L and ICa,T, respectively) [32, 33]. Additional new mechanisms are still being discovered: hyperpolarization-activated inwardrectifying Cl− current [34]; Ca2+-activated nonspecific current, carried by transient receptor potential channel TRPM4 [35]; and the two-pore-domain K+ channels, ORK1 (K+ leak or background current) [36] and TREK1 [37]. A variety of two-pore-domain K+ channels (TASK1, TREK1, TWIK1, TWIK2) are known to be expressed in the rat SN [38] raising the scope for further involvement of these channels in diastolic depolarization. Thus, a multiplicity of plasma membrane ionic currents is thought to contribute to the pacemaker potential, and the idea of a unique plasma membrane pacemaker current underlying pacemaking is inapt. Currently, the focus revolves around the magnitude of the individual contribution of each of the abovementioned ionic currents to the pacemaker potential. The case for If as the chief contributor has long been championed by DiFrancesco [30, 39]. In a number of species, the ion channels primarily responsible for If, HCN4 (main) and HCN1, are highly expressed in the SN [2, 12, 20]. Mutation in the gene coding HCN4 causes sinus bradycardia in humans [40], and conditional knockout of HCN4 in the adult mouse has been shown to cause deep bradycardia [41]. Additionally, pharmacological intervention with ivabradine, an If blocker recently approved for clinical use in Europe, is known to reduce heart rate in human [42]. The subcellular Ca2+-clock mechanism is based on accumulating evidence in recent years suggesting that spontaneous Ca2+ release from the sarcoplasmic reticulum is critical to the generation of the pacemaker potential in the SN [43–49]. The proposed mechanism involves spontaneous Ca2+ release from the sarcoplasmic reticulum via the ryanodine receptors activating the Na+-Ca2+ exchanger and generating an inward current (INaCa) [44, 46, 50] that causes membrane depolarization which, on reaching threshold level for activation of L-type Ca2+ channels, triggers an action potential. Inhibiting INaCa by either partially or wholly substituting Na+ in the extracellular solution with lithium (Li+) has been demonstrated to abolish SN pacemaking in isolated rabbit and guinea pig SN cells [45, 48]. Mutations in genes encoding
S.J.R.J. Logantha et al.
components of the Ca2+-clock, for example, the ryanodine receptor channel (RYR2) and the sarcoplasmic reticulum Ca2+ storage protein calsequestrin (CASQ2), are known to cause catecholaminergic polymorphic ventricular tachycardia, and this has been associated with sinus bradycardia and heart block [51–53]. The detrimental effect on SN function caused by experimental inhibition or dysfunction of the subcellular Ca2+-clock mechanism provides compelling evidence supporting the importance of this mechanism to pacemaking and kindles controversy over its relative importance over the membrane voltage-clock. However, given that evidence supporting both mechanisms currently exists [54], it is safe to advocate that mutual entrainment of both clock mechanisms underlies normal SN function [22–25]. The pacemaker potential on reaching threshold level triggers an action potential with a slow upstroke (phase 0), without an early repolarization (phase 1), and with a prominent plateau (phase 2) (Fig. 3.2c). Consequently, the action potential in SN is longer in duration compared to that in surrounding atrial myocytes [55]. Depolarization during phase 1 is due to smaller and slower ICa,T and ICa,L and not by the fast Na+ current (INa),which is the case in the working myocardium [19, 20]. The SN shows high (vs. atria) expression of specialized Ca2+ channels, Cav1.3 and Cav3.1, that are more appropriate for pacemaking [12]. INa is either small or absent in the center of the SN because the Na+ channel isoform Nav1.5 is poorly expressed or not expressed in this tissue, whereas it is highly expressed in the working myocardium in the human and other species [11, 12, 56]. However, another Na+ channel isoform Nav1.1, although much less abundant than Nav1.5 in the SN, is preferentially expressed [11] and is responsible for part of INa (at least in the mouse) [57]. Repolarization of the SN (phase 3, Fig. 3.2c), like in the rest of the working myocardium, is the result of inactivation of ICa,L and the activation of a variety of K+ currents including the transient outward K+ current (Ito) and ultrarapid K+ current (possibly) (IK,ur) and rapid and slow delayed rectifier K+ currents (IK,r and IK,s, respectively) [9]. In the human, some K+ channels are more poorly expressed in the SN (e.g., ERG channel responsible for IK,r and Kv1.5 responsible for IK,ur) [12]; this is expected to slow the repolarization phase and may account for the longer action potential [55]. A summary of major ion channel expression profile at the mRNA level in the SN with reference to atrial myocardium is provided in Table 3.1. Moving from the center to the periphery of the SN, marked transition in the characteristics of the action potential is observed: the MDP becomes more negative and the action potential upstroke becomes faster, duration becomes shorter, and paradoxically the intrinsic pacemaker activity becomes faster (Fig. 3.2c) [55]. In the rabbit, these changes are partly due to an increase in the density of If, INa, and IK,r [9] and are thought to enable the SN drive the surrounding atrial
Ionic current IK,1 IK,1 IK,1 If If INa INa ICa,T ICa,L ICa,L Ito Ito Ito IK,ur IK,r IK,s – – – INaCa 4
0
1
2
3
Data collated from Chandler et al. [12], Greener et al. [56], and Gaborit et al. [136] ▲ higher expression, ▼ lower expression, = no difference vs. atrial muscle
Ca2+-handling
Gap junction
Ion channel
mRNA Kir2.1 Kir2.2 Kir2.3 HCN1 HCN4 Nav1.1 Nav1.5 Cav3.1 Cav1.2 Cav1.3 Kv1.4 Kv4.2 Kv4.3 Kv1.5 ERG KvLQT1 Cx40 Cx43 Cx45 NCX1 SERCA2 RYR2
Action potential phase
Human heart regions (expression level vs. atrial muscle) AV node Inferior Sinus Paranodal Transitional nodal Compact node area area extension node ▼ ▼ ▼ ▼ ▼ = = = = = ▼ = = = = ▲ = = = ▲ ▲ = ▲ ▲ ▲ = = = ▲ = ▼ ▼ ▼ ▼ ▼ ▲ = ▲ ▲ ▲ ▼ = = = = ▲ = ▲ ▲ ▲ = ▼ = = ▲ ▲ ▲ ▲ ▲ ▲ ▼ ▼ = = = ▼ = ▼ ▼ ▼ ▼ = = = ▲ = = = ▼ = ▼ = = = ▲ ▼ = ▼ ▼ ▼ = = = = = = = = ▼ = ▼ = = = = ▼ = = ▼ ▼ Penetrating bundle = = = = ▲ ▲ = ▲ ▼ ▲ ▲ ▲ = ▼ ▲ = ▲ ▼ = = = =
Purkinje fibers ▲ ▼ ▼ ▼ ▼ = = ▼ ▼ ▼ ▲ = = ▼ = ▲ = = ▼ ▼ ▼ ▼
Ventricular muscle ▲ ▼ = = = = = ▼ = = ▲ = = ▼ = = = = = = = =
Table 3.1 Ion channel, connexins, and Ca2+-handling protein expression profile at the mRNA level in the human sinus node, paranodal area, atrioventricular conduction axis, Purkinje fibers, and ventricular muscle relative to atrial muscle
3 Molecular Basis of Arrhythmias Associated with the Cardiac Conduction System 23
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myocardium [58]. As mentioned earlier, in the human we have proposed that the paranodal area (periphery of the SN) enables propagation of the action potential from the SN to the atrial myocardium [4]. In the absence of functional recordings from human tissue, computer modelling studies support this critical role of the paranodal area in electrical propagation [4]. At the center of the SN, electrical coupling between myocytes is poor [9, 15], and this partly insulates the center from the hyperpolarizing influence of the atrial muscle [15, 59] and is responsible for the slow conduction velocity: 2–6 cm/s vs. 70 cm/s in atrial myocardium [9, 60]. Based on expression patterns of weak coupling (hence small conductance) connexin 45 (Cx45) and connexin 30.2 (Cx30.2) in the center of the SN and intermediate (Cx40) and large conductance (Cx43) connexins in the periphery, it has been proposed that electrical coupling gradually improves on moving from the center to the periphery [15, 61], enabling the SN to effectively drive the atrial myocardium [59].
Molecular Determinants of Pathology Dysfunction of the SN is common with aging, and its incidence increases exponentially with age [62]; however, dysfunction can also be inherited and in some families it has been linked to certain ion channel mutations [40, 63]. With aging, a decline in the intrinsic heart rate has been observed in humans and in laboratory animals [62, 64], and elderly people account for the vast majority of pacemaker implantations in the USA [65]. SN dysfunction is often also associated with common heart ailments including atrial fibrillation [66, 67], heart failure [68–70], myocardial infarction [38], and pulmonary hypertension [71]. Histopathological investigations have revealed an important role for degenerative fibrosis in the etiology of SN dysfunction [72, 73]. Tissue fibrosis and upregulation of fibrosis genes have been observed in the SN of the aging mouse [74]. In another mouse study, angiotensin II caused SN cell oxidation by activating NADPH oxidase, leading to increased activation of Ca2+/calmodulin-dependent protein kinase II (CaMKII), cell apoptosis, and SN dysfunction [75]. Transgenic mice that lacked functional NADPH oxidase and those with CaMKII inhibition were highly resistant to apoptosis and SN dysfunction suggesting that CaMKII-triggered cell death contributed to SN dysfunction [75]. In a rat model of pulmonary hypertension with SN dysfunction, upregulation of fibrosis genes was observed in the SN [71]; however, no obvious fibrosis was observed and the notion that SN dysfunction is the result of degenerative fibrosis alone has been challenged [64, 76, 77]. Alternatively, it has been suggested that remodelling of ion channel expression pattern could be responsible, thus opening up a Pandora’s box of a whole spectrum of ion channels and associated proteins in the etiology of SN dysfunction. Remodelling of several channel proteins including HCN, Na+, K+, Ca2+, and connexins involved in SN
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dysfunction has now been identified [38, 67, 70, 74, 77–83]. Fibrosis and ion channel remodelling might be interrelated [74, 84]. Age-dependent fibrosis has been observed in SN of knockout mouse where one copy of the SCN5A gene that encodes Nav1.5 responsible for INa was disrupted [74]. In cultured human cardiac myocytes and fibroblasts inhibiting the Na+ channel with Nav1.5-E3 antibody directly increases the fibrosis gene, TGF-β (1) [74]. Another fibrosis gene, NF-κB, has been shown to bind to the promoter region of SCN5A and regulate transcription of the gene [85]. Thus, evidence supports both fibrosis and ion channel remodelling could result in SN dysfunction.
Atrioventricular Node Anatomy The AV node is part of the electrical conduit from the atria to the ventricles that is usually referred to as the AV conduction axis (AVCA) and is a critical component of the CCS. It is located at the base of the interatrial septum, at the apex of the triangle of Koch (Figs. 3.1 and 3.3) [86, 87], bound by the ostium of the coronary sinus, the septal leaflet of the tricuspid valve, and the tendon of Todaro (Fig. 3.3). Anatomically, the AVCA can be divided into four regions: the transitional area (TA), inferior nodal extension (INE), compact node (CN), and penetrating bundle (PB) as shown in Fig. 3.3 [88]. Electrical activity initiated in the SN travels via two different routes or pathways in the atria before reaching the AVCA (Fig. 3.3) [89–91]. The fast pathway is via the interatrial septum and traverses the TA myocytes and connects to the CN, which is a half-oval structure of specialized myocytes set against the central fibrous body (Fig. 3.3). The myocytes in the CN are smaller than atrial and ventricular myocytes [86]. The central fibrous body is the strongest part of the so-called fibrous skeleton of the AVCA [92]. The slow pathway is along the length of the terminal crest, through the narrow strip of tissue between the coronary sinus and the hinge of the septal leaflet of the tricuspid valve, into the INE before arriving at the CN (Fig. 3.3) [86, 93, 94]. Moving superiorly, the CN tissue becomes embedded within the central fibrous body, with the site of insulation proposed by Tawara [95] as a landmark for the division between the CN and the PB (Fig. 3.3). The PB runs a short course and emerges on the crown of the interventricular septum as the His bundle (Figs. 3.1 and 3.3) which then divides to form the left bundle branch (LBB) and right bundle branch (RBB) (Fig. 3.1) [86, 88]. Function The principal function of the AVCA is to conduct electrical activity from the atria to the ventricles in a harmonized fashion, so as to introduce a delay between atrial and
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Molecular Basis of Arrhythmias Associated with the Cardiac Conduction System
Posterior Crista terminalis
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Fig. 3.3 Schematic diagram of the rabbit atrioventricular conduction axis (AVCA) showing the transitional zone/area, inferior nodal extension, compact node, and penetrating bundle. The relative location of the inferior vena cava (IVC), tendon of Todaro, coronary sinus (CS), tricuspid valve (TV), fossa ovalis (FO), and central fibrous body (CFB) are also shown. Below, three Masson trichrome-stained sections through AVCA at levels indicated. Myocytes are stained red and connective tissue stained blue. The area demarcated by red dotted line shows inferior nodal extension (INE) in the left section, compact node (CN) in the middle section, and the penetrating bundle (PB) in the right section. AM denotes atrial myocardium and VM denotes ventricular myocardium [88]
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ventricular systole, thereby allowing atrial systole and complete ventricular filling prior to initiation of ventricular systole. In disease, the relatively long refractory period observed in some areas of the AVCA comes to aid by reducing the frequency of action potentials transmitted to the ventricles, and this protects the ventricles from atrial tachycardias. Also, when the SN fails, specialized myocytes of the AVCA can step in as the pacemaker of the heart, albeit at a slower rate [96]. A variety of action potential morphologies have been observed in the AVCA of many species [97–103]. The electrical properties underlying the different action potential morphologies have been investigated in myocytes isolated from the rabbit AVCA [103]. Cell capacitance, a measure of cell size, correlated negatively with the rate of diastolic depolarization and positively with the MDP and maximum upstroke velocity (dV/dtmax) of the action potential [103]. The nodal (N)-type myocytes are the smallest amongst AVCA myocytes [103] and are thought to occupy the INE and the CN, while the atrio-nodal (AN) and nodo-His (NH) myocytes are intermediate cells that are
thought to be present in the TA region and PB, respectively [88]. The N myocytes show a less negative MDP, exhibit diastolic depolarization and lower dV/dtmax (Ca2+-dependent upstroke), and are of smaller amplitude than AN cells and are capable of pacemaking [100, 104]. The less negative MDP is a consequence of smaller (or lack of) IK,1 [105] and reduced expression levels of the related Kir2.1 mRNA [56, 88]. This suits pacemaking and as discussed earlier for the SN, a plethora of mechanisms are likely to be involved in N cell pacemaker activity. In a number of species including rat, rabbit, and human, expression of the HCN4 channel is abundant in all areas of the AVCA, particularly in the INE and CN, and based on this evidence, HCN4 is thought to be the most important isoform responsible for If in this tissue [56, 88, 106]. However, within the AVCA region, there is heterogeneity in the expression of the pacemaker current, If [105]. In a study of the rabbit AVCA myocytes [101], almost all myocytes that were oval-shaped showing N- or NH-type action potentials exhibited If, whereas only a small proportion (~10 %)
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of rod-shaped myocytes showing AN-type action potential exhibited this current. The importance of If to pacemaking is evident from the increased cycle length (by 55 %) caused by blocking this current with 2 mM Cs+ [96]. In the last five years, evidence supporting the Ca2+-clock mechanism has also been accumulating. Spontaneous action potentials in isolated rabbit AV nodal myocytes could be slowed or stopped by inhibiting the Na+-Ca2+ exchanger with KB-7943 or the sarcoplasmic reticulum Ca2+ ATPase pump with either thapsigargin or cyclopiazonic acid [107]. In spontaneously beating AV nodal tissue preparations, disabling the ryanodine receptor Ca2+ release channel using ryanodine (2 μM) increases the cycle length [108]. Thus, inhibiting one of the crucial components of the Ca2+-clock severely affects spontaneous activity in the AV node, suggesting the importance of the Ca2+-clock mechanism to pacemaking in this tissue. Pacemaking myocytes of the AVCA show slow action potential upstroke because of dependence on ICa,L [109], rather than the fast INa which is absent [103]. In the rabbit, Cav1.3 is highly expressed, and this isoform and not Cav1.2 (as is the case elsewhere in the heart) is thought to chiefly contribute to ICa,L in the AVCA pacemaker myocytes [88]. The Cav1.3 channel has a more negative threshold for activation than Cav1.2 and this might help in pacemaking. Another voltagedependent Ca2+ channel with a more negative activation threshold, Cav3.1 which is responsible for ICa,T, is abundantly expressed particularly in the human CN, and Cav3.1 channel knockout slows AVCA conduction in mouse [56, 110]. ICa,T is considered to contribute to the diastolic depolarization and could play an important role in pacemaking [33]. Although fast INa is absent in N-type myocytes, INa is present (positively correlates with cell size) in all other AVCA cell types [56, 88, 103, 106] and is generally considered important for effective conduction through the AVCA: Mice with SCN5A (encodes Nav1.5 channel responsible for INa) gene knockout and humans with mutations affecting Na+ channel proteins exhibit impaired conduction via AVCA [111–113]. Electrical coupling in the AVCA is poor as evident from the slow diffusion of fluorescein between N-type myocytes in the rabbit [114]. This is attributed to a combination of two factors: the type of gap junctions and the number of intercellular connections. As already stated, the N-type myocytes are considered to be localized in the INE and CN areas, and in these areas of the rat, rabbit, and human, the main gap junction protein expressed is the small conductance Cx45 [61, 115, 116] while the large conductance Cx43 is either poorly expressed or absent [56, 88, 106]. Additionally, the TA also shows low expression of Cx43. The intermediate conductance Cx40 is not expressed in proximal part of the AVCA (e.g., INE), but is present in the CN and the PB that continues distally [56, 88, 106]. Interestingly, the PB can be divided lengthwise (i.e., along the direction of impulse
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propagation) into two halves based on Cx40 and Cx43 expression [94, 106], possibly explaining the observation of two conduction pathways within the His bundle [117]. Based on ion channel expression profile and voltage clamp data, computer modelling studies have predicted that the slow conduction along the human AVCA is the result of low expression of both Cx43 (hence, slow cell-to-cell conduction) and Nav1.5 (hence, slow action potential upstroke) [104]. Table 1 summarizes ion channel, connexin, and Ca2+handling protein expression pattern at mRNA level in different regions of the AVCA vs. atrial muscle.
Atrioventricular Node Pathophysiology The fast and slow conduction pathways of the AVCA (Fig. 3.3) can act as the substrate for atrioventricular nodal reentrant tachycardia (AVNRT) wherein a reentrant circuit is established with electrical activation travelling down one pathway (usually the slow) and up the other (usually the fast) causing AVNRT. In the rabbit and human heart, these pathways have been elucidated using a variety of electrical mapping strategies [86, 93, 118, 119]. Rotation of electrical activity around the two pathways has been demonstrated experimentally in the rabbit heart using fluorescent optical imaging techniques [120]. Histological examination of these regions suggested that the fast pathway corresponds to the TA, whereas the slow pathway corresponds to the INE [86, 120]. The refractory period of AN-type myocytes that participate in the fast pathway is longer than the refractory period of both N-type myocytes that make up the slow pathway and that of atrial myocytes [104]. Consequently, a premature stimulus would activate the slow pathway but not the fast pathway due to the longer refractory periods of its myocytes. By the time the activation reaches the CN, the refractoriness of the fast pathway would have passed, thus setting the scene for slow-fast AVNRT [104, 120]. Impairment of conduction through the AVCA results in AV block, commonly referred to as heart block (Fig. 3.4). Based on the degree of impairment, heart block is categorized into three classes: firstdegree heart block involves a delay in AVCA conduction seen by prolongation of the PR interval on the electrocardiograph (ECG, Fig. 3.4a–c) [121], second-degree heart block where not all atrial rhythms are transmitted resulting in some P waves not accompanied by QRS complex on the ECG (Fig. 3.4d), and third-degree heart block where AVCA completely fails to conduct (Fig. 3.4e) [121]. A ventricular escape rhythm (e.g., from Purkinje network) is usually present in such cases. Heart block is commonly idiopathic; however, it may also be inherited [63]. It could be secondary to ischemic heart disease, cardiomyopathy, heart failure [122], or increased vagal tone. The incidence of heart block increases with age and interestingly, is common in athletes [123, 124].
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Molecular Basis of Arrhythmias Associated with the Cardiac Conduction System R
a
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Fig. 3.4 Conduction abnormalities in the atrioventricular conduction axis. (a) Shape of normal ECG. Contraction of atria is associated with “P” wave, “QRS” complex occurs when the ventricles contract, and “T” wave is associated with ventricular relaxation (i.e., return to resting state). (b) Normal ECG recording showing one-one conduction where every P wave is followed by a QRS complex. One QRS complex occurs per second and the R-R interval is 1 s. (c) First-degree heart block where one-one conduction exists, but with a prolonged P-R interval which is a sign of conduction delay. (d) Second-degree heart block where one P wave is not followed by a QRS complex. (e) Third-degree heart block showing a lack of relationship between P waves (arrows) and QRS complexes. Abnormally shaped QRS complexes result from abnormal spread of depolarization from a ventricular ectopic focus (Modified from Hampton [121])
His Bundle, Bundle Branches, and Purkinje Network Anatomy The distal ventricular portion of the CCS ensures the synchronous activation of the ventricular myocardium which is important for efficient blood pumping. The His bundle is continuous with the distal end of the AVCA, is insulated by collagenous tissue and, in the normal heart, provides the only AV conduction pathway. At the crown of
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the interventricular septum, the bundle bifurcates into asymmetric LBB and RBB (Fig. 3.1) [125, 126], which are insulated from the underlying myocardium by connective tissue sheaths [127]. The LBB is a wide fanlike structure, whereas the RBB is a thick cord-like structure [126]. The LBB traverses the upper half of the septum before detaching itself from the underlying endocardium to form free-running false tendons that traverse the ventricular chamber (Fig. 3.5a). The false tendons reattach at the free wall of the left ventricle, forming a complex subendocardial network that is spread over a large segment of the free wall and terminates predominantly towards the papillary muscles. The RBB emerges beneath the membranous septum and runs towards the apex of the heart on the septal endocardium. Free-running strands extend from the RBB towards the apex of the right ventricle [95, 125, 126, 128]. At the terminal end of the Purkinje network, the insulating sheath of connective tissue is lost, and this allows the propagation of action potentials to the ventricular working myocardium [129, 130]. At the terminal Purkinje-ventricular junction, transitional myocytes with intermediate properties are found [131]. Immunolabelling for Cx43 and Cx40 shows that they are both expressed in the terminal Purkinje fibers (PF, Fig. 3.5b).
Function The principal function of the His-Purkinje system is to rapidly conduct electrical activity throughout the ventricles and orchestrate rhythmic ventricular contraction. Additionally, this system can act as the ventricular pacemaker in the event of a heart block (e.g., Fig. 3.4e). Conduction velocity in the His-Purkinje system is amongst the fastest in the heart: 2.3 m/s compared to 0.75 m/s in the ventricular muscle [132]. One factor enabling the fast conduction is the shape of intercellular junction and Cx43 and Cx40 expression. Contrary to the characteristic staircase configuration of ventricular intercellular junctions, Purkinje myocytes possess “fingerlike” cell endings, and intercellular junctions are formed by the interdigitation of these conical fingers [133]. In bovine PFs, a study of connexin expression revealed that Cx43 is concentrated in sections of plasma membrane facing adjacent PFs and not in membrane sections facing the surrounding connective tissue [134]. In addition to Cx43 [134, 135], PFs express Cx40 [126, 136], suggesting that they are extremely well coupled for rapid impulse propagation (Fig. 3.5c). This is unlike the SN or the CN of the AVCA where Cx45 is predominantly expressed. The pattern of connexin distribution, however, varies in different regions of the His-Purkinje system. The proximal His bundle and bundle branches show Cx40 expression, whereas in terminal PFs, both Cx40 and Cx43 are found co-localized (Fig. 3.5c) [135]. Genetically modified mice with Cx40 deficiency show impaired electrical conduction in the LBB and also exhibit RBB block [137],
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Fig. 3.5 Anatomy, histology, and electrical properties of Purkinje fibers (PF). (a) Magnified view of freerunning PF in the rabbit left ventricle [126]. (b) Typical spontaneous action potential recorded in an isolated kid (young goat) PF preparation. The vertical scale represents membrane potential and horizontal scale represents time (Modified from Weidmann [150]). (c) Caveolin3 (Cav3), a marker of myocytes, is expressed in the cell membrane of rabbit left ventricular myocardium (VM) and PF (red signal, top left panel), whereas Cx40 is expressed only in the PF myocytes and not in the VM (green signal, top right panel). In the terminal PFs, both Cx43 (red signal, bottom left panel) and Cx40 (green signal, bottom right panel) are expressed, whereas in the VM (adjacent to these PF myocytes) mainly Cx43 is expressed (red signal, bottom left). This indicates that PF myocytes may communicate with VM mainly via gap junctions made of Cx43
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demonstrating the importance of connexin expression for effective conduction in the His-Purkinje system. The second factor enabling the high conduction velocity in PFs is the characteristic of their action potential. The action potential is unlike that in nodal myocytes, but more like ventricular myocytes. In comparison to the ventricular action potential, the Purkinje cell action potential has a faster dV/dtmax, a higher amplitude, a more pronounced phase 1 and a much negative plateau potential, and, most important of all, a longer duration (mouse [138], rabbit [139], dog [140, 141]). The fast upstroke velocity and higher amplitude of the action potential are conducive to fast conduction in PFs. In the rabbit at least, the difference in action potential characteristics in the PFs vs. ventricular myocytes is thought to be a result of ICa,T in PFs but not in ventricular myocytes and increased density of INa and INa,L and decreased density of ICa,L, IK,r, IK,s, and IK,1 in the PFs [142]. These
20 µm
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differences in ionic current densities are consistent with their corresponding ion channel mRNA expression levels in the rabbit as well as in human PFs (Table 3.1) [126, 136]. Thus, a combination of strong electrical coupling provided by connexins and an action potential configuration determines the high conduction velocity in the His-Purkinje system. Due to their long action potential duration, PFs are prone to certain drug-induced early afterdepolarizations (EADs) [139, 143–147] and life-threatening arrhythmias such as torsades de pointes. Women are more prone to develop torsades de pointes, and this is thought to be due to longer Purkinje action potential duration as evidenced in the dog [148, 149]. In the absence of electrical activation from the atrium (e.g., artificial experimental condition or during heart block), PFs can show pacemaking (Fig. 3.5b), albeit at a slower rate and in a less robust fashion than SN or AV node.
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Molecular Basis of Arrhythmias Associated with the Cardiac Conduction System
Pacemaker action potential with phase 4 diastolic depolarization has been observed in the mouse [138], dog [141, 150–152], kid (i.e., young goat) [150], and sheep [150, 153] PFs. The ionic currents thought to contribute to the diastolic depolarization in PFs include If [153–155], ICa,T [142], a voltage- and time-dependent K+ current (IK,dd) [156], and a voltage- and time-dependent inward Na+ current (INa3) [157, 158]. During regular sinus rhythm, rapid excitatory impulses inhibit pacemaking in PFs by a process of “overdrive suppression,” wherein PFs are excited at frequencies higher than that of their intrinsic rates, leading to increased influx of Na+ [159], followed by enhanced electrogenic Na+/ K+ pump activity that results in hyperpolarization of the MDP preventing pacemaking [160–162]. However, if the interval between consecutive excitations is large enough (like in bradycardia), Ca2+ is released from the sarcoplasmic reticulum spontaneously, and this elicits full-fledged Ca2+ waves in PFs [146, 163]. Some of the released Ca2+ is extruded out of the cell by the Na+-Ca2+ exchanger resulting in a depolarizing inward current (Iti) that causes delayed afterdepolarizations, which on reaching threshold could elicit premature action potentials [146, 163]. PFs can thus act as ectopic pacemakers, but this type of pacemaker activity is abnormal and usually occurs when PFs are in a Ca2+overloaded state, and this has all the hallmarks of Ca2+-clock mechanism [164]. This, despite the low expression levels of Ca2+-handling proteins such as RYR2, RYR3, SERCA2a, and NCX1 in PFs [126, 136], perhaps significantly affects the contractile function but not pacemaking as low expression levels of Ca2+-handling proteins are also observed in the SN and AV node. An additional level of complexity in PFs is that they have two levels of stable resting membrane potentials. This is made possible by a lower IK,1 density and lower expression of the corresponding Kir2.1 channel [126, 165]. The steadystate current-voltage relationship of the canine PF is shallow and N-shaped and crosses the current axis twice, i.e., net current is zero at two voltage levels [166, 167]. As a consequence, canine PFs can switch between two levels of stable resting potential, one near −90 mV and one near −50 mV [166, 168]. Functionally, this is important because at more negative resting potentials, the action potential upstroke is INa-dependent (fast conducting) [153], whereas at the less negative resting potential, the action potential is Ca2+dependent (slow) [169, 170]. In closed loops of PFs, the slow conducting action potential is known to cause reentry, and this has been suggested to underlie some idioventricular rhythms and ventricular tachycardia [171].
Molecular Determinants of Pathology Impaired conduction in the His-Purkinje system plays a major role in the genesis of ventricular arrhythmias [172]. A variety of reentrant circuits involving either one or both
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His bundle branches are known to cause ventricular tachycardia [173–175]. Impaired conduction could lead to bundle branch block; while a block in the RBB is usually asymptomatic, LBB block can cause left ventricular dysfunction with abnormal chamber filling times and left ventricular ejection fractions [176]. The prevalence of bundle branch block increases with age [177] and is also associated with a variety of heart ailments including coronary artery disease and congestive heart failure [178]. In a recent clinical study [179], nearly 26 % of heart failure patients were found to have LBB. In animal models of heart failure (ventricular tachypacing model), major remodelling of ion channel expression has been observed [180]. In the canine heart failure model, downregulation of Kir2.1, Nav1.5, Kv3.4, Kv4.3, Cx40, and Cx43 in the PFs coupled with slowed conduction and altered action potential characteristics has been observed [180–183]. The Purkinje-ventricular junction is considered an important source of triggered activity generating arrhythmias [184–188]. The long action potential duration and higher susceptibility to EADs lead to the torsades de pointes arrhythmias in patients with long QT syndrome [155, 189]. The Purkinje network is thought to be the source of arrhythmogenic Ca2+ release events in catecholaminergic polymorphic ventricular tachycardia, an inherited arrhythmogenic disease, wherein stress induces sudden cardiac death [190–192].
Summary Our knowledge of the anatomy of the CCS and understanding of its functioning has expanded immensely in the last 20 years. With advances in technology, we have learned much about the molecular makeup of the CCS and the basis of its electrical activity, and this has not only complemented past observations of many electrophysiologists but also opened new avenues for further research. We are now beginning to uncover the type and extent of ion channel remodelling that occurs in animal models of heart disease such as atrial fibrillation and heart failure. With such research a better picture is emerging regarding dysfunction of the CCS in humans, and this raises the possibility of designing new treatments in the clinic.
References 1. Keith A, Flack M. The form and nature of the muscular connections between the primary divisions of the vertebrate heart. J Anat Physiol. 1907;41:172–89. 2. Dobrzynski H, Boyett MR, Anderson RH. New insights into pacemaker activity: promoting understanding of sick sinus syndrome. Circulation. 2007;115:1921–32.
30 3. Wiese C, Grieskamp T, Airik R, Mommersteeg MT, Gardiwal A, de Gier-de VC, et al. Formation of the sinus node head and differentiation of sinus node myocardium are independently regulated by Tbx18 and Tbx3. Circ Res. 2009;104:388–97. 4. Chandler N, Aslanidi O, Buckley D, Inada S, Birchall S, Atkinson A, et al. Computer three-dimensional anatomical reconstruction of the human sinus node and a novel paranodal area. Anat Rec (Hoboken). 2011;294:970–9. 5. James TN, Sherf L, Fine G, Morales AR. Comparative ultrastructure of the sinus node in man and dog. Circulation. 1966;34:139–63. 6. Taylor JJ, D’Agrosa LS, Burns EM. The pacemaker cell of the sinoatrial node of the rabbit. Am J Physiol. 1978;235:H407–12. 7. Bleeker WK, Mackaay AJ, Masson-Pévet M, Bouman LN, Becker AE. Functional and morphological organization of the rabbit sinus node. Circ Res. 1980;46:11–22. 8. Opthof T, de Jonge B, Mackaay AJ, Bleeker WK, Masson-Pevet M, Jongsma HJ, et al. Functional and morphological organization of the guinea-pig sinoatrial node compared with the rabbit sinoatrial node. J Mol Cell Cardiol. 1985;17:549–64. 9. Boyett MR, Honjo H, Kodama I. The sinoatrial node, a heterogeneous pacemaker structure. Cardiovasc Res. 2000;47:658–87. 10. Christoffels VM, Smits GJ, Kispert A, Moorman AFM. Development of the pacemaker tissues of the heart. Circ Res. 2010; 106:240–54. 11. Tellez JO, Dobrzynski H, Greener ID, Graham GM, Laing E, Honjo H, et al. Differential expression of ion channel transcripts in atrial muscle and sinoatrial node in rabbit. Circ Res. 2006;99: 1384–93. 12. Chandler NJ, Greener ID, Tellez JO, Inada S, Musa H, Molenaar P, et al. Molecular architecture of the human sinus node – insights into the function of the cardiac pacemaker. Circulation. 2009;119: 1562–75. 13. Sanchez-Quintana D, Cabera JA, Farre J, Climent V, Anderson RH, Ho SY. Sinus node revisited in the era of electroanatomical mapping and catheter ablation. Heart. 2005;91:189–94. 14. Liu J, Dobrzynski H, Yanni J, Boyett MR, Lei M. Organisation of the mouse sinoatrial node: structure and expression of HCN channels. Cardiovasc Res. 2007;73:729–38. 15. Boyett MR, Inada S, Yoo S, Li J, Liu J, Tellez J, et al. Connexins in the sinoatrial and atrioventricular nodes. Adv Cardiol. 2006;42: 175–97. 16. Bromberg BI, Hand DE, Schuessler RB, Boineau JP. Primary negativity does not predict dominant pacemaker location: implications for sinoatrial conduction. Am J Physiol. 1995;269:H877–87. 17. Fedorov VV, Schuessler RB, Hemphill M, Ambrosi CM, Chang R, Voloshina AS, et al. Structural and functional evidence for discrete exit pathways that connect the canine sinoatrial node and atria. Circ Res. 2009;104:915–23. 18. Fedorov VV, Glukhov AV, Chang R. Conduction barriers and pathways of the sino-atrial pacemaker complex: their role in normal rhythm and atrial arrhythmias. Am J Physiol. 2012;302:H1773–83. 19. Irisawa H, Brown HF, Giles W. Cardiac pacemaking in the sino-atrial node. Physiol Rev. 1993;73:197–227. 20. Mangoni ME, Nargeot J. Genesis and regulation of the heart automaticity. Physiol Rev. 2008;88:919–82. 21. Noma A, Nakayama T, Kurachi Y, Irisawa H. Resting K conductances in pacemaker and non-pacemaker heart cells of the rabbit. Jpn J Physiol. 1984;34:245–54. 22. Maltsev VA, Lakatta EG. Dynamic interactions of an intracellular Ca2+ clock and membrane ion channel clock underlie robust initiation and regulation of cardiac pacemaker function. Cardiovasc Res. 2008;77:274–84. 23. Maltsev VA, Lakatta EG. Synergism of coupled subsarcolemmal Ca2+ clocks and sarcolemmal voltage clocks confers robust and flexible pacemaker function in a novel pacemaker cell model. Am J Physiol. 2009;296:H594–615.
S.J.R.J. Logantha et al. 24. Gao Z, Chen B, Joiner ML, Wu Y, Guan X, Koval OM, et al. If and SR Ca2+ release both contribute to pacemaker activity in canine sinoatrial node cells. J Mol Cell Cardiol. 2010;49:33–40. 25. Lakatta EG, Maltsev VA, Vinogradova TM. A coupled SYSTEM of intracellular Ca2+ clocks and surface membrane voltage clocks controls the timekeeping mechanism of the heart’s pacemaker. Circ Res. 2010;106:659–73. 26. Dudel J, Trautwein W. The mechanism of formation of automatic rhythmical impulses in heart muscle. Pflugers Arch. 1958;267: 553–65. 27. Neher E, Sakmann B. Single-channel currents recorded from membrane of denervated frog muscle fibres. Nature. 1976;260:799–802. 28. Taniguchi J, Kokubun S, Noma A, Irisawa H. Spontaneously active cells isolated from the sino-atrial and atrio-ventricular nodes of the rabbit heart. Jpn J Physiol. 1981;31:547–58. 29. Maylie J, Morad M, Weiss J. A study of pace-maker potential in rabbit sino-atrial node: measurement of potassium activity under voltage-clamp conditions. J Physiol. 1981;311:161–78. 30. Difrancesco D. The contribution of the ‘pacemaker’ current (if) to generation of spontaneous activity in rabbit sino-atrial node myocytes. J Physiol. 1991;434:23–40. 31. Guo J, Ono K, Noma A. A sustained inward current activated at the diastolic potential range in rabbit sino-atrial node cells. J Physiol. 1995;483:1–13. 32. Yanagihara K, Noma A, Irisawa H. Reconstruction of sino-atrial node pacemaker potential based on the voltage clamp experiments. Jpn J Physiol. 1980;30:841–57. 33. Nilius B. Possible functional significance of a novel type of cardiac Ca channel. Biomed Biochim Acta. 1986;45:K37–45. 34. Huang ZM, Prasad C, Britton FC, Ye LL, Hatton WJ, Duan D. Functional role of CLC-2 chloride inward rectifier channels in cardiac sinoatrial nodal pacemaker cells. J Mol Cell Cardiol. 2009;47:121–32. 35. Demion M, Bois P, Launay P, Guinamard R. TRPM4, a Ca2+activated nonselective cation channel in mouse sino-atrial node cells. Cardiovasc Res. 2007;73:531–8. 36. Lalevee N, Monier B, Senatore S, Perrin L, Semeriva M. Control of cardiac rhythm by ORK1, a Drosophila two-pore domain potassium channel. Curr Biol. 2006;16:1502–8. 37. Froese A, Breher SS, Waldeyer C, Schindler RF, Nikolaev VO, Rinné S, et al. Popeye domain containing proteins are essential for stress-mediated modulation of cardiac pacemaking in mice. J Clin Invest. 2012;122:1119–30. 38. Tellez J, Maczewski M, Yanni J, Sutyagin P, Mackiewicz U, Atkinson A, et al. Ageing-dependent remodelling of ion channel and Ca2+ clock genes underlying sinoatrial node pacemaking. Exp Physiol. 2011;96:1163–78. 39. Difrancesco D. The role of the funny current in pacemaker activity. Circ Res. 2010;106:434–46. 40. Milanesi R, Baruscotti M, Gnecchi-Ruscone T, DiFrancesco D. Familial sinus bradycardia associated with a mutation in the cardiac pacemaker channel. N Engl J Med. 2006;354:151–7. 41. Baruscotti M, Bucchi A, Viscomi C, Mandelli G, Consalez G, Gnecchi-Rusconi T, et al. Deep bradycardia and heart block caused by inducible cardiac-specific knockout of the pacemaker channel gene Hcn4. Proc Natl Acad Sci USA. 2011;108:1705–10. 42. Fox K, Ford I, Steg PG, Tendera M, Ferrari R. Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372:807–16. 43. Rigg L, Terrar DA. Possible role of calcium release from the sarcoplasmic reticulum in pacemaking in guinea-pig sino-atrial node. Exp Physiol. 1996;81:877–80. 44. Huser J, Blatter LA, Lipsius SL. Intracellular Ca2+ release contributes to automaticity in cat atrial pacemaker cells. J Physiol. 2000;524:415–22.
3
Molecular Basis of Arrhythmias Associated with the Cardiac Conduction System
45. Bogdanov KY, Vinogradova TM, Lakatta EG. Sinoatrial nodal cell ryanodine receptor and Na+-Ca2+ exchanger: molecular partners in pacemaker regulation. Circ Res. 2001;88:1254–8. 46. Vinogradova TM, Bogdanov KY, Lakatta EG. Novel perspectives on the beating rate of the heart. Circ Res. 2002;91:e3. 47. Vinogradova TM, Zhou YY, Maltsev V, Lyashkov A, Stern M, Lakatta EG. Rhythmic ryanodine receptor Ca2+ releases during diastolic depolarization of sinoatrial pacemaker cells do not require membrane depolarization. Circ Res. 2004;94:802–9. 48. Sanders L, Rakovic S, Lowe M, Mattick PA, Terrar DA. Fundamental importance of Na+-Ca2+ exchange for the pacemaking mechanism in guinea-pig sino-atrial node. J Physiol. 2006;571:639–49. 49. Lakatta EG, Vinogradova TM, Maltsev VA. The missing link in the mystery of normal automaticity of cardiac pacemaker cells. Ann NY Acad Sci. 2008;1123:41–57. 50. Li J, Qu J, Nathan RD. Ionic basis of ryanodine’s negative chronotropic effect on pacemaker cells isolated from the sinoatrial node. Am J Physiol. 1997;273:H2481–9. 51. Postma AV, Denjoy I, Hoorntje TM, Lupoglazoff JM, Da Costa A, Sebillon P, et al. Absence of calsequestrin 2 causes severe forms of catecholaminergic polymorphic ventricular tachycardia. Circ Res. 2002;91:e21–6. 52. Postma AV, Denjoy I, Kamblock J, Alders M, Lupoglazoff JM, Vaksmann G, et al. Catecholaminergic polymorphic ventricular tachycardia: RYR2 mutations, bradycardia, and follow up of the patients. J Med Genet. 2005;42:863–70. 53. Bhuiyan ZA, Van den Berg MP, Van Tintelen JP, Bink-Boelkens MT, Wiesfeld AC, Alders M, et al. Expanding spectrum of human RYR2-related disease: new electrocardiographic, structural, and genetic features. Circulation. 2007;116:1569–76. 54. Lakatta EG, DiFrancesco D. What keeps us ticking: a funny current, a calcium clock, or both? J Mol Cell Cardiol. 2009;47:157–70. 55. Boyett MR, Honjo H, Yamamoto M, Nikmaram MR, Niwa R, Kodama I. Downward gradient in action potential duration along the conduction path in and around the sinoatrial node. Am J Physiol. 1999;276:H686–98. 56. Greener ID, Monfredi O, Inada S, Chandler NJ, Tellez JO, Atkinson A, et al. Molecular architecture of the human specialised atrioventricular conduction axis. J Mol Cell Cardiol. 2011;50:642–51. 57. Lei M, Jones SA, Liu J, Lancaster MK, Fung SS, Dobrzynski H, et al. Requirement of neuronal- and cardiac-type sodium channels for murine sinoatrial node pacemaking. J Physiol. 2004;559: 835–48. 58. Boyett MR, Tellez JO, Dobrzynski H. The sinoatrial node – its complex structure and unique ion channel gene programme. In: Zipes DP, Jalife J, editors. Cardiac electrophysiology: from cell to bedside. 5th ed. Philadelphia: WB Saunders Company/Elsevier Science; 2009. p. 127–38. 59. Joyner RW, van Capelle FJL. Propagation through electrically coupled cells: how a small SA node drives a large atrium. Biophys J. 1986;50:1157–64. 60. Sano T, Yamagishi S. Spread of excitation from the sinus node. Circ Res. 1965;16:423–30. 61. Coppen SR, Severs NJ. Diversity of connexin expression patterns in the atrioventricular node: vestigial consequence or functional specialization? J Cardiovasc Electrophysiol. 2002;13:625–6. 62. Benditt DG, Sakaguchi S, Goldstein MA. Sinus node dysfunction: pathophysiology, clinical features, evaluation, and treatment. In: Zipes DP, Jalife J, editors. Cardiac electrophysiology: from cell to bedside. 2nd ed. Philadelphia: WB Saunders Company; 1995. p. 1215–47. 63. Park DS, Fishman GI. The cardiac conduction system. Circulation. 2011;123:904–15. 64. Alings AMW, Bouman LN. Electrophysiology of the ageing rabbit and cat sinoatrial node - a comparative study. Eur Heart J. 1993;14:1278–88.
31
65. Lamas GA, Pashos CL, Normand SL, McNeil B. Permanent pacemaker selection and subsequent survival in elderly Medicare pacemaker recipients. Circulation. 1995;91:1063–9. 66. Elvan A, Wylie K, Zipes DP. Pacing-induced chronic atrial fibrillation impairs sinus node function in dogs. Electrophysiological remodeling. Circulation. 1996;94:2953–60. 67. Yeh YH, Burstein B, Qi XY, Sakabe M, Chartier D, Comtois P, et al. Funny current downregulation and sinus node dysfunction associated with atrial tachyarrhythmia: a molecular basis for tachycardia-bradycardia syndrome. Circulation. 2009;119:1576–85. 68. Opthof T, Coronel R, Rademaker HM, Vermeulen JT, Wilms-Schopman FJ, Janse MJ. Changes in sinus node function in a rabbit model of heart failure with ventricular arrhythmias and sudden death. Circulation. 2000;101:2975–80. 69. Sanders P, Kistler PM, Morton JB, Spence SJ, Kalman JM. Remodeling of sinus node function in patients with congestive heart failure: reduction in sinus node reserve. Circulation. 2004;110:897–903. 70. Zicha S, Fernández-Velasco M, Lonardo G, L’Heureux N, Nattel S. Sinus node dysfunction and hyperpolarization-activated (HCN) channel subunit remodeling in a canine heart failure model. Cardiovasc Res. 2005;66:472–81. 71. Yanni JF, Yamanushi TT, Dobrzynski H, Boyett MR. Remodelling of the extracellular matrix in the rat sinoatrial node in congestive heart failure. Proc Physiol Soc. 2009;15:C26. 72. de Melo SR, de Souza RR, Mandarim-de-Lacerda CA. Stereologic study of the sinoatrial node of rats - age related changes. Biogerontology. 2002;3:383–90. 73. Adan V, Crown LA. Diagnosis and treatment of sick sinus syndrome. Am Fam Physician. 2003;67:1725–32. 74. Hao X, Zhang Y, Zhang X, Nirmalan M, Davies L, Konstantinou D, et al. TGF-β1-mediated fibrosis and ion channel remodeling are key mechanisms in producing the sinus node dysfunction associated with SCN5A deficiency and aging. Circ Arrhythm Electrophysiol. 2011;4:397–406. 75. Swaminathan PD, Purohit A, Soni S, Voigt N, Singh MV, Glukhov AV, et al. Oxidized CaMKII causes cardiac sinus node dysfunction in mice. J Clin Invest. 2011;121:3277–88. 76. Ailings AMW, Abbas RF, Bouman LN. Age-related changes in structure and relative collagen content of the human and feline sinoatrial node. A comparative study. Eur Heart J. 1995;16:1655–67. 77. Yanni J, Tellez JO, Sutyagin PV, Boyett MR, Dobrzynski H. Structural remodelling of the sinoatrial node in obese old rats. J Mol Cell Cardiol. 2010;48:653–62. 78. Verkerk AO, Wilders R, Coronel R, Ravesloot JH, Verheijck EE. Ionic remodeling of sinoatrial node cells by heart failure. Circulation. 2003;108:760–6. 79. Jones SA, Lancaster MK, Boyett MR. Ageing-related changes of connexins and conduction within the sinoatrial node. J Physiol. 2004;560:429–37. 80. Jones SA, Boyett MR, Lancaster MK. Declining into failure: the age-dependent loss of the L-type calcium channel within the sinoatrial node. Circulation. 2007;115:1183–90. 81. Joung B, Lin SF, Chen Z, Antoun PS, Maruyama M, Han S, et al. Mechanisms of sinoatrial node dysfunction in a canine model of pacing-induced atrial fibrillation. Heart Rhythm. 2010;7:88–95. 82. Yamanushi TT, Yanni J, Dobrzynski H, Kabuto H, Boyett MR. Changes in ion channel expression in right-sided congestive heart failure. J Mol Cell Cardiol. 2010;48:S73. 83. Yanni J, Cai XJ, Yamanushi T, Tellez JO, Jones C, Hutcheon R, et al. Two pathways to sinoatrial node dysfunction in heart failure. Proc Physiol Soc. 2011;23:PC162. 84. van Veen TA, Stein M, Royer A, Le Quang K, Charpentier F, Colledge WH, et al. Impaired impulse propagation in Scn5aknockout mice: combined contribution of excitability, connexin expression, and tissue architecture in relation to aging. Circulation. 2005;112:1927–35.
32 85. Shang LL, Sanyal S, Pfahnl AE, Jiao Z, Allen J, Liu H, et al. NF-kappaB-dependent transcriptional regulation of the cardiac scn5a sodium channel by angiotensin II. Am J Physiol. 2008;294:C372–9. 86. Li J, Greener ID, Inada S, Nikolski VP, Yamamoto M, Hancox JC, et al. Computer three-dimensional reconstruction of the atrioventricular node. Circ Res. 2008;102:975–85. 87. Anderson RH, Yanni J, Boyett MR, Chandler NJ, Dobrzynski H. The anatomy of the cardiac conduction system. Clin Anat. 2009;22:99–113. 88. Greener ID, Tellez JO, Dobrzynski H, Yamamoto M, Graham GM, Billeter R, et al. Ion channel transcript expression at the rabbit atrioventricular conduction axis. Circ Arrhythm Electrophysiol. 2009;2:305–15. 89. Moe GK, Preston JB, Burlington H. Physiologic evidence for a dual A-V transmission system. Circ Res. 1956;4:357–75. 90. Spach MS, Lieberman M, Scott JG, Barr RC, Johnson EA, Kootsey JM. Excitation sequences of the atrial septum and the AV node in isolated hearts of the dog and rabbit. Circ Res. 1971;29: 156–72. 91. Meijler FL, Janse MJ. Morphology and electrophysiology of the mammalian atrioventricular node. Physiol Rev. 1988;68:608–47. 92. Anderson RH, Ho SY. The morphology of the cardiac conduction system. Novartis Found Symp. 2003;250:6–17; discussion 18–24, 276–9. 93. Inoue S, Becker AE. Posterior extensions of the human compact atrioventricular node: a neglected anatomic feature of potential clinical significance. Circulation. 1998;97:188–93. 94. Hucker WJ, McCain ML, Laughner JI, Iaizzo PA, Efimov IR. Connexin 43 expression delineates two discrete pathways in the human atrioventricular junction. Anat Rec. 2008;291:204–15. 95. Tawara S. The conduction system of the mammalian heart: an anatomico-histological study of the atrioventricular bundle and the Purkinje fibers. London: Imperial College Press; 2000. 96. Dobrzynski H, Nikolski VP, Sambelashvili AT, Greener ID, Yamamoto M, Boyett MR, et al. Site of origin and molecular substrate of atrioventricular junctional rhythm in the rabbit heart. Circ Res. 2003;93:1102–10. 97. deCarvalho AP, De Mello WC, Hoffman BF. Electrophysiological evidence for specialized fiber types in rabbit atrium. Am J Physiol. 1959;196:483–8. 98. Zipes DP, Mendez C. Action of manganese ions and tetrodotoxin on atrioventricular nodal transmembrane potentials in isolated rabbit hearts. Circ Res. 1973;32:447–54. 99. Anderson RH, Davies MJ, Becker AE. Atrioventricular ring specialized tissue in the normal heart. Eur J Cardiol. 1974;2:219–30. 100. Billette J. Atrioventricular nodal activation during periodic premature stimulation of the atrium. Am J Physiol. 1987;252:H163–77. 101. Munk AA, Adjemian RA, Zhao J, Ogbaghebriel A, Shrier A. Electrophysiological properties of morphologically distinct cells isolated from the rabbit atrioventricular node. J Physiol. 1996;493: 801–18. 102. Patterson E, Scherlag BJ. Anatomic and functional fast atrioventricular conduction pathway. J Cardiovasc Electrophysiol. 2002; 13:945–9. 103. Ren FX, Niu XL, Ou Y, Han ZH, Ling FD, Zhou SS, et al. Morphological and electrophysiological properties of single myocardial cells from Koch triangle of rabbit heart. Chin Med J (Engl). 2006;119:2075–84. 104. Inada S, Hancox JC, Zhang H, Boyett MR. One-dimensional mathematical model of the atrioventricular node including atrionodal, nodal, and nodal-his cells. Biophys J. 2009;97:2117–27. 105. Hancox JC, Yuill KH, Mitcheson JS, Convery MK. Progress and gaps in understanding the electrophysiological properties of morphologically normal cells from the cardiac atrioventricular node. Int J Bifurcation Chaos. 2003;13:3675–91.
S.J.R.J. Logantha et al. 106. Yoo S, Dobrzynski H, Fedorov VV, Xu SZ, Yamanushi TT, Jones SA, et al. Localization of Na+ channel isoforms at the atrioventricular junction and atrioventricular node in the rat. Circulation. 2006;114:1360–71. 107. Cheng H, Smith GL, Hancox JC, Orchard CH. Inhibition of spontaneous activity of rabbit atrioventricular node cells by KB-R7943 and inhibitors of sarcoplasmic reticulum Ca2+ ATPase. Cell Calcium. 2011;49:56–65. 108. Nikmaram MR, Liu J, Abdelrahman M, Dobrzynski H, Boyett MR, Lei M. Characterization of the effects of ryanodine, TTX, E-4031 and 4-AP on the sinoatrial and atrioventricular nodes. Prog Biophys Mol Biol. 2008;96:452–64. 109. Hancox JC, Levi AJ. L-type calcium current in rod- and spindleshaped myocytes isolated from rabbit atrioventricular node. Am J Physiol. 1994;267:H1670–80. 110. Mangoni ME, Traboulsie A, Leoni AL, Couette B, Marger L, Le Quang K, et al. Bradycardia and slowing of the atrioventricular conduction in mice lacking CaV3.1/alpha1G T-type calcium channels. Circ Res. 2006;98:1422–30. 111. Papadatos GA, Wallerstein PM, Head CE, Ratcliff R, Brady PA, Benndorf K, et al. Slowed conduction and ventricular tachycardia after targeted disruption of the cardiac sodium channel gene Scn5a. ProcNatlAcadSci USA. 2002;99:6210–5. 112. Schott JJ, Alshinawi C, Kyndt F, Probst V, Hoorntje TM, Hulsbeek M, et al. Cardiac conduction defects associate with mutations in SCN5A. Nat Genet. 1999;23:20–1. 113. Watanabe H, Koopmann TT, Le Scouarnec S, Yang T, Ingram CR, Schott JJ, et al. Sodium channel beta1 subunit mutations associated with Brugada syndrome and cardiac conduction disease in humans. J Clin Invest. 2008;118:2260–8. 114. Pollack GH. Intercellular coupling in the atrioventricular node and other tissues of the rabbit heart. J Physiol. 1976;255:275–98. 115. Coppen SR, Severs NJ, Gourdie RG. Connexin45 (alpha 6) expression delineates an extended conduction system in the embryonic and mature rodent heart. Dev Genet. 1999;24:82–90. 116. Severs NJ, Rothery S, Dupont E, Coppen SR, Yeh HI, Ko YS, et al. Immunocytochemical analysis of connexin expression in the healthy and diseased cardiovascular system. Microsc Res Tech. 2001;52:301–22. 117. Zhang Y, Bharati S, Mowrey KA, Zhuang S, Tchou PJ, Mazgalev TN. His electrogram alternans reveal dual-wavefront inputs into and longitudinal dissociation within the bundle of His. Circulation. 2001;104:832–8. 118. McGuire MA, Bourke JP, Robotin MC, Johnson DC, MeldrumHanna W, Nunn GR, et al. High resolution mapping of Koch’s triangle using sixty electrodes in humans with atrioventricular junctional (AV nodal) reentrant tachycardia. Circulation. 1993;88: 2315–28. 119. Kurian T, Ambrosi C, Hucker W, Fedorov VV, Efimov IR. Anatomy and electrophysiology of the human AV node. Pacing Clin Electrophysiol. 2010;33:754–62. 120. Nikolski VP, Jones SA, Lancaster MK, Boyett MR, Efimov IR. Cx43 and dual-pathway electrophysiology of the atrioventricular node and atrioventricular nodal reentry. Circ Res. 2003;92:469–75. 121. Hampton JR. The ECG, made easy. 6th ed. Edinburgh: Churchill Livingstone; 2003. 122. Crisel RK, Farzaneh-Far R, Na B, Whooley MA. First-degree atrioventricular block is associated with heart failure and death in persons with stable coronary artery disease: data from the Heart and Soul Study. Eur Heart J. 2011;32:1875–80. 123. Piccini JP, Calkins H. Arrhythmia management in the elderly. In: Gerstenblith G, editor. Cardiovascular disease in the elderly. Totowa: Humana Press; 2005. p. 261–300. 124. Maron BJ, Pelliccia A. The heart of trained athletes: cardiac remodelling and the risks of sports, including sudden death. Circulation. 2006;114:1633–44.
3
Molecular Basis of Arrhythmias Associated with the Cardiac Conduction System
125. Miquerol L, Meysen S, Mangoni M, Bois P, van Rijen HV, Abran P, et al. Architectural and functional asymmetry of the HisPurkinje system of the murine heart. Cardiovasc Res. 2004;63: 77–86. 126. Atkinson A, Inada S, Li J, Tellez JO, Yanni J, Sleiman RN, et al. Anatomical and molecular mapping of the left and right ventricular His-Purkinje networks. J Mol Cell Cardiol. 2011;51:689–701. 127. Ansari A, Ho SY, Anderson RH. Distribution of the Purkinje fibres in the sheep heart. Anat Rec. 1999;254:92–7. 128. Massing GK, James TN. Anatomical configuration of the His bundle and bundle branches in the human heart. Circulation. 1976;53:609–21. 129. Tranum-Jensen J, Wilde AA, Vermeulen JT, Janse MJ. Morphology of electrophysiologically identified junctions between Purkinje fibers and ventricular muscle in rabbit and pig hearts. Circ Res. 1991;69:429–37. 130. Ryu S, Yamamoto S, Andersen CR, Nakazawa K, Miyake F, James TN. Intramural Purkinje cell network of sheep ventricles as the terminal pathway of conduction system. Anat Rec. 2009;292: 12–22. 131. Severs NJ. The cardiac muscle cell. Bioessays. 2000;2:188–99. 132. Desplantez T, Dupont E, Severs NJ, Weingart R. Gap junction channels and cardiac impulse propagation. J Membr Biol. 2007; 18:13–28. 133. Di Maio A, TerKeurs HE, Franzini-Armstrong C. T-tubule profiles in Purkinje fibres of mammalian myocardium. J Muscle Res Cell Motil. 2007;28:115–21. 134. Oosthoek PW, Virágh S, Lamers WH, Moorman AF. Immunohistochemical delineation of the conduction system. II: the atrioventricular node and Purkinje fibers. Circ Res. 1993;73: 482–91. 135. Gourdie RG, Severs NJ, Green CR, Rothery S, Germroth P, Thompson RP. The spatial distribution and relative abundance of gap-junctional connexin40 and connexin43 correlate to functional properties of components of the cardiac atrioventricular conduction system. J Cell Sci. 1993;105:985–91. 136. Gaborit N, Le Bouter S, Szuts V, Varro A, Escande D, Nattel S, et al. Regional and tissue specific transcript signatures of ion channel genes in the non-diseased human heart. J Physiol. 2007;582:675–93. 137. van Rijen HV, van Veen TA, van Kempen MJ, Wilms-Schopman FJ, Potse M, Krueger O, et al. Impaired conduction in the bundle branches of mouse hearts lacking the gap junction protein connexin40. Circulation. 2001;103:1591–8. 138. Anumonwo JM, Tallini YN, Vetter FJ, Jalife J. Action potential characteristics and arrhythmogenic properties of the cardiac conduction system of the murine heart. Circ Res. 2001;89:329–35. 139. Persson F, Andersson B, Duker G, Jacobson I, Carlsson L. Functional effects of the late sodium current inhibition by AZD7009 and lidocaine in rabbit isolated atrial and ventricular tissue and Purkinje fibre. Eur J Pharmacol. 2007;558:133–43. 140. Baláti B, Iost N, Simon J, Varró A, Papp JG. Analysis of the electrophysiological effects of ambasilide, a new antiarrhythmic agent, in canine isolated ventricular muscle and purkinje fibers. Gen Pharmacol. 2000;34:85–93. 141. Koncz I, Szél T, Bitay M, Cerbai E, Jaeger K, Fülöp F, et al. Electrophysiological effects of ivabradine in dog and human cardiac preparations: potential antiarrhythmic actions. Eur J Pharmacol. 2011;668:419–26. 142. Aslanidi OV, Sleiman RN, Boyett MR, Hancox JC, Zhang H. Ionic mechanisms for electrical heterogeneity between rabbit Purkinje fiber and ventricular cells. Biophys J. 2010;98:2420–31. 143. Roden DM, Hoffman BF. Action potential prolongation and induction of abnormal automaticity by low quinidine concentrations in canine Purkinje fibers. Relationship to potassium and cycle length. Circ Res. 1985;56:857–67.
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144. Nattel S, Quantz MA. Pharmacological response of quinidine induced early afterdepolarisations in canine cardiac Purkinje fibres: insights into underlying ionic mechanisms. Cardiovasc Res. 1988;22:808–17. 145. Kaseda S, Gilmour Jr RF, Zipes DP. Depressant effect of magnesium on early afterdepolarizations and triggered activity induced by cesium, quinidine, and 4-aminopyridine in canine cardiac Purkinje fibers. Am Heart J. 1989;118:458–66. 146. Boyden PA, Pu J, Pinto J, Keurs HE. Ca2+ transients and Ca2+ waves in purkinje cells: role in action potential initiation. Circ Res. 2000;86:448–55. 147. Cordeiro JM, Bridge JH, Spitzer KW. Early and delayed afterdepolarizations in rabbit heart Purkinje cells viewed by confocal microscopy. Cell Calcium. 2001;29:289–97. 148. Abi-Gerges N, Small BG, Lawrence CL, Hammond TG, Valentin JP, Pollard CE. Evidence for gender differences in electrophysiological properties of canine Purkinje fibres. Br J Pharmacol. 2004;142:1255–64. 149. Abi-Gerges N, Small BG, Lawrence CL, Hammond TG, Valentin JP, Pollard CE. Gender differences in the slow delayed (IKs) but not in inward (IK1) rectifier K+ currents of canine Purkinje fibre cardiac action potential: key roles for IKs, β-adrenoceptor stimulation, pacing rate and gender. Br J Pharmacol. 2006;147:653–60. 150. Weidmann S. Resting and action potentials of cardiac muscle. Ann NY Acad Sci. 1957;65:663–78. 151. Davis LD, Temte JV. Electrophysiological actions of lidocaine on canine ventricular muscle and Purkinje fibers. Circ Res. 1969;24: 639–55. 152. Kus T, Sasyniuk BI. Electrophysiological actions of disopyramide phosphate on canine ventricular muscle and purkinje fibers. Circ Res. 1975;37:844–54. 153. Callewaert G, Carmeliet E, Vereecke J. Single cardiac Purkinje cells: general electrophysiology and voltage-clamp analysis of the pace-maker current. J Physiol. 1984;349:643–61. 154. Yu H, Chang F, Cohen IS. Pacemaker current if in adult canine cardiac ventricular myocytes. J Physiol. 1995;485:469–83. 155. Schram G, Pourrier M, Melnyk P, Nattel S. Differential distribution of cardiac ion channel expression as a basis for regional specialization in electrical function. Circ Res. 2002;90:939–50. 156. Vassalle M, Yu H, Cohen IS. The pacemaker current in cardiac Purkinje myocytes. J Gen Physiol. 1995;106:559–78. 157. Rota M, Vassalle M. Patch-clamp analysis in canine cardiac Purkinje cells of a novel sodium component in the pacemaker range. J Physiol. 2003;548:147–65. 158. Vassalle M. The vicissitudes of the pacemaker current IKdd of cardiac purkinje fibers. Biomed Sci. 2007;14:699–716. 159. Boyett MR, Hart G, Levi AJ, Roberts A. Effects of repetitive activity on developed force and intracellular sodium in isolated sheep and dog Purkinje fibres. J Physiol. 1987;388:295–322. 160. Vassalle M. Electrogenic suppression of automaticity in sheep and dog purkinje fibers. Circ Res. 1970;27:361–77. 161. Kline RP, Kupersmith J. Effects of extracellular potassium accumulation and sodium pump activation on automatic canine Purkinje fibres. J Physiol. 1982;324:507–33. 162. Boyett MR, Fedida D. Changes in the electrical activity of dog cardiac Purkinje fibres at high heart rates. J Physiol. 1984;350: 361–91. 163. Boyden PA, Dun W, Barbhaiya C, TerKeurs HE. 2APB- and JTV519(K201)-sensitive micro Ca2+ waves in arrhythmogenic Purkinje cells that survive in infarcted canine heart. Heart Rhythm. 2004;1:218–26. 164. Tsien RW, Kass RS, Weingart R. Cellular and subcellular mechanisms of cardiac pacemaker oscillations. J Exp Biol. 1979;81: 205–15. 165. Cordeiro JM, Spitzer KW, Giles WR. Repolarizing K+ currents in rabbit heart Purkinje cells. J Physiol. 1998;508:811–23.
34 166. Gadsby DC, Cranefield PF. Two levels of resting potential in cardiac Purkinje fibers. J Gen Physiol. 1977;70:725–46. 167. Boyden PA, Albala A, Dresdner Jr KP. Electrophysiology and ultrastructure of canine subendocardial Purkinje cells isolated from control and 24-hour infarcted hearts. Circ Res. 1989;65:955–70. 168. Wiggins JR, Cranefield PF. Two levels of resting potential in canine cardiac Purkinje fibers exposed to sodium-free solutions. Circ Res. 1976;39:466–74. 169. Molyvdas PA, Sperelakis N. Comparison of the effects of several calcium antagonistic drugs on the electrical activity of guinea pig Purkinje fibers. Eur J Pharmacol. 1983;88:205–14. 170. Amerini S, Giotti A, Mugelli A. Effect of verapamil and diltiazem on calcium-dependent electrical activity in cardiac Purkinje fibres. Br J Pharmacol. 1985;85:89–96. 171. Wit AL, Cranefield PF, Hoffman BF. Slow conduction and reentry in the ventricular conducting system. II. Single and sustained circus movement in networks of canine and bovine Purkinje fibers. Circ Res. 1972;30:11–22. 172. Scheinman MM. Role of the His-Purkinje system in the genesis of cardiac arrhythmia. Heart Rhythm. 2009;6:1050–8. 173. Crijns HJ, Smeets JL, Rodriguez LM, Meijer A, Wellens HJ. Cure of interfascicular reentrant ventricular tachycardia by ablation of the anterior fascicle of the left bundle branch. J Cardiovasc Electrophysiol. 1995;6:486–92. 174. Balasundaram R, Rao HB, Kalavakolanu S, Narasimhan C. Catheter ablation of bundle branch reentrant ventricular tachycardia. Heart Rhythm. 2008;5:S68–72. 175. Wright M, Sacher F, Haïssaguerre M. Catheter ablation for patients with ventricular fibrillation. Curr Opin Cardiol. 2009;24: 56–60. 176. Grines CL, Bashore TM, Boudoulas H, Olson S, Shafer P, Wooley CF. Functional abnormalities in isolated left bundle branch block. The effect of interventricular asynchrony. Circulation. 1989;79:845–53. 177. Eriksson P, Hansson PO, Eriksson H, Dellborg M. Bundle-branch block in a general male population: the study of men born 1913. Circulation. 1998;98:2494–500. 178. Maddali M. Cardiac pacing in left bundle/bifascicular block patients. Ann Card Anaesth. 2010;13:7–15. 179. Padeletti L, Valleggi A, Vergaro G, Lucà F, Rao CM, Perrotta L, et al. Concordant versus discordant left bundle branch block in heart failure patients: novel clinical value of an old electrocardiographic diagnosis. J Card Fail. 2010;16:320–6.
S.J.R.J. Logantha et al. 180. Maguy A, Le Bouter S, Comtois P, Chartier D, Villeneuve L, Wakili R, et al. Ion channel subunit expression changes in cardiac Purkinje fibers: a potential role in conduction abnormalities associated with congestive heart failure. Circ Res. 2009;104: 1113–22. 181. Burstein B, Comtois P, Michael G, Nishida K, Villeneuve L, Yeh YH, et al. Changes in connexin expression and the atrial fibrillation substrate in congestive heart failure. Circ Res. 2009; 105:1213–22. 182. Han W, Chartier D, Li D, Nattel S. Ionic remodeling of cardiac Purkinje cells by congestive heart failure. Circulation. 2001;104: 2095–3100. 183. Han W, Bao W, Wang Z, Nattel S. Comparison of ion-channel subunit expression in canine cardiac Purkinje fibers and ventricular muscle. Circ Res. 2002;91:790–7. 184. Berenfeld O, Jalife J. Purkinje-muscle reentry as a mechanism of polymorphic ventricular arrhythmias in a 3-dimensional model of the ventricles. Circ Res. 1998;82:1063–77. 185. Gilmour Jr RF, Watanabe M. Dynamics of circus movement re-entry across canine Purkinje fibre-muscle junctions. J Physiol. 1994;476:473–85. 186. Li ZY, Wang YH, Maldonado C, Kupersmith J. Role of junctional zone cells between Purkinje fibres and ventricular muscle in arrhythmogenesis. Cardiovasc Res. 1994;28:1277–84. 187. Mazur A, Kusniec J, Strasberg B. Bundle branch reentrant ventricular tachycardia. Indian Pacing Electrophysiol J. 2005;5:86–95. 188. Nogami A. Purkinje-related arrhythmias part I: monomorphic ventricular tachycardias. Pacing Clin Electrophysiol. 2011;34:624–50. 189. Ben Caref E, Boutjdir M, Himel HD, El-Sherif N. Role of subendocardial Purkinje network in triggering torsade de pointes arrhythmia in experimental long QT syndrome. Europace. 2008;10:1218–23. 190. Leenhardt A, Lucet V, Denjoy I, Grau F, Ngoc DD, Coumel P. Catecholaminergic polymorphic ventricular tachycardia in children. A 7-year follow-up of 21 patients. Circulation. 1995;91: 1512–9. 191. Herron TJ, Milstein ML, Anumonwo J, Priori SG, Jalife J. Purkinje cell calcium dysregulation is the cellular mechanism that underlies catecholaminergic polymorphic ventricular tachycardia. Heart Rhythm. 2010;7:1122–8. 192. Kang G, Giovannone SF, Liu N, Liu FY, Zhang J, Priori SG, et al. Purkinje cells from RyR2 mutant mice are highly arrhythmogenic but responsive to targeted therapy. Circ Res. 2010;107:512–9.
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Functional Anatomy in Arrhythmias and Vascular Support of the Conduction System Cristian Stătescu, Radu A. Sascău, and Cătălina Arsenescu Georgescu
Abstract
The cardiac conduction system is composed of the sinoatrial node (SAN), the atrioventricular node (AVN), the His bundle, the right and left bundle branches, the fascicles, and the Purkinje fibers. Spreading of the pacemaking impulse from atrial to ventricular myocardium is delayed at the AVN located at the base of the interatrial septum. From the AV node, the propagation of the pacemaking impulse accelerates along the AV bundle and bundle branches, finally activating ventricular muscle via the Purkinje fiber network system. The atrioventricular node (AVN) and bundle (AVB) normally penetrate the right fibrous trigone (central fibrous body) at the atrioventricular junction. The SAN artery comes off of either the proximal right coronary artery (60–70 %) or the proximal circumflex artery. Alternative sources of arterial supply to the atrioventricular-conducting pathway include the descending septal artery, the first septal perforating artery, and anterior atrial branches inclusively the Kugel anastomotic artery. Anatomic structures related to arrhythmias include cavotricuspid isthmus, subthebesian pouch, septal isthmus, and pulmonary veins. Other anatomic arrhythmogenic elements are the ligament of Marshall, lipomatous hypertrophy of the interatrial septum, and cardiac autonomic nervous system. Keywords
Anatomy • Arrhythmias • Conduction system • Vascular support
C. Stătescu, MD, PhD (*) Cardiology and Internal Medicine, “Gr.T. Popa” University of Medicine and Pharmacy, Iaşi, Romania Electrophysiology and Pacing Department, “George I.M. Georgescu” Cardiovascular Diseases Institute, Iaşi, Romania e-mail:
[email protected] R.A. Sascău, MD, PhD Cardiology and Internal Medicine, “Gr.T. Popa” University of Medicine and Pharmacy, Iaşi, Romania Echocardiography Department, “George I.M. Georgescu” Cardiovascular Diseases Institute, Iaşi, Romania C.A. Georgescu, MD, PhD, FESC Cardiology and Internal Medicine, “Gr.T. Popa” University of Medicine and Pharmacy, Iaşi, Romania Cardiology Department, “George I.M. Georgescu” Cardiovascular Diseases Institute, Iaşi, Romania
A.S. Kibos et al. (eds.), Cardiac Arrhythmias, DOI 10.1007/978-1-4471-5316-0_4, © Springer-Verlag London 2014
Introduction Electrophysiological and anatomical studies have established powerful evidence about heart conduction system and its electrical liaison patterns. This system has an important role, to provide regular myocardial stimulation that generates physiological contraction of the heart. Since anatomical variation of the conduction system and associated structures is something common, it is very important to know these normal variations, especially before interventional procedures to avoid complications or to titrate the ablation energy in specific regions of the heart to avoid damage of extracardiac structures in close proximity to the heart or coronary arteries.
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Cardiac Conduction System The cardiac conduction system is a complex structure consists of specialized myocytes and it is composed of the sinoatrial node (SAN), the atrioventicular node (AVN), the His bundle, the right and left bundle branches, the fascicles, and the Purkinje fibers [1]. SAN is a heterogeneous tissue built in the right atrial wall which generates pacemaking impulses. The myocardial cells can regularly beat without a special external trigger. The SAN is functioning as the “pacemaker” of the heart. Its cells set the beating rhythm of the rest of the myocardium because they have the most rapid intrinsic rate of excitation. The pacemaking action potential is initiated by a slow, diastolic depolarization that is regulated by several different ion currents, including T- and L-type calcium currents and the sustained inward current [2], which can be modulated by autonomic neurons. Moreover, the hyperpolarizationactivated If (“funny”) current plays a major role in generating an action potential in the SAN. This funny ion current is conducted by the gene family of hyperpolarization-activated and cyclic nucleotide-gated channels which are first supervised by the activity of beta-adrenergic and muscarinic receptors [3]. Atrial myocardium is in direct contact with the SAN, subepicardial, and the AVN, subendocardial [4]. It was not proven that between the SAN and AVN morphologically distinct conduction pathway exists, but due to a particular geometric arrangement of working muscle fibers, functional pathways could be responsible for the conduction among the two structures throughout distinct preferential routes. Spreading of the pacemaking impulse from atrial to ventricular myocardium is delayed at the AVN located at the base of the interatrial septum [5]. The diastolic filling is assured by this AV delay facilitating an effective ejection of blood from the atrial chambers before the initiation of ventricular contraction. Whereas the inferior region of the node consists of cells that are more regularly aligned, the superior and right margins of the AVN contain loosely connected fibers. In the medial portion of the node, there are peripheral cells that contain few myofibrils. In many avian species it was documented an AV-ring with an almost identical role to that of the mammalian AVN [6]. The His bundle passes through the right fibrous trigone (central fibrous body) and penetrate the junction of the membranous and muscular septum before it splits into the right and left ventricular bundle branches [7]. The right bundle branch is like a strap structure with a 1 mm diameter that keeps going along the septal and moderator bands to attain at the anterior papillary muscle. On the other way, the left bundle branch forms a loose layer of conduction fibers that divides along the left side of interventricular septum into three indistinct fascicles [8]. From the AVN, the propagation of the pacemaking impulse accelerates along the AV bundle and bundle
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branches, finally activating ventricular muscle via the Purkinje fiber network system. Thus, the main function of the ventricular conduction network is to rapidly propagate and transmit impulses to the ventricular muscle. The fast conduction cells are scattered throughout the myocardium, but can be distinguished from ventricular muscle cells by their distinct electrophysiological and molecular characteristics. They exhibit faster action potential upstroke, prolonged action potential duration, higher membrane diastolic potential, and greater electrical restitution properties.
Right Atrium The right atrium (RA) has three components: an appendage, a venous component (sinus venosus), and a vestibule.
Crista Terminalis The crista terminalis is a fibromuscular crest defined by the junction of the sinus venosus and the primitive RA. In the upper part it arches anterior to the superior vena cava orifice, prolongs to the area of the interatrial notch, and merges with the interatrial bundle, known as the Bachmann’s bundle. The inferior edge of the crista terminalis near the inferior vena cava orifice is not well defined and blends with small trabeculations of the inferior part of the cavotricuspid isthmus. The anterior pectinate muscles rise from the crista terminalis and unfold anteriorly like a series of relatively thick bundles. The most prominent anterior pectinate muscle is the septum spurious. It measures up to 4.5 mm and is present in 80 % of cases and should not be mistaken for interatrial septal defect. Several forms of atrial tachyarrhythmias are directly correlated with the crista terminalis. It is proven that development of atrial flutter depends on the thickness of the crista terminalis [9]. The anisotropic conduction with a fast velocity in the longitudinal direction and a slow velocity in the transversal direction is one of the most important functional characteristic of the crista terminalis (up to 10:1 longitudinal/transversal conduction velocity ratio) due to the higher density of gap junctions at the end of the connections [10]. The crista terminalis serves, due to this feature, as a functional block that prevents shortcuts in the impulse spreading in the intercaval region, thereby, serving as a lateral stabilizer to the reentry circuit of atrial flutter. The crista terminalis can be crossed in the transversal way by the activation wavefronts in some forms of atypical atrial flutters. The crista terminalis participates in the genesis of common type atrial flutter too. Moreover, the crista terminalis itself serves as an important arrhythmogenic substrate for atrial tachycardias potentially reflecting the presence of pacemaking activity cells.
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Functional Anatomy in Arrhythmias and Vascular Support of the Conduction System
The Vestibule The vestibule is a smooth muscular ridge surrounding the tricuspid orifice. Sulcus terminalis is a fat-filled cradle on the epicardial side that corresponds internally to the crista terminalis. It is known also as the terminal groove.
SAN SAN is a subepicardial, spindle-shaped structure at the superior cavoatrial junction that extends along the crista terminalis toward the inferior vena cava [11]. It gradually penetrates musculature of the crest to rest in the subendocardium and surrounds its own artery, which can course centrally (70 %) or eccentrically within the node. Histologically, it is constituted of slightly smaller cells than normal working cells. The position and length of SAN varies throughout crista terminalis. The SAN structure has a mean length of 20 ± 3 mm [12]. With age, the amount of connective tissue increases with respect to the area occupied by the nodal cells. The constitutive parts of the node are the head, the body, and the tail. It has been described in various shapes such as fusiform, horseshoe, or crescent-like. The SAN and the terminal segment of its common artery are located in the terminal groove, close to the superior cavoatrial junction. Sinus venosus is located mainly in the posterolateral wall of the right atrium between the orifices of the superior vena cava (SVC) and inferior vena cava (IVC) [13].
Interatrial Septum The true atrial septum is made up of the flap valve of the foramen ovale and part of its anteroinferior margin. The superior rim of the fossa or the septum secundum is the infolded wall between the SVC and the right pulmonary veins (PV) assigned as the interatrial groove and is not a genuine septum. The patent interatrial septal defect or patent foramen ovale (PFO) results from the incomplete fusion of the flap of the foramen ovale against the atrial septum. The PFO is usually less than 5 mm in diameter. Pre-procedural anatomic knowledge of the atrial septum can minimize complications of transseptal approaches [14]. A PFO is often associated with atrial septal aneurysm and the Chiari network [15].
The Septal Components of the AV Junction These conduct the cardiac impulse from the atrium to the ventricles. The central fibrous block, the apex of Koch triangle, comes anterior and superior to the muscular AV septum. The right fibrous trigone and the membranous septum
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make up the central fibrous body, which blend together the aortic, mitral, and tricuspid valves. The left atrium (LA) like the right atrium consists of an appendage, a venous component, and a vestibule [16]. The left atrial appendage is derived from primitive atrium and has a rugged, trabeculated surface. Due to its narrow neck with the atrium, the appendage is a potential site for thrombus deposition. Posteriorly located is the venous component with pulmonary vein orifices at each corner. The mitral orifice is surrounded by the vestibular component. The left atrium, in its greater portion, which includes the venous component, the vestibule, and the septal component is smooth walled.
The Bundles The right bundle branch arises from the distal portion of the AV bundle and forms a cord-like structure that goes along the septal and moderator bands toward the anterior tricuspid papillary muscle. Alternatively, the left bundle branch is made by a broad fenestrated sheet of subendocardial conduction fibers that spread along the septal surface of the left ventricle [17]. The right and left bundle branches receive dual blood supply from the septal perforators of the left anterior descending coronary artery and posterior descending coronary arteries. Left ventricular pseudo-tendons can contain conduction tissue from the left bundle branch. The left bundle branch can be disrupted following surgical myectomy, whereas the right bundle branch can be damaged during percutaneous alcohol septal ablation [18]. Following right ventriculotomy for reconstruction of the right ventricular outflow tract, the electrocardiogram shows a pattern of right bundle branch block, even though the right bundle is not disrupted.
AVN The atrioventricular node (AVN) and bundle (AVB) normally penetrate the right fibrous trigone (central fibrous body) at the atrioventricular junction. The crucial landmark for identification of the atrioventricular CCS is the boundary between the inferior portion of the membranous and muscular parts of the interventricular septum [19]. The atrioventricular node lies directly above the insertion of the septal leaflet of the tricuspid valve and just beneath the right atrial (RA) endocardium. The atrioventricular junction is a structure encompassing the AV node with its posterior, septal, and left atrial (LA) approaches, as well as the His bundle and its splitting parts. In subendocardial structure, with small dimensions, the AV node is located within the interatrial septum, at the distal convergence of the preferential internodal conduction pathways that course through the atria from the sinus node (Fig. 4.1).
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Fig. 4.2 Koch triangle. AV atrioventricular Fig. 4.1 Conduction system of the heart. SA sinoatrial, RA right atrium, AV atrioventricular, RV right ventricle
The AVN is slightly larger than the AVB and is positioned cranial to the AVB. Its shape is variable, taking the form of a reversed triangle, ellipse, fan, or star [20]. Generally, the AVN is situated in the Koch triangle between tricuspid valve attachment, tendon of Todaro, and coronary sinus ostium. AVN has two parts, a compact one and an area of transitional cells. The transitional cell zone has the highest rate of spontaneous diastolic depolarization and consists of cells constituting the atrial approaches to the compact AV node. Some groups of cells from the compact node have extensions into the central fibrous body and the annulus of the mitral and tricuspid valves. These cells appear to be the site of most of the conduction delay through the AV node. The penetrating His bundle, which continues distally the AVN, is surrounded by the connective tissue of the central fibrous body and is therefore a conducting tract that takes information to the ventricles [21].
Koch Triangle The Koch triangle, structure situated in the RA, anterior to the coronary sinus orifice, presents the apex—the central fibrous body of the heart and the point of penetration of the His bundle. This area is bordered posteriorly by a fibrous extension from the Eustachian valve named the tendon of Todaro and anteriorly by the attachment of the septal leaflet of the tricuspid valve (Fig. 4.2). The base of the triangle contains the slow pathway and the midportion contains the compact AV node, fast pathway. Moreover, the base of the triangle is bordered by the coronary sinus ostium and anteriorly by
the septal isthmus [22]. In patients with atrial fibrillation, the Koch triangle is a habituate ablation place for the treatment of atrioventricular nodal reentrant tachycardia and atrioventricular conduction modification. Slow pathway ablation is mostly used in the treatment of atrioventricular nodal reentrant tachycardia. In the electrophysiology laboratory the site of recording the His bundle activity and the ostium of the coronary sinus are anatomic markers for location of the Koch triangle and for guiding the delivery of ablative energy.
Vascular Supply SAN Artery The SAN artery comes off of either the proximal right coronary artery (60–70 %) or the proximal circumflex artery [23]. In less than 1 % of humans, the SAN artery may originate directly from the right coronary sinus, distal right coronary artery, or descending aorta. These anatomic variants and their knowledge can be important prior to surgery [24]. Information regarding the termination of the SAN artery may be imperative when planning a superior transseptal approach in mitral valve surgery [25]. The SAN artery crosses the superior and posterior border of the interatrial septum in 54 % of the hearts. Terminal SAN artery goes closer to the superior aspect of the interatrial septum in selected groups when the artery is moving behind the vena cava (47 %) [26]. Such anatomy predisposes the SAN artery to be injured during a superior transseptal approach to the mitral valve. Another significant variant of the SAN artery is the existence of a left S-shaped SAN artery arising from the proximal LCX, seen in 8 % of the cadaveric hearts studies
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Functional Anatomy in Arrhythmias and Vascular Support of the Conduction System
and in 14 % of the coronary CT studies [27]. This artery is larger than the normal SAN variant and supplies almost the entire left atrium, an important part of the interatrial septum and right atrium, part of the sinus, and the atrioventricular nodal areas. This artery passes in the sulcus between the left superior pulmonary vein and the left atrial appendage [28]. In this location, the artery becomes susceptible to injury during catheter or surgical ablation procedures on the left atrium.
Alternative Sources of Arterial Supply to the Atrioventricular Conducting Pathway These include the descending septal artery, the first septal perforating artery, and anterior atrial branches inclusively the Kugel anastomotic artery [29]. The Kugel anastomotic artery was first described by MA Kugel as a large atrial artery (arteria anastomotica auricularis magna) [30]. The Kugel artery is a rare, but an important collateral between the proximal circumflex artery (LCX) and the right coronary artery (RCA) and for whichever artery that supplies the crux of the heart. It may anastomose with the AVN artery after it passes anterior to the mitral valve ring and coursing in the basal interatrial septum. The first septal perforating artery is a branch of the left anterior descending coronary artery which supplies the basal septum with divisions to the conduction system including His bundle and proximal bundle branches. The right Kugel anastomotic artery may be a continuum of either the right superior septal vessel, a conus branch, or branch of SAN artery [31]. For the AV node this is not a primary arterial supply, but its terminal branches can connect with right superior septal artery. Only the proximal two-thirds of the AV node are supplied by the AV nodal artery; the distal segment of the AV node has a dual blood supply in 80 % of the human hearts from the same AV nodal artery and the left anterior descending (LAD) artery. In 90 % of patients, the AV nodal artery originates from the RCA. During acute myocardial infarction (AMI), conduction disturbances in the AV node are usually the consequence of an occlusion proximal to the origin of the AV nodal artery. Therefore, the conduction abnormalities are usually associated with inferior AMI. The AV nodal tissue merges with the His bundle, which runs through the inferior portion of the membranous interventricular septum and, then, continues along the left side of the crest of the muscular interventricular septum. Generally it is a dual blood supply for the His bundle from both the AV nodal artery and branches of the LAD artery. Unlike the SA and AV nodes, the bundle of His and Purkinje system have relatively little autonomic innervation. The complete heart block is a common complication after alcohol septal ablation for the treatment of hypertrophic obstructive cardiomyopathy.
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Interatrial Myocardial Connections Anterosuperior Interatrial Connection Bachmann’s bundle (BB) ensures rapid interatrial conduction, being the preferential interatrial electrical connection structure and therefore leads to physiological biatrial contraction [32]. Bachmann’s bundle, situated at the anterosuperior margin of the interatrial groove, consists of a subepicardial smooth band of muscle fibers. The main vascular supply of Bachmann’s bundle is from SAN artery and its branches. Changes in the musculature of BB could block or prolong interatrial conduction resulting in abnormal atrial excitability, manifested with atrial dysfunction, AF, and other types of arrhythmias. BB is less visible in patients with severe coronary artery disease, interatrial conduction block, and atrial fibrillation [33]. In the absence of BB, the area is replaced by fat, and this may suggest a connection between these conditions and the altered BB fibers.
Posteroinferior Interatrial Connection and the Coronary Sinus There are other muscular bridges of varying numbers and sizes that provide interatrial connections, in addition to the anterosuperior interatrial muscle bridge of BB. The coronary sinus is approximately 30–45 mm long and 10–12 mm in diameter, but can be found also highly variable morphologic features [34]. The beginning of the coronary sinus is marked by either internally by the Vieussens valve or an outer constriction, an opening of the oblique vein of Marshall. Around the CS is a striated myocardial sleeve outside its adventitia, which continues into the right atrium [35]. This myocardial extension into the CS is electrically continuous at one or more points to the right and left atrium. The coronary sinus is used as a supportive ductus for catheter treatment of arrhythmias [36]. In fact there exist anatomic variants of the CS, including unroofed sinus, ectasia, stenosis, diverticulum or atresia. The majority of coronary sinus diverticulum is located usually at its junction with the middle cardiac vein, along its inferior part. A CS diverticulum may form the anatomic basis of posteroseptal or left posterior accessory pathways. A coronary sinus diverticulum differs from a subthebesian pouch, this being defined as a recess of the right atrial crista terminalis extending below the orifice of the coronary sinus. In patients with AV junctional reentrant tachycardia, proximal CS is shown to be larger than in healthy patients and resembles a wind sock [37].
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Anatomic Elements Related to Arrhythmias Cavotricuspid Isthmus The right atrial cavotricuspid isthmus is the area between the IVC and tricuspid valve. The proportion of muscular component is variable and, in general, it has muscular extensions from the crista terminalis. The free border of the Eustachian ridge continues as a tendon in the musculature of the sinus septum, described as the tendon of Todaro. This site is the target of catheter ablation techniques that have become the treatment of choice for isthmus-dependent atrial flutter. This region varies in size among individuals and across the phases of the cardiac cycle. The ablation can be hampered by many anatomic obstacles such as aneurismal pouches, an enlarged Eustachian ridge, or even a concave deformation of the entire isthmus.
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catheter ablation of right middle PV. In certain cases, a supernumerary PV exists and shows an aberrant insertion with a perpendicular position in relation to the LA posterior wall. This supernumerary branch usually drains the upper lobe of the right lung and characteristically passes behind the bronchus intermedius [40].
Septal Isthmus The septal isthmus is part of the right atrial vestibule located between the edge of the coronary sinus ostium and the attachment of the septal tricuspid valve. The ablation of the slow pathway in AV node reentrant tachycardia is frequently made in this portion. The septal part is also an ablation target for isthmus-dependent atrial flutter cases.
Other Anatomic Arrhythmogenic Structures Subthebesian Pouch The atrial wall inferior to the orifice of the coronary sinus is usually pouch-like and described as the sinus of Keith, or sub-Eustachian sinus. It is anterior to the orifice of the IVC and subthebesian rather than subeustachian. It has a special arrangement of muscle fibers which can be the substrate for the reentrant circuit during atrial flutter. A cause of procedural difficulty could be the depth of the subthebesian pouch.
Pulmonary Veins It is well established that myocardial sleeves of the PVs, in particular the superior veins, are crucial sources of triggers, which initiate atrial fibrillation (AF) [38]. Imaging studies have demonstrated that the anatomy of the LA and PVs is commonly variable. The PV ostia are ellipsoid with a longer supero-inferior diameter. This veins are demonstrated being larger in AF versus non-AF patients, in men versus women, and in persistent versus paroxysmal patterns of AF. The distance from the ostium to the first order branch defines the PV trunk. The ostia of the superior pulmonary vein are larger (19–20 mm) than the inferior pulmonary vein ostia (16– 17 mm) [39]. It is important to report the ostial diameters of each vein and the length to the first order branch because these measurements influence the selection of circular catheter size. Conjoined PV is very common (>25 %) and more frequently seen on the left branches than in the right branches. Moreover, the supernumerary veins are also identified. The most frequent pattern consists in a separate right middle pulmonary vein (25 %), which drains the middle lobe of the lung. One or two separate middle lobe vein ostia can be seen in 26 % of patients. The ectopic focus originating from the right middle PV could induce AF, and this is cured by
There are also other anatomic arrhythmogenic structures like ligament of Marshall and left superior vena cava, lipomatous hypertrophy of the interatrial septum, and cardiac autonomic nervous system.
Ligament of Marshall and Left SVC In most hearts (70 %) the oblique vein or ligament of Marshall (developmental remnant of the embryonic left SVC) is <3 mm from the endocardium of the left lateral ridge of the LA and contains muscular connections to the left PVs [38]. On angio-CT studies the vestige of the oblique vein can be detected. Sometimes, in isolated cases, there is a persistent left SVC draining into the CS, in 0.3 % of the normal population, and can be the source of atrial fibrillation [41].
Lipomatous Hypertrophy of the Interatrial Septum The multidetector computed tomography can be used to help diagnose lipomatous hypertrophy of the interatrial septum, being characterized by accumulation and deposition of fat in the interatrial septum. This condition commonly occurs in elderly, obese women. It is important to note that it can cause atrial arrhythmias or obstructive flow symptoms, while in most cases it is asymptomatic [42].
Cardiac Autonomic Nervous System Cardiac ganglionic plexi are located in the epicardial layer and are surrounded by adipose tissue. They are concentrated
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Functional Anatomy in Arrhythmias and Vascular Support of the Conduction System
along the interatrial groove near the SA (SVC-right pulmonary vein fat pad) and AV nodes (IVC-LA fat pad) [43]. A smaller part is also located on the atrial appendage-atrial junctions, the superior and anterior left atrial surfaces, the base of the ventricles, and the base of the great vessels. The beginning and maintenance of AF are facilitated by vagal stimulation that shortens the atrial effective refractory period. The ablation success at patients undergoing circumferential PV ablation for paroxysmal AF can be improved by adding the LA ganglion plexus to other ablation targets [44].
Conclusion The heart has a special system for the generation of rhythmic electrical impulses that lead to contraction of the heart muscle and effective fast spreading of these impulses through the entire heart. This excitoconductor system of the heart is susceptible to damage by heart disease, especially coronary flow decrease following cardiac ischemia. Anatomical variations of blood supply are sometimes the reason for. The consequences are the emergence of some species of arrhythmias, conduction disorders, or abnormal sequence of contraction of the ventricular chambers that lead to impaired left ventricular ejection fraction and sometimes to severe heart failure and death. Knowledge of the anatomical structures of the heart’s conduction system and their relationships with the generation of arrhythmias is a useful topical issue for both the clinician and the electrophysiologist or surgeon.
References 1. Malouf JF, Edwards WD, Tajik AJ, Seward JB. Functional anatomy of the heart. In: Fuster V, Alexander RW, O’Rourke RA, et al., editors. The heart. 11th ed. New York: McGraw-Hill; 2004. p. 75–83. 2. Kaupp UB, Seifert R. Molecular diversity of pacemaker ion channels. Annu Rev Physiol. 2001;63:235–57. 3. Robinson RB, Siegelbaum SA. Hyperpolarization-activated cation currents: from molecules to physiological function. Annu Rev Physiol. 2003;65:453–80. 4. Sanchez-Quintana D, Ho SY. Anatomy of cardiac nodes and atrioventricular specialized conduction system. Rev Esp Cardiol. 2003;56:1085–92. 5. Tawara S. Das reizleitungssystem des s¨augetierherzens. Eine anatomischhistologische studie ¨uber das atrioventrikularb¨undel und die Purkinjeschenf¨aden. Jena: Verlag von Gustav Fischer; 1906. 6. Szabó E, Virágh S, Challice CE. The structure of the atrioventricular conducting system in the avian heart. Anat Rec. 1986;215:1–9. 7. Anderson RH, Brown NA. The anatomy of the heart revisited. Anat Rec. 1996;246:1–7. 8. Edwards WD. Applied anatomy of the heart. In: Giuliani ER, Fuster V, Gersh BJ, McGoon MD, McGoon DC, editors. Cardiology: fundamentals and practice. 2nd ed. St. Louis: MosbyYear Book; 1991. p. 47–112. 9. Mizumaki K, Fujiki A, Nagasawa H, et al. Relation between transverse conduction capability and the anatomy of the crista terminalis in patients with atrial flutter and atrial fibrillation: analysis by intracardiac echocardiography. Circ J. 2002;66:1113–8.
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10. Saffiz JE, Kanter HL, Green KG. Tissue-specific determinants of anisotropic conduction velocity in canine atrial and ventricular myocardium. Circ Res. 1994;74:1065–70. 11. Sanchez-Quintana D, Cabrera JA, Farré J, Climent V, Anderson RH, Ho SY. Sinus node revisited in the era of electroanatomical mapping and catheter ablation. Heart. 2005;91:189–94. 12. Matsuyama TA, Inoue S, Kobayashi Y, et al. Anatomical diversity and age-related histological changes in the human right atrial posterolateral wall. Europace. 2004;6:307–15. 13. Saremi F, Krishnan S. Cardiac conduction system: anatomic landmarks relevant to interventional electrophysiologic techniques demonstrated with 64-detector CT. Radiographics. 2007;27: 1539–67. 14. Saremi F, Channual S, Raney A, et al. Imaging of patent foramen ovale with 64-slice MDCT. Radiology. 2008;249:483–92. 15. Schneider B, Hofmann T, Justen MH, Meinertz T. Chiari’s network: normal anatomic variant or risk factor for arterial embolic events? J Am Coll Cardiol. 1995;26:203–10. 16. Morady F. Catheter ablation of supraventricular arrhythmias: state of the art. J Cardiovasc Electrophysiol. 2004;15:124–39. 17. Edwards WD. Cardiac anatomy and examination of cardiac specimens. In: Emmanouilides G, Reimenschneider T, Allen H, Gutgesell H, editors. Moss & Adams’ heart disease in infants, children, and adolescents. 5th ed. Baltimore: Williams & Wilkins; 1995. p. 70–105. 18. Talreja DR, Nishimura RA, Edwards WD, et al. Alcohol septal ablation versus surgical septal myectomy: comparison of effects on atrioventricular conduction tissue. J Am Coll Cardiol. 2004;44:2329–32. 19. Asami I. Anatomy of the conduction system of human: location, connection, and method. Igaku no ayumi. 1958;27:329–31. 20. Kawashima T, Sasaki H. A macroscopic anatomical investigation of atrioventricular bundle locational variation relative to the membranous part of the ventricular septum in elderly human heart. Surg Radiol Anat. 2005;27:206–13. 21. Anderson RH, Ho HY, Becker AE. Anatomy of the human atrioventricular junctions revisited. Anat Rec. 2000;260:81–91. 22. Ho SY, Anderson RH. How constant anatomically is the tendon of Todaro as a marker for the triangle of Koch? J Cardiovasc Electrophysiol. 2000;11:83–9. 23. Anderson KR, Ho SY, Anderson RH. Location and vascular supply of sinus node in human heart. Br Heart J. 1979;41:28–32. 24. Tuncer C, Batyraliev T, Yilmaz R, et al. Origin and distribution anomalies of the left anterior descending artery in 70,850 adult patients: Multicenter Data collection. Catheter Cardiovasc Interv. 2006;68:574–85. 25. Guiraudon GM, Ofiesh JG, Kaushik R. Extended vertical transatrial septal approach to the mitral valve. Ann Thorac Surg. 1991;52:1058–62. 26. Farhood Saremi MD, Maria Torrone MD, Nooshin Yashar BS. Cardiac conduction system: delineation of anatomic landmarks with multidetector CT. Indian Pacing Electrophysiol J. 2009;9(6):318–33. 27. Nerantzis C, Avgoustakis D. An S-shaped atrial artery supplying the sinus node area. An anatomical study. Chest. 1980;78:274–8. 28. Saremi F, Channual S, Abolhoda A, et al. MDCT of the S-shaped sinoatrial node artery. Am J Roentgenol. 2008;190:1569–75. 29. Nerantzis CE, Marianou SK, Koulouris SN, Agapitos EB, Papaioannou JA, Vlahos LJ. Kugel’s artery: an anatomical and angiographic study using a new technique. Tex Heart Inst J. 2004;31:267–70. 30. Kugel MA. Anatomical studies on the coronary arteries and their branches. I. Arteria anastomotica auricularis magna. Am Heart J. 1927;3:260–70. 31. Singh M, Edwards WD, Holmes Jr DR, Tajil AJ, Nishimura RA. Anatomy of the first septal perforating artery: a study with implications for ablation therapy for hypertrophic cardiomyopathy. Mayo Clin Proc. 2001;76:799–802.
42 32. Lemery R, Guiraudon G, Veinot JP. Anatomic description of the Bachmann’s bundle and its relation to the atrial septum. Am J Cardiol. 2003;91:1482–5. 33. Leier C, Meacham J, Shaal S. Prolonged atrial conduction: a major predisposing factor for the development of atrial flutter. Circulation. 1978;57:213–6. 34. El-Maasarany S, Ferrett CG, Firth A, et al. The coronary sinus conduit function: anatomical study (relationship to adjacent structures). Europace. 2005;7:475–81. 35. Chauvin M, Shah DC, Haïssaguerre M, Marcellin L, Brechenmacher C. The anatomic basis of connections between the coronary sinus musculature and the left atrium in humans. Circulation. 2000;101:647–52. 36. Sun Y, Arruda M, Otomo K, et al. Coronary sinus ventricular accessory connections producing posteroseptal and left posterior accessory pathways: incidence and electrophysiological identification. Circulation. 2002;106:1362–7. 37. Ong MG, Lee PC, Tai CT, et al. Coronary sinus morphology in different types of supraventricular tachycardias. J Interv Card Electrophysiol. 2006;15:21–6. 38. Cabrera JA, Ho SY, Climent V, Sanchez-Quintana D. The architecture of the left lateral atrial wall: a particular anatomic region with
C. Stătescu et al.
39.
40.
41.
42.
43.
44.
implications for ablation of atrial fibrillation. Eur Heart J. 2008;29:356–62. Schwartzman D, Lacomis J, Wigginton WG. Characterization of left atrium and distal pulmonary vein morphology using multidimensional computed tomography. J Am Coll Cardiol. 2003;41:1349–57. Christoffels VM, Moorman AFM. Development of the cardiac conduction system: why are some regions of the heart more arrhythmogenic than others? Circ Arrhyth Electrophysiol. 2009;2:195–207. Lin WS, Tai CT, Hsieh MH, et al. Catheter ablation of paroxysmal atrial fibrillation initiated by non-pulmonary vein ectopy. Circulation. 2003;107:3176–83. Xanthos T, Giannakopoulos N, Papadimitriou L. Lipomatous hypertrophy of the interatrial septum: a pathological and clinical approach. Int J Cardiol. 2007;121:4–8. Armour JA, Murphy DA, et al. Gross and microscopic anatomy of the human intrinsic cardiac nervous system. Anat Rec. 1997;247:289–98. Pappone C, Santinelli V, Manguso F, et al. Pulmonary vein denervation enhances long-term benefit after circumferential ablation for paroxysmal atrial fibrillation. Circulation. 2004;109: 327–34.
5
Autonomic Control of Cardiac Arrhythmia Kieran E. Brack and G. André Ng
Abstract
The autonomic nervous system controls virtually all aspects of bodily function, and this is perfectly illustrated in the control of the heart. The autonomic nervous system is not only responsible for the “flight and fight” response but is also important for the instantaneous beat-to-beat control of cardiac function. This fine control is vital because the heart is a highly sophisticated organ, and management by both sympathetic and parasympathetic divisions helps maintain cardiac function within physiological limits. Equally, the autonomic nervous system has a significant impact in pathology. Abnormal autonomic control is a hallmark in many cardiac diseases which may actually precipitate and maintain cardiac dysfunction. An important example of the way by which activity of the autonomic nervous system affects the heart is the influence on cardiac rhythm. In this chapter we focus on two major cardiac arrhythmias, namely, atrial and ventricular fibrillations, which not only carry the most significant burden in clinical practice but also the highest risk of fatality and morbidity. Both of these arrhythmias are intimately associated with the autonomic nervous system and provide a perfect example of complex and heterogeneous control. Our understanding in this fascinating area of autonomic cardiac control is key to the development of successful treatment for these important conditions. Keywords
Sympathetic • Parasympathetic • Vagus • Atrial arrhythmia • Ventricular arrhythmia • Fibrillation
Introduction
K.E. Brack, BSc, PhD Department of Cardiovascular Sciences, University of Leicester, Leicester, UK G.A. Ng, MBChB, PhD, FRCP(Glasg), FRCP, FESC (*) Department of Cardiovascular Sciences, University of Leicester, Leicester, UK Department of Cardiology, Glenfield Hospital, University Hospitals of Leicester NHS Trust, Leicester, UK Leicester Cardiovascular Biomedical Research Unit, National Institute for Health Research, Leicester, UK e-mail:
[email protected] A.S. Kibos et al. (eds.), Cardiac Arrhythmias, DOI 10.1007/978-1-4471-5316-0_5, © Springer-Verlag London 2014
The classical effects of the two branches of the autonomic nervous system, namely, sympathetic and parasympathetic systems, on the heart are well known. Sympathetic activity causes positive effects on heart rate (chronotropy), atrioventricular conduction (dromotropy), and contractile function (inotropy), whereas the parasympathetic system generally has opposite effects. Action of the parasympathetic system tends to be more instantaneous allowing beat-by-beat control, whereas a certain “lag” is present in the response to sympathetic activation, although both systems interact to maintain stable control of the heart. The effects of autonomic activity on cardiac electrophysiology are largely mediated via neuronally released neurotransmitters and interaction 43
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with ion channels. This neurocardiological interface is important for homeostatic physiological and pathological control including the pathogenesis of cardiac arrhythmias. Atrial and ventricular fibrillation are cardiac arrhythmias with a significant clinical burden. Atrial fibrillation (AF) is the most common clinical arrhythmia affecting 1–2 % of the population in Europe [1]. It is estimated that one in four 40-year-old adults will develop AF during their lifetime [2]. AF is a significant risk factor in stroke and thromboembolism and can lead to cardiomyopathy or heart failure. Ventricular fibrillation (VF), on the other hand, is the leading cause of sudden cardiac death (SCD) with annual death tolls of between 300,000 and 350,000 in Europe with a significant variation in prevalence and out of hospital survival rates across member countries [3, 4]. Despite considerable research, effective treatment and prophylactic therapy for either arrhythmia are lacking. Neurocardiological control is significant in both AF and VF, and this chapter will discuss how the autonomic nervous system is involved.
Cardiac Autonomic Innervation Sympathetic and parasympathetic fibers innervate all regions of the heart [5, 6]. Sympathetic fibers innervating the heart arise primarily from the thoracic vertebrae of the spinal cord with preganglionic nerves distributed to various bilateral paravertebral ganglia including the superior and middle cervical ganglia and the cervicothoracic (or stellate) ganglia. Postganglionic fibers converge at the cardiac plexus, which is a group of nerves and blood vessels at the aortic arch, before innervating the sinoatrial and atrioventricular nodes and atrial and ventricular myocardium. Parasympathetic fibers are carried in the tenth cranial nerve (the vagus) with origins in both the nucleus ambiguous and the dorsal motor nucleus of the vagus in the brainstem. From there the vagi from both sides approach the heart within the same sheath as the common carotid arteries and like sympathetic fibers converge at the cardiac plexus. Until recently, interpretation of neural effects on the heart was confined to the effects of centrally derived extrinsic sympathetic and parasympathetic inputs. However, it is now known that neurocardiac control is more complex due to an extensive independent network of neurons within the heart, i.e., intrinsic cardiac nerves that constitute a “little brain” [7] capable of modulating functions of the heart [8]. These intrinsic neurons occur primarily, but not exclusively, in epicardial fat and form integrative circuits throughout the heart and function as “ganglionic plexuses” (GPs). GPs are distributed throughout the heart and act as local control networks to provide beat-to-beat regulation of the heart and may also react to pathological stimuli such as ischemia and heart failure (HF) [9]. GPs are principally located on the (1) posterior
K.E. Brack and G.A. Ng
atrial surface; (2) base of aorta/pulmonary arteries; (3) anterior ventricular surface: proximal portions of the anterior descending and circumflex arteries; and (4) on their ventral surface, and an example of GP position in humans is shown in Fig. 5.1 [10]. There are comparable GPs in different species with results demonstrated on their cardiac effects, including pathogenesis of arrhythmia. GPs are unevenly distributed and are more prevalent in supraventricular tissues. Plexuses contain a wide variety of neuronal structures and have complex synaptology incorporating sympathetic and parasympathetic elements, inter- and intra-ganglionic neurons, and afferent neurons which relay sensory information [11, 12]. More importantly, there are several puzzling features of cardiac disease that may be the result of abnormal ganglionic plexus activity or altered intrinsic–extrinsic interaction (see later).
Atrial Fibrillation AF is characterized by fast irregular chaotic atrial activity with no identifiable P wave on the ECG and is typically conducted to the ventricle with an irregular response. AF is clinically classified into paroxysmal, persistent, and permanent forms. Paroxysmal AF occurs periodically and can last from minutes to days and spontaneously reverts to sinus rhythm. Persistent AF is characterized when the rhythm lasts >48 h with sinus rhythm achieved via electrical or pharmacological cardioversion, while permanent AF can no longer be converted back to sinus rhythm. The underlying cause of AF is multifactorial, but it is widely accepted that a key contributing factor is the result of ectopic firing from the pulmonary veins (PVs) [13]. Autonomic mechanisms are considered important [14] especially in the light of the location of ganglionic input in this region, recently reviewed by Shen et al. [15].
Autonomic Nervous System and AF Three types of autonomically mediated AF are described and each has distinct characteristics. The first type is considered solely adrenergic in nature and is typically triggered by strong activation of the sympathetic nervous system, such as situations of extreme emotional stress or exercise. AF in these situations occurs mainly during the day. The second type of autonomic AF is parasympathetic in nature occurring when vagal tone is high, such as at rest or after eating a meal, typically taking place at night. Interestingly, this type is more prevalent in young healthy males, and there is a lower tendency for vagal AF to progress onto permanent AF which is preceded by slow heart rates. The last type of AF is where mixed sympathetic–parasympathetic mechanisms are involved.
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Fig. 5.1 Ganglionated plexus (GPs) location in the human heart. Posterior (upper) and superior (lower) views illustrating GP locations of the atria and ventricles. Key: PA pulmonary artery, SVC superior
vena cava, IVC inferior vena cava, RV right ventricle, LV left ventricle (Reproduced with permission from Armour et al. [10])
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Fig. 5.2 Adrenergic and cholinergic mechanisms on spontaneous AF. Upper: catecholamine-mediated atrial fibrillation (a) and its prevention by atropine (b) perfused through the sinus node artery. Lower: AF induced by 1 μm acetylcholine (ACh) (c) and 0.1 μm ACh and 2 μm
isoproterenol (d). Key: CL cycle length, E1 and E2 atrial bipolar electrograms, P2 blood pressure recording, II standard electrocardiographic lead II (Reproduced with permission from Sharifov et al. [20])
It has been known for a long time that vagus nerve stimulation predisposes to AF, a method which has been popularly used to experimentally produce AF as described by the classical study by Scherf et al. in 1947 [16]. More recently the role of parasympathetic modulation of AF was highlighted from studies showing that GP stimulation can induce AF [17] with GP ablation being capable of preventing AF [18] particularly from the SVC–Ao fat pad, also known as the “third fat pad” [19]. This fat pad relays and integrates information from the vagus, such as vagalinduced effective refractory period shortening. Radiofrequency ablation of the right atrium and SVO–Ao fat pad, but not the left, prevented AF that was previously inducible by the vagus. An example of how mixed sympathetic and parasympathetic mechanisms modulate AF was illustrated by an elegant study by Sharifov et al. [20], using pharmacological autonomic agonists. Injected into the sinus node artery, adrenaline induced AF spontaneously and was prevented by atropine (Fig. 5.2a, b). Acetylcholine (ACh) promoted AF but was not inhibited by the β-blocker propanolol. AChinduced AF was augmented by isoprenaline (Fig. 5.2c, d),
suggesting that cholinergic stimulation is primarily responsible for spontaneous AF initiation and that sympathetic tone modulates the initiation and maintenance of cholinergically mediated AF. This study provides indirect evidence of the role of mixed autonomic mechanisms in AF. Direct evidence comes from studies recording autonomic nerve activity. As shown in Fig. 5.3 [21], there were clear increases in parasympathetic activity recorded from the superior cardiac branch of the left vagus and left stellate ganglia prior to and during atrial tachycardia/AF. This study documented a diurnal variation of susceptibility to these arrhythmias, which reflects known variations in autonomic tone, thus supporting the notion that autonomic activity is involved in AF.
Cellular Mechanisms Using “sleeves” of excised pulmonary veins from dogs [22], ectopic firing from pulmonary veins was induced using highfrequency autonomic stimulation. The resultant ectopy was associated with action potential duration (APD) shortening,
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Fig. 5.3 Autonomic nerve activity promoting atrial tachycardia and atrial fibrillation. Raw data of left atrial electrogram (LA), vagal nerve activity (VNA), stellate ganglia nerve activity (SGNA), and electrocardiogram with a paroxysm of atrial tachycardia (upper) and paroxysmal AF induced by simultaneous increases in VNA and SGNA (lower) (Modified from Tan et al. [21])
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hyperpolarization of the resting membrane potential, and the development of early afterdepolarizations (EADs) (Fig. 5.4). Responses were blocked using ryanodine, suggesting that the augmentation of intracellular calcium with adrenergic activation in combination with APD shortening from cholinergic activity contributes towards EADs and the resultant triggered activity. Adrenergic and cholinergic nerves are heterogeneously distributed around the PVs. While adrenergic nerves are more abundant than cholinergic nerves (Fig. 5.5a) in all regions, both types preferentially innervate the epicardium and are tightly packed around the PV–atrial junction (Fig. 5.5b) [23]. These findings have important implications as catheter ablation at these locations will not be selective against sympathetic or parasympathetic inputs. Despite this, ablation of these regions appears to selectively stimulate the characteristic effects of parasympathetic-induced bradycardia [24]. The continued attenuation of vagal reflexes has been suggested as a good prognostic marker of ablation success with Pappone et al. [24] reporting that patients who had no AF recurrence following ablation had continued reduced vagal tone which led the authors to propose vagal denervation during ablation with the aim to abolish vagal bradycardia. This however should be handled with caution, as the disruption of vagal innervation at the atrial level may lead to effects in the ventricle, since changes within the intrinsic cardiac autonomic nervous system can result in remote cardiac changes [25]. Osman et al. [26] highlighted what could happen in the ventricle after PV ablation for AF. In this report, VF was easily induced after successful PV ablation supporting the notion that ablation in the atria with vagal denervation could be dangerous. On the other hand, vagal stimulation does not always lead to AF. Li et al. [27] demonstrated that low-level vagus nerve stimulation, using a voltage below which elicits a change in heart rate or atrioventricular
conduction, can paradoxically protect from focal AF and atrial remodeling [28].
Ventricular Fibrillation and the Autonomic Nervous System Clinical and Preclinical Evidence Similar to the situation with AF, VF is significantly affected by the autonomic nervous system and is reflected by data showing a circadian variability in SCD occurrence [29] with low mortality rates during the night and high rates peaking during the day between 6 a.m. and 12 p.m. This pattern matches the circadian pattern of measures of autonomic tone, e.g., heart rate variability (HRV, Fig. 5.6 [29, 30]). Extensive preclinical and clinical data on HRV and baroreceptor reflex sensitivity (BRS) support a causal link with lethal arrhythmia, mortality, and autonomic tone. A number of HRV measures are regarded as independent risk markers, including the standard deviation of the RR interval (SDNN) [31] and power spectral analysis [32], a notion underpinned with data from the UK-Heart and ATRAMI studies in patients with HF [33, 34] and with previous MI [35] where decreased measures of HRV are associated with increased mortality (Fig. 5.7). These data are supported by numerous animal studies where increased BRS is significantly associated with reduced arrhythmic death in dogs with healed MI [36–38]. Recordings of vagal activity in dogs subjected to coronary artery occlusion (CAO) support the notion that increased vagal tone is beneficial for survival. Carati et al. [39] demonstrated that dogs survived when parasympathetic nerve activity increased following occlusion and animals were destined to die with depressed vagal responses.
48 Fig. 5.4 Mechanisms of autonomic modulation of atrial fibrillation. Suppression of autonomic-induced arrhythmia by atropine, atenolol, and ryanodine. Intracellular action potential and bipolar electrograms prestimulation, during a 300-ms duration stimulus train of 0.1-ms duration stimuli at 100 Hz (60–110 V), during the same stimulus train introduced during and following (a) atropine (3.2 × 10−8 M), (b) atenolol (3.2 × 10−8 M), and (c) ryanodine (10−5 M). Note: Atropine reversibly prevented both action potential shortening and triggered arrhythmia formation, while atenolol and ryanodine did not prevent action potential shortening with autonomic stimulation but prevented early afterdepolarization (EAD) formation and triggered arrhythmia (Used with permission from Patterson et al. [22])
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Heart Failure The link between the autonomic nervous system and SCD is particularly evident in HF where it is accepted that the increased likelihood of SCD is predicted by a low ejection fraction (EF). A classical hallmark of HF, and also in patients following an MI, is abnormal autonomic control (or “autonomic imbalance”), namely, high sympathetic activity and low vagal tone, and occurs in all aspects of cardiovascular regulation, e.g., alterations of afferent signaling, central processing, and ganglionic and efferent innervation in addition to alterations to the heart itself. Changes in autonomic activity appear early in HF and often precede other changes typical of the disease. Vagal tone significantly decreased 3 days after cardiac dysfunction and preceded sympathetic overactivity in a dog HF model [40]. In patients with cardiac dysfunction, sympathetic
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activation occurred before symptoms [41]. Irrespective of the relative timing that autonomic dysfunction ensues, there is strong evidence that the relationship between impaired neurocardiological control and increased mortality is the result of an increased vulnerability to lethal ventricular arrhythmias [42]. The clinical and prognostic significance of sympathetic overactivation is well known and forms the rationale for β-blockers as standard HF therapy. Parasympathetic regulation, on the other hand, has received much less attention.
The Sympathetic Nervous System and Ventricular Arrhythmias A direct link between recorded sympathetic activity and ventricular arrhythmia was elegantly demonstrated in a dog model of SCD. Ventricular tachyarrhythmia was associated
5
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Autonomic Control of Cardiac Arrhythmia
Fig. 5.5 Heterogeneous innervation of the atria. Upper: longitudinal (a) and transmural (b) autonomic nerve distribution. Lower: circumferential distribution of autonomic nerves at the pulmonary vein–left atrium junction. AO aorta. Key: ChAT anticholine acetyltransferase, LA left atrium, TH antityrosine hydroxylase, CS coronary sinus, IVC inferior vena cava, LA left atrium, LI left inferior pulmonary vein, LS left superior pulmonary vein, PA pulmonary artery, PV pulmonary veins, RI right inferior pulmonary vein, RS right superior pulmonary vein, SVC superior vena cava, VOM vein of Marshall (Reproduced with permission from Tan et al. [26])
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with two distinct types of sympathetic activity, i.e., low- and high-amplitude bursts [43]. As shown in Fig. 5.8, VF was triggered after an increase in low-amplitude burst discharge activity (LABDA). The underlying mechanisms of sympathetically mediated ventricular tachyarrhythmia may include changes in ion channel activity which may have direct or indirect effects on ventricular repolarization, refractoriness, or dynamics of the QT interval [44]. The precise contribution of these various mechanisms is not well understood.
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Electrical restitution is an electrophysiological property of the myocardium, whereby action potential duration (APD) is dependent on the preceding diastolic interval (DI). APD is inversely related to heart rate and shortens at fast heart rates or during an ectopic beat (short DI). The relationship between APD and DI is plotted as a curve, i.e., restitution curve, and the maximum slope of this curve is often used as a surrogate marker for VF inducibility [45] and is supported by mathematical [46] and experimental studies [47]. In situations
K.E. Brack and G.A. Ng
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where there is a steep slope (>1), a small change in DI causes larger changes in APD promoting dynamic electrical activity instability resulting in oscillations and alternans. On the other hand, drugs or maneuvers (see later) which reduce
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restitution slope prevent VF induction, supporting the notion that electrical restitution slope is important in VF initiation. In order to investigate the mechanisms underlying the autonomic modulation of VF, we developed an in vitro Langendorff perfused innervated rabbit heart preparation [48]. This model allows controlled stimulation of autonomic nerves and has several advantages over traditionally used in vivo and in vitro techniques as it is without the confounding influence of underlying tonic autonomic activity, hemodynamic reflexes, circulating hormones, or anesthetics. Stimulating sympathetic inputs from within the spinal cord reduced the current required to induce VF, i.e., VF threshold (VFT), indicating an increased susceptibility to VF. Slope of the electrical restitution curve was increased [49] suggesting a causal link between restitution and VFT (see Fig. 5.9) and is supported by data using β-adrenergic receptor agonists [50].
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Fig. 5.6 Circadian variation of sudden cardiac death (SCD) and heart rate variability. Circadian variation in the number of deaths attributed to SCD (Upper) and the rMSSD parameter of heart rate variability (Lower) (Modified from Willich et al. [29] and Bonnemeier et al. [30])
Being an organ requiring coordinated processes, there is a natural heterogeneity within the heart for its function which is also reflected in autonomic control with implications in arrhythmogenesis. There is consensus that unilateral stimulation of the sympathetic input results in differential effects. Pioneering studies by Randall et al. demonstrate that rightsided stimulation increases heart rate to a larger extent than the left, while the left-sided input preferentially affects the atrioventricular node and increases left ventricular contractility to a greater extent than the right [51]. These differential effects are extended to ventricular electrophysiology where stimulation/ablation of either stellate ganglia has differing effects on refractoriness, ECG, and VF induction [52–54]. Removing the right stellate ganglia (stellectomy) or left-sided sympathetic stimulation (SNS) is associated
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51
Autonomic Control of Cardiac Arrhythmia 0.2
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Fig. 5.9 Autonomic modulation of restitution, ERP, and VFT. (a) Standard restitution curves at baseline and during sympathetic (SS) and vagus nerve stimulation (VS) with maximum slopes indicated by dashed lines. (b) First derivative of the fitted curves in (a) for maximum slope calculation. (c) Effect of SS and VS on maximum slope of standard restitution, effective refractory period (ERP), and ventricular fibrillation threshold (VFT). (d) Percentage change of data in (c) (Reproduced with permission from Ng et al. [49])
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Fig. 5.8 Sympathetic nerve activity promoting VF. Raw data showing increased left stellate ganglion nerve activity (SGNA) preceding VF. (a) Increased low-amplitude burst discharge activity (LABDA) resulted in accelerated idioventricular rhythm. (b) VF occurred approximately 40 s later. (c) A 6-s recording from (b). Key: INA integrated nerve activity, P P wave [dissociated from ventricular activation due to complete AV block] (Reproduced with permission from Zhou et al. [43])
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with an increased susceptibility to ventricular tachycardia (VT) with a greater occurrence of early (EADs) and delayed afterdepolarizations (DADs), while right SNS has less of an effect [55, 56]. Differential intraventricular effects are also apparent, with left SNS resulting in a greater shortening of
APD at the left ventricular base [57]. This has important clinical implications as surgical removal of the left thoracic sympathetic inputs has been proposed as an anti-arrhythmic therapy for MI [58], catecholamine polymorphic VF [59], and VT storm [60].
52
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Fig. 5.10 Regional variation of the effects of sympathetic nerve stimulation, expression of adrenergic nerves, and ion channels. Upper: heterogeneity of restitution loops over the left ventricle. Restitution loops were measured during sympathetic nerve stimulation (SNS, open circles) and show shorter minimum action potential duration (APD) compared with pacing alone (pace, closed circles) at the apex (a) and base (b). Lower left: Western blot comparing apex–base differences in KvLQT1 and tyrosine hydroxylase. Top: β-actin controls. Middle: tyrosine hydroxylase (TH a surrogate for sympathetic nerves is greater at the base). Bottom: KCNQ1 (KvLQT1), the pore-forming main protein subunit responsible for IKS expressed higher at the base. Lower right: density histograms comparing KCNQ1 and TH levels (Modified from Ng et al. [65])
K.E. Brack and G.A. Ng
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The differences in the functional response to sympathetic nerve stimulation can be due to heterogeneous sympathetic innervation and/or differences in ion channel distribution, which are ultimately responsible for ventricular electrophysiology. It is known that catecholamine levels are higher at base of the LV [61] with histological data showing a significant base to apex distribution of sympathetic nerves in human [62] and rabbit hearts [63]. The greater basal APD shortening during SNS may significantly alter the spatial properties of ventricular restitution and increase heterogeneity of repolarization, which is a well-recognized substrate for arrhythmia initiation [64]. During sinus rhythm it is known that stimulation of sympathetic nerves reverses the direction of repolarization [65], from an apex → base direction to a base → apex, owing to the differential response at the LV base (see Fig. 5.10). In this example, APD is plotted against DI during sympathetic stimulation and compared to matched changes in heart rate using pacing. Changes in APD were associated with increased levels of sympathetic nerves and the slow-activating delayed rectifier current (IKs). These changes may be relevant to
Tyr. H.
arrhythmogenesis as a result of increased dispersion of repolarization [66, 67]. Transmurally, sympathetic stimulation can promote triggered activity (DADs) within the LV mid-wall [68].
Long QT Long QT syndrome (LQTS) occurs when there is abnormal ventricular repolarization manifesting as a prolongation in APD and QT interval. SCD is prevalent in LQTS, and arrhythmias in congenital LQTS subtypes 1–2, accounting for >95 % of LQTS, are precipitated by sympathetic activation [69] such as that seen during exercise or emotional stress. Arrhythmias in LQTS 3 are associated more with a bradycardic disposition and possibly parasympathetic influence, although data is lacking. In LQTS1, it is thought that the defect in IKs which is β-adrenergic sensitive is likely to explain why ventricular repolarization fails to shorten, despite an increase in heart rate with adrenergic activation. Ganglionectomy [70] is anti-arrhythmic in this setting.
5
Autonomic Control of Cardiac Arrhythmia
LV Epi
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53 Dog
Fig. 5.11 Vagal innervation of the left (LV) and right (RV) ventricle. Left: images (10× mag) of the epicardial and endocardial surfaces of the LV and RV with vagal fibers stained white. Low densities of thick vagal nerves are on the epicardium, whereas greater densities of finer vagal fibers are seen the endocardium. Right: dorsoposterior view of a 1-month-old dog heart. Vagal fibers are black. Note the large quantity of epicardial nerves on the left atrium that proceed to the ventricle. The arrow
points to the contact site of the extrinsic autonomic nerves. Key: AzV root of the azygos vein, ICV orifice of the inferior vena cava, Lau left auricle, LIPV root of the left inferior pulmonary vein, LSPV root of the left superior pulmonary vein, LV left ventricle, RA right atrium, RIPV root of the right inferior pulmonary vein, RSPV root of the right superior pulmonary vein, RV right ventricle, SVC root of the superior vena cava. Scale bar 2 mm (Reproduced with permission of Ulphani et al. [5] and Taggart et al. [74])
The Parasympathetic Nervous System and Ventricular Arrhythmias
Direct Anti-VF Protection: Studies in the Isolated Innervated Rabbit Heart
Vagal postganglionic nerves primarily modulate cardiac activity through the release of acetylcholine (ACh) acting on postsynaptic muscarinic receptors (mAChRs) to slow heart rate (bradycardia), delay atrioventricular conduction (dromotropy), and reduce atrial force (inotropy) with little effect on ventricular performance. The lack of evidence to support a direct negative ventricular inotropic effect reflects historical data which suggested against a significant cholinergic innervation in the ventricle. This view is outdated as modern techniques reveal a dense and intricate network of AChcontaining nerves in both ventricles of all species studied [71–76] (see Fig. 5.11). While vagal innervation is less extensive than sympathetic nerves, it should be noted that the vagus reduces the effects of adrenergic activation and significantly affects arrhythmogenesis directly as well. The possibility that stimulating the vagus could suppress or prevent the occurrence of ventricular arrhythmias was first shown over 150 years ago by Einbrodt [77] who used an inductorium to electrically induce VF and demonstrated that it was more difficult to induce VF during vagus nerve stimulation (VNS). This has since been supported by numerous studies illustrating a protective effect of the vagus in the ventricles, but many of these studies are in vivo or involve proarrhythmic triggers such ischemia making interpretation of direct antifibrillatory effects difficult. The few studies on the latter, however, do support a vagus-mediated anti-VF protection [78, 79].
The early studies in un-diseased myocardium illustrate that VNS significantly increased VFT [80]. These data were, however, in vivo and it is unclear if there was adequate β-blockade, and as such these data may reflect indirect effects. Using the innervated rabbit heart preparation [45], the effects of VNS on electrical restitution and VFT were studied. VNS caused a flattening of the electrical restitution slope while simultaneously increasing VFT [49] with prolongation of monophasic APD and effective refractory period (see Fig. 5.12). VFT was inversely correlated with the slope of the electrical restitution curve, in keeping with the restitution hypothesis, and the effects occurred in the absence of background sympathetic tone strongly supporting a direct anti-arrhythmic action.
VNS, Ventricular Arrhythmias, and Coronary Artery Occlusion (CAO) CAO and the restoration of blood flow (reperfusion) are well-known triggers of arrhythmia and are a major cause of fatality during and after an infarct. There is, however, evidence from in vivo studies under anesthesia in experimentally induced VF that VNS is protective under these conditions [81–83]. Conversely, bilateral vagotomy or atropine perfusion increases arrhythmic mortality in anesthetized cats during [84] and following CAO [85].
K.E. Brack and G.A. Ng
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Fig. 5.12 Nitric oxide mediates the anti-arrhythmic effect of vagus nerve stimulation (VNS). (a, b) The effect of vagus nerve stimulation on electrical restitution (a) and the restitution slope (b) and how this effect is abolished by perfusion with NG-nitro-L-arginine (L-NA) and restored by L-arginine (L-ARG). (c–e) The effect of L-NA and L-NA and L-Arg on VNSinduced changes in restitution slope, effective refractory period (ERP), and ventricular fibrillation threshold (VFT) respectively (Reproduced with permission from Brack et al. [89])
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Studies in a Canine Model of SCD To overcome the confounding influence of anesthetics in experimental animal studies, Peter Schwartz developed a model of SCD in conscious dogs [86]. In this model, a myocardial infarct is produced via a left anterior descending coronary artery ligation, and animals are instrumented with a balloon (to occlude the left circumflex artery at a later date). Animals are allowed to recover for 1 month, and surviving animals then have exercise test and during the last minute of exercise, the left circumflex artery is occluded for a period of 2 min. This combination of adrenergic activation and myocardial ischemia results in a reproducible and quantifiable measure of SCD, with VF occurring in 50–60 % of all postMI dogs [36]. In the majority of dogs that survived, there was a reduction in heart rate, suggesting that active vagal reflexes are protective and were later confirmed when De Ferrari et al. [37] directly measured BRS and demonstrated that protection was significantly associated with indirect measures of preserved vagal reflexes.
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Mechanisms Underlying the Anti-arrhythmic Effect of Vagus Nerve Stimulation, Heart Rate Reduction, and Ventricular Refractoriness An obvious aspect to consider for VNS is the resultant bradycardia. Reducing heart rate using the If blocker ivabradine increases VFT [87], suggesting that the effect of VNS may be due to heart rate. Indeed, the protective effect of VNS from CAO was either reduced [83] or abolished [86] when heart rate was controlled. In the dog model of SCD, VNS prevented VF in 55 % of animals that were rate controlled vs. 92 % of control dogs in sinus rhythm, suggesting that bradycardia “is important but not essential” [86]. The mechanism whereby a reduction in rate protects from arrhythmias is not entirely clear, but may include rate-dependent alterations in APD, refractoriness, and dispersion of both factors. It is recognized that VNS prolongs ventricular APD and ERP [49, 88–90], which are inversely correlated to heart rate, and that slower heart rates decrease the dispersion during ischemia [79]. Nevertheless, vagal stimulation provides substantial
5
Autonomic Control of Cardiac Arrhythmia
heart rate independent protection against VF in ischemic hearts [79] and un-diseased hearts using the innervated heart preparation [49].
Accentuated Antagonism In the intact organism, both divisions of the autonomic system are tonically active. At rest, vagal tone predominates with sympathetic tone predominating during the day. In disease situation such as myocardial ischemia and heart failure, activity of both systems is disturbed (see earlier). This is important because sympathetic and parasympathetic nerves interact with one another. Samaan first illustrated that VNS reduced the heart rate effect of SNS [91], later termed “accentuated antagonism” [92]. Accentuated antagonism also occurs in the control of ventricular performance [93] and arrhythmogenesis. Kolman et al. [80] demonstrated that VNS protection was only evident during simultaneous SNS. Similarly, the anti-arrhythmic effect of the cholinergic agonist methylcholine was augmented during norepinephrine perfusion [94]. Interestingly, the protective effect of VNS was reported to be abolished during CAO and propranolol administration [78], although this is at odds with other studies. The abolition of VNS-mediated protection during ischemia may however imply that sympathetic activity could reduce the effect of the vagus, because reflex sympathetic activity is increasing during this ischemic period. At the cellular level, interaction between sympathetic and vagal nerves can occur in 2 forms: via pre- and/or postjunctional mechanisms. As an example, for effects of vagal activity on sympathetic stimulation, ACh binds to muscarinic acetylcholine receptors (mAChRs), primarily the M3 subtype present on the presynaptic sympathetic nerve terminals to inhibit noradrenaline release and principally the M2 subtype on cardiac myocytes to modulate intracellular cAMP at a number of stages [95]. Conversely, the release and hence downstream effects of vagal stimulated via ACh release can be modulated postsynaptically by sympathetic activity through noradrenaline and co-released neuropeptide Y (NPY) [96, 97].
Muscarinic Receptor Activation and Nitric Oxide (NO) mAChRs are activated by ACh and there are five subtypes (m1–5). A reduction of arrhythmia protection using the mAChR antagonist atropine suggests that mAChR activation is key. In autonomically intact dogs, spontaneous ischemiainduced VF increased in vivo following IV atropine [82], with similar conclusions drawn from control experiments in the dog model of SCD [86, 88]. This is supported by data during direct VNS where atropine abolished protection
55
[78, 88]. The mAChR agonist choline is cardioprotective against ischemia-induced arrhythmias, an effect that is blocked by the m3AChR antagonist 4-DAMP [98]. Despite these convincing studies illustrating a near total abolition of vagal protection in the presence of atropine, studies in the un-diseased innervated heart preparation suggest otherwise. In this work, the vagus-mediated bradycardia and prolongation of effective refractory period were blocked by atropine, but the anti-VF effect during VNS was not [99]. Instead, the vagal protection was abolished using the nonspecific NO synthase inhibitor L-NA, suggesting that NO and not ACh is important and is supported by data where L-arginine [89] (a substrate for NO synthesis) reversed the inhibition of L-NA (Fig. 5.12). Direct evidence of vagally mediated NO release has since been reported using the fluorescent indicator DAF-2 confirming that neuronal NO synthase (nNOS) mediates the release of NO [100] (Fig. 5.13). In addition, the protective effect of vagally released NO is supported by data using NO donors. Nitroglycerine epicardially applied during CAO [101] or sodium nitroprusside perfusion [102] during experimentally induced VF in un-diseased hearts mimics the effect of VNS. More importantly, data using the innervated heart preparation [99] rule out any influence from the coronary endothelium, a significant large source of NO, or vasoactive intestinal peptide (VIP) which is released alongside ACh [103]. It has been suggested that vagally released ACh and NO can act through parallel independent signaling pathways [104]. Given that NO production and protection during VNS occur through nNOS in a manner independent of the endothelium, VIP, or ACh, the possibility of separate parasympathetic–nitrergic antifibrillatory neurons in the ventricle has been suggested [105]. In support of this, nNOS is present in many intrinsic parasympathetic neurons [106] with a subpopulation of NO-only-containing fibers shown to course towards the ventricle [107].
Anti-inflammatory Action Over the past 15 years, it has become increasingly evident that the inflammatory response is under control by the autonomic nervous system in a process termed “the inflammatory reflex” [108]. Upon activation, locally released inflammatory cytokines such as tumor necrosis factor (TNF) activate sensory nerves relaying information to central processes. After processing, efferent activity is altered to regulate the injury response. Vagotomy not only augments the cytokine response to injury but HRV is also inversely correlated to cytokine levels [109]. Lower levels of cytokines are generally thought to be beneficial to restrict the inflammatory response following myocardial ischemia, HF, and myocarditis—where arrhythmias significantly contribute to mortality.
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K.E. Brack and G.A. Ng
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How the inflammatory reflex regulates arrhythmia is not understood but may involve both direct anti-arrhythmic actions and indirect effects which ameliorate disease-related structural and biochemical phenotypes. VNS improves survival following CAO by reducing infarct size [110] with beneficial increases in myocardial ATP, reduced levels of apoptosis, and cell swelling via inhibition of the mitochondrial permeability transition pore [111]. This is blocked by atropine with subsequent upregulation of TNF-α and activation of the cell survival TNF receptor 2, nuclear factor kappa-B, and pAkt pathways [111]. In macrophages, TNF-α can promote connexin-43 expression and gap junction formation [112]. This could correct ischemia-induced conduction abnormalities and is increased during VNS which was more importantly linked to the protection of ischemia-induced VT [113]. The significance of inflammation in chronic heart failure is somewhat unclear, although serum and cardiac levels of inflammatory cytokines are increased. Their levels are significantly reduced during VNS (reviewed by Li and Olshansky [114]). The reduction of cytokines is suggested to occur through ACh acting on nicotinic ACh receptors (nAChRs), primarily the α-7 subtype, on macrophages [115]. However, α-7 nAChRs are also found on intracardiac nerves and cardiac myocytes [116], raising the possibility that extra-macrophage α-7 nAChRs may be involved in reducing inflammation in addition to mediating the functional effects of autonomic nerves [117].
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Genetic upregulation of cardiac TNF-α is used in experimental HF models, highlighting its pathological significance. These animals show increased arrhythmia including AT, AF, non-sustained VT, and ventricular ectopy [118]. Hearts from these animals had prolonged APD and smaller potassium currents [119, 120] and dysregulated intracellular calcium homeostasis leading to altered contractile function, mirroring those seen in clinical HF. In addition, cytokines indirectly increase arrhythmias by promoting the formation of nonconductive scar and fibrotic tissue [121].
Non-arrhythmic Beneficial Effects of VNS Chronic low-level VNS is of benefit in the treatment of HF by reversing the detrimental effects of HF [122] even at low stimulation intensities insufficient to change heart rate (reviewed by De Ferrari and Schwartz [123] and Sabbah et al. [124]). Clinically, VNS is being tested in two clinical trials, namely, INOVATE-HF [125] and NECTAR-HF [126], and its use in HF is reviewed elsewhere [127]. Conclusions
While it has been acknowledged for a long time that the autonomic nervous system is important in atrial and ventricular arrhythmias, the significant role that they play in
5
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their initiation and maintenance and the possibility that nerve stimulation (as opposed to pharmacological analogue manipulation) could be exploited as a novel therapeutic modality have only received recent attention. Much more needs to be known in relation to the cellular mechanisms and downstream pathways. The autonomic nervous system may hold the key to the prevention and successful treatment of these important arrhythmias.
References 1. Nieuwlaat R, Capucci A, Camm AJ, Olsson SB, Andresen D, Davies DW, Cobbe S, Breithardt G, Le Heuzey JY, Prins MH, Levy S, Crijns HJ. Atrial fibrillation management: a prospective survey in ESC member countries: the Euro Heart Survey on Atrial Fibrillation. Eur Heart J. 2005;26:2422–34. 2. Lloyd-Jones DM, Wang TJ, Leip EP, Larson MG, Levy D, Vasan RS, D’Agostino RB, Massaro JM, Beiser A, Wolf PA, Benjamin EJ. Lifetime risk for development of atrial fibrillation: the Framingham Heart Study. Circulation. 2004;110:1042–6. 3. Priori SG, Aliot E, Blømstrom-Lundqvist C, Bossaert L, Breithardt G, Brugada P, Camm JA, Cappato R, Cobbe SM, Di Mario C, Maron BJ, McKenna WJ, Pedersen AK, Ravens U, Schwartz PJ, Trusz-Gluza M, Vardas P, Wellens HJJ, Zipes DP. Task force on sudden cardiac death, European society of cardiology. Europace. 2002;4:3–18. 4. Atwood C, Eisenberg MS, Herlitz J, Rea TD. Incidence of EMStreated out of hospital cardiac arrest in Europe. Resuscitation. 2005;67:75–80. 5. Ulphani JS, Cain JH, Inderyas F, Gordon D, Gikas PV, Shade G, Mayor D, Arora R, Kadish AH, Goldberger JJ. Quantitative analysis of parasympathetic innervation of the porcine heart. Heart Rhythm. 2010;7:1113–9. 6. Randall WC, Rohse WG. The augmentor action of the sympathetic cardiac nerves. Circ Res. 1956;4(4):470–5. 7. Armour JA. Potential clinical relevance of the little brain on the mammalian heart. Exp Physiol. 2008;93(2):165–76. 8. Ardell JL. Structure and function of mammalian intrinsic cardiac neurons. In: Armour JA, Ardell JL, editors. Neurocardiology. New York: Oxford University Press; 1994. p. 95–114. 9. Bibevski S, Dunlap ME. Ganglionic mechanisms contribute to diminished vagal control in heart failure. Circulation. 1999; 99(22):2958–63. 10. Armour JA, Murphy DA, Yuan BX, Macdonald S, Hopkins DA. Gross and microscopic anatomy of the human intrinsic cardiac nervous system. Anat Rec. 1997;247:289–98. 11. Batulevicius D, Pauziene N, Pauza DH. Architecture and agerelated analysis of the neuronal number of the guinea pig intrinsic cardiac nerve plexus. Anat Rec. 2005;187:225–43. 12. Armour JA, Kember GC. Cardiac sensory neurons. In: Armour JA, Ardell JL, editors. Basic and clinical neurocardiology. New York: Oxford University Press; 2004. p. 79–117. 13. Haissaguerre M, Jais P, Shah DC, Takahashi A, Hocini M, Quiniou G, Garrigue S, Le Mouroux A, Le Metayer P, Clementy J. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. NEJM. 1998;339:659–66. 14. Chen PS, Tan AY. Autonomic nerve activity and atrial fibrillation. Heart Rhythm. 2007;4:S61–4. 15. Shen MJ, Choi EK, Tan AY, Lin SF, Fishbein MV, Chen LS, Chen PS. Neural mechanisms of atrial arrhythmias. Nat Rev. 2012;9:30–9. 16. Scherf D. Studies on auricular tachycardia caused by aconitine administration. Proc Soc Exp Biol Med. 1947;64(2):233–9.
57 17. Page P, Armour JA, Yin Y, Vermeulen M, Nadeau R, Cardinal R. Differential effects of cervical vagosympathetic and mediastinal nerve activation on atrial arrhythmia formation in dogs. Auton Neurosci. 2006;128(1–2):9–18. 18. Lu Z, Scherlag BJ, Lin J, Yu L, Guo JH, Niu G, Jackman WM, Lazzara R, Jiang H, Po SS. Autonomic mechanism for the initiation of rapid firing from atria and pulmonary veins: evidence by ablation of ganglionated plexuses. J Cardiovasc Electrophys. 2009;84(2):245–52. 19. Chiou CW, Eble JN, Zipes DP. Efferent vagal innervation of the canine atria and sinus and atrioventricular nodes. The third fat pad. Circulation. 1997;95(11):2573–84. 20. Sharifov OF, Fedorov VV, Beloshapko GG, Glukhov AV, Yushmanova AV, Rosenshtraukh LV. Roles of adrenergic and cholinergic stimulation in spontaneous atrial fibrillation in dogs. J Am Coll Cardiol. 2004;43(3):483–90. 21. Tan AY, Zhou S, Ogawa M, Song J, Chu M, Li H, Fishbein MC, Lin SF, Chen LS, Chen PS. Neural mechanisms of paroxysmal atrial fibrillation and paroxysmal atrial tachycardia in ambulatory canines. Circulation. 2008;118(9):916–25. 22. Patterson E, Po SS, Scherlag BJ, Lazzara R. Triggered firing in pulmonary veins initiated by in vitro autonomic nerve stimulation. Heart Rhythm. 2005;2(6):624–31. 23. Tan AY, Li H, Wachsmann-Hogiu S, Chen LS, Chen PS, Fishbein MC. Autonomic innervation and segmental muscular disconnections at the human pulmonary vein-atrial junction: implications for catheter ablation of atrial-pulmonary vein junction. J Am Coll Cardiol. 2006;48(1):132–43. 24. Pappone C, Santinelli V, Manguso F, Vicedomini G, Gugliotta F, Augello G, Mazzone P, Tortoriello V, Landoni G, Zangrillo A, Lang C, Tomita T, Mesas C, Mastella E, Alfieri O. Pulmonary vein denervation enhances long-term benefit after circumferential ablation for paroxysmal atrial fibrillation. Circulation. 2004;109(3): 327–34. 25. Ali IM, Bulter CK, Armour JA, Murphy DA. Modification of supraventricular tachyarrhythmias by stimulating atrial neurons. Ann Thorac Surg. 1990;50:251–6. 26. Osman F, Kundu S, Tuan J, Jeilan M, Stafford PJ, Andre NG. Ganglionic plexus ablation during pulmonary vein isolation– predisposing to ventricular arrhythmias? Indian Pacing Electrophysiol J. 2010;10(2):104–7. 27. Li S, Scherlag BJ, Yu L, Sheng X, Zhang Y, Ali R, Dong Y, Ghias M, Po SS. Low-level vagosympathetic stimulation. A paradox and potential new modality for the treatment of focal atrial fibrillation. Circ Arrhyth Electrophysiol. 2009;2:645–51. 28. Sheng X, Scherlag BJ, Yu L, Li S, Ali R, Zhang Y, Fu G, Nakagawa H, Jackson WM, Lazzare R, Po SS. Prevention and reversal of atrial fibrillation inducibility and autonomic remodelling by low-level vagosympathetic nerve stimulation. JACC. 2011;57(5):563–71. 29. Willich SN, Levy D, Rocco MB, Tofler GH, Stone PH, Muller JE. Circadian variation in the incidence of sudden cardiac death in the Framingham Heart Study population. Am J Cardiol. 1987; 60(10):801–6. 30. Bonnemeier H, Richardt G, Potratz J, Wiegand UK, Brandes A, Kluge N, Katus HA. Circadian profile of cardiac autonomic nervous modulation in healthy subjects: differing effects of aging and gender on heart rate variability. J Cardiovasc Electrophysiol. 2003;14(8):791–9. 31. Kleiger RE, Miller JP, Bigger JT, Moss AJ. Decreased heart rate variability and its association with increased mortality after acute myocardial infarction. Am J Cardiol. 1987;59(4):256–62. 32. Bigger JT, Fleiss JL, Steinman RC, Rolnitzky LM, Kleiger RE, Rottman JN. Frequency domain measures of heart period variability and mortality after myocardial infarction. Circulation. 1992;85(1):164–71.
58 33. Nolan J, Batin PD, Andrews R, Lindsay SJ, Brooksby P, Mullen M, Baig W, Flapan AD, Cowley A, Prescott RJ, Neilson JM, Fox KA. Prospective study of heart rate variability and mortality in chronic heart failure: results of the United Kingdom heart failure evaluation and assessment of risk trial (UK-heart). Circulation. 1998;98(15):1510–6. 34. La Rovere MT, Pinna GD, Maestri R, Robbi E, Caporotondi A, Guazzotti G, Sleight P, Febo O. Prognostic implications of baroreflex sensitivity in heart failure patients in the beta-blocking era. J Am Coll Cardiol. 2009;53(2):193–9. 35. La Rovere MT, Bigger JT, Marcus FI, Mortara A, Schwartx PJ. Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarction. ATRAMI (Autonomic Tone and Reflexes After Myocardial Infarction) Investigators. Lancet. 1998;351(9101):478–84. 36. Schwartz PJ, Vanoli E, Stramba-Badiale M, De Ferrari GM, Billman GE, Foreman RD. Autonomic mechanisms and sudden death. New insights from analysis of baroreceptor reflexes in conscious dogs with and without a myocardial infarction. Circulation. 1988;78(4):969–79. 37. De Ferrari GM, Vanoli E, Stramba-Badiale M, Hull Jr SS, Foreman RD, Schwartz PJ. Vagal reflexes and survival during acute myocardial ischemia in conscious dogs with healed myocardial infarction. AJP. 1991;261(1):H63–9. 38. Billman G, Schwartz P, Stone H. Baroreceptor reflex control of heart rate: a predictor of sudden cardiac death. Circulation. 1982;66(4):874–80. 39. Cerati D, Schwartz P. Single cardiac vagal fiber activity, acute myocardial ischemia, and risk for sudden death. Circ Res. 1991;69(5):1389–401. 40. Ishise H, Asanoi H, Ishizaka S, Joho S, Kameyama T, Umeno K, Inoue H. Time course of sympathovagal imbalance and left ventricular dysfunction in conscious dogs with heart failure. J Appl Physiol. 1998;84(4):1234–41. 41. Grassi G, Seravalle G, Bertinieri G, Turri C, Stella ML, Scopelliti F, Mancia G. Sympathetic and reflex abnormalities in heart failure secondary to ischaemic or idiopathic dilated cardiomyopathy. Clin Sci (Lond). 2001;101(2):141–6. 42. Schwartz PJ. The autonomic nervous system and sudden death. Eur Heart J. 1998;19(F):F72–80. 43. Zhou S, Jung BC, Tan AY, Trang VQ, Gholmieh G, Han SW, Lin SF, Fishbein MC, Chen PS, Chen LS. Spontaneous stellate ganglion nerve activity and ventricular arrhythmia in a canine model of sudden death. Heart Rhythm. 2008;5(1):131–9. 44. Piccirillo G, Magrì D, Ogawa M, Song J, Chong VJ, Han S, Joung B, Choi EK, Hwang S, Chen LS, Lin SF, Chen PS. Autonomic nervous system activity measured directly and QT interval variability in normal and pacing-induced tachycardia heart failure dogs. J Am Coll Cardiol. 2009;54(9):840–50. 45. Garfinkel A, Kim YH, Voroshilovsky O, Qu Z, Kil JR, Lee MH, Karagueuzian HS, Weiss JN, Chen PS. Preventing ventricular fibrillation by flattening cardiac restitution. Proc Natl Acad Sci. 2000;97(11):6061–6. 46. Nolasco JB, Dahlen RW. A graphic method for the study of alternation in cardiac action potentials. J Appl Physiol. 1968;25(2): 191–6. 47. Gilmour RF, Chialvo DR. Electrical restitution, critical mass, and the riddle of fibrillation. J Cardiovasc Electrophysiol. 1999;10(8): 1087–9. 48. Ng GA, Brack KE, Coote JH. Effects of direct sympathetic and vagus nerve stimulation on the physiology of the whole heart–a novel model of isolated Langendorff perfused rabbit heart with intact dual autonomic innervation. Exp Physiol. 2001;86(3):319–29. 49. Ng GA, Brack KE, Patel VH, Coote JH. Autonomic modulation of electrical restitution, alternans and ventricular fibrillation initiation in the isolated heart. Cardiovasc Res. 2007;73(4):750–60.
K.E. Brack and G.A. Ng 50. Taggart P, Sutton P, Chalabi Z, Boyett MR, Simon R, Elliott D, Gill JS. Effect of adrenergic stimulation on action potential duration restitution in humans. Circulation. 2003;107(2):285–9. 51. Ardell JL, Randall WC, Cannon WJ, Schmacht DC, Tasdemiroglu E. Differential sympathetic regulation of automatic, conductile, and contractile tissue in dog heart. AJP. 1988;255:H1050–9. 52. Haws CW, Burgess MJ. Effects of bilateral and unilateral stellate stimulation on canine ventricular refractory periods at sites overlapping innervation. Circ Res. 1978;42(2):195–8. 53. Yanowitz F, Preston JB, Abildskov JA. Functional distribution of right and left stellate innervation to the ventricles. Production of neurogenic electrocardiographic changes by unilateral alteration of sympathetic tone. Circ Res. 1966;18(4):416–28. 54. Schwartz PJ, Snebold NG, Brown AM. Effects of unilateral cardiac sympathetic denervation on the ventricular fibrillation threshold. Am J Cardiol. 1976;37(7):1034–40. 55. Hanich RF, Levine JH, Spear JF, Moore EN. Autonomic modulation of ventricular arrhythmia in cesium chloride-induced long QT syndrome. Circulation. 1988;77(5):1149–61. 56. Priori S, Mantica M, Schwartz PJ. Delayed afterdepolarizations elicited in vivo by left stellate ganglion stimulation. Circulation. 1988;78(1):178–85. 57. Winter J, Tanko AS, Brack KE, Ng GA. Differential cardiac responses to unilateral sympathetic nerve stimulation in the isolated innervated rabbit heart. Auton Neurosci. 2010;166:4–14. 58. Schwartz PJ. Prevention of sudden cardiac death after a first myocardial infarction by pharmacologic or surgical antiadrenergic interventions. JCE. 1992;3(1):2–16. 59. Wilde AA, Bhuiyan ZA, Crotti L, Facchini M, De Ferrari GM, Paul T, Ferrandi C, Koolbergen DR, Odero A, Schwartz PJ. Left cardiac sympathetic denervation for catecholaminergic polymorphic ventricular tachycardia. NEJM. 2008;358(19):2024–9. 60. Bourke T, Vaseghi M, Michowitz Y, Sankhla V, Shah M, Swapna N, Boyle NG, Mahajan A, Narasimhan C, Lokhandwala Y, Shivkumar K. Neuraxial modulation for refractory ventricular arrhythmias: value of thoracic epidural anaesthesia and surgical left cardiac sympathetic denervation. Circulation. 2010;121(21): 2255–62. 61. Dahlström A, Mya-Tu M, Fuxe K, Zetterström BE. Observations on adrenergic innervation of dog heart. Am J Physiol. 1965;209(4): 689–92. 62. Kawano H, Okada R, Yano K. Histological study on the distribution of autonomic nerves in the human heart. Heart Vessels. 2003;18(1):32–9. 63. Mantravadi R, Gabris B, Liu T, Choi BR, de Groat WC, Ng GA, Salama G. Autonomic nerve stimulation reverses ventricular repolarization sequence in rabbit hearts. Circ Res. 2007;100(7):e72–80. 64. Han J, Moe GK. Nonuniform recovery of excitability in ventricular muscle. Circ Res. 1964;14:44–60. 65. Ng GA, Mantravadi R, Walker WH, Ortin WG, Choi BR, de Groat W, Salama G. Sympathetic nerve stimulation produces spatial heterogeneities of action potential restitution. Heart Rhythm. 2009;6(5):696–706. 66. Kuo CS, Munakata K, Reddy CP, Surawicz B. Characteristics and possible mechanism of ventricular arrhythmia dependent on the dispersion of action potential durations. Circulation. 1983;67(6): 1356–67. 67. Laurita KR, Girouard SD, Akar FG, Rosenbaum DS. Modulated dispersion explains changes in arrhythmia vulnerability during premature stimulation of the heart. Circulation. 1998;98(24):2774–80. 68. Zhang C, Xu D, Li Y, Liu N, Wang L, Lu Z. Effect of autonomic nervous system on the transmural dispersion of ventricular repolarization in intact canine. J Huazhong Univ Sci Technolog Med Sci. 2004;24(1):37–40. 69. Volders PG, Stengl M, van Opstal JM, Gerlach U, Spätjens RL, Beekman JD, Sipido KR, Vos MA. Probing the contribution of
5
Autonomic Control of Cardiac Arrhythmia
70.
71.
72.
73.
74. 75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
87.
IKs to canine ventricular repolarization. Key role of β-adrenergic receptor stimulation. Circulation. 2003;107:2753–60. Schwartz PJ, Priori SG, Cerrone M, Spazzolini C, Odero A, Napolitano C, Bloise R, De Ferrari GM, Klersy C, Moss AJ, Zareba W, Robinson JL, Hall WJ, Brink PA, Toivonen L, Epstein AE, Li C, Hu D. Left cardiac sympathetic denervation in the management of high risk patients affected by long QT syndrome. Circulation. 2004;109:1826–33. Rysevaite K, Saburkina I, Pauziene N, Vaitkevicius R, Noujaim SF, Jalife J, Pauza DH. Immunohistochemical characterization of the intrinsic cardiac neural plexus in whole-mount mouse heart preparations. Heart Rhythm. 2011;8(5):731–8. Batulevicius D, Pauziene N, Pauza DH. Architecture and agerelated analysis of the neuronal number of the guinea pig intrinsic cardiac nerve plexus. Ann Anat. 2005;187(3):225–43. Johnson TA, Gray AL, Lauenstein JM, Newton SS, Massari VJ. Parasympathetic control of the heart. I. An interventriculo-septal ganglion is the major source of the vagal intracardiac innervation of the ventricles. J Appl Physiol. 2004;96(6):2265–72. Taggart P, Critchley H, Lambiase PD. Heart-brain interactions in cardiac arrhythmia. Heart. 2011;97:698–708. Saburkina I, Rysevaite K, Pauziene N, Mischke K, Schauerte P, Jalife J, Pauza DH. Epicardial neural ganglionated plexus of ovine heart: anatomic basis for experimental cardiac electrophysiology and nerve protective cardiac surgery. Heart Rhythm. 2010;7(7): 942–50. Pauza DH, Skripka V, Pauziene N, Stropus R. Morphology, distribution, and variability of the epicardiac neural ganglionated subplexuses in the human heart. Anat Rec. 2000;259(4):353–82. Einbrodt E. Ueber Herzreizung und ihr Verhaeltnis zum Blutdruck. Akademie der Wissenschaften (Vienna) Sitzungsberichte. 1859; 38:345. Yoon MS, Han J, Tse WW, Rogers R. Effects of vagal stimulation, atropine, and propranolol on fibrillation threshold of normal and ischemic ventricles. Am Heart J. 1977;93(1):60–5. Kent KM, Smith ER, Redwood DR, Epstein SE. Electrical stability of acutely ischemic myocardium. Influences of heart rate and vagal stimulation. Circulation. 1973;47(2):291–8. Kolman B, Verrier R, Lown B. The effect of vagus nerve stimulation upon vulnerability of the canine ventricle: role of sympatheticparasympathetic interactions. Circulation. 1975;52(4):578–85. Scherlag BJ, Helfant RH, Haft JI, Damato AN. Electrophysiology underlying ventricular arrhythmias due to coronary ligation. Am J Physiol. 1970;219(6):1665–71. Goldstein RE, Karsh RB, Smith ER, Orlando M, Norman D, Farnham G, Redwood DR, Epstein SE. Influence of atropine and of vagally mediated bradycardia on the occurrence of ventricular arrhythmias following acute coronary occlusion in closed-chest dogs. Circulation. 1973;47(6):1180–90. Waxman H, Cain M, Greenspan A, Josephson M. Termination of ventricular tachycardia with ventricular stimulation: salutary effect of increased current strength. Circulation. 1982;65(4): 800–4. Corr PB, Gillis RA. Role of the vagus nerves in the cardiovascular changes induced by coronary occlusion. Circulation. 1974;49(1): 86–97. Zuanetti G, De Ferrari GM, Priori SG, Schwartz PJ. Protective effect of vagal stimulation on reperfusion arrhythmias in cats. Circ Res. 1987;61:429–35. Schwartz PJ, Billman GE, Stone HL. Autonomic mechanisms in ventricular fibrillation induced by myocardial ischemia during exercise in dogs with healed myocardial infarction. An experimental preparation for sudden cardiac death. Circulation. 1984;69(4):790–800. Vaillant F, Timour Q, Descotes J, Manati W, Belhani D, Bui-Xuan B, Tabib A, Bricca G, Chevalier P. Ivabradine induces an increase
59
88.
89.
90.
91. 92. 93.
94.
95.
96. 97.
98.
99.
100.
101.
102.
103. 104.
105.
in ventricular fibrillation threshold during acute myocardial ischemia: an experimental study. J Cardiovasc Pharmacol. 2008;52(6): 548–54. Vanoli E, De Ferrari GM, Stramba-Badiale M, Hull Jr SS, Foreman RD, Schwartz PJ. Vagal stimulation and prevention of sudden death in conscious dogs with a healed myocardial infarction. Circ Res. 1991;68(5):1471–81. Brack KE, Patel VH, Coote JH, Ng GA. Nitric oxide mediates the vagal protective effect on ventricular fibrillation via effects on action potential duration restitution in the rabbit heart. J Physiol. 2007;583:695–704. Martins JB, Zipes DB. Effects of sympathetic and vagal nerves on recovery properties of the endocardium and epicardium of the canine left ventricle. Circ Res. 1980;46(1):100–10. Samaan A. Antagonistic cardiac nerves and heart rate. J Physiol. 1935;83:332–40. Levy MN. Sympathetic and parasympathetic interactions of the heart. Circ Res. 1971;29:437–45. Brack KE, Coote JH, Ng GA. Vagus nerve stimulation inhibits the increase in the Ca2+ transient and left ventricular force caused by sympathetic nerve stimulation but has no direct effects alone – epicardial Ca2+ fluorescence studies using fura-2 AM in the isolated innervated beating rabbit heart. Exp Physiol. 2010;95(1): 80–92. Rabinowitz S, Verrier R, Lown B. Muscarinic effects of vagosympathetic trunk stimulation on the repetitive extrasystole (RE) threshold. Circulation. 1976;53(4):622–7. Muscholl E. Peripheral muscarinic control of norepinephrine release in the cardiovascular system. Am J Physiol. 1980;239(6): H713–20. Potter EK. Neuropeptide Y, as an autonomic neurotransmitter. Pharmacol Ther. 1988;37(2):251–73. Herring N, Lokale MN, Danson EJ, Heaton DA, Paterson DJ. Neuropeptide Y reduces acetylcholine release and vagal bradycardia via a Y2 receptor-mediated, protein kinase C-dependent pathway. JMCC. 2008;44(3):477–85. Wang S, Han H, Jiang Y, Wang C, Song H, Pan Z, Du J, Fan Y, Du Z, Liu Y. Activation of cardiac M3 muscarinic acetylcholine receptors has cardioprotective effects against ischaemiainduced arrhythmia. Clin Exp Pharm Physiol. 2012. doi:10.111/j. 1440-1681.2012.05672.x. Brack KE, Coote JH, Ng GA. Vagus nerve stimulation protects against ventricular fibrillation independent of muscarinic receptor activation. Cardiovasc Res. 2010;91(3):437–46. Brack KE, Patel VH, Mantravardi R, Coote JH, Ng GA. Direct evidence of nitric oxide release from neuronal nitric oxide synthase activation in the left ventricle as a result of cervical vagus nerve stimulation. J Physiol. 2009;587(Pt 12):3045–54. Kumar K, Nguyen K, Waxman S, Nearing BD, Wellenius GA, Zhao SX, Verrier RL. Potent antifibrillatory effects of intrapericardial nitro-glycerine in the ischemic porcine heart. JACC. 2003;41(10):1831–7. Patel VH, Brack KE, Kundu S, Coote JH, Ng GA. The effect of nitric oxide on electrical restitution and ventricular fibrillation in the isolated rabbit heart: mechanism underlying the antifibrillatory effects of vagus nerve activity. Eur Heart J. 2004;25(Supp. 1):68 [abstract]. Henning RJ, Sawmiller DR. Vasoactive intestinal peptide: cardiovascular effects. Cardiovasc Res. 2001;49(1):27–37. Jumrussirikul P, Dinerman J, Dawson TM, Dawson VL, Ekelund U, Georgakopoulos D, Schramm LP, Calkins H, Snyder SH, Hare JM, Berger RD. Interaction between neuronal nitric oxide synthase and inhibitory G protein activity in heart rate regulation in conscious mice. JCE. 1998;102(7):1279–85. Jones JF. Cardiac defibrillator neurones. J Physiol. 2009;587 (Pt 12):2715.
60 106. Singh S, Gray T, Wurster RD. Nitric oxide and carbon monoxide synthesizing enzymes and soluble guanylyl cyclase within neurons of adult human cardiac ganglia. Auton Neurosci. 2009;145(1–2):93–8. 107. Hoover DB, Isaacs ER, Jaques F, Hoard JL, Page P, Armour JA. Novel neurotransmitters of the human intrinsic cardiac nervous system. Neuroscience. 2009;164(3):1170–9. 108. Tracey KJ. The inflammatory reflex. Nature. 2001;420:853–9. 109. Sloan RP, McCreath H, Tracey KJ, Sidney S, Liu K, Seeman T. RR interval variability is inversely related to inflammatory markers: the CARDIA study. Mol Med. 2007;13(3–4):178–84. 110. Katare RG, Anod M, Kakinuma Y, Arikawa M, Handa T, Yamasaki F, Sato T. Vagal stimulation prevents reperfusion injury through inhibition of opening of mitochondrial permeability transition pore independent of the bradycardia effect. J Thoraci Cardiovasc Surg. 2009;137(1):223–30. 111. Katare RG, Ando M, Kakinuma Y, Arikawa M, Yamasaki F, Sato T. Differential regulation of TNF receptors by vagal nerve stimulation protects heart against acute ischemic injury. JMCC. 2010;49(2):234–44. 112. Eugenin EA, Branes MC, Berman J, Saez JC. TNF- αplus IFN-γ induce connexin43 expression and formation of gap junctions between human monocytes/macrophages that enhance physiological responses. J Immunol. 2003;170:1320–8. 113. Ando M, Katare RG, Kakinuma Y, Zhang D, Yamasaki F, Muramoto K, Sato T. Efferent vagal nerve stimulation protects heart against ischemia induced arrhythmia by preserving connecix43 expression. Circulation. 2005;112:164–70. 114. Li W, Olshansky B. Inflammatory cytokines and nitric oxide in heart failure and potential modulation by vagus nerve stimulation. Heart Fail Rev. 2011;16(2):137–45. 115. Wang H, Yu M, Ochani M, Amella CA, Tanovic M, Susarla S, Li JH, Wang H, Yang H, Ulloa L, Al-Abed Y, Czura CJ, Tracey KJ. Nicotinic acetylcholine receptor [alpha]7 subunit is an essential regulator of inflammation. Nature. 2003;421(6921):384–8. 116. Dvorakova M, Lips KS, Bruggmann D, Slavikova J, Kuncova J, Kummer W. Developmental changes in the expression of nicotinic acetylcholine receptor α-subunits in the rat heart. Cell Tissue Res. 2005;319:201–9.
K.E. Brack and G.A. Ng 117. Deck J, Bibevski S, Gnecchi-Ruscone T, Bellina V, Montano N, Dunlap ME. α7-nicotinic acetylcholine receptor subunit is not required for parasympathetic control of the heart in the mouse. Physiol Genomics. 2005;22:86–92. 118. London B, Baker LC, Lee JS, Shusterman V, Choi BR, Kubota T, McTiernan CF, Feldman AM, Salama G. Calcium-dependent arrhythmias in transgenic mice with heart failure. AJP. 2003;284(2):H431–41. 119. Janczewski AM, Kadokami T, Lemster B, Frye CS, McTiernan CF, Feldman AM. Morphological and functional changes in cardiac myocytes isolated from mice overexpressing TNF-alpha. AJP. 2003;284(3):H960–9. 120. Petkova-Kirova PS, Gursoy E, Mehdi H, McTiernan CF, London B, Salama G. Electrical remodeling of cardiac myocytes from mice with heart failure due to the overexpression of tumor necrosis factor-alpha. AJP. 2006;290(5):H2098–107. 121. Klein RM, Vester EG, Brehm MU, Dees H, Picard F, Niederacher D, Beckmann MW, Strauer BE. Inflammation of the myocardium as an arrhythmia trigger. Z Kardiol. 2000;89 Suppl 3: 24–35. 122. Li M, Zheng C, Sato T, Kawada T, Sugimachi M, Sunagawa K. Vagal nerve stimulation markedly improves long-term survival after chronic heart failure in rats. Circulation. 2004;109(1): 120–4. 123. De Ferrari GM, Schwartz PJ. Vagus nerve stimulation: from preclinical to clinical application: challenges and future directions. Heart Fail Rev. 2011;16(2):195–203. 124. Sabbah HN, Ilsar I, Zaretsky A, Rastogi S, Wang M, Gupta RC. Vagus nerve stimulation in experimental heart failure. Heart Fail Rev. 2011;16(2):171–8. 125. http://clinicaltrials.gov/ct2/show/NCT01385176?term=NECTAR &rank=1. 126. http://clinicaltrials.gov/ct2/show/NCT01303718?term=INOVATE &rank=1. 127. Olshansky B, Sabbah HN, Hauptman PJ, Colucci WS. Parasympathetic nervous system and heart failure. Pathophysiology and potential implications for therapy. Circulation. 2008;118: 863–71.
6
Neural Mechanisms of Arrhythmia Hyung-Wook Park and Jeong-Gwan Cho
Abstract
Cardiac autonomic nervous system consists of extrinsic (sympathetic and parasympathetic) and intrinsic (ganglionated plexus concentrated within epicardial fat pads) components. Complex interactions exist between the sympathetic and parasympathetic nervous system on the atrial and ventricular electrophysiologic properties. Disturbed autonomic nervous “balance” of the sympathetic and parasympathetic nerve activity to the heart potentiates the development of arrhythmia. The intrinsic nervous system is thought to be able to function independently and fulfill a number of important interactive and modulatory functions including modulation of arrhythmia substrate. Modulating autonomic tone by ablating or stimulating extrinsic and intrinsic nervous system is emerging as a promising novel therapy in cardiac arrhythmia. Further studies will determine if this new method can be used as an effective means of treating some forms of clinical arrhythmia. Keywords
Autonomic • Nerve • Arrhythmia • Mechanism
Role of Autonomic Nervous System in Cardiac Arrhythmia The heart is an organ with an intrinsic nervous system that is readily called as a “little brain” (Fig. 6.1) [1]. Through a complex hierarchy of feedback control circuits, afferent and efferent neurons communicate in ganglia. These reside in the heart (intrinsic cardiac ganglia) and outside the heart in the chest cavity (intrathoracic extracardiac ganglia or extrinsic cardiac ganglia). More than seven regions with intrinsic ganglia have been identified in the large mammalian heart, around at the level of the atria and atrioventricular ring. Although the heart is under continuous influence of the central nervous system,
H.-W. Park, MD, PhD • J.-G. Cho, MD, PhD (*) Department of Cardiovascular Medicine, Chonnam National University Hospital, Jebongro 42, Donggu, Gwangju, South Korea e-mail:
[email protected] A.S. Kibos et al. (eds.), Cardiac Arrhythmias, DOI 10.1007/978-1-4471-5316-0_6, © Springer-Verlag London 2014
the cardiac intrinsic nervous system is known to have autonomy. This means that intrinsic cardiac ganglia can operate independently to some extent [2]. Changes in autonomic tone influence cardiac electrophysiologic properties. Ventricular tachyarrhythmia is often sympathetically dependent in structural heart disease, whereas paroxysmal atrial fibrillation seems to be vagally mediated in young individuals without structural disease. Before the molecular genetic era, the adrenergic dependence of ventricular arrhythmias was often explained by the sympathetic imbalance theory, which claimed that the left and right components of cardiac sympathetic innervations may not be uniformly distributed in the heart. In the past a few decades, our insights into the functional anatomy and molecular characteristics of the cardiac autonomic nervous system have been greatly advanced. Despite this the mechanisms of sympathetic-triggered arrhythmias in individual patients remain largely obscure. Mainstream therapies such as adrenergic receptor blockade, catheter ablation, and/or implantable cardiac defibrillators, although often successful in suppressing symptoms and preventing/converting 61
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Higher center Afferent neurons Dorsal root and nodose ganlia
CNS
Medulla Spinal cord neurons
Local circuit neurons
Efferent sympathetic neurons
Intrathoracic extracardiac ganglia
Afferent neurons
Local circuit neurons Efferent sympathetic neurons
Efferent parasympathetic neurons Afferent neurons
Intrinsic cardiac ganglia
Circulating catecholamines
Heart
Fig. 6.1 Proposed model for the cardiac neuronal hierarchy that emphasizes its intrathoracic components. The regional cardiac mechanosensory and chemosensory milieu is transduced by afferent neuronal somata located not only in nodose and dorsal root ganglia but also in intrathoracic intrinsic and extrinsic cardiac ganglia. This information
engenders intrathoracic as well as central (medullary and spinal cord) reflexes. The lower right-hand box indicates that circulating catecholamines influence cardiomyocytes not only directly but also indirectly via intrinsic cardiac adrenergic neurons (Source: Armour [1]. Reproduced with permission)
arrhythmia, are not mechanism specific and can have important side effects. Clinically, alterations of autonomic tone, involving the sympathetic and parasympathetic nervous systems, are implicated in initiating atrial and ventricular arrhythmia. Sympathetic and parasympathetic nerves are located closely together around the heart, especially arrhythmogenic foci like the human pulmonary veins. A shift toward an increase in sympathetic tone or toward a loss of vagal tone has been observed before postoperative paroxysmal AF, before the onset of atrial flutter, and before paroxysmal AF occurring during sleep, whereas a shift toward vagal predominance was observed in young patients with lone AF and nocturnal episodes of paroxysmal AF [3].
the paroxysmal autonomic nerve system (ANS) discharge. Prior studies have demonstrated that the cardiac ANS plays a critical role in the dynamics of arrhythmia initiation and maintenance. Hyperactivity of the intrinsic cardiac ANS causes the release of excessive amounts of acetylcholine and catecholamines and may lead to rapid firing from pulmonary veins in paroxysmal atrial fibrillation or Purkinje fiber of ventricular myocytes (Fig. 6.2). An animal model of paroxysmal AF is necessary to test the hypothesis that spontaneous ANS discharges can serve as triggers of paroxysmal AF. Tan et al. [4] implanted Data Sciences International (DSI, St Paul, Minnesota, USA) transmitters to directly record left stellate ganglion nerve activity, left vagal nerve activity, and left atrium local bipolar electrograms or surface electrocardiography simultaneously in ambulatory dogs over several weeks. The authors found that simultaneous sympathovagal discharges were the most common triggers of paroxysmal atrial tachycardia and paroxysmal AF. Sharifov et al. [5] reported that combined isoproterenol and acetylcholine infusion is more effective than acetylcholine alone in the induction of atrial fibrillation. These results suggest that simultaneous sympathetic and parasympathetic (sympathovagal) discharge is particularly profibrillatory.
Sympathetic–Parasympathetic and Extrinsic–Intrinsic Cardiac Autonomic Nervous System Interaction The close interaction between nerve structures and myocytes likely plays a role in the generation of ectopic activities. The exact mechanisms by which the arrhythmogenic foci are triggered remain elusive. One possible immediate trigger is
6
Neural Mechanisms of Arrhythmia
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NICOTINE INJECTION
RAGP DAGP LAGP IVC-IAGP RVGP
heat rate effects tachycardia post-bradycardia atrial tachydysrhythmias AV nodal block
13/13 8/13 0/13 7/11
7/8 2/8 2/8 3/6
5/10 2/10 1/10 2/9
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SVC PA CMVPG
PA LA
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RA
DAGP CS
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IVC-IAGP IVC
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Fig. 6.2 The influence that nicotine-sensitive neurons located in major atrial and ventricular cardiac ganglionated plexuses exert on select canine cardiac indices. Note that atrial tachydysrhythmias were induced by nicotine-sensitive neuronal somata within the dorsal and left atrial as well as cranial ventricular ganglionated plexuses. Abbreviations: RAGP right atrial ganglionated plexus, DAGP dorsal atrial ganglionated
plexus, LAGP left atrial ganglionated plexus, IVC–IAGP inferior vena cava–inferior atrial ganglionated plexus, RVGP right ventricular ganglionated plexus, VSVGP ventral septal ventricular ganglionated plexus, CMVGP cranial medial ventricular ganglionated plexus (Source: Armour [1]. Reproduced with permission)
The extrinsic and intrinsic cardiac ANS can function interdependently as well as independently; that is, each system can modulate the activity of the other through efferent and afferent connections. Also, there is evidence for heightened atrial sympathetic innervations in patients who have persistent AF, suggesting that potential autonomic substrate modification may serve as part of a remodeled atrial substrate for atrial fibrillation maintenance. Chronic rapid atrial pacing increases the innervations of the atrial sympathetic nerve system, which may play a role in the pacing-induced AF. These results suggest that the remodeling of intrinsic cardiac ANS may be involved in AF perpetuation. Prior studies have implied that interactions between the extrinsic cardiac nerve activity (ECNA) and intrinsic cardiac nerve activity (ICNA) may have a significant impact on cardiac electrophysiology.
during long-term follow-up. In catecholaminergic polymorphic VT or after first myocardial infarction, left stellectomy also holds promise as antiarrhythmic therapy, but reported patient numbers are limited and there is little information regarding treatment failures. In any case, the success stories of left cardiac sympathetic denervation stress the significance of sympathetic imbalance for VT/ventricular fibrillation. Myocardial infarction results in heterogeneous loss of efferent sympathetic innervations in noninfarcted apical sites as early as 5–10 min after coronary occlusion, with more complete denervation occurring over time. This denervation process is followed by neural remodeling characterized by nerve sprouting and heterogeneous sympathetic hyperinnervation throughout the myocardium. Although the magnitude of nerve sprouting varies from subjects to subject, there is an association between the density of sympathetic nerves and occurrence of cardiac arrhythmia. Rapid pacing also causes significant neural remodeling characterized by heterogeneous increase of sympathetic innervations and extensive nerve sprouting. These results further support the hypothesis that ANS activity is important in the generation of paroxysmal AF. In both clinical and experimental studies, initiation and perpetuation of arrhythmia have been shown to be mediated at least in part by the ANS activation. Both parasympathetic and sympathetic stimulation have been demonstrated to be proarrhythmic in
Structural and Functional Remodeling and Modulation of Autonomic Nerve Activity Although the sympathetic imbalance theory has been relegated by many investigators with the rise of the molecular genetic era in the 1990s, the success of surgical left cardiac sympathetic denervation in high-risk patients with long-QT syndrome is widely recognized [6, 7]. Still, this therapy may not be entirely effective in preventing all cardiac events
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the atrium and ventricle through refractory period shortening and increased heterogeneity of repolarization. It appears that structural remodeling of AF may lead to conduction heterogeneity in the atrium and create fixed substrate for reentry and facilitate the development of AF. Neural remodeling contributes to a more dynamic AF substrate that is dependent on the autonomic state of the atrium. A recent experimental canine vagal AF study reported that ablation of the autonomic ganglia at the base of the pulmonary veins suppresses vagally induced effective refractory period shortening, suggesting that ganglionated plexi ablation may contribute to the effectiveness of pulmonary veindirected ablation procedure. However, the effectiveness of autonomic modulation as an adjunctive therapeutic strategy to catheter ablation of AF has been inconsistent. Although favorable results have been obtained by Nakagawa et al. and Pappone et al. [8, 9], others found no beneficial or deleterious outcomes in patients who had denervation compared with those who did not. These findings are also underlined by animal studies by Hirose et al. [10], in which partial vagal denervation of the high right atrium was found to increase inducibility of AF. In conclusion, there are complex but close associations between autonomic nervous system and arrhythmia in experimental and clinical settings. In the atria, simultaneous sympathovagal activation is a common trigger of paroxysmal atrial tachyarrhythmia. Ventricular arrhythmias are triggered by sympathetic activation. Both structural and neural remodeling increase the incidence of arrhythmia and sudden cardiac death. The interactions between the ANS and arrhythmia are more complex than currently understood. Perhaps a degree of individual variability accounts for discrepancies in
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the results of therapies targeting autonomic nerve activity modulation, with some patients having more pronounced autonomic triggers than others.
References 1. Armour JA. Potential clinical relevance of the ‘little brain’ on the mammalian heart. Exp Physiol. 2008;93:165–76. 2. Cardinal R, Page P, Vermeulen M, et al. Spatially divergent cardiac responses to nicotinic stimulation of ganglionated plexus neurons in the canine heart. Auton Neurosci. 2009;145:55–62. 3. Patterson E, Po SS, Scherlag BJ, et al. Triggered firing in pulmonary veins initiated by in vitro autonomic nerve stimulation. Heart Rhythm. 2005;2:624–31. 4. Tan AY, Li H, Wachsmann-Hogiu S, et al. Autonomic innervation and segmental muscular disconnections at the human pulmonary vein-atrial junction: implications for catheter ablation of atrialpulmonary vein junction. J Am Coll Cardiol. 2006;48:132–43. 5. Sharifov OF, Fedorov VV, Beloshapko GG, et al. Roles of adrenergic and cholinergic stimulation in spontaneous atrial fibrillation in dogs. J Am Coll Cardiol. 2004;43:483–90. 6. Schwartz PJ. Idiopathic long QT syndrome: progress and questions. Am Heart J. 1985;109:399–411. 7. Schwartz PJ, Priori SG, Cerrone M, et al. Left cardiac sympathetic denervation in the management of high-risk patients affected by the long-QT syndrome. Circulation. 2004;109:1826–33. 8. Nakagawa H, Scherlag BJ, Wu R, et al. Addition of selective ablation of autonomic ganglia to pulmonary vein antrum isolation for treatment of paroxysmal and persistent atrial fibrillation. Circulation. 2006;110, III459. 9. Pappone C, Santinelli V, Manguso F, et al. Pulmonary vein denervation enhances long-term benefit after circumferential ablation for paroxysmal atrial fibrillation. Circulation. 2004;109:327–34. 10. Hirose M, Leatmanoratn Z, Laurita KR, et al. Partial vagal denervation increases vulnerability to vagally induced atrial fibrillation. J Cardiovasc Electrophysiol. 2002;13:1272–9. Circulation. 2004;109: 1826–33.
7
Understanding the Genetic Basis of Atrial Fibrillation: Towards a Pharmacogenetic Approach for Arrhythmia Treatment Jason D. Roberts and Michael H. Gollob
Abstract
Atrial fibrillation is the most common sustained cardiac arrhythmia, and affected individuals suffer from increased rates of heart failure, stroke, and death. Despite the enormous clinical burden that it exerts on patients and health care systems, contemporary treatment strategies have only modest efficacy which likely stems from our limited understanding of its underlying pathophysiology. Epidemiological studies have provided unequivocal evidence that the arrhythmia has a substantial heritable component. Subsequent investigations into the genetics underlying AF have suggested that there is considerable interindividual variability in the pathophysiology characterizing the arrhythmia. This heterogeneity may partly account for the poor treatment efficacy of current therapies. Subdividing AF into mechanistic subtypes on the basis of genotype serves to illustrate the heterogeneous nature of the arrhythmia and may ultimately help to guide treatment strategies. A pharmacogenetic approach to the management of AF may lead to dramatic improvements in treatment efficacy and improved patient outcomes. Keywords
Atrial fibrillation • Pharmacogenetics • Genes
Introduction Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, is associated with a reduced quality of life and an increased risk of stroke and death [1–3]. Annual health care costs associated with treating the condition in the USA have been estimated at 6.65 billion $ [4]. In addition to the considerable burden on affected patients and health care systems, the prevalence of AF has been projected to nearly triple by the year 2050 [5]. Unfortunately, present strategies for treating the arrhythmia suffer from limited efficacy and high J.D. Roberts, MD • M.H. Gollob, MD (*) Inherited Arrhythmia Clinic and Research Laboratory, University of Ottawa Heart Institute, Rm H350, 40 Ruskin Street, Ottawa, ON, K1Y 4W7, Canada e-mail:
[email protected]
A.S. Kibos et al. (eds.), Cardiac Arrhythmias, DOI 10.1007/978-1-4471-5316-0_7, © Springer-Verlag London 2014
rates of adverse events [6, 7]. These clinical realities likely stem from our limited understanding of the mechanisms of AF, a notion that is reflected by persistent disagreement regarding its underlying pathophysiology [8]. Recognition that AF has a heritable component has led to an intensive search for the genetic culprits responsible for the disorder. The identification of genes that predispose to the arrhythmia has begun to provide further insight into the factors that govern its initiation and maintenance [9]. Improved insight into the pathophysiology of the condition guided by a sophisticated understanding of the genetic underpinnings promises to lead to more innovative treatment strategies that will ameliorate the care of affected patients. Based on the diverse genetic culprits that have been identified thus far, it has become increasingly clear that AF is a heterogeneous disorder that will likely necessitate a personalized therapeutic approach in order to optimize treatment outcomes [9].
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AF as a Genetic Disease A variety of clinical features including advanced age, structural heart disease, and hypertension have been identified as risk factors for AF [10]. Although the majority of AF subjects develop the arrhythmia in the context of preexisting forms of cardiovascular disease, approximately 15 % of cases occur in otherwise healthy individuals [11]. The development of AF in the absence of traditional risk factors, referred to as lone AF, suggested a potential role for genetics as a mediator of disease. Indeed, a family with lone AF transmitted with an autosomal dominant pattern of inheritance was first documented by Wolff in 1943 [12]. Epidemiological studies have found that individuals with a first-degree relative with lone AF carry a seven to eightfold increased risk of developing the arrhythmia [13]. Even more dramatic, the presence of an affected sibling was associated with a 70- and 34-fold increased risk of developing AF in males and females, respectively [14]. Although more pronounced in the context of lone AF, the form of the arrhythmia associated with structural heart disease has also been shown to have a heritable component. A prospective cohort analysis from the Framingham Heart Study involving 2,243 subjects found that parental AF conferred a 1.85-fold increased risk for development of the arrhythmia in offspring [15]. A similar study from Iceland involving 5,269 patients corroborated the latter result identifying a 1.77-fold increased risk of developing the arrhythmia in first-degree relatives [16]. Importantly, this greater vulnerability to AF is not attenuated by adjustment for traditional risk factors linked to the arrhythmia suggesting that the heightened risk is secondary to an underlying genetic etiology [17]. Collectively, these findings provide convincing epidemiological evidence to suggest that genetics play a critical role in the development of both lone and structural AF.
AF as a Single-Gene Disease The existence of families with a Mendelian pattern of inheritance of AF has enabled investigators to conduct genetic linkage studies in order to map the location of the culprit gene. The first genetic linkage study for AF involved a small Spanish family that transmitted the arrhythmia in an autosomal dominant fashion [18]. The culprit locus was mapped to a region on the long arm of chromosome 10 (10q22-24). However, since this report in 1997, the responsible gene has never been identified. A single genetic culprit for familial AF was excluded following linkage analysis in a separate family from the USA whose subtype of lone AF did not segregate with markers from the 10q22-24 region [19]. There have been three additional genetic loci that have been mapped in families with autosomal dominant forms of lone AF whose culprit mutations have
J.D. Roberts and M.H. Gollob
remained elusive, namely, 5p15, 6q14-16, and 10p11-12 [20–22]. Unfortunately, the inability to identify the responsible gene in these cases has precluded further insights into the pathogenesis of these specific familial forms of AF.
The First Genetic Culprit: KCNQ1 The first causative gene responsible for familial AF was found in 2003. The culprit locus on this occasion was mapped to the short arm of chromosome 11 (11p15.5) in a four generation Chinese family with an autosomal dominant pattern of inheritance for lone AF [23]. Chromosome 11p15.5 was noted to contain the KCNQ1 gene, which encodes the poreforming α-subunit of the slow component of the delayed rectifier potassium current (IKs). Loss-of-function mutations within KCNQ1 had previously been recognized as the cause for long QT syndrome type 1, a cardiac channelopathy associated with malignant ventricular arrhythmias and sudden cardiac death [24]. Given its biological plausibility based on its established link with a cardiac arrhythmic disorder, KCNQ1 was considered an ideal candidate gene. Sequencing of KCNQ1 identified a Ser140Gly mutation that segregated with AF cases within the family. The apparent significance of the Ser140Gly mutation was further strengthened by its absence in 376 chromosomes from healthy controls and its being a highly conserved residue across different species. Following identification of the putative culprit mutation, in vitro functional studies using COS-7 cells found that co-expression of mutant Ser140Gly KCNQ1 with KCNE1, the β-subunit of IKs, resulted in markedly increased current density relative to the wild-type gene. These findings suggested that the Ser140Gly mutation resulted in a gain-offunction leading to increased IKs. Given that IKs is responsible for repolarization of cardiomyocytes, a gain-of-function mutation would be hypothesized to result in more rapid repolarization of cells leading to a shortened effective refractory period (ERP). The refractory period refers to the length of time that a cell requires following depolarization before it can be re-excited [25]. The presence of a shortened effective refractory period within atrial cardiomyocytes is felt to contribute to the development of a substrate capable of supporting multiple circuit reentry which may predispose to a form of AF reflective of the multiple wavelet hypothesis [26]. The importance of KCNQ1 in the pathogenesis of AF has been further strengthened by additional linkage analyses and reports which have identified KCNQ1 mutations in familial cases of the arrhythmia [27–29]. Consistent with the initial KCNQ1 mutation, functional studies have confirmed gainof-function effects predicted to result in a net increase in IKs [27, 28]. It should be noted that 9 of the 16 individuals from the original family possessing the KCNQ1 Ser140Gly had prolonged QT intervals on 12-lead electrocardiography which is inconsistent with a gain-of-function effect, since an
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Understanding the Genetic Basis of Atrial Fibrillation: Towards a Pharmacogenetic Approach for Arrhythmia Treatment
increased IKs should potentially result in a shortened QT interval [23]. The explanation for this discrepancy remains unclear, but may be reflective of different electrical properties in the atria and ventricles or may be secondary to an inability to accurately recapitulate the electrical milieu of the heart with in vitro functional models.
Other Gain-of-Function Potassium Channel Mutations Since the landmark discovery implicating a mutant form of KCNQ1 as being causative for AF, numerous other gain-offunction potassium channel mutations have been identified in familial and sporadic cases of the arrhythmia. Candidate gene approaches which screened AF cases for mutations within multiple potassium channel genes have led to further insight into the role of three additional potassium channel genes in AF pathogenesis secondary to gain-of-function mutations, namely, KCNE2, KCNJ2,and KCNE5 [30–32]. An identical mutation within KCNE2, which encodes the β-subunit of the rapid component of the delayed rectifier potassium current (IKr), was discovered in 2 of 28 unrelated Chinese kindreds with familial AF [30]. The probands within both families were found to carry an Arg27Cys mutation that appeared to segregate with affected members from both kindreds and were absent from 462 healthy controls. It should be noted that there were multiple unaffected members in each family that carried the KCNE2 Arg27Cys mutation. This apparent discrepancy may be accounted for on the basis of low penetrance or may also potentially reflect the possibility that KCNE2 Arg27Cys is a disease-contributing as opposed to a disease-causing variant. The term disease-contributing implies that the genetic variant is not sufficient to cause a disease in isolation, but requires additional genetic and/or environmental factors in order to trigger expression of the disease phenotype. Ensuing functional work on the mutant form of KCNE2 was suggestive of a gain-of-function that would result in acceleration of cardiomyocyte repolarization. Of note, co-expression of Arg27Cys KCNE2 with KCNH2, the α-subunit of IKr, did not result in a change in current relative to wild type; however, an increased current was observed when KCNE2 Arg27Cys was co-expressed with KCNQ1. Previous work with COS cells had suggested that KCNE2 and KCNQ1 may interact to generate a background current that is not voltage dependent [33]. It was hypothesized that the mutant form of KCNE2 may predispose to AF through a background current accelerating cellular repolarization. A KCNJ2 gene mutation was identified in a single AF proband following screening of 30 Chinese AF kindreds for mutations within 10 ion channel or channel-binding related genes (KCNQ1, KCNH2, SCN5A, ANK-B, KCNJ2, KCNE1-5) [31]. KCNJ2 encodes Kir2.1 which is responsible for the cardiac inward rectifier potassium current IK1.
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This channel mediates a potassium current that contributes to the resting membrane potential of the cell and influences cardiac excitability and repolarization. It is also the causative gene for congenital long QT syndrome type 7, also referred to as Andersen-Tawil syndrome [34]. The proband and the other four affected family members were all found to carry a Val93Ile mutation within KCNJ2, a mutation that was absent from 420 healthy individuals. There were two healthy family members that carried the mutation; however, their unaffected status may have been secondary to incomplete penetrance or their relatively young ages (33 and 42 years old). Functional analysis of the mutant protein revealed increased current density consistent with a gain-of-function effect. The putative predisposing mechanism of Val93Ile KCNJ2 for AF involves enhanced repolarization and a reduction in refractory period, as hypothesized with KCNQ1 and KCNE2. The final potassium channel gene implicated in the pathogenesis of AF through an acceleration of cardiomyocyte repolarization is KCNE5 [32]. Investigators screened 158 AF cases for mutations within the coding region of KCNE5 and identified a Leu65Phe mutation in a 66-year-old female with a persistent form of the arrhythmia. She had no family history of AF, unlike the familial forms of the arrhythmia observed with the previous potassium channel genes, and had risk factors including hypertension and ischemic heart disease. Although the possibility of a de novo mutation cannot be excluded given that other family members were not screened, the sporadic nature of this case, coupled with the presence of preexisting risk factors, suggests that KCNE5 Leu65Phe may actually reflect a disease-contributing genetic variant as opposed to a disease-causing mutation for AF. The mutation was absent from 200 control subjects, and subsequent functional work revealed that the mutant KCNE5 protein led to an increased IKs. Unlike KCNE2, KCNE5 encodes an inhibitory β-subunit that leads to a reduction in IKs. Co-expression of wild-type KCNE5 with KCNQ1/KCNE1 within CHO cells resulted in reduced IKs, while mutant KCNE5 Leu65Phe led to increased IKs. The authors concluded that KCNE5 Leu65Phe results in the loss of the inhibitory function of this subunit on IKs, leading to increased IKs (gain-of-function).
Mechanistic Subtype of AF-1: Gain-of-Function Potassium Channels and Enhanced Atrial Action Potential Repolarization The finding that gain-of-function potassium channel mutations predispose to AF has led to an appreciation that enhanced atrial repolarization accounts for a mechanistic subtype of the arrhythmia (Table 7.1). This subtype of the arrhythmia likely has an underlying pathophysiology driving its initiation and maintenance consistent with the multiple wavelet hypothesis [26]. The multiple wavelet hypothesis has been the dominant conceptual model of AF over the past
J.D. Roberts and M.H. Gollob
68 Table 7.1 Mechanistic subclassification of lone AF and putative pharmacogenetic strategy AF subclassification Enhanced atrial action potential repolarization
Delayed atrial action potential repolarization Conduction velocity heterogeneity Cellular hyperexcitability Hormonal modulation of atrial electrophysiology Cholinergic
Culprit gene(s) KCNQ1 KCNE2 KCNJ2 KCNE5 KCNA5 SCN5A GJA5 GJA1 SCN5A NPPA Unknown
Functional effect Enhanced slow component of the delayed rectifier potassium current (IKs) Enhanced KCNQ1-KCNE2 potassium current Enhanced inward rectifier current (IK1) Enhanced IKs Decreased ultrarapid component of the delayed rectifier potassium current (Ikur) Hyperpolarizing shift in Nav1.5 inactivation Heterogeneous reduction in gap junction conduction
Putative pharmacogenetic strategy Potassium channel blockade
Depolarizing shift in Nav1.5 inactivation Increased circulating levels of mutant ANP
Sodium channel blockade Unknown
Enhanced cholinergic sensitivity
Cholinergic antagonist
Unknown
Gap junction modifier
Modified from Roberts and Gollob [9]
50 years and suggests that the irregular atrial activity characterizing AF arises from multiple self-perpetuating microreentrant circuits which exhibit spatial and temporal variability. Based on this model, increasing numbers of reentrant wavelets within the atria should favor the maintenance of AF. A wavelet is a small wave of depolarizing current that may circle back upon itself to form a microreentrant circuit. The number of wavelets that can be supported by atria of a given size is inversely proportional to the refractory period of atrial tissue [35]. Gain-of-function potassium channel mutations accelerate cardiomyocyte repolarization resulting in a reduction in refractory period. The reduced refractory period of atrial tissue is capable of supporting increased numbers of reentrant wavelets resulting in an increased ability to support the multiple self-perpetuating microreentrant circuits which define the form of AF predicted by the multiple wavelet hypothesis. Pharmacogenetic Implications
The theory that prolonging the refractory period of atrial cardiomyocytes may disrupt the microreentrant circuits required for the maintenance of AF has served as the explanation accounting for the ability of potassium channel blockers to terminate the arrhythmia [8]. Potassium channel blockers prolong atrial repolarization, thereby reducing the potential number of circulating wavelets that can be supported by atria of a given size. The efficacy of potassium channel blockers for either terminating or preventing AF exhibits substantial interindividual variability [36]. An explanation accounting for this lack of consistency has been lacking; however, insights derived from these genetic investigations into the arrhythmia provide some clarification. A subgroup of affected individuals appear to possess a form of the arrhythmia that is driven by enhanced atrial repolarization and hence a reduced refractory period of atrial tissue. This form of the arrhythmia may be expected to have an increased
likelihood of responding favorably to medications such as potassium channel blockers through a normalization of atrial repolarization and hence the refractory period of atrial tissue. In contrast, a form of the arrhythmia driven by an alternative mechanism may exhibit minimal or even a detrimental response to potassium channel blockade.
Mechanistic Subtype of AF-2: Loss-of-function Potassium and Sodium Channels and Delayed Atrial Action Potential Repolarization Loss-of-Function Potassium Channel Mutations The initial potassium channel gene mutations implicated in the development of AF had been shown to result in gain-offunction effects based on in vitro functional analysis. An alternative form of AF driven by opposing pathophysiology had been suggested by previous work that noted the development of a polymorphic atrial tachycardia that subsequently degenerated into AF following injection of cesium chloride, a potassium channel blocker, into the sinus node artery of dogs [37]. These findings led the investigators to coin the term “atrial torsade” and suggested that loss-of-function potassium channel gene mutations may also predispose to AF. Subsequent screening for potassium channel mutations in AF identified a novel nonsense mutation (E375X) within the KCNA5 gene [38]. KCNA5 encodes an atrial-specific voltage-gated potassium channel, Kv1.5, which is responsible for the ultrarapid component of the delayed rectifier potassium current (IKur). The KCNA5 E375X nonsense mutation resulted in a truncated protein lacking the S4–S6 voltage sensor, the pore region, and the C-terminus. Despite the subject coming from a family with multiple other affected family members, it was not possible to stringently assess genotype-phenotype segregation due to multiple individuals declining to participate in the study.
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Understanding the Genetic Basis of Atrial Fibrillation: Towards a Pharmacogenetic Approach for Arrhythmia Treatment
Functional studies involving HEK293 cells revealed that the truncated form of KCNA5 arising from the E375X mutation was unable to conduct current, consistent with a loss-offunction effect [38]. In addition, when co-expressed with wild-type KCNA5, cells exhibited a significant reduction in current density compatible with a dominant negative effect which accounted for the disease phenotype in the setting of a heterozygous loss-of-function mutation. In vitro studies using human atrial myocytes and in vivo studies with a murine model found that administration of 4-aminopyridine, a known blocker of IKur, dramatically increased the incidence of early afterdepolarizations. The authors hypothesized that increased early afterdepolarizations, associated with a prolonged atrial action potential duration, could result in initiation of AF akin to that seen in torsade de pointes within the ventricles as occurs with loss-of-function potassium channels in long QT syndrome. The importance of loss-offunction KCNA5 mutations in the pathogenesis of AF has been reaffirmed by subsequent reports [39, 40].
Loss-of-Function Sodium Channel Mutations The initial rapid depolarization characterizing Phase 0 of the cardiac action potential is mediated by Nav1.5, whose poreforming α-subunit is encoded by the SCN5A gene. The SCN5A gene had been implicated in numerous arrhythmic disorders including the Brugada syndrome, congenital long QT syndrome type 3, and sick sinus syndrome [41–43]. Given its obvious importance with the electrical properties of the heart, investigators began screening patients with AF for mutations within SCN5A. A study involving 375 patients with a mixture of lone (118) and structural AF (257) identified 8 novel mutations in 10 different subjects that were absent from 360 healthy controls [44]. The variants involved highly conserved residues within SCN5A and segregated with disease in all six of the familial cases. Functional studies were not performed; however, this report provided strong evidence that mutations within SCN5A represented an important cause of AF in patients with and without heart disease. The first SCN5A mutation associated with AF that was functionally characterized was found following the screening of 57 patients with lone AF or AF with hypertension and a confirmed family history of the arrhythmia [45]. A single novel mutation was found, Asn1986Lys, which was absent from 300 ethnically matched controls. The affected father of the proband also carried the mutation; however, further genetic profiling of the family was not possible due to lack of consent. Expression of the mutant gene within Xenopus laevis oocytes suggested a loss-of-function effect as evidenced by a significant hyperpolarizing shift in the midpoint of steady-state inactivation. This alteration was predicted to prolong the atrial action potential duration, and therefore, the SCN5A Asn1986Lys was hypothesized to predispose to AF through a manner akin to the aforementioned atrial torsade.
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Pharmacogenetic Implications
Loss-of-function potassium and sodium channel mutations result in a mechanistic subtype of AF characterized by delayed atrial repolarization. In contrast to the enhanced atrial repolarization subtype of AF, potassium channel blockade and further prolongation of the cardiac action potential would be hypothesized to have minimal efficacy and may exacerbate arrhythmogenesis in this subtype. These different mechanistic forms of AF with opposing pathophysiology may result in an identical clinical phenotype; however, the response to similar treatment strategies would likely differ markedly. This concept effectively illustrates the potential value of a pharmacogenetic approach to therapy and may serve to account for the substantial interindividual variability observed with identical treatment strategies. While cases of AF characterized by enhanced atrial repolarization would likely benefit from medical therapy that prolongs (and hence normalizes) the atrial action potential, effective treatment of AF cases that develop secondary to delayed atrial repolarization would be expected to require medical agents that shorten (and hence normalize) the atrial action potential.
Mechanistic Subtype of AF-3: Gap Junction Impairment and Conduction Velocity Heterogeneity Connexins Connexin proteins form specialized channels, termed gap junctions, at the intercellular junction between adjacent cells which permit the flow of charged ions between the cytoplasmic compartments of neighboring cells [46]. The resultant intercellular communication facilitates coordinated propagation of cardiac action potentials enabling the myocardium to depolarize in an organized manner. Connexin proteins oligomerize into hexameric structures known as connexons or hemichannels, which form functional gap junctions through interacting with hemichannels from adjacent cells [46]. The two most highly expressed connexin isoforms within the heart are connexin 40 and 43 [47]. Notably, connexin 40 is exclusively expressed within atrial myocytes and is absent from ventricular cells [47]. The importance of connexins to AF has been suggested by animal studies which revealed that connexin 40 knockout mice exhibited an increased vulnerability to atrial tachyarrhythmias [48]. Given the apparent importance of connexin 40 on atrial electrophysiology, our group screened 15 patients with sporadic, lone AF for somatic mutations within connexin 40 [49]. We hypothesized that somatic (atrial tissue-specific) mutations, as opposed to heritable germline mutations, may account for the development of AF in healthy individuals with no family history of the arrhythmia. DNA was obtained from both peripheral blood lymphocytes and resected atrial
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tissue of patients who had undergone an open-heart pulmonary vein isolation procedure. In 4 of the 15 patients, genetic mutations within the connexin 40 gene (GJA5) were identified. Findings consistent with a tissue-specific or somatic basis of the mutations were found in three of the four patients, as evidenced by the presence of the mutation within the resected atrial tissue and not in peripheral blood lymphocytes. This observation supported the concept that tissuespecific mutations, analogous to the genetic basis of most cancers, may lead to the development of common cardiac arrhythmic disorders. Since myocardial cells do not divide, a somatic mutation must have occurred in an early myocardial progenitor cell during embryogenesis leading to genetic mosaicism within the atrial tissue. All of the mutations occurred within the highly conserved transmembrane-spanning domains of the connexin 40 protein [49]. The three somatic mutations included Gly38Asp, Pro88Ser, and Met163Val, while the only germline mutation was Ala96Ser. Functional studies of the mutant connexin proteins were performed in a gap junction-deficient cell line, N2A cells. Cells expressing the Pro88Ser mutation showed a profound trafficking defect, showing intracellular retention of the mutant protein. In contrast, cells expressing the Ala96Ser mutation displayed appropriate trafficking; however, functional electrical cell-to-cell coupling through these channels was significantly reduced. Immunostaining of atrial tissue from the patient carrying the Pro88Ser mutation exhibited a mosaic pattern of abnormal gap junction formation and intracellular retention of connexin 40. Lastly, these mutant connexins demonstrated a dominant negative effect on wildtype Cx40, as well as a trans-dominant negative effect on wild-type Cx43. This latter finding provides strong support for the concept of heteromeric interaction of Cx40 and Cx43 in hemichannel formation. Following this initial report, we subsequently identified a novel somatic frameshift mutation within connexin 43 in a sporadic case of lone AF [50]. The frameshift mutation (c.932delC) was identified in an otherwise healthy female who was diagnosed with AF at 48 years of age following a longstanding history of palpitations. The single base pair deletion resulted in a truncated C-terminal domain of connexin 43 containing 36 aberrant amino acids. Subcloning of polymerase chain reaction products from left atrial tissue was consistent with genetic mosaicism, while protein trafficking studies revealed intracellular retention of the mutant protein. As observed with connexin 40 mutants, the aberrant form of connexin 43 abolished gap junction formation in the presence of both wild-type connexins 40 and 43 consistent with dominant and trans-dominant negative loss-of-function effects, respectively. Collectively, these findings provide compelling evidence that somatic or atrial-specific genetic defects within both connexins 40 and 43 predispose to the development of
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sporadic, lone AF [49, 50]. The presence of genetic mosaicism in the context of these loss-of-function connexin mutations is likely critical for their role in promoting arrhythmogenesis within atrial tissue. A predisposition to the chaotic electrical reentry circuits characterizing AF will likely be greater in the presence of an arrhythmogenic substrate which exhibits substantial regional variability in conduction velocity. The heterogeneous distribution of gap junctions observed on immunostaining of atrial tissue in our patients is likely indicative of such a substrate [49]. Furthermore, the general notion that regional variability of cardiac electrical properties is proarrhythmic provides support for a potential broader role of genetic mosaicism in the pathogenesis of AF. It should be noted, however, that genetic mosaicism does not appear to be a prerequisite for the development of AF in the presence of connexin mutations. Since our original findings, multiple reports have emerged in the literature implicating connexin 40 mutations in cases of familial AF [51, 52]. Recently, a common genetic variant within the promoter region of connexin 40 has also been found to associate with the arrhythmia [53]. Pharmacogenetic Implications
The importance of connexins in the pathogenesis of AF emphasizes the potential clinical role for treatments targeting gap junctions. Medications that enhance gap junction activity may serve to normalize conduction velocity resulting in a reduction in regional electrical heterogeneity within the atria. The RXP series of connexin 43-binding peptides have been shown in vitro to prevent cardiac gap junction closure and action potential propagation blocks in response to acidification [54]. Rotigaptide and GAP-134 are additional anti-arrhythmic peptides which have been suggested to exert anti-arrhythmic effects in animal models of arrhythmia including AF [55, 56]. Further work in this area will be required prior to its use in the clinical milieu; however, its targeted use in patients suffering from AF characterized by this mechanistic subtype of conduction velocity heterogeneity has the potential to be highly efficacious.
Mechanistic Subtype of AF-4: Cellular Hyperexcitability Initial studies had implicated loss-of-function SCN5A mutations in the development of AF; however, the arrhythmogenic potential of gain-of-function SCN5A mutations had also been well documented in long QT syndrome type 3 [42]. Long QT syndrome type 3 develops secondary to an SCN5A gain-offunction effect that prolongs cardiac repolarization through an increased late sodium current [57]. The importance of SCN5A gain-of-function mutations in AF pathogenesis was confirmed following investigations involving a four generation Japanese
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Understanding the Genetic Basis of Atrial Fibrillation: Towards a Pharmacogenetic Approach for Arrhythmia Treatment
family with an autosomal dominant form of AF that carried a novel SCN5A Met1875Thr mutation [58]. The novel variant exhibited perfect genotype-phenotype segregation within the family, consistent with its being fully penetrant, and was also absent from 210 ethnically matched controls. The proband was noted to have increased right atrial excitability during radiofrequency catheter ablation for AF. Functional analysis of Met1875Thr revealed a pronounced depolarizing shift in the midpoint of steady-state inactivation consistent with a gain-of-function effect. No increased late sodium current was observed accounting for the presence of normal QT intervals within affected individuals. A second study from our group involving a mother and son with lone AF identified a Lys1493Arg mutation involving a highly conserved residue within the DIII-IV linker located six amino acids downstream from the fast inactivation motif of sodium channels [59]. Biophysical studies demonstrated a significant positive shift in the voltage dependence of inactivation and a large ramp current near resting membrane potential, consistent with a gain-of-function. When expressed in HL-1 atrial cardiomyocytes, enhanced cellular excitability was observed in the form of spontaneous action potential depolarizations and a lower threshold for action potential firing as compared to wild-type cells. Collectively, these studies suggest that gain-of-function mutations within SCN5A are associated with AF. The existing evidence suggests that SCN5A gain-offunction mutations predispose to AF by enhancing cellular hyperexcitability. The depolarizing shift in steady-state inactivation increases the probability that the channel will be in the open conformation and capable of conducting current [59]. This alteration in the gating of the Nav1.5-mediated current will presumably result in a predisposition for cells to reach threshold potential and fire, consistent with enhanced automaticity. This increase in focal discharges has the potential to serve as the trigger for AF. In addition, Nav1.5 channels have recently been identified in the autonomic ganglia that surround the pulmonary veins [60]. Mutations within SCN5A may therefore result in neuronal hyperexcitability that may trigger AF through a parasympathetic pathway and contribute to the rapidly firing ectopic foci observed in the region of the pulmonary veins in some patients with the arrhythmia. Pharmacogenetic Implications
The notion that a subgroup of patients with AF may suffer from a form of the arrhythmia characterized by cellular hyperexcitability secondary to excessive sodium channel activity intuitively alludes to a potential treatment strategy. It is reasonable to suspect that administration of sodium channel blockers to subjects with this form of the disorder may prove efficacious. Medications such as flecainide and propafenone are known to work extremely well in certain
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patients with lone AF, and their selective efficacy may be concentrated largely within this mechanistic subtype. Their ability to reduce cellular hyperexcitability may prevent the triggers that lead to the initiation of AF. Their ability to directly address the underlying pathophysiology within this subtype may be associated with a high degree of treatment efficacy and a low rate of adverse events.
Mechanistic Subclass of AF-5: ANP Modulation of Atrial Electrophysiology The most recent gene to be associated with AF does not implicate an ion channel, but instead involves a circulating hormone, the atrial natriuretic peptide (ANP). Although known to be important in cardiac physiology, ANP had been largely viewed as cardioprotective in the setting of heart failure [61]. It was known, however, to be capable of modulating the electrical activities of the heart, and there were reports of its effects on specific ion channels [62, 63]. However, little work had been done on ANP in the context of AF, and previous studies examining ANP levels as a biomarker in AF had been negative [64]. Linkage analysis of a Caucasian family of northern European ancestry with autosomal dominant AF mapped the causative locus to the small arm of chromosome 1 (1p36-35) [65]. Review of the genes within this region revealed the presence of NPPA, the gene-encoding ANP, and subsequent sequencing revealed a two base pair deletion in exon 3 that resulted in a frameshift associated with loss of the stop codon. Extension of the reading frame results in an elongated peptide that is 40 amino acids in length relative to the 28-amino acid length of the wild type. The deletion was present in all of the affected family members and absent in unaffected family members and 560 control patients. Functional studies involving an isolated rat whole-heart model suggested that the mutant ANP resulted in shortened action potential duration and reduced effective refractory period; however, the mechanism was not entirely clear. ANP mediates its effects on cells through binding to natriuretic peptide receptors that possess intracellular guanylate cyclase activity [66]. Previous work has suggested that ANP molecules with an elongated C-terminus may be more resistant to degradation and therefore may circulate at higher levels [67]. Therefore, the authors hypothesized that increased circulating ANP may result in elevated intracellular levels of cGMP that may in turn, through an unknown mechanism, reduce the effective refractory period. Triggered by the insight that ANP may influence vulnerability for AF, our group screened for a potential association between common genetic variants within NPPA and AF. Notably, two common genetic variants that create nonsynonymous amino acid changes within NPPA, rs5063 and
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rs5065, had previously been implicated in conditions associated with AF [68, 69]. A small Chinese study had suggested that the presence of rs5063 resulted in an increased risk of AF [70]. However, our study involving 620 AF cases and 2,446 controls found no association between either single-nucleotide polymorphism (SNP) or the risk of AF [71].
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Genome-Wide Association Studies The previous discussion has focused on rare genetic variants as being causative for AF; however, genome-wide association studies have also provided evidence implicating common genetic variants in the pathogenesis of the arrhythmia. To date, there have been three common genetic variants, or SNPs, that have been found to associate with an increased risk of AF development.
Pharmacogenetic Implications
Given that the mechanism through which NPPA predisposes to AF remains unclear, it is difficult to speculate on potential pharmacogenetic treatment strategies. The findings suggesting that the 40 amino acid form of ANP was resistant to degradation may imply that increased circulating levels of the hormone may predispose to AF [65]. This could potentially provide insight into the increased risk of AF in the context of congestive heart failure [72]. In the event that increased levels of ANP do predispose to AF, effective treatment may involve medications that block the extracellular binding domain of natriuretic peptide receptors or alternatively the intracellular guanylate cyclase activity. The observation that the mutant form of ANP reduced the cardiac effective refractory period also alludes to a potential role for agents that prolong the cardiac action potential such as potassium channel blockers.
Mechanistic Subclass of AF-6: Cholinergic (Vagal) AF The autonomic nervous system has been recognized as a critical component of arrhythmogenesis. In the setting of lone AF, the sentinel observations of the eminent electrophysiologist Phillipe Coumel have implicated the parasympathetic nervous system as a major culprit [73]. Common triggers for the onset of paroxysms of AF in young individuals with structurally normal hearts include states associated with high vagal tone including sleep and the postprandial period. The mechanism through which the parasympathetic nervous system mediates lone AF appears to be in part dependent upon IKAch [74]. Activation of IKAch triggers an efflux of potassium ions which leads to shortening of the atrial action potential duration and the corresponding refractory period. The heterogeneous vagal innervation of the atria has the potential to result in regional variation of refractory periods [75]. The resultant dispersion in cellular refractoriness throughout the atria has the potential to serve as an ideal substrate for reentry and arrhythmogenesis. To date, there have been no genetic culprits identified within vagal pathways that predispose to AF. Given its obvious importance in the pathogenesis of the arrhythmia, we anticipate that genetic culprits within this mechanistic subclass will emerge in the coming years.
4q25 The first genome-wide association study performed for AF involved 550 patients with AF or flutter and 4,476 control patients from Iceland [76]. Investigators discovered an association with SNPs on chromosome 4q25, the most significant being rs2200733 with an odds ratio of 1.84 (95 % confidence intervals: 1.54–2.21). Replication studies using additional samples from Iceland (2,251 cases and 13,238 controls), Sweden (143 cases and 738 controls), the USA (636 cases and 804 controls), and China (333 cases and 2,836 controls) further reinforced the association with rs2200733. The odds ratio for the combined European population was 1.72, while that for the Chinese cohort was 1.42. The haplotype block corresponding to the associated SNPs does not contain a known gene, and therefore, the mechanism for this association is currently unknown. The primary genetic suspect has been PITX2, the nearest known gene in the region, which encodes a transcription factor involved in cardiac development. Following identification of this possible association, investigations using animal models have suggested that reduced expression of PITX2 may predispose to an increased vulnerability to AF, although the underlying mechanisms remain unclear [77, 78]. 16q22 Following identification of the 4q25 locus, two subsequent genome-wide association studies concurrently identified separate SNPs, rs7193343 and rs2106261, that both localized to an intronic region within the ZFHX3 gene on chromosome 16q22 [79, 80]. ZFHX3 encodes a transcription factor whose function in the heart is currently unclear. The ZFHX3 gene has recently been implicated in a vasculitis involving the coronary arteries (Kawasaki disease) [81]. The association of 16q22 with AF was weaker than 4q25 in subjects of European ancestry and did not originally replicate in a Chinese population [79]. As with the 4q25 locus, further work is necessary in order to better appreciate the apparent relationship between these SNPs within16q22 and AF. 1q21 The initial two common genetic variants linked with AF were identified predominantly in the context of AF associated with structural heart disease. A third GWAS was performed which focused exclusively on lone AF [82].
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Understanding the Genetic Basis of Atrial Fibrillation: Towards a Pharmacogenetic Approach for Arrhythmia Treatment
The study involved 1,335 lone AF cases and 12,844 unaffected controls and identified a third common genetic variant that associated with the arrhythmia (adjusted odds ratio of 1.56) which was subsequently replicated in two independent lone AF cohorts. The genetic variant, rs13376333, localizes to chromosome 1q21 and is intronic to KCNN3. KCNN3 is a calcium-activated potassium channel that is felt to influence atrial repolarization. Pharmacogenetic Implications
The potential pharmacogenetic applications for common genetic variants associated with AF are potentially quite broad due to their presence in a large proportion of individuals with the arrhythmia. However, this is presently precluded by our relative lack of insight into the mechanisms through which these common genetic variants predispose to the arrhythmia. Clarifying their precise role in AF pathogenesis will be necessary prior to their involvement in pharmacogenetic strategies. Preliminary work alluding to their possible future impact has begun to emerge, including a study which found that the presence of AF-associated 4q25 SNPs resulted in a decreased efficacy of AF ablation [83]. Larger studies will likely be required prior to translation of these concepts into the clinical realm. Lastly, since these SNPs confer a relatively small contribution to disease vulnerability as compared to single-gene diseases, pharmacologic modulation of the pathways identified through GWAS may not have a large impact on arrhythmia suppression.
Summary AF is the most common cardiac arrhythmia and is associated with increased rates of heart failure, stroke, and death. However, despite its clinical impact, current treatment strategies have relatively modest efficacy which is likely driven by our limited understanding of its underlying pathophysiology. Clinical and epidemiological findings have provided unequivocal evidence that the arrhythmia has a substantial heritable component. Subsequent investigations into the genetics underlying AF have suggested that there is considerable interindividual variability in the pathophysiology resulting in the development of the arrhythmia. This heterogeneity may partly account for the poor treatment efficacy of many contemporary therapies. Subdividing AF into mechanistic subtypes on the basis of genotype serves to illustrate the heterogeneous nature of the arrhythmia and may ultimately help to guide treatment strategies. We anticipate that a pharmacogenetic approach to the management of AF will lead to dramatic improvements in treatment efficacy leading to better patient outcomes and a reduction in the burden that this arrhythmia is currently exerting on health care systems.
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References 1. Dorian P, Guerra PG, Kerr CR, et al. Validation of a new simple scale to measure symptoms in atrial fibrillation: the Canadian Cardiovascular Society Severity in Atrial Fibrillation scale. Circ Arrhythm Electrophysiol. 2009;2:218–24. 2. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke. 1991;22:983–8. 3. Benjamin EJ, Wolf PA, D’Agostino RB, et al. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation. 1998;98:946–52. 4. Coyne KS, Paramore C, Grandy S, et al. Assessing the direct costs of treating nonvalvular atrial fibrillation in the United States. Value Health. 2006;9:348–56. 5. Miyasaka Y, Barnes ME, Gersh BJ, et al. Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence. Circulation. 2006;114:119–25. 6. The atrial fibrillation follow-up investigation of rhythm management (AFFIRM) investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med. 2002;347:1825–33. 7. Shah R, Freeman J, Shilane D, et al. Procedural complications, rehospitalizations, and repeat procedures after catheter ablation for atrial fibrillation. J Am Coll Cardiol. 2012;59:143–9. 8. Nattel S. New ideas about atrial fibrillation 50 years on. Nature. 2002;415:219–26. 9. Roberts JD, Gollob MH. Impact of genetic discoveries on the classification of lone atrial fibrillation. J Am Coll Cardiol. 2010;55:705–12. 10. Benjamin EJ, Levy D, Vaziri SM. Independent risk factors for atrial fibrillation in a population-based cohort: The Framingham Heart study. JAMA. 1994;271:840–4. 11. Kopecky SL, Gersh BJ, McGoon MD, et al. The natural history of lone atrial fibrillation. A population-based study over three decades. N Engl J Med. 1987;317:669–74. 12. Wolff L. Familial auricular fibrillation. N Engl J Med. 1943;229:396–7. 13. Marcus GM, Smith LM, Vittinghoff E, et al. A first-degree family history in lone atrial fibrillation patients. Heart Rhythm. 2008;5:826–30. 14. Ellinor PT, Yoerger DM, Ruskin JN, et al. Familial aggregation in lone atrial fibrillation. Hum Genet. 2005;188:179–84. 15. Fox CS, Parise H, D’Agostino Sr RB, Lloyd-Jones DM, Vasan RS, Wang TJ, Levy D, Wolf PA, Benjamin EJ. Parental atrial fibrillation as a risk factor for atrial fibrillation in offspring. JAMA. 2004;291:2851–5. 16. Arnar DO, Thorvaldsson S, Manolio TA, Thorgeirsson G, Kristjansson K, Hakonarson H, Stefansson K. Familial aggregation of atrial fibrillation in Iceland. Eur Heart J. 2006;27:708–12. 17. Lubitz SA, Yin X, Fontes JD, et al. Association between familial atrial fibrillation and risk of new-onset atrial fibrillation. JAMA. 2010;304:2263–9. 18. Brugada R, Tapscott T, Czernuszewicz GZ, et al. Identification of a genetic locus for familial atrial fibrillation. N Engl J Med. 1997;336:905–11. 19. Darbar D, Herron KJ, Ballew JD, et al. Familial atrial fibrillation is a genetically heterogeneous disorder. J Am Coll Cardiol. 2003;41:2185–92. 20. Darbar D, Hardy A, Haines JL, et al. Prolonged signal-averaged P-wave duration as an intermediate phenotype for familial atrial fibrillation. J Am Coll Cardiol. 2008;51:1083–9. 21. Ellinor PT, Shin JT, Moore RK, Yoerger DM, et al. Locus for atrial fibrillation maps to chromosome 6q14-16. Circulation. 2003;107:2880–3.
74 22. Volders PG, Zhu Q, Timmermans C, et al. Mapping a novel locus for familial atrial fibrillation on chromosome 10p11-q21. Heart Rhythm. 2007;4:469–75. 23. Chen YH, Xu WJ, Bendahhou S, et al. KCNQ1 gain-of-function mutation in familial atrial fibrillation. Science. 2003;299:251–4. 24. Wang Q, Curran ME, Splawski I, et al. Positional cloning of a novel potassium channel gene: KvLQT1 mutations cause cardiac arrhythmias. Nat Genet. 1996;12:17–23. 25. Katz AM. Cardiac ion channels. N Engl J Med. 1993;328:1244–51. 26. Moe GK, Rheinboldt WC, Abildskov JA. A computer model of atrial fibrillation. Am Heart J. 1964;67:200–20. 27. Das S, Makino S, Melman YF, et al. Mutation in the S3 segment of KCNQ1 results in familial lone atrial fibrillation. Heart Rhythm. 2009;6:1146–53. 28. Otway R, Vandenberg JI, Guo G, et al. Stretch-sensitive KCNQ1 mutation. A link between genetic and environmental factors in the pathogenesis of atrial fibrillation? J Am Coll Cardiol. 2007;49:578–86. 29. Lundby A, Ravn LS, Svendsen JH, et al. KCNQ1 mutation Q147R is associated with atrial fibrillation and prolonged QT interval. Heart Rhythm. 2007;4:1532–41. 30. Yang Y, Xia M, Jin Q, et al. Identification of a KCNE2 gain-offunction mutation in patients with familial atrial fibrillation. Am J Hum Genet. 2004;75:899–905. 31. Xia M, Jin Q, Bendahhaou S, et al. A Kir2.1 gain-of-function mutation underlies familial atrial fibrillation. Biochem Biophys Res Commun. 2005;332:1012–9. 32. Ravn LS, Aizawa Y, Pollevick GD, et al. Gain of function in IKs secondary to a mutation in KCNE5 associated with atrial fibrillation. Heart Rhythm. 2008;5:427–35. 33. Tinel N, Diochot S, Borsotto M, et al. KCNE2 confers background current characteristics to the cardiac KCNQ1 potassium channel. EMBO J. 2000;19:6326–30. 34. Plaster NM, Tawil R, Tristani-Firouzi M, et al. Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen’s syndrome. Cell. 2001;105:511–9. 35. Rensma PL, Allessie MA, Lammers WJ, et al. Length of excitation wave and susceptibility to reentrant atrial arrhythmias in normal conscious dogs. Circ Res. 1988;62:395–410. 36. Singh S, Zoble RG, Yellen L, et al. Efficacy and safety of oral dofetilide in converting to and maintaining sinus rhythm in patients with chronic atrial fibrillation or atrial flutter: the symptomatic atrial fibrillation investigative research on dofetilide (SAFIRE-D) study. Circulation. 2000;102:2385–90. 37. Satoh T, Zipes DP. Cesium-induced atrial tachycardia degenerating into atrial fibrillation in dogs: atrial torsades de pointes? J Cardiovasc Electrophysiol. 1998;9:970–5. 38. Olson TM, Alekseev AE, Liu XK, et al. Kv1.5 channelopathy due to KCNA5 loss-of-function mutation causes human atrial fibrillation. Hum Mol Genet. 2006;15:2185–91. 39. Yang Y, Li J, Lin X, et al. Novel KCNA5 loss-of-function mutations responsible for atrial fibrillation. J Hum Genet. 2009;54:277–83. 40. Yang T, Yang P, Roden DM, et al. Novel KCNA5 mutation implicates tyrosine kinase signaling in human atrial fibrillation. Heart Rhythm. 2010;7:1246–52. 41. Chen Q, Kirsch GE, Zhang D, et al. Genetic basis and molecular mechanisms for idiopathic ventricular fibrillation. Nature. 1998;392:293–6. 42. Wang Q, Shen J, Splawski I, et al. SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Cell. 1995;80:805–11. 43. Benson DW, Wang DW, Dyment M, et al. Congenital sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A). J Clin Invest. 2003;112:1019–28.
J.D. Roberts and M.H. Gollob 44. Darbar D, Kannankeril PJ, Donahue BS, et al. Cardiac sodium channel (SCN5A) variants associated with atrial fibrillation. Circulation. 2008;117:1927–35. 45. Ellinor PT, Nam EG, Shea MA, et al. Cardiac sodium channel mutation in atrial fibrillation. Heart Rhythm. 2008;5:99–105. 46. Herve JC, Bourmeyster N, Sarrouilhe D, et al. Gap junctional complexes: from partners to functions. Prog Biophys Mol Biol. 2007;94:29–65. 47. Vozzi C, Dupont E, Coppen SR, et al. Chamber-related differences in connexin expression in the human heart. J Mol Cell Cardiol. 1999;31:991–1003. 48. Hagendorff A, Schumacher B, Kirchhoff S, et al. Conduction disturbances and increased atrial vulnerability in Connexin40-deficient mice analyzed by transesophageal stimulation. Circulation. 1999;99:1508–15. 49. Gollob MH, Jones DL, Krahn AD, et al. Somatic mutations in the connexin 40 gene (GJA5) in atrial fibrillation. N Engl J Med. 2006;354:2677–88. 50. Thibodeau IL, Xu J, Li Q, et al. Paradigm of genetic mosaicism and lone atrial fibrillation: physiological characterization of a connexin 43-deletion mutant identified from atrial tissue. Circulation. 2010;122:236–44. 51. Yang YQ, Liu X, Zhang XL, et al. Novel connexin40 missense mutations in patients with familial atrial fibrillation. Europace. 2010;12:1421–7. 52. Yang YQ, Zhang XL, Wang XH, et al. Connexin40 nonsense mutation in familial atrial fibrillation. Int J Mol Med. 2010;26: 605–10. 53. Wirka RC, Gore S, Van Wagoner DR, et al. A common connexin-40 gene promoter variant affects connexin-40 expression in human atria and is associated with atrial fibrillation. Circ Arrhythm Electrophysiol. 2011;4:87–93. 54. Verma V, Larsen BD, Coombs W, et al. Novel pharmacophores of connexin43 based on the “RXP” series of Cx43-binding peptides. Circ Res. 2009;105:176–84. 55. Macia E, Dolmatova E, Cabo C, et al. Characterization of gap junction remodeling in epicardial border zone of healing canine infarcts and electrophysiological effects of partial reversal by rotigaptide. Circ Arrhythm Electrophysiol. 2011;4:344–51. 56. Laurent G, Leong-Poi H, Mangat I, et al. Effects of chronic gap junction conduction-enhancing antiarrhythmic peptide GAP-134 administration on experimental atrial fibrillation in dogs. Circ Arrhythm Electrophysiol. 2009;2:171–8. 57. Bennett PB, Yazawa K, Makita N, et al. Molecular mechanism for an inherited cardiac arrhythmia. Nature. 1995;376: 683–5. 58. Makiyama T, Akao M, Shizuta S, et al. A novel SCN5A gain-offunction mutation M1875T associated with familial atrial fibrillation. J Am Coll Cardiol. 2008;52:1326–34. 59. Li Q, Huang H, Liu G, et al. Gain-of-function mutation of Nav1.5 in atrial fibrillation enhances cellular excitability and lowers the threshold for action potential firing. Biochem Biophys Res Commun. 2009;380:132–7. 60. Scornik FS, Desai M, Brugada R, et al. Functional expression of “cardiac-type” Nav1.5 sodium channel in canine intracardiac ganglia. Heart Rhythm. 2006;3:842–50. 61. Rubattu S, Sciarretta S, Valenti V, et al. Natriuretic peptides: an update on bioactivity, potential therapeutic use, and implication in cardiovascular diseases. Am J Hypertens. 2008;21:733–41. 62. Sorbera LA, Morad M. Atrionatriuretic peptide transforms cardiac sodium channels into calcium-conducting channels. Science. 1990;247:969–73. 63. Perrin MJ, Gollob MH. The role of atrial natriuretic peptide in modulating cardiac electrophysiology. Heart Rhythm. 2012;9(4): 610–5.
7
Understanding the Genetic Basis of Atrial Fibrillation: Towards a Pharmacogenetic Approach for Arrhythmia Treatment
64. Ellinor PT, Low AF, Patton KK, et al. Discordant atrial natriuretic peptide and brain natriuretic peptide levels in lone atrial fibrillation. J Am Coll Cardiol. 2005;45:82–6. 65. Hodgson-Zingman DM, Karst ML, Zingman LV, et al. Atrial natriuretic peptide frameshift mutation in familial atrial fibrillation. N Engl J Med. 2008;359:158–65. 66. Levin ER, Gardner DG, Samson WK. Natriuretic peptides. N Engl J Med. 1998;339:321–8. 67. Chen HH, Lainchbury JG, Burnett Jr JC. Natriuretic peptide receptors and neutral endopeptidase in mediating the renal actions of a new therapeutic synthetic natriuretic peptide Dendroaspis natriuretic peptide. J Am Coll Cardiol. 2002;40:1186–91. 68. Conen D, Glynn RJ, Buring JE, et al. Natriuretic peptide precursor A gene polymorphisms and risk of blood pressure progression and incident hypertension. Hypertension. 2007;50:1114–9. 69. Rubattu S, Ridker P, Stampfer MJ, et al. The gene encoding atrial natriuretic peptide and the risk of human stroke. Circulation. 1999;100:1722–6. 70. Ren X, Xu C, Zhan C, et al. Identification of NPPA variants associated with atrial fibrillation in a Chinese Gene ID population. Clin Chim Acta. 2010;411:481–5. 71. Roberts JD, Davies RW, Lubitz SA, et al. Evaluation of nonsynonymous NPPA single nucleotide polymorphisms in atrial fibrillation. Europace. 2010;12:1078–83. 72. Wang TJ, Larson MG, Levy D, et al. Temporal relations of atrial fibrillation and congestive heart failure and their joint influence on mortality: the Framingham Heart Study. Circulation. 2003;107:2920–5. 73. Coumel P, Attuel P, Lavallee J, et al. The atrial arrhythmia syndrome of vagal origin. Arch Mal Coeur Vaiss. 1978;71:645–56.
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74. Kovoor P, Wickman K, Maguire CT, et al. Evaluation of the role of IKACh in atrial fibrillation using a mouse knockout model. J Am Coll Cardiol. 2001;37:2136–43. 75. Liu L, Nattel S. Differing sympathetic and vagal effects on atrial fibrillation in dogs: role of refractoriness heterogeneity. Am J Physiol. 1997;273:H805–16. 76. Gudbjartsson DF, Arnar DO, Helgadottir A, et al. Variants conferring risk of atrial fibrillation on chromosome 4q25. Nature. 2007;448:353–7. 77. Wang J, Klysik E, Sood S, et al. Pitx2 prevents susceptibility to atrial arrhythmias by inhibiting left-sided pacemaker specification. Proc Natl Acad Sci USA. 2010;107:9753–8. 78. Chinchilla A, Daimi H, Lozano-Velasco E, et al. PITX2 insufficiency leads to atrial electrical and structural remodeling linked to arrhythmogenesis. Circ Cardiovasc Genet. 2011;4:269–79. 79. Benjamin EJ, Rice KM, Arking DE, et al. Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry. Nat Genet. 2009;41:879–81. 80. Gudbjartsson DF, Holm H, Gretarsdottir S, et al. A sequence variant in ZFHX3 on 16q22 associates with atrial fibrillation and ischemic stroke. Nat Genet. 2009;41:876–8. 81. Burgner D, Davila S, Breunis WB, et al. A genome-wide association study identifies novel and functionally related susceptibility Loci for Kawasaki disease. PLoS Genet. 2009;5:e1000319. 82. Ellinor PT, Lunetta KL, Glazer NL, et al. Common variants in KCNN3 are associated with lone atrial fibrillation. Nat Genet. 2010;42:240–4. 83. Husser D, Adams V, Piorkowski C, Hindricks G, Bollman A. Chromosome 4q25 variants and atrial fibrillation recurrence after catheter ablation. J Am Coll Cardiol. 2010;55:747–53.
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Importance of Isthmus Structure in the Right Atrium Jiunn-Lee Lin, Ling-Ping Lai, Liang-Yu Lin, Chia-Ti Tsai, and Chih-Chieh Yu
Abstract
Being the chamber receiving systemic venous return, the right atrium is a structure of morphological mosaic, comprising the smooth vestibule, the septum, the trabeculated appendage and junctional crista terminalis, the Eustachian ridge, the fanning pectinate muscle, and the tendon of Todaro. The mosaic milieu by itself predisposes to the formation of reentrant atrial tachyarrhythmias. Meanwhile, the right atrium is also common with secondary isthmus structures resulting from surgical iatrogenic scars or stretch-related spontaneous scars. Inside the heterogenous scars, between adjacent scars, and between natural structural barriers and the scars, there are also facilitated opportunities of creating clinical microreentrant (focal) and macroreentrant atrial tachyarrhythmias. Keywords
Right atrium • Isthmus • Atrial arrhythmia
Anatomy of the Right Atrium Right atrium in the normal heart is the chamber receiving venous return from the superior vena cava, inferior vena cava, and heart itself from the coronary sinus. As shown in Fig. 8.1, the right atrial chamber comprises of a smooth vestibule area inserting to the tricuspid leaflets, a septal surface, and a heavily trabeculated appendage. The right atrial appendage makes extensive junction with smooth-walled venous parts at the terminal groove, which matches the terminal crest or crista terminalis in the inner surface. In morphological right atrium, thick crista terminalis fans out
J.-L. Lin, MD, PhD (*) L.-P. Lai, MD, PhD • L.-Y. Lin, MD, PhD C.-T. Tsai, MD, PhD Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan ROC e-mail:
[email protected] C.-C. Yu, MD Department of Integrated Diagnostics and Therapeutics, National Taiwan University Hospital, Taipei, Taiwan ROC A.S. Kibos et al. (eds.), Cardiac Arrhythmias, DOI 10.1007/978-1-4471-5316-0_8, © Springer-Verlag London 2014
pectinate muscles in parallel and laterally into the appendage. These muscle bundles extend around the tricuspid annulus and converging into the diverticulum inferior to the Thebesian valve bordering the coronary sinus orifice. In the majority, flap-like fibrous or muscular fold takes origin from the inferior vena cava as well as the coronary sinus ostium, constituting the Eustachian and Thebesian valves or ridges (if remnant in structure) [1, 2]. Further to the septal surface, a muscular or fibrous fold can be found to continue with the Eustachian valve, i.e., the tendon of Todaro, to separate the coronary sinus from the fossa ovalis (Fig. 8.2). The tendon of Todaro finally inserts to the central fibrous body surrounding the aortic root and pulmonary trunk [2]. The tendon of Todaro together with the tricuspid annulus and the roof of the coronary sinus constitutes the triangle of Koch, which accommodates the atrioventricular node and relevant atrial inputs (Fig. 8.2). Focusing the morphological characteristics of the right atrium, it’s easily impressed by the thick folds (e.g., crista terminalis) and heavy trabeculation (e.g., pectinate muscles in atrial appendage) in the chamber. The convergence of the crista terminalis and pectinate muscles into the hinge of tricuspid leaflets, together with the valves or ridges guarding at the 77
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Fig. 8.1 Figure (a) is a simulated right anterior oblique view of the inside of the right atrium displayed by incising the lateral atrial wall and reflecting it back. The terminal crest separates the smooth wall of the venous sinus from the rough wall of the appendage. Figure (b) shows the broad triangular-shaped appendage The dotted oval marks the sinus
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Fig. 8.2 (a) A diagram showing the area of the so-called isthmus, posterior and inferior to the triangle of Koch. The open star marks the area of the so-called subeustachian sinus. A smaller recess (closed star) is occasionally found directly inferior to the coronary sinus, (b) a heart speci-
men displayed in simulated right anterior oblique projection of 30–40° to show the septal (SI) and inferior (II) isthmic areas of the right atrium relative to the hinge line of the tricuspid valve (dotted line). The Thebesian valve is fenestrated (From Cabrera et al. [2], with permission)
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Range 22–47 20–43 16–32 19–40 0–20 0–18 8–15 7–19 6–14
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Fig. 8.3 This 4-chamber section shows the borders of the quadrilateral, its three sectors, and its dimensions (in mm) in 28 specimens. In addition to the so-called subeustachian recess (open star), there is a smaller recess (closed star) adjacent to the orifice of the coronary sinus
(CS). Note the distal branches TV of the terminal crest. ICV inferior caval vein, MV mitral valve, OF oval fossa, RPV right pulmonary vein, SS sinus septum, TC terminal crest (From Cabrera et al. [2], with permission)
orifices of the inferior vena cava and the coronary sinus, creates an anatomical environment full of potential isthmus structures with compromised conduction safety factor. Further, various surgical techniques in the correction of congenital and acquired heart diseases may as well produce iatrogenic fixed or functional obstacles, mostly thick scars in the right atrium and facilitate the formation of new isthmus tracts at risk of micro- or macroreentry. In the following, we will target at both inherent and noninherent isthmus structures existing in the right atrium and correlating the structural characteristics to respective isthmus-related atrial tachyarrhythmias.
quadrilateral area is bordered by the Eustachian valve or ridge posteriorly and the hinge of tricuspid leaflets anteriorly (Fig. 8.3). The superior border is the smooth vestibule between the lower margin of the coronary sinus and the hinge of the septal leaflet of the tricuspid valve. The inferior border is between the inferior margin of the orifice of the inferior vena cava and the smooth vestibule near the tricuspid annulus. Cabrera et al. [3] further subdivided the isthmic quadrilateral area into inferolateral, inferior (or central), and paraseptal isthmus, according to the underlying variations in muscle thickness, anatomical relations with coronary vessels, and atrioventricular nodal extension (Fig. 8.4).
Isthmus Structures in the Right Atrium The isthmus structures inherent in the right atrium are located mainly at the floor of the chamber and constructed largely by the crista terminalis, the extension of the crista terminalis, and the pectinate muscles fanning out of the crest. The isthmic
Paraseptal Isthmus The paraseptal isthmus marks the base of the triangle of Koch. The isthmus is guarded posteriorly by the tendon of
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c Fig. 8.4 (a) The endocardial surface of the right atrial isthmus is displayed to show the three levels. Note the pouch at the central isthmus and the distal ramifications of the terminal (Term.) crest that feed into the inferolateral isthmus. (b, c) The isthmus viewed in profile. The histological section shows myocardium in red and fibrous tissue in green.
The anterior sector corresponds to the vestibule leading to the tricuspid valve (TV) and is related to the right coronary artery (RCA). The posterior sector is closest to the orifice of the inferior caval vein and contains the Eustachian valve or ridge (ER) [Masson’s trichrome stain] (From Cabrera et al. [3], with permission)
Todaro, i.e., the extension of Eustachian valve, and anteriorly by the septal leaflet [3–5]. The length of the paraseptal isthmus is 24 ± 4 mm (range 14–33 mm). The muscular content of the paraseptal isthmus is the thickest in the isthmus quadrilateral, ranging from 3.1 to 4.3 mm from posterior to anterior sectors [3]. In the macroreentrant circuit of isthmus-dependent atrial flutter, the paraseptal isthmus is close to the exit site of the obligatory isthmus tract of the counterclockwise-rotating atrial flutter or the entrance site of the clockwise-rotating atrial flutter. Concealed entrainment of the counterclockwiserotating atrial flutter could be well demonstrated by overdrive pacing during tachycardia from the lower rim of the coronary sinus orifice (Fig. 8.5a). The postpacing intervals after the last paced beat from a duodecapolar electrode catheter recording parallel to the crista terminalis were identical to the tachycardia cycle length, indicating the site at the paraseptal isthmus functions as one end of the protected isthmus of the atrial flutter circuit [6]. On the other hand, Cabrera et al. [3] also demonstrated the presence of the posterior extension of the compact atrioventricular node at the paraseptal isthmus in 10 % of the autopsy hearts by histology, implicating the close neighborhood of the isthmus to the entrance of the posterior input of the compact atrioventricular node in humans. Apparently, the paraseptal isthmus could also be acting as an essential
component in the circuit of atrioventricular nodal reentrant tachycardia, particularly the slow pathway. The topological relationship to the posterior atrioventricular node extension, together with the significant thickness of the underlying muscles, makes the paraseptal isthmus an inappropriate site for transcatheter ablation of the isthmus-dependent atrial flutter.
Inferior Isthmus (or Central Isthmus) The inferior isthmus (Fig. 8.4), also known as central isthmus, has the thinnest muscular wall (average 1.2–3.5 mm) and extends over 19 ± 4 mm (range 13–26 mm) [3]. In the inferior isthmus, distal ramifications of the crista terminalis continue as oblique or longitudinal muscle fibers running from middle sector to anterior sector of the isthmus, or traverses through a recess, i.e., the subeustachian sinus, toward beneath the orifice of the coronary sinus. Also guarded by the Eustachian valve and the tricuspid annulus, the inferior isthmus is the core of the protected and obligated tract of typical and reversed typical atrial flutter. In structural point of view, however, the inferior or better called central isthmus varies hugely in detailed anatomical structures, ranging from thick or membranous Eustachian valve, membranous pouches, or obliquely oriented muscle bundles continuing
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Fig. 8.5 Demonstration of entrainment with concealed fusion by pacing at the coronary sinus ostium (CSO) for counterclockwise atrial flutter (a) and by pacing at the LLRA for clockwise atrial flutter (b). The short stimulus to onset of the ECG flutter wave interval in both situa-
tions indicates that the coronary sinus ostium was the exit of the slow conduction zone in counterclockwise atrial flutter and the low lateral right atrium was the exit in clockwise atrial flutter. The asterisk indicates the last entrained beat (From Lin et al. [6], with permission)
from the crista terminalis to the sinus septum in the posterior sector, to mainly fibrofatty membranes with sparse myocardial bundles (1–2 mm thick) at the middle sector and longitudinally oriented muscle fibers in the anterior sector (Figs. 8.3 and 8.6). The variations in the organization, branching and crisscrossing of the muscle bundles (distal pectinate muscles) at the inferior isthmus, and the depression of wave front propagation safety factor definitely aggravate the anisotropism and create the environment suitable for slow conduction [2–5].
In the circuit of isthmus-dependent atrial flutter, the inferolateral isthmus functions as the other end of the protected isthmus bordered by the Eustachian valve and the tricuspid annulus. Overdrive pacing at the low lateral right atrium close to the inferolateral isthmus can also demonstrate the concealed entrainment with identical surface ECG flutter waves and intracardiac activation sequence mapped by a duodecapolar electrode catheter positioned in parallel with the crista terminalis [6]. The postpacing interval after the last paced beat confirms the inferolateral isthmus as the entrance site of the protected isthmus of the counterclockwise-rotating typical atrial flutter or the exit site of the clockwise-rotating reversed typical atrial flutter (Fig. 8.5b). Electrophysiologic characteristics of the right atrial isthmic quadrilateral comprising the paraseptal, inferior, and inferolateral isthmus structures are distinct as the result of the mixture of nonuniform anisotropic muscle bundles, membranous pouches, recesses, and vestibules. The conduction velocity passing through the protected isthmic tract has been demonstrated to be slower in patients with clinical typical atrial flutter, ranging 0.42–0.46 m/s in either direction, than that in whom without atrial flutter (Fig. 8.7) [6, 7]. However, another study reported the transisthmus conduction is equally depressed in patients with or without atrial flutter [8]. The
Inferolateral Isthmus The inferolateral isthmus contains the final ramification of the crista terminalis and extends a length of 30 ± 3 mm (range 18–36 mm). The muscle thickness at the inferolateral isthmus averages 1.6–4.1 mm, just between that of the paraseptal and the inferior (central) isthmus. The posterior and middle sectors of the isthmus consisted of densely packed, obliquely oriented muscle bundles fanning out from the crista terminalis, inserting into the smooth vestibule at the anterior sector (Fig. 8.6). Variations in the muscular structure and orientation are much less frequent [2–5].
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Fig. 8.6 (a) The pattern of arrangement of subendocardial fibers as seen in 8 of 14 specimens. The double-headed arrows indicate the main orientations. (b) Obliquely orientated muscle fibers of the posterior sector. (c) A thick muscular bundle continues from the terminal crest to insert into the sinus septum. The middle sector is mainly membranous with fine crisscrossing muscular fibers and tendinous strands. (d) This
case shows a mainly longitudinal arrangement of the fibers in the anterior sector. A anterior sector, CS coronary sinus, EV Eustachian valve, ICV inferior caval vein, M middle sector, OF oval fossa, P posterior sector, TC terminal crest, VS vestibular sector, X intersecting fibers, ☆ subeustachian sinus (From Cabrera et al. [2], with permission)
disparity could be partly attributed to atrial chamber enlargement after prolonged or frequent attacks of atrial flutter [9]. In addition, the anatomical features at the protected tract extending from inferolateral, inferior, to paraseptal isthmus set the specific condition required for inducing specific circulating patterns of typical atrial flutter. Our study demonstrated much more frequent induction of counterclockwise-rotating typical atrial flutter by overdrive pacing at the coronary sinus orifice area, close to the paraseptal isthmus (Fig. 8.8), whereas overdrive pacing at the low lateral right atrium, close to the inferolateral isthmus, induces more the clockwise-rotating reversed typical atrial flutter (Fig. 8.9). The circumferential duodecapolar electrode catheter mapping revealed the conduction block at the entrance of the pro-
tected isthmus as the first step, followed by the initiation of the macroreentrant circulation in the right atrium, repenetration of the slow-conducting protected isthmus, and finally exiting the isthmus tract (Figs. 8.8 and 8.9).
Anatomical Variations at the Inferior Isthmus In Fig. 8.10, an illustration of the anatomy of cavotricuspid isthmus reveals multiple potential variations in anatomical structure of the crista terminalis, the pectinate muscle orientation, the Eustachian valve or ridge, and the Thebesian valve. Further delineation of the arrangement of subendocardial muscle fibers, shown in Fig. 8.6, reveals anatomical variations
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Fig. 8.7 The retrograde right atrial (RA) activation sequence of Halo catheter mapping by low lateral right atrium (LLRA) pacing (left two panels) and coronary sinus ostium (CSO) pacing (right two panels) in sinus rhythm in a patient with atrial flutter (atrial flutter +) and a patient without atrial flutter (atrial flutter −). Note that in the patient without atrial flutter, the collision site of the RA free wall and RA septal wave fronts is at Halo 5. However, in the patient with atrial flutter, the collision site shifts to Halo 7 during LLRA pacing and to Halo 3 during coronary sinus ostium pacing. The pacing cycle length was 250 ms, in 100 mm/s (From Lin et al. [6], with permission)
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Fig. 8.8 Induction of counterclockwise atrial flutter by pacing at the coronary sinus ostium site at the cycle length of 240 ms. Note the abrupt unidirectional block across the isthmus (between Halo 1 and 10) and the initiation of the counterclockwise atrial flutter (cycle length 244 ms), after repenetration of the right atrial wave front from the low
lateral right atrial end to the coronary sinus ostium end of the isthmus. (See diagram.) CSOP coronary sinus ostium pacing, CT crista terminalis, ER Eustachian ridge, S pacing spike. The asterisk indicates the pacing site (From Lin et al. [6], with permission)
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Fig. 8.9 Induction of clockwise atrial flutter by pacing at the low lateral right atrial (LLRA) site at the cycle length of 200 ms. Note the abrupt unidirectional block between Halo 1 and Halo 10 (i.e., the isthmus zone) and the initiation of clockwise atrial flutter (cycle length
224 ms) after repenetration of the right atrial wave front from the coronary sinus ostium end to the LLRA end of the isthmus. (See diagram.) CT crista terminalis, ER Eustachian ridge, LLRAP LLRA pacing, S pacing spike (From Lin et al. [6], with permission)
in the thickness, orientation, and insertion sites of the pectinate muscles as well as the mainly membranous pouches with fine interlacing muscle fibers and tendinous tendons at the posterior and middle sectors of the inferior isthmus [2, 4, 5]. Takahashi et al. [10] and our previous study have demonstrated that the preexistence of double potentials clustering mostly near the inferior vena cava orifice resulted in inherent partial cavotricuspid isthmus block during typical atrial flutter (Figs. 8.11 and 8.12). The recorded double potentials presented with wider interspike intervals when approaching to the border of the inferior vena cava orifice, while leaving clear the vestibular portion near the hinge of the tricuspid leaflets. Relevant anatomical correlation indicates a close relationship with local pouchlike recesses between branches of pectinate muscles or the sparsity of muscle fibers in the mainly membranous middle sector of the inferior or central isthmus (Fig. 8.6). The partial cavotricuspid isthmus block can be aggravated by surgical trauma during cardiopulmonary bypass procedure, e.g., vena cava cannulation [11]. Fig. 8.10 Illustration of the anatomy of the cavotricuspid isthmus including variations. Cavotricuspid isthmus extends from the tricuspid valve (TCV) to the inferior vena cava (IVC); in this particular illustration pectinate muscles are seen encroaching on to the CVTI. When this occurs, often a small vestigial remnant of the Thebesian valve (vestigial) is seen. Note, pectinates crossing the crista terminalis (CT) and forming a second crista are also shown in this figure. Medial refers to closer to the interatrial septum, and lateral refers to closer to the free wall of the right atrium. IVC inferior vena cava, EV valve of the Eustachian ridge, FO fossa ovalis, ER Eustachian ridge, CS coronary sinus, TCV tricuspid valve, CT crista terminalis, CVTI cavotricuspid isthmus (From Gami et al. [25], with permission)
Triangle of Koch The boundaries of the triangle of Koch are the tendon of Todaro posteriorly and the attachment of the septal leaflet of the tricuspid valve anteriorly. The two lateral borders converge at the apex of the triangle, near the membranous septum. The base of the triangle is the orifice of the coronary sinus [12] (Fig. 8.13). The importance of the landmark is to
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Fig. 8.11 Three-dimensional CARTO magnetic mapping during isthmus-dependent atrial flutter (AFL) in a patient with coronary artery disease, status post coronary artery bypass grafting surgery. (a) Activation sequence map. (b) Bipolar voltage map. Mapping was undertaken during AFL. As shown (caudal LAO view), the “head” to “tail” activation time around TA (red to purple) was equal to the AFL cycle length (222 ms). The barrier of double potentials (light blue dots) recorded during AFL was
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Fig. 8.12 Demonstration of the functional isthmus during coronary sinus pacing in a patient with coronary artery disease and recurrent atrial flutter by CARTO mapping. (a) Activation sequence map. (b) Bipolar voltage map. As shown in the caudal LAO view (panel a), double potentials (light blue dots) were densely clustered and formed a partially blocking barrier at the medial third of the cavotricuspid isthmus (CTI) close to the inferior vena cava (IVC) border. As shown in the left rectangles of
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shown to be distributed closely to the IVC border of the cavotricuspid isthmus (CTI) from lateral third to medial third of the isthmus. The interspike intervals (numbers in milliseconds in the left rectangles of panel a) of local double potentials were widest near the IVC. (b) Distribution of the abnormally low-voltage (≤0.5 mV) area in the CTI in the same caudal view as in panel a. Areas with local electrogram amplitude >0.5 mV are displayed in purple (From Lai et al. [11], with permission)
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panel a, the interspike intervals (number in milliseconds) of double potentials recorded during coronary sinus pacing were widest near the IVC border. The locations of the double potentials (light blue dots) were partially matched with those of the abnormally low-voltage areas within the CTI. Areas of local electrogram voltage >0.5 mV are displayed in purple. S pacing spike (From Lai et al. [11], with permission)
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help identify the location of the histologically specialized atrioventricular conduction axis, particularly the compact atrioventricular node. The triangle of Koch is not exactly an obligatory isthmus for reentry circuits like atrial flutter. The tendon of Todaro, a continuum from the Eustachian valve, doesn’t seem to function as an anatomical barrier around the compact node either. Instead, transition cells of anterosuperior approach converge broad atrial inputs from the interatrial septum into the anterior atrioventricular nodal input, functioning as the “fast pathway” in the model of dual atrioventricular nodal pathway physiology proposed by Mazgalev et al. [13] (Fig. 8.14). Meanwhile, transition cells of inferior-posterior approach converges atrial inputs from the inferior and the paraseptal isthmus and pass between the tendon of Todaro and the tricuspid annulus to the posterior atrioventricular nodal input, functioning as the slow pathway (Fig. 8.14). However, despite all the models, it remains uncertain about the necessity of the atrium tissue in the atrioventricular nodal reentrant tachycardia circuit [13, 14]. Clinical evidence of dissociated atrial activity during atrioventricular nodal reentry tachycardia does exist (Fig. 8.15) and suggests a negligible role of the atrium. However, even with observation of the mostly transient phenomenon, it is in debate about the substrate responsible for the upper turnaround or upper common pathway in the circuit. Whether it’d be the transitional cell cap or mixing with some atrial tissue or just the node itself is unknown. Taking as a whole, unlike that in flutter isthmus, the boundaries of the triangle of Koch don’t function like isthmus structures with protected borders at all.
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Left anterior oblique view
Scar-Related Isthmus Structures in the Right Atrium Besides isthmus structures inherent to normal heart, there are pathological conditions responsible for noninherent isthmuses locating over the free wall or septal site in abnormal right atrium, including isthmuses related to surgical scar, spontaneous scar, and spontaneous leak of inherent anatomic barrier like crista terminalis.
Surgical Scar-Related Isthmus Structure Traditional surgical approach for the correction of atrial septal defects, tetralogy of Fallot, and the Fontan procedure often involves right atriotomy procedure in the protocol [15–17]. The scars usually distribute over free wall of the right atrium and create various isthmus tracts in the scar, between the scars, or between the scar and an anatomical barrier. Excellent examples have been demonstrated by 3-dimensinal electroanatomical mapping and confirmed by targeted ablation of the channel-like isthmus tracts to eliminate relevant macroreentrant tachycardias, often noted as atypical atrial flutter. Figures 8.16 and 8.17 illustrated the isthmus channels between right atrial free wall scars in patients of atrial septal defect and tetralogy of Fallot after surgical correction. Figure 8.18 illustrated multiple electrophysiologically confirmed scar-related isthmus tracts and related reentrant circuits in postoperative congenital heart disease patients reported by Nakagawa et al. [15]. As shown, not only the
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Importance of Isthmus Structure in the Right Atrium
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Rabbit AV nodal axis (anterograde propagation)
Human AV nodal axis (anterograde propagation) S P
PB
“Fast” pathway
His bundle
CFB
A I
“Fast” pathway
PB
CFB
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IAS TrV
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AV N
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FO
Compact cell region
Lower cells Slow pathway
Inferior nodal extensions
TT CS IVC
CrT
His bundle
TT Transitional envelope
CS IVC
Inferior nodal extensions
CrT
Transitional envelope Slow pathway
Fig. 8.14 Model illustrating some features of the dual-pathway atrioventricular nodal electrophysiology in the rabbit (left) and human (right) heart. The region of the triangle of Koch is shown in attitudinal orientation. AVN indicates atrioventricular node, PB penetrating bundle, CFB central fibrous body, FO fossa ovalis, TT tendon of Todaro, IVC inferior vena cava, CS coronary sinus, CrT crista terminalis, IAS
interatrial septum, TrV tricuspid valve. Orientation is shown by the “compass.” Wavy arrow indicates slow pathway; dashed arrow, fast pathway; small left-to-right arrows, electrical impulses from directions other than inferior; small right-to-left arrows, reentrant exit (From Mazgalev et al. [13], with permission)
dense scars from scalpel and suture lesions but also low-voltage areas could all cause channel-like isthmus structures by themselves or together with natural anatomic barriers, e.g., orifices of inferior vena cava, superior vena cava, and tricuspid ring. The new isthmus formation and subsequent new atrial tachyarrhythmias share a lot in common with animal experiments of atypical atrial flutter induced by right atrial incision and suture, right atrial crush injury, or acute pericarditis models [18–20].
circuits. Similar to surgical scars, spontaneous scars in the free wall or septum of the right atrium can be responsible for multiple isthmus structures inside of scars, between scars, or between scars and an anatomic barrier. These noninherent isthmuses are as arrhythmogenic as inherent ones or even more vulnerable.
Spontaneous Scar-Related Isthmus Structures
Few reports utilizing noncontact mapping or electroanatomical mapping technologies have been able to demonstrate conduction gaps at the natural barrier structure like crista terminalis [23, 24]. Figure 8.20 demonstrated an example of upper loop reentry in the right atrium, utilizing a conduction gap at the mid-crista terminalis [23]. Similar gap at the inferior portion of crista terminalis has also been reported as a critical isthmus in lower loop reentry surrounding the inferior vena cava orifice [24]. The pathophysiologic mechanism responsible for the conduction gap-related isthmus structure in the natural barrier of crista terminalis remains unknown either.
Less commonly, right atrial macroreentrant tachycardias can be found in patients without prior surgery [21, 22]. The underlying pathophysiologic mechanism remains uncertain regarding the formation of spontaneous scars over right atrial free wall. Figure 8.19 demonstrated two examples of spontaneous scarring at right atrial free wall. The isthmus tracts between the spontaneous scar and the inferior vena cava orifice as well as that in between two scar patches become the obligatory slow-conducting channels in the macroreentrant
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I
50 mm/s
500 ms
S1
S1
S1
S1
S2
S1
S1
S1
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V1 A
A
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HRA
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H
H
H
H
H
AH
H
A
H
H
His Md
His Ds
CS Ps
CS Md
CS Ds
RVA
Fig. 8.15 Induction of atrioventricular nodal reentry tachycardia with complete ventriculoatrial block during tachycardia. CS coronary sinus, HRA high right atrium, RVA right ventricle apex (From Yu et al. [26], with permission)
Clinical Implications Right atrium is a cardiac chamber of morphological mosaic, combining smooth-walled venous portion and the vestibule versus heavily trabeculated atrial appendage. The in-depth understanding of the isthmus structures originating from the
anatomy would facilitate the topological-electrophysiological correlation in managing clinical atrial tachyarrhythmias. Meanwhile, keeping in mind the potential of new scar-related isthmus structure formation in apparently normal hearts or postsurgical conditions would help the definitive solution of incessant atypical atrial flutter or atrial tachycardias as well.
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Right posterior oblique projection Activation map
a SVC
b
183 ms
Voltage map
0.05 mV
– 157 ms Concealed entertainment PPI = TCL
6.1 mV
SVC
Entertainment PPI = TCL
Channel Scar
+ 60 ms Scar “Blind alley” Ablation
IVC
Scar (no potential) Double potentials Fragmented potential SVC, IVC Ablation site
Fig. 8.16 (a) Activation map during MacroAT in ASD patient shows continuous activation around smaller upper dense scar (gray area with gray tags) and line of double potentials (pink tags) and through channel (width 1.6 cm) between scars. Larger lower scar extends to IVC. (b)
IVC
1.0 cm
Bipolar voltage map shows large area of low voltage (red and orange) containing two dense scars with narrow channel (From Nakagawa et al. [15], with permission)
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RAO projection Activation map
133 ms
6.4 mV
Voltage map
SVC
SVC
Scar
–177 ms
0.1 mV
Entertainment site 1 Concealed fusion PPI = TCL (Channel entrance)
RF 1 Channel IVC
Entertainment site 2 Concealed fusion PPI = TCL (Channel exit)
Fig. 8.17 Short conduction time across channel during MacroAT in ToF patient. Reentry propagates around upper dense scar and line of double potentials (upper pink tags) and through channel (width 0.7 cm) between upper and lower dense scars. Entrainment at channel entrance (site 1) and exit (site 2) produced concealed fusion and PPI = TCL.
Scar IVC 1.0 cm
Time across channel (from site 1 to site 2) was 30 ms, only 11 % of TCL. Note line of double potentials extending from lower dense scar to IVC. One stationary RF application within channel (brown tag) terminated tachycardia at 2.2 s. RAO indicates right anterior oblique (From Nakagawa et al. [15], with permission)
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Importance of Isthmus Structure in the Right Atrium
Fig. 8.18 Schematic representation of activation and voltage maps for patients (Pts) with ASD (a), ToF (b), and Fontan procedure (c). Maps in Pts 6 and 16 were obtained during atrial pacing. Other maps were obtained during MacroAT. Orange represents low-voltage area, gray represents dense scar, and white indicates lines of double potentials. Yellow stars indicate ablation sites that terminated MacroAT. Green stars represent ablation sites within other channels identified from original map. Blue dots (Pts 10 and 14) indicate ablation sites of focal tachycardia (From Nakagawa et al. [15], with permission)
a
ASD repair
SVC
Anterior scar
IVC Pt 1
b
SVC
SVC
IVC
IVC
Pt 2
Pt 3
Correction of tetralogy of fallot Area of low voltage (≤0.5 mV) SVC SVC Anterior scar
IVC Pt 7
c
91
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SVC
Area of low voltage (≤0.5 mV) SVC SVC
IVC
IVC Line of double potentials Pt 4 Pt 5
IVC
Pt 6
Line of double potentials SVC SVC
IVC Pt 9
IVC No channel (focal AT) Pt 10
Fontan procedure Conduit SVC
IVC
IVC Scar Pt 11
Incomplete block
SVC
SVC
IVC
Area of low voltage (≤0.5 mV) Pt 12 Pt 13
IVC
SVC
SVC
IVC
IVC
Lines of double potentials Pt 14
Pt 15
Pt 16
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a
b
SVC
SVC 125ms
150ms
TA
-151ms
-149ms
TA
IVC
IVC
Fig. 8.19 Activation maps demonstrating tachycardia circuits around regions of scarring (gray) in the lateral right atrial free wall. The right atria are oriented so that the lateral wall is en face. Earliest activation is indicated in red and latest in purple. (a) Clockwise tachycardia circuit around the scar in a patient with prior cavotricuspid isthmus ablation. Note the “early meets late” (red/purple) region between the scar and the inferior vena cava (IVC), where ablation successfully terminated the
a
Fig. 8.20 Isopotential maps showing the activation sequence (frames 1–6) of single-loop reentry in the right lateral view. Color scale for each isopotential map has been set so that white indicates most negative potential and blue indicates least negative potential. The activation wave front proceeds through the channel between the CT and the central obstacle (frame 1), activates the low anterior wall (frame 2), and turns around the line of block (frame 3). Then the wave front propagates upward to the roof in front of the right atrial appendage (frame 4), turns around the superior vena cava (SVC) to activate the posterior wall (frame 5), and spreads over the top of the crista terminalis (CT) to complete the reentrant circuit (frame 6). The virtual electrograms (virtual 10–14) on the line of block showed double potentials. HIS His bundle region, IVC inferior vena cava, RAA right atrial appendage, TV tricuspid valve (From Tai et al. [27], with permission)
tachycardia. (b) Tachycardia circling in an anticlockwise fashion initially through a “channel” between two areas of scarring. Ablation within the channel caused an increase in tachycardia cycle length, and further ablation between the lower scar and the IVC terminated the tachycardia. SVC superior vena cava, TA tricuspid annulus (From Stevenson et al. [22], with permission)
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Importance of Isthmus Structure in the Right Atrium
Fig. 8.20 (continued)
93
b
References 1. Ho SY, Anderson RH, Sánchez-Quintana D. Atrial structure and fibres: morphologic bases of atrial conduction. Cardiovasc Res. 2002;54:325–36. 2. Cabrera JA, Sánchez-Quintana D, Ho SY, Medina A, Anderson RH. The architecture of the atrial musculature between the orifice of the inferior caval vein and the tricuspid valve: the anatomy of the isthmus. J Cardiovasc Electrophysiol. 2007;9:1186–95. 3. Cabrera JA, Sánchez-Quintana D, Farré J, Rubio JM, Ho SY. The inferior right atrial isthmus: further architectural insights for current and coming ablation technologies. J Cardiovasc Electrophysiol. 2005;16:402–8. 4. Waki K, Saito T, Becker AE. Right atrial flutter isthmus revisited: normal anatomy favors nonuniform anisotropic conduction. J Cardiovasc Electrophysiol. 2000;11:90–4. 5. Asirvatham SJ. Correlative anatomy and electrophysiology for the interventional electrophysiologist: right atrial flutter. J Cardiovasc Electrophysiol. 2009;20:113–22. 6. Lin JL, Lai LP, Lin JL, Tseng YZ, Lien WP, Huang SKS. Electrophysiological determinant for induction of isthmus dependent counterclockwise and clockwise atrial flutter in humans. Heart. 1999;81:73–81. 7. Feld GK, Mollerus M, Birgersdotter-Green U, et al. Conduction velocity in the tricuspid valve-inferior vena cava isthmus is slower in patients with type I atrial flutter compared to those without a history of atrial flutter. J Cardiovasc Electrophysiol. 1997;8: 1338–48. 8. Tai CT, Chen SA, Chiang CE, et al. Characterization of low right atrial isthmus as the slow conduction zone and pharmacological target in typical atrial flutter. Circulation. 1997;96:2601–11. 9. Cabrera JA, Sanchez-Quintana D, Ho SY, et al. Angiographic anatomy of the right atrial isthmus in patients with and without history of common atrial flutter. Circulation. 1999;99:3017–23. 10. Takahashi A, Shah DC, Jais P, et al. Partial cavotricuspid isthmus block before ablation in patients with typical atrial flutter. J Am Coll Cardiol. 1999;33:1996–2002. 11. Lai LP, Lin JL, Lin JM, Du CC, Tseng YZ, Huang SKS. Use of double-potential barrier to identify functional isthmus at the cavotricuspid isthmus for facilitating catheter ablation of isthmusdependent atrial flutter. J Cardiovasc Electrophysiol. 2004;15: 396–401. 12. Sánchez-Quintana D, Davies DW, Ho SY, Oslizlok P, Anderson RH. Architecture of the atrial musculature in and around the triangle of Koch: Its potential relevance to atrioventricular nodal reentry. J Cardiovasc Electrophysiol. 1997;8:1396–407.
13. Mazgalev TN, Ho SY, Anderson RH. Anatomic-electrophysiological correlations concerning the pathways for atrioventricular conduction. Circulation. 2001;103:2660–7. 14. Inoue S, Becker AE. Posterior extensions of the human compact atrioventricular node: a neglected anatomic feature of potential clinical significance. Circulation. 1998;97:188–93. 15. Nakagawa H, Shah N, Matsudaria K, et al. Characterization of reentrant circuit in macroreentrant right atrial tachycardia after surgical repair of congenital heart disease. Isolated channels between scars allow “focal” ablation. Circulation. 2001;103:699–709. 16. Della Bella P, Fraticelli A, Tondo C, Riva S, Fassini G, Carbucicchio C. Atypical atrial flutter: clinical features, electrophysiological characteristics and response to radiofrequency catheter ablation. Europace. 2002;4:241–53. 17. Markowitz SM, Brodman RF, Stein KM, et al. Lesional tachycardias related to mitral valve surgery. J Am Coll Cardiol. 2002;39:1973–83. 18. Frame LH, Page PL, Boyden PA, Fenoglio Jr JJ, Hoffman BF. Circus movement in the canine atrium around the tricuspid ring during experimental atrial flutter and during reentry in vitro. Circulation. 1987;76:1155–75. 19. Okumura K, Plumb VJ, Page PL, Waldo AL. Atrial activation sequence during atrial flutter in the canine pericarditis model and its effects on the polarity of the flutter wave in the electrocardiogram. J Am Coll Cardiol. 1991;17:509–18. 20. Feld GK, Shahandeh-Rad F. Activation patterns in experimental canine atrial flutter produced by right atrial crush injury. J Am Coll Cardiol. 1992;20:441–51. 21. Kall JG, Rubenstein DS, Kopp DE, et al. Atypical atrial flutter originating in the right atrial free wall. Circulation. 2000;101:270–9. 22. Stevenson IH, Kistler PM, Spence SJ, et al. Scar-related right atrial macroreentrant tachycardia in patients without prior atrial surgery: electroanatomic characterization and ablation outcome. Heart Rhythm. 2005;2:594–601. 23. Tai CT, Huang JL, Lin YK, et al. Noncontact three-dimensional mapping and ablation of upper loop re-entry originating in the right atrium. J Am Coll Cardiol. 2002;40:746–53. 24. Yang Y, Cheng J, Bochoeyer A, et al. Atypical right atrial flutter patterns. Circulation. 2001;103:3092–8. 25. Gami AS, et al. Electrophysiological anatomy of typical atrial flutter: the posterior boundary and causes for difficulty with ablation. J Cardiovasc Electrophysiol. 2010;21:144–9. 26. Yu CC, et al. Proximal common pathway in the circuit of atrioventricular nodal reentrant tachycardia. J Formos Med Assoc. 2005;104:951–4. 27. Tai CT, et al. Non-contact mapping to guide radiofrequency ablation of atypical right atrial flutter. J Am Coll Cardiol. 2004;44:1080–6.
9
Channelopathies and Heart Disease Bogdan Amuzescu, Bogdan Istrate, and Sorin Musat
Abstract
Channelopathies represent diseases caused by mutations in the genes encoding ion channels or associated proteins. With the advent of novel electrophysiology and molecular biology techniques, a wide variety of ion channels have been identified in different regions of the working myocardium or conduction system, and their biophysical and pharmacological properties, as well as involvement in different pathophysiology processes, are thoroughly characterized. This wealth of knowledge offers a better understanding of the intricate chemical and electrical events underlying a large class of rare heart diseases, most of them associated with arrhythmias, and also reveals novel mechanisms in the most frequent cardiovascular diseases and their complications. Within the present chapter we tackled the challenging task of presenting a comprehensive review of this rapidly expanding domain, with the hope of rendering relevant information for specialists with an interest in this highly exciting field of research. Keywords
Arrhythmia • Ion channel • Channelopathy • Long QT syndrome • Short QT syndrome • Brugada syndrome • Familial atrial fibrillation • Cardiac conduction disease • Idiopathic sick sinus syndrome • Catecholaminergic polymorphic ventricular tachycardia
Introduction Ion channels represent molecular players indispensible for integration of living organisms in the environment. They are responsible for our extraordinary performances, from the ability to do gymnastics to the perception in colors of the world and language interpretation; all these processes require rapid communication between neurons [1]. The amount of knowledge related to the functional architecture of these proteins, their biophysical and pharmacological properties, the B. Amuzescu, MD, PhD (*) • B. Istrate, PhD Department of Biophysics and Physiology, Faculty of Biology, University of Bucharest, Splaiul Independentei 91-95, Bucharest 005095, Romania e-mail:
[email protected] S. Musat, MD, PhD Themis Pathology SRL, HistoBest Diagnostics, Bucharest, Romania A.S. Kibos et al. (eds.), Cardiac Arrhythmias, DOI 10.1007/978-1-4471-5316-0_9, © Springer-Verlag London 2014
mechanisms for regulating their activity, the classification and discovery of their physiological roles, and the involvement in pathophysiology processes progressed exponentially in the second half of the twentieth century, dominating the stage of molecular biology, in a similar way to deciphering the structure of biomolecules and metabolic pathways during the first half. From this perspective, ion channels are the equivalent of enzymes. The understanding of the contribution of each type of ion channel or transporter and the corresponding current to the shape of the action potential (AP) in cardiomyocytes, as recorded with different microelectrode techniques, progressed steadily over more than five decades, largely due to the major contribution of the group of Prof. Denis Noble in developing mathematical models to describe cardiac cell electrophysiology. Thus, FitzHugh reproduced approximately the shape of a cardiac AP featuring a plateau phase starting from the Hodgkin-Huxley model, using a marked 95
96
delay in repolarization obtained by reducing the amplitude and activation speed of the K+ current and of the inactivation speed of the Na+ current (multiplication of K+ channel activation gate time constant τn by 100 or more and of Na+ channel inactivation gate time constant τh with one-third) [2]. The cardiac Purkinje fiber model developed by Noble in 1962, based on experiments performed with Otto Hutter [3, 4], proving the existence in these cells of two types of K+ currents, the delayed rectifier current IK and the inward rectifier current IK1, revealed an energy-sparing mechanism to maintain a depolarization plateau over long periods, due to the pronounced inward rectification of IK1, leading to a lower transmembrane conductance during the plateau than in the resting state, in agreement with the experimental results of Weidmann [5]. The price paid for this “pact of nature with the devil,” allowing prolonged action potentials with an energy consumption at least one order of magnitude lower than otherwise, was a fragility of the repolarization process and easy triggering of arrhythmias. The first successful voltage clamp experiments in cardiomyocytes were achieved in 1964 [6], leading to the discovery of the cardiac calcium current [7], and of multiple components of IK with distinct kinetics, originally named IX1 and IX2, now referred to as IKr and IKs [8, 9], incorporated in the McAllister-Noble-Tsien model [10]. The Na+/Ca2+ exchanger [11] was incorporated later in electrophysiology models [12], since early results suggested that Na+/Ca2+ exchange is electroneutral, featuring a 2:1 stoichiometry. This model also incorporated the “funny” (queer, anomalous rectifier, hyperpolarization-activated, or pacemaker) current If, an inward current activated by hyperpolarization [13]. The advent of novel cellular and molecular electrophysiology methods, especially the patch-clamp technique [14, 15], in combination with molecular biology approaches, such as cloning and sequencing of genes encoding the main and ancillary subunits, mutagenesis and expression in heterologous systems, in vitro or in vivo silencing, targeted knockout animal models, led to the identification of a variety of ion channels and transporters involved in shaping the AP in different cardiomyocyte populations, pacemaking, electrical wave propagation, vagal and sympathetic control of heart rate, and other physiological properties of the myocardium, as well as diverse regulatory processes involved in cardiac physiology and pathophysiology. Table 9.1 presents a summary of cardiac ion channels and transporters, and detailed comprehensive descriptions can be found elsewhere [16, 17]. Inherited mutations in the genes of several cardiac ion channels result in clinical syndromes, consisting either in isolated cardiac diseases or complex pathological entities, featuring, beyond altered cardiac functions, multiple developmental abnormalities. The majority of cardiac channelopathies are associated with phenotypes consisting in proarrhythmogenic conditions, such as long QT (LQT), short QT (SQT), and Brugada (BrS) syndromes, as listed in
B. Amuzescu et al.
Table 9.2. In the remainder of the chapter, we will present an overview of the basic structural and functional properties of the main classes of cardiac ion channels involved in channelopathies, together with brief descriptions of the pathological conditions associated with mutations in the corresponding genes.
Mutations in Cardiac Na+ Channels Sodium channels are made of pore-forming α-subunits, as well as β- and other auxiliary subunits [18]. The β-subunit regulates membrane channel expression, as well as channel gating and interaction with other structures [19]. The cardiac Na+ channel is formed of the main α-subunit Nav1.5, encoded by the gene SCN5A, composed of 2016 residues, with an apparent molecular mass of ~240 kDa, and auxiliary β1–β4 subunits, with a molecular mass of ~30–35 kDa, all of them expressed in the heart. Six alternative splicing isoforms of SCN5A have been described to date. Several intracellular proteins directly bind to Nav1.5 and contribute to its regulation: ankyrin, fibroblast growth factor homologous factor 1B (FHF1B), calmodulin, Nedd4-like ubiquitin-protein ligases, and syntrophin proteins (Fig. 9.1a). The α-subunit is composed of four homologous domains, each comprising six transmembrane α-helices: the pore-forming domains S5–S6, including between them the pore loop and selectivity filter, and the voltage-sensing domain S1–S4, including the voltage sensor S4, featuring positively charged residues at each third position, involved in channel activation [20, 21]. The intracellular linker between domains III and IV features a cluster of three hydrophobic residues (IFM) facilitating intermolecular interactions that underlie fast inactivation. The primary amino acid sequence of this region is highly conserved between species and Na+ channel subtypes. Its tertiary structure has been resolved by NMR spectroscopy [22], taking a putative form of a tilting disk that folds into the membrane to occlude the pore. The intracellular C-terminal domain, composed of 243 residues, is also involved in inactivation gating. It features a proximal structured region, comprising several α-helices (H1–H5), of which H1 and H2 bind FHF1B, the calmodulin (CaM)-binding domain within the IQ motif [23], and a distal unstructured part containing the Nedd4-like PY motif and a PDZ domain-binding syntrophin (Fig. 9.1b). Mutations in these protein-protein interaction domains have specific consequences. Thus, mutations in the region of interaction with FHF1B (residues 1773–1832) result in several forms of LQT-3 and BrS. The LQT-3 mutation D1790G disrupts the binding with the channel, cancelling the FHF1B-induced voltage shift of steady-state inactivation. There are five syntrophin isoforms (α1, β1, β2, γ1, γ2), encoded by distinct genes and differentially expressed [24], acting as adapter proteins for protein kinases, NO
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Table 9.1 Overview of cardiac ion channels and transporters Current Candidate gene Voltage-gated channels Nav1.5/SCN5A INa Cav1.2/CACNA1c ICaL Cav3.2/CACNA1h Kv4.2,4.3/KCND2,3 Kv1.4/KCNA4 Kv11.1/HERG/KCNH2 MiRP1/KCNE2 KvLQT1/KCNQ1 IKs MinK/KCNE1 MiRP2/KCNE3 Kv1.5/KCNA5 IKur Kv1.7/KCNA7 K2P IKp Kv1.2/KCNA2 IK slow Kir2.1/KCNJ2 IK1 HCN2,HCN4 If Calcium release channels RYR2 IRyR ITPR1,2,3 IIP3R Ligand-gated channels Kir3.1,3.2,3.3,3.4/GIRK1-4 IK(ACh) Kir6.2 IK(ATP) ClC2? ICl(Ca) CFTR ICl(cAMP) Mechanosensitive channels ClC3 ICl(swell) TRP? INS(stretch) Gap junctions Cx43/GJA1, Cx45/GJC1, Ij Cx40/GJA5 ICaT Ito fast Ito slow IKr
Transporters and pumps ATP1A1,A2,A3, ATP1B1,B2 INaK NCX1 INaCa ATP2A2 IpCa
Activator
Role in AP
Vm Vm
Rapid depol. Depol. and plateau
Vm Vm Vm Vm
Depol.-Pacemaker Early repol. Early repol. Plateau-repol.
Vm
Plateau-repol.
Vm
Auxiliary subunits
Blockers
β1–4 α2δ,β1, β2, β3, β4,γ1, γ2, γ3, γ4, γ5, γ6, γ7, γ8 β KChIP2 β1, β2 MiRP1 MinK MinK MiRP2
TTX, STX DHP, ΦAA
Plateau-repol.
–
μM 4AP
Vm Vm Vm Vm
Plateau-repol. Plateau-repol. Resting pot. Pacemaker
– – – –
Ba TEA Ba ZD7288
[Ca]i IP3
Plateau-repol. Plateau-repol.
– –
– –
ACh Pinacidil [Ca]i cAMP
↓Pacemaker ↓APD & Pacemaker Early repol. ↑Repol.
– SUR1 – –
Tertiapin-Q Glibenclamide DIDS, niflumate 9 AC, DNDS
Swelling Stretch
↓APD? Pacemaker?
– –
Gd, DIDS Gd
Vm, Vj Low [Ca]i High pH
AP propagation
TJP1, SRC, SGSM3, 1-heptanol CIP150, CNST, CSNK1D
[Na]i, [K]o – –
Resting pot. Ca2+ in/outflow Ca2+ reuptake
– – –
Mibefradil, Ni 4AP, 2,3DAP 4AP, 2,3DAP Dofetilide, E4031 Chromanol293
Cardiac glycosides – Thapsigargin
Adapted from Bers [17] The nomenclature for Kv channels is based on homology to Drosophila gene families referred to as Shaker, Shab, Shaw, and Shal for Kv1.x, Kv2.x, Kv3.x, and Kv4.x Abbreviations: AP action potential, APD action potential duration, Vm transmembrane potential, TTX tetrodotoxin, STX saxitoxin, DHP dihydropyridine, ΦAA phenylalkylamine, TEA tetraethylammonium, 4AP 4-aminopyridine, 2,3DAP 2,3-diaminopyridine, DIDS 4,4’-diisothiocyanatostilbene2,2’-disulfonic acid, DNDS 4,4’-dinitrostilbene-2,2’-disulfonic acid, 9AC 9-aminoacridine, ACh acetylcholine
synthase, and membrane proteins to dystrophin, in the socalled large dystrophin-associated protein complexes. Mutations in the dystrophin gene (DMD) are relatively frequent, resulting in Duchenne and Becker muscular dystrophies and X-linked cardiomyopathies with cardiac conduction defects, repolarization abnormalities, and heart failure [25]. A missense mutation (A390V) in the α1syntrophin gene (SNTA1) was found in a patient with recurrent syncope and markedly prolonged QT interval (QTc,
530 ms). This mutation disrupts the association of α1syntrophin with the cardiac isoform of plasma membrane Ca2+ ATPase (PMCA4b), which inhibits another syntrophinassociated protein and neuronal nitric oxide synthase (nNOS), increasing NO synthesis and direct nitrosylation of Nav1.5 (Fig. 9.1c). This results in an increased late Na+ current, characteristic for LQT-3 [26]. Both neural (nNOS or NOS1) and endothelial (eNOS or NOS3) isoforms are constitutively expressed throughout the heart, and the inducible
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98 Table 9.2 Classification of long QT (LQT), short QT (SQT), Brugada (BrS) syndromes, and other arrhythmogenic conditions resulting from genetic abnormalities
Type Gene Long QT syndromes LQT1 KCNQ1 LQT2 KCNH2 LQT3 SCN5A LQT4 ANK2 LQT5 KCNE1 LQT6 KCNE2 LQT7 KCNJ2 LQT8 CACNA1C LQT9 CAV3 LQT10 SCN4B LQT11 AKAP9
Protein
Functional alteration
IKs K+ channel α subunit IKr K+ channel α subunit INa Na+ channel α subunit Ankyrin B IKs K+ channel β subunit IKr K+ channel β subunit IK1 K+ channel subunit ICaL Ca2+ channel α subunit ICaL-attached caveolin 3 VW domain INa Na+ channel β4 subunit A kinase anchor protein 450 KD (Yotiao)-KCNQ1 α1 syntrophin attached to INa IK(ACh) Kir3.4 (GIRK4) subunit
Loss of function Loss of function Gain of function Loss of function Loss of function Loss of function Loss of function Gain of function Gain of function Gain of function Loss of function
LQT12 SNTA1 LQT13 KCNJ5 Short QT syndromes SQT1 KCNH2 IKr K+ channel α subunit SQT2 KCNQ1 IKs K+ channel α subunit SQT3 KCNJ2 IK1 K+ channel subunit Brugada syndromes BrS1 SCN5A INa Na+ channel α subunit BrS2 GPD1L G-3-PD 1 BrS3 CACNA1C ICaL Ca2+ channel α subunit BrS4 CACNB2b ICaL Ca2+ channel β subunit BrS5 SCN1B INa Na+ channel β1 subunit BrS6 KCNE3 MiRP2 BrS7 SCN3B INa Na+ channel β3 subunit BrS8 HCN4 If pacemaker channel subunit BrS other ANKYRIN-B Ankyrin B Catecholaminergic polymorphic ventricular tachycardia – RYR2 Cardiac ryanodine receptor – CASQ2 Calsequestrin Idiopathic sick sinus syndrome SSS1 HCN4 If pacemaker channel subunit SSS2 SCN5A INa Na+ channel α subunit Cardiac conduction disease SCN5A INa Na+ channel α subunit Familial atrial fibrillation ATFB1 ADRB1/ADRA2 β-/α-adrenergic receptor GPRK5 G-protein-coupled receptor kinase ATFB2 Locus 6q14–q16 ATFB3 KCNQ1 IKs K+ channel α-subunit ATFB4 KCNE2 IKr K+ channel β-subunit ATFB5 PITX2 Transcription factor PITX2 on 4q25 ATFB6 NPPA Atrial natriuretic peptide on 1p36.22 ATFB7 KCNA5 Kv1.5 channel α subunit ATFB8 ZFHX3 Zinc finger homebox 3 (α-fetoprotein enhancer-binding protein) on 16q22 ATFB9 KCNJ2 IK1 K+ channel subunit ATFB10 SCN5A INa Na+ channel α subunit ATFB11 GJA5 Ij Cx40 α subunit ATFB12 SUR2(ABCC9) IK(ATP) SUR2A subunit – KCNH2 IKr K+ channel α subunit Adapted from Grant [37]
Gain of function Loss of function Gain of function Gain of function Gain of function Loss of function Altered function Loss of function Loss of function Loss of function Gain of function Loss of function Loss of function Altered function Gain of function Gain of function Loss of function Loss of function Loss of function Candidate genes on 10q22–q24 Gain of function Gain of function – – Loss of function – Gain of function Gain of function Loss of function Loss of ATP reg. Gain of function
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Channelopathies and Heart Disease
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α-subunit/ NaV1.5
a
b
C-terminus of NaV 1.5 and interacting proteins
NH2
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1773-1832 Segment
PDZ binding motif SIV -COOH PDZ
ww Nedd4-like
syntrophin dystrophin
PMCA4b
SCN5A
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calmodulin
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ankyrin
Nedd4-like 1
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Brugada syndrome
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lnt.7
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891
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1406 1595
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941
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35
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1644 1645
1777
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27
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618 615
COOH
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493
1740
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319 393 298 226
1232
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367 369 294
1784
1325 1293
1102
965 1053
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535
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567
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1500 1502 1501
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Fig. 9.1 (a) Transmembrane topology of Nav1.5 α-subunit, the two associated β-subunits, and interaction with regulatory proteins. (b) The C-terminus of Nav1.5 and binding sequences for interacting proteins (Reprinted from Abriel and Kass [19], ©2005 with permission from Elsevier). (c) The nNOS complex bound to Nav1.5 (Reprinted from
Ueda et al. [26] ©2008 National Academy of Sciences, USA, with permission). (d) Point mutations in the SCN5A gene resulting in different clinical phenotypes (Reprinted from Herbert and Chahine [331] ©2006 Canadian Science Publishing, with permission)
isoform (iNOS or NOS2) is expressed under pathological conditions. Genome-wide association studies suggest that polymorphisms in the nNOS regulator (NOS1AP or CAPON) result in LQT phenotypes [27, 28]. If the genotype/phenotype relationship is supported by additional studies, SNTA1 would join the LQT-9 gene CAV3 [29] and the LQT-10 gene SCN4b [30] as a rare LQT susceptibility gene (LQT12) acting on Nav1.5 to cause a net “gain of function” via increased late INa. A mutation (A1924T) naturally occurring in the CaM-binding IQ motif abolished the enhancement by CaM of the transition in a slow inactivated state [31]. Other studies suggest that binding of CaM to the IQ motif modulates the interaction between the inactivation gate (the III–IV linker) and the C-terminal domain [32]. Of the three known ankyrin isoforms (G, B, and R), only the first two modulate Nav1.5, binding to a nine-residue sequence (1047–1055) within the II–III linker. A BrS mutation within this region, E1053K [33] cancels ankyrin G binding to the channel, also prevent-
ing the normal trafficking toward the intercalated disks [34]. A specific ankyrin B mutation generated LQT-4 syndrome in a French family [35], and other four loss-of-function mutations were found in patients with arrhythmic disorders, including sudden death [36]. Within the α-subunit itself, a multitude of point mutations have been identified, which influence permeation, gating, or regulation properties, resulting in distinct pathologies (Fig. 9.1d). Systematic mutagenesis scans of the residues in the selectivity filter identified a ring of charged residues in the pore loop of the four domains (D, E, K, A) essential for Na+ selectivity. Thus, the lysine (K) in domain III is critical for Na+:K+ selectivity, while mutation of multiple residues in domain IV renders the channel non-cation selective [37]. Mutations in the cardiac voltage-gated Na+ channel isoform Nav1.5 underlie several disease phenotypes, including long QT syndrome type 3 (LQT-3), Brugada syndrome type 1 (BrS1), isolated cardiac conduction disease (ICCD), progressive
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familial heart block type 1A (PFHB1A), also known as Lenègre-Lev disease or progressive cardiac conduction defect (PCCD), sick sinus syndrome type 1 (SSS1), familial paroxysmal ventricular fibrillation type 1 (VF1), sudden infant death syndrome (SIDS) (partly associated with LQT-3), familial atrial standstill (FAS), dilated cardiomyopathy type 1E (CMD1E), and familial atrial fibrillation type 10 (ATFB10). Typically, Na+ channel-linked syndromes are characterized by episodic attacks and heterogeneous phenotypic manifestations [38, 39]. Generally, LQT-3 syndromes result from mutationinduced disruption of channel inactivation, as originally identified in the ΔKPQ mutation, a three-residue deletion in the intracellular linker between domains III and IV involved in fast inactivation. The mutation results in a persistent non-inactivating current [40, 41] which prolongs the AP plateau and may generate early afterdepolarizations (EAD) [42]. Alterations of gating resulting in gain of function are found in at least three distinct forms: via transient inactivation failure (as found in the ΔKPQ mutation), producing sustained channel activity at the plateau potential [43, 44], via steady-state channel reopening (window current) occurring at potentials where steady-state inactivation and activation overlap [41], and via channel reopening under nonequilibrium conditions during repolarization, resulting from faster recovery from inactivation at activating potentials, as found for the I1768V mutation [45]. Conversely, Na+ channel mutations resulting in loss of function cause Brugada syndrome, an arrhythmic syndrome characterized by right bundle branch block, ST-segment elevation, and severe ventricular tachyarrhythmias [46]. Several mutations with inactivation failure, resulting in LQT-3, have been found in the C-terminal domain of Nav1.5: E1784K, Y1795C, and 1795insD [47–49]. The 1795insD mutation, the insertion of an aspartate residue in the C-terminus, can result in two distinct clinical syndromes: LQT-3 and Brugada. This apparently paradoxical behavior has been attributed to the intrinsic electrophysiological heterogeneity due to nonuniform levels of expression within the myocardium. Clancy and Rudy used Markov models for the wild-type and 1795insD Na+ channel gating included in isolated cell electrophysiology models for epicardial, endocardial, and midmyocardial ventricular cardiomyocytes, generated from the Luo-Rudy dynamic model by varying IKr and IKs maximal conductance surface densities, to demonstrate that cellular AP shapes characteristic for both syndromes can be achieved by mutant channels, depending on the cellular context and pacing rate [50]. Thus, in epicardial cells with mutant Na+ channels, there is an alternating morphology at fast pacing rates (cycle length CL = 300 ms), between spike and dome with a notch (“coved dome”) and loss of dome, and a coved dome at every beat for slow pacing rates (CL = 750 or 1,000 ms). At slow rates (CL = 1,000 ms), M cell models with mutant Na+ channels develop arrhythmogenic EADs. At fast rates, mutation-induced
B. Amuzescu et al.
changes in epicardial AP morphologies cause dispersion of plateau potentials and a voltage gradient from epicardial to M cells, manifest on the ECG as ST-segment elevation, indicative of Brugada syndrome. For coved-dome morphologies of epicardial AP, the transmural voltage gradient is reversed during phase 3 repolarization, causing T-wave inversion on the ECG. At slow rates (CL = 850 ms), the mutation prolongs APD in M cells compared to wild type, reflected as QT prolongation on ECG. Other mutations at the same position resulting in multiple phenotypes are Y1795H, causing Brugada syndrome, and Y1795C, causing LQT-3. The mutation G1406R in the S5–S6 linker region of domain III caused either BrS or ICCD in several families [51]. Deletion of a lysine in the linker between domains III and IV (ΔK1500) is associated with either BrS, LQT-3, or ICCD [52]. Beyond clinical syndromes, mutations or polymorphisms may exert pharmacological effects, by modifying drug binding [53] or increasing predisposition to drug-induced arrhythmia [54]. Flecainide proved to be a useful diagnostic tool, by producing QT prolongation in carriers of some LQT-3 mutations and evoking ST-segment elevation in patients with predisposition to Brugada syndrome [55]. In some cases, flecainide has been reported to provoke BrS features (ST-segment elevation) in patients with LQT-3 mutations [56] and to preferentially block some LQT-3 or BrS-linked mutant Na+ channels [53, 57–59]. Flecainide preferentially blocks persistent INa in the ΔKPQ mutant [60]. Flecainide, but not lidocaine, has a stronger interaction with a C-terminal D1790G LQT-3 mutant than with wild-type channels, correcting the disease phenotype [53, 61]. Some LQT-associated mutations were more sensitive to blockade by mexiletine than wild-type channels. In three of these mutations, ΔKPQ, N1325S, and R1644H, mexiletine produced a stronger block of the late Na+ current than of the peak Na+ current [62]. Cardiac Na+ channels are a target for phosphorylation by protein kinase A (PKA), protein kinase C (PKC), Ca-calmodulin kinase, or receptor or Src tyrosine kinases. Mediators acting via tyrosine kinases include insulin and the epidermal growth factor [63–65]. Another modulator of cardiac Na+ channels is glycerol-3-phosphate dehydrogenase 1-like kinase, recently identified in a large family with Brugada syndrome via positional cloning of a locus on chromosome 3p24 distinct from the SCN5A locus, 3p21. A mutation (A280V) of a conserved residue in this enzyme reduced Nav1.5 surface expression by 31 % in co-expression systems [66].
Mutations in Cardiac Ca2+ Channels Voltage-gated calcium channels can be classified into highvoltage activated (HVA) and low-voltage activated (LVA). The first group comprises several types: L (large, lasting),
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Channelopathies and Heart Disease Genes CACNA1X Cav1
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Proteins
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101 Channel types
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γ β1 β2 β3 β4
S S
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LVA:
α2 δ 1 α2 δ 2 α2 δ 3 α2 δ 4
In
β Ca2+
? Ca2+
Fig. 9.2 (a) The three families of voltage-gated Ca2+ channels. (b, c) The general architecture of high-voltage-activated (HVA) and low-voltage-activated (LVA) Ca2+ channels, including main (α) and
ancillary subunits (Reprinted from Zamponi et al. [72], ©2009 with permission from Springer)
N (neuronal), P/Q, and R, with distinct functional and pharmacological properties (Fig. 9.2a). The second group contains the T type (tiny, transient), represented by three isoforms for the main subunit, Cav3.1–3.3 (α1G, α1H, α1I), of which two are expressed in the heart, Cav3.1 and Cav3.2 [67]. The T-type Ca2+ current was first described in cardiomyocytes, via whole cell patch clamp in dog atrium [68] or single-channel recordings in guinea pig ventricular myocytes [69]. Actually, T-type channels are present, to a variable extent, only in atrial and conduction cells (e.g., Purkinje fibers) and may contribute to the late diastolic depolarization in some pacemaker cells [70, 71], while the only other type found in myocardium, the L type, is abundant in all cardiomyocytes, located mainly in the t-tubules. The Cav1 family (Cav1.1–1.4) encodes L-type Ca2+ channels, of which Cav1.2 is expressed in the myocardium. These channels are heteromultimers, composed of a pore-forming α1 subunit and ancillary β, α2δ, and in some cases also a γ-subunit, in a fixed stoichiometry α1:α2:β:δ = 1:1:1:1 (Fig. 9.2b). Vertebrates express four different types of calcium channel β-subunits (β1 to β4), four different types of α2δ-subunits (α2δ1 to α2δ4), and eight different γ-subunits [72]. Three of the four types of β-subunits (β1–β3) are retrieved in the heart [73] but also in the brain and spleen. Although present in all tissues, β2 is a skeletal muscle isoform [74]; β3 is expressed mostly in brain, smooth muscle, and ovary; and β4 is expressed predominantly in the cerebellum and kidney. The γ-subunits, including four transmembrane helices, are found only in skeletal muscle (γ1) or at neuronal level (γ2–γ8), functioning as auxiliary subunits for AMPA glutamate receptors. The auxiliary subunits β and α2δ regulate channel activity. The β-subunits, located on the cytoplasmic side of the membrane, interact with the linker between domains I and II of the main subunit, accelerating activation and inactivation kinetics, modulating G-protein
inhibition, and also increasing channel expression approximately tenfold. The α2δ-subunit is encoded by a single gene, the product of which is posttranslationally cleaved into a transmembrane δ-subunit bridged to the extracellular α2-subunit by a disulfide link. The α2δ-subunit also regulates Ca2+ current density and activation/inactivation kinetics. The MIDAS-like motif in the VWFA domain of α2δ binds divalent metal cations and is required to promote trafficking of the α1-subunit to the cell membrane by an integrin-like switch. To date there are 35 known splice variant isoforms of the calcium channel main subunit. The pore loop of each domain contains an essential glutamate residue. Together, these residues form a charged ring (EEEE) critical for calcium selectivity. Mutation of a single glutamate residue from this ring results in a channel selective for monovalent cations [75]. The C-terminal domain features multiple Ca2+ binding sites and Ca2+/CaM-dependent kinase activity. Cav1.2 gating is both voltage and Ca2+ dependent. Variations of calcium concentration in the vicinity of the channel endodomain modulate its inactivation kinetics. A recently proposed Markov model for the L-type Ca2+ channel gating [76] represents voltage-dependent (VDI) and calcium-dependent inactivation (CDI) as completely separate events. Ca2+-dependent inactivation can occur irrespective of the channel state along the voltage-dependent pathway; therefore the state diagram comprises two homologous tiers connected by every pair of equivalent states: an upper voltage-gating mode (Mode V) and a lower Ca2+gating mode (Mode Ca). Mode V diagram features a single open state and two voltage-inactivated states, fast and slow. CDI involves Ca2+ binding to CaM, tethered to a region of the C-terminus known as the IQ motif. Mutations to either the IQ motif [77, 78] or CaM [79, 80] eliminate CDI. During prolonged depolarizations, Ca2+ reuptake in the sarcoplasmic reticulum can produce recovery from CDI and trigger
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EADs, which may result in severe arrhythmias. Although the cardiac-specific α1-subunit (α1C) is similar to that of voltage-gated Na+ channels, composed of the same four domains, mutations of the cardiac L-type Ca2+ channel gene CACNA1C leading to clinical syndromes are far less frequent than those of the Na+ channel gene SCN5A, perhaps because most mutations have consequences too severe to be compatible with life, resulting in spontaneous abortions. A recently identified channelopathy resulting from a point mutation in the Cav1.2 gene (CACNA1C) is Timothy syndrome, a multisystem disease combining LQT syndrome, cognitive abnormalities, immune deficiency, hypoglycemia, and syndactyly. The disorder was named in honor of Dr. Katherine W. Timothy, who was among the first to identify a case of severe LQT syndrome and syndactyly and performed much of the phenotypic analysis that revealed other abnormalities. Further studies [81, 82] identified five infant cases, three males and two females, with long QT syndrome, syndactyly, and transient 2:1 atrioventricular block, all with negative family history, of which four died suddenly at an early age. Two of them also presented cardiovascular malformations, such as patent ductus arteriosus or a tiny membranous ventricular septal defect and patent foramen ovale. Splawski et al. [83] performed an in-depth study on a group of 17 children with severe QT prolongation, syndactyly, abnormal teeth, baldness at birth, life-threatening arrhythmias, and various congenital heart malformations, such as patent ductus arteriosus, patent foramen ovale, ventricular septal defects, tetralogy of Fallot, and premature death in 10 cases, at an average age of 2.5 years [83]. Some cases presented dysmorphic faces, with flat nasal bridge, small upper jaw, low-set ears, or small or misplaced teeth. Of the surviving group, many presented neurological abnormalities consisting in developmental delays in motor skills, language, generalized cognitive impairment, and autism. The study led to the identification of a new unique mutation in exon 8A of the CACNA1C gene, G406R. This mutation of glycine to arginine converts a neighboring serine to a consensus site for phosphorylation by calmodulin kinase, which promotes a slow-gating mode, increasing intracellular Ca2+ entry. A subsequent study [84] identified de novo missense mutations G406R and G402S in exon 8, a splice variant analog of exon 8A, in two patients with a severe variant of Timothy syndrome without syndactyly, resulting in a variety highly expressed in heart and brain, amounting to approximately 80 % of CACNA1C mRNA. A recent study [85] proposes a drug therapy for Timothy syndrome, roscovitine, a compound that increases the VDI of Cav1.2, restoring the electrical and Ca2+-signaling properties of cardiomyocytes derived from induced pluripotent stem cells obtained from epithelial cells of these patients. While mutations found in Timothy syndrome are characterized by a gain of function of Cav1.2, a recent screening study performed on 82 patients with Brugada syndrome [86]
B. Amuzescu et al.
identified loss-of-function missense mutations in the main subunit gene CACNA1C (A39V and G490R) and in the β2 subunit gene CACNB2 (S481L). The study comprised whole-cell patch-clamp recordings in CHO-K1 cells cotransfected with cDNAs encoding wild-type or mutant sequences of subunits α1C, β2, and α2δ. These mutations underlie novel clinical entities consisting in ST-segment elevation in the right precordial ECG leads, a shorter-than-normal QT interval, and a history of sudden cardiac death. These CACNA1C and CACNB2-mediated syndromes can be considered as BrS types 3 and 4, or short QT syndromes (SQTS) types 4 or 5, depending on the specific definition of SQT and correction formula used for the QT interval. Thus, corrected QT intervals (QTc) were ≤360 ms in the three patients with mutations and in the range from 330 to 370 ms among probands and clinically affected family members, with a reduced rate adaptation of the QT interval. Quinidine normalized the QT interval and prevented stimulation-induced ventricular tachycardia. One of the two BrS3 cases was a 41-year-old man of Turkish descent, presenting atrial fibrillation and a QTc of 346 ms, with further ST-segment elevation in V1 and V2 upon ajmaline administration and inducible ventricular tachycardia, with a brother who died of cardiac arrest at age 45 and two daughters with QTc intervals of 360 and 373 ms. The other was a 44-year-old man of European descent with prominent ST-segment elevation in V1, saddleback ST-segment elevation in V2, a prominent J wave in lead III, and a QTc of 360 ms, presenting also facioscapulohumeral muscular dystrophy, and his mother had two syncopal episodes at age 48 resulting in sudden cardiac death. The BrS4 case was a 25-year-old man of European descent who presented with aborted sudden cardiac death, with a QTc of 330 ms, with coved-type ST-segment elevation in V1 and V2 after ajmaline challenge, and with a 23-year-old brother with a 2-year history of syncope. Programmed atrial stimulation induced atrial fibrillation in both brothers and AV nodal reentrant tachycardia in the younger one. Of the ten family members tested, six featured ST-segment elevations ≥2 mm at baseline or after ajmaline and a shortened QTc. Although T-type Ca2+ channels (Fig. 9.2a, c) are expressed to a lesser extent in the myocardium compared to L type, and therefore T channelopathies are less prone to feature cardiac abnormalities, important changes in Cav3 expression occur in different stages of cell differentiation or in certain pathological processes. In the heart of most mammalian species, T currents are robustly expressed in embryonic heart, in both atrial and ventricular myocytes, but are absent or much reduced in postnatal ventricular myocytes [87]. In rat myocardium, Cav3.2 is the predominant subtype at embryonic days E9.5 and E18, as revealed by qPCR analysis, while Cav3.1 increases from E9.5 to E18 but reaches lower levels compared to Cav3.2. In contrast, Cav3.1 is more widely expressed than Cav3.2 in adulthood, although ICaT was
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Channelopathies and Heart Disease
undetectable in adult ventricular myocytes [88]. Similarly, ICaT has never been recorded in any adult human heart tissue. Like other fetal genes reexpressed upon ventricular remodeling, T-type channels decrease during development but reappear under pathological conditions such as pressure-overload cardiac hypertrophy, myocardial infarction, and heart failure [89–92]. Given the relatively high Ni2+ sensitivity of this reexpressed ICaT, the main underlying type may be Cav3.2. Remodeling is often associated to Ca2+ overload, and presumably the T-type current provides a continuous Ca2+ inflow into the cell, a hypothesis offering a rationale to the pharmacological use of ICaT antagonists. It has been shown that tachycardia-induced atrial remodeling downregulates ICaL without reducing ICaT [93]. Consequently, long-term therapy with mibefradil was attempted and shown to be highly effective, more than verapamil, in preventing the induction and maintenance of atrial fibrillation in dogs subjected to 7 days of rapid atrial activation. However, mibefradil as adjunct therapy in chronic heart failure patients demonstrates poor outcomes [94]. ICaT expression is also upregulated by several endocrine signals, such as insulin-like growth factor 1 (IGF-1), endothelin 1 (ET-1) following activation of protein kinase C, aldosterone, angiotensin II, or β-adrenergic stimulation. Following the observation that infants develop hypertrophic cardiomyopathy in approximately 30 % of diabetic pregnancies, it was shown that after 48 h in 25 mM glucose, ICaT increases significantly, as well as the expression of α1G and α1H mRNAs. High glucose also significantly increases ventricular cell proliferation and the proportion of cells in the S phase of the cell cycle, both effects being reversed by Ni2+ or mibefradil. After a clinical trial demonstrated the beneficial effect on the cardiac function of spironolactone, an aldosterone antagonist [95], this hormone has been considered a major cardiovascular risk factor, able to increase dose dependently the spontaneous heart rate. This effect was prevented by Ni2+ and mibefradil, as well as by actinomycin D and spironolactone, and reduced by RU486, suggesting a mixed mineralocorticoid/glucocorticoid receptor-dependent transcriptional mechanism for T-type Ca2+ channel upregulation, with a rapid onset of action, after only 24 h of exposure to aldosterone. Mineralocorticoid antagonists are effective in reducing tachycardia, arrhythmias, and ventricular fibrillation in congestive heart failure [96].
Mutations in Cardiac K+ Channels In contrast to the relative uniformity of Na+ channels, K+ channels manifest a surprising variety. Thus, three main classes of K+ channels have been identified within the myocardium: voltage-gated K+ channels (IKs, IKr, Ito, and IKur), inward rectifier K+ channels (IK1, IK(ACh), and IK(ATP)), and background K+ channels, such as TASK-1 or TWIK-1/2 [37].
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As previously stated, the delicate balance between inward depolarizing currents and outward repolarizing currents during the cardiac AP plateau represents an energy-sparing mechanism, at the cost of rendering the repolarization process fragile [97]. Therefore, a wide variety of factors, including mutations, that interfere with the function of repolarizing K+ channels, may trigger severe arrhythmias. Two components of the delayed rectifier K+ current with distinct kinetics were first identified in cardiomyocytes by Noble and Tsien, receiving the names IX1 and IX2 [8, 9]. Further studies [98, 99] characterized these two components, renamed IKr and IKs. IKr activates and inactivates rapidly, displays marked inward rectification, and is selectively blocked by lanthanum and class III antiarrhythmic drugs dofetilide, E4031, almokalant, and sotalol, while IKs is sensitive to clofilium, NE-10064, NE-10133, L-768673, and HMR-1556 [100–102]. Some myocytes, e.g., those in guinea pig node, express only IKs [103], while others, e.g., cat or rat ventricular cells, express only IKr [104, 105]. The fastest component of this type, IKur (ultrarapid), formerly known also as Iss (steadystate) or Isus (sustained) [106], was found in human and rat atrium [107, 108] and a similar current, IKp (plateau), in ventricular myocytes [109]. Several studies have evidenced the regional differences in membrane surface density for delayed rectifier and transient outward channels, especially their ventricular transmural gradient, and their important role in shaping the AP and setting the order of repolarization in these territories. Thus, in dog ventricle IKs density is higher in epicardial and endocardial cells than in the midmyocardium [110]. In guinea pig left ventricular free wall, IKr density is higher in subepicardial than in midmyocardial or subendocardial myocytes [111, 112], while at the base the densities of IKr and IKs are lower in endocardial than in midmyocardial or epicardial cells. In human [113] or canine [114] left ventricle, Ito density is 5 to 6-fold higher in epicardial and midmyocardial than in endocardial cells.
Slow Delayed Rectifier K+ Current (IKs) Voltage-gated K+ channels consist of main pore-forming α-subunits, with a homo- or heterotetrameric quaternary structure, accessory β-subunits, as well as associated interacting cytoskeletal proteins, such as those in the KChAP (K+ channel associated protein) and KChIP (K+ channel interacting protein) group. The main subunits of IKs and IKr are encoded by KCNQ1 (KvLQT1) and KCNH2 (Kv11.1 or hERG), respectively, and the corresponding β-subunits by KCNE1 (MinK) and KCNE2 (MiRP1–MinK-related peptide 1), respectively. MinK and MiRP1 are single membrane-spanning proteins with extracellular amino termini, showing oxidoreductase activity, which regulate α-subunit functions, including gating, response to sympathetic stimulation, and drugs.
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KCNQ1 shares topological homology with other voltagegated K+ channels with 676 residues per subunit [115]. β-adrenergic stimulation increases IKs through PKAdependent phosphorylation, via a complex including PKA, protein phosphatase 1 (PP1), and the adaptor protein Yotiao [116]. Yotiao is bound to a leucine zipper motif in the C-terminus of KvLQT1, in turn binding and recruiting PKA and PP1. The complex regulates the phosphorylation of Ser27 in the N-terminus of the channel, which increases current amplitude by increasing activation rate and reducing deactivation rate, resulting in faster repolarization. Mutations in the KCNQ1 gene are at the origin of long QT syndrome type 1 (LQT1), also known as Romano-Ward syndrome (RWS), an autosomal dominant disease lacking extracardiac features, the Jervell and Lange-Nielsen syndrome type 1 (JLNS1), an autosomal recessive disorder characterized by congenital deafness, QT prolongation, syncopal attacks due to ventricular arrhythmias, and a high risk of sudden death, familial atrial fibrillation type 3 (ATFB3), and short QT syndrome type 2 (SQT2). Mutations in KCNQ1 (the gene encoding KvLQT1) and KCNH2 (the gene encoding hERG) account for more than 80 % of autosomal dominant LQTS [37]. Mutations of the α-subunit KCNJ2 and the β-subunits of KvLQT1 (MinK) or hERG (MiRP1) are minor causes of LQTS. A screening study on 262 unrelated individuals with LQT syndrome identified mutations in 177 individuals (68 %), of which 87 % were accounted for by KCNQ1 (42 %) and KCNH2 (45 %), 5 % by associated β-subunits KCNE1 (3 %) and KCNE2 (2 %), and 8 % by SCN5A [117]. Most of the mutations leading to LQT-1 exert a dominantnegative effect, coassembling with normal subunits but impairing their function. Polymorphisms of these genes may also increase susceptibility to drug-induced LQTS. More than 30 mutations have been identified in KCNQ1 and KCNE1. Many of them reduce IKs via dominant-negative effects [118–120], reduced responsiveness to β-adrenergic signaling [121, 122], or alterations in channel gating [117, 123–125]. In some instances there is a complete loss of current, resulting from assembly of nonfunctional channels or failure of channel trafficking to the plasma membrane [118, 119, 126, 127]. Mutations affecting gating can either reduce the channel activation rate, e.g., R539W KCNQ1 [128], R555C KCNQ1 [129], or increase channel deactivation, e.g., S74L KCNE1 [130], V74F and W87R KCNE1 [119], and W248R KCNQ1 [131]. G589D KCNQ1 disrupts the leucine zipper motif, preventing cAMP-dependent regulation of IKs, resulting in LQT1. KCNE1 is also required for this cAMP-dependent IKs regulation [122]. Even if KvLQT1 phosphorylation is independent of coassembly with MinK, transduction of phosphorylated channels in the physiologically required increase in reserve channel activity requires the β-subunit. Several KCNE1 point mutations disrupting the physiological effects of KvLQT1 phosphorylation result in LQT-5, the
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KCNE1-specific form of LQTS. Thus, the W87R mutation speeds channel deactivation, which is not slowed by cAMP. The D76N mutation ablates functional regulation of the channels by cAMP. A specific LQT-1 mutation in the pore region of KCNQ1, L273F, presents slow voltage-dependent inactivation, which, in experimental settings, delays entry of Ba2+ ions to the pore, trapping them by slowing their exit from the selectivity filter. External K+ ions accelerate inactivation kinetics and exacerbate Ba2+ trapping [132]. In 1964, Ward reported two cases of syncope related to ventricular fibrillation in a brother and sister with long QT on resting ECG, a feature retrieved in their mother [133]. The cases lacked deafness, making this syndrome distinct from the autosomal recessive Jervell and Lange-Nielsen syndrome, described in 1957 in a family in which four of six children, born to unrelated parents, had congenital deafness and prolonged QT interval and died suddenly in childhood [134]. However, the new syndrome was called RomanoWard, since Romano et al. described it 1 year before [135]. A further study concluded that in Japan females are more severely affected than males [136]. Another study found out that affected individuals were hypokalemic and benefited from K+ administration [137]. The resting heart rate of Romano-Ward syndrome patients was significantly slower in newborn and children under age 3, due to a right-sided sympathetic deficiency [138]. This hypothesis was confirmed by cardiac SPECT screening with I123-MIBG, an analog of norepinephrine and guanethidine, in five LQTS patients with at least one episode of torsades de pointes, ventricular fibrillation, or syncope, all of them presenting reduced or absent MIBG uptake in the inferior septal parts of the left ventricle compared to a control group [139]. In a screening study for 5 LQT-associated cardiac channel genes in 541 unrelated patients, Tester et al. identified 211 different pathogenic mutations in 272 patients (50 %), of which 29 (11 %) had double LQTS mutations, 16 of them (8 %) in two distinct LQTS genes (biallelic digenic) [140]. Patients with multiple mutations were younger at diagnosis, but no significant genotype/phenotype correlation associated with location or type of mutation could be identified. Another study [141] searched for linkage with HLA A, B, C, DR, and GLO loci in a family with ten cases of Romano-Ward syndrome presenting the same HLA haplotype [142] without any positive evidence. However, a further study on families of Japanese and European descent found an association between LQT phenotype and specific HLA DR genes [143]. Their data proved that DR2 has a protective effect, and DR7 may increase susceptibility to the LQT syndrome, particularly in males. Thus, LQT-1 syndrome may be influenced by genes on chromosomes 6 and 11, possibly with a sex-specific effect. Congenital syndromes involving QT interval prolongation and syncope or sudden death were first described in the late 1950s and early 1960s, although syncope associated
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Channelopathies and Heart Disease
with the initiation of quinidine therapy had been recognized since the 1920s, and the availability of ECG monitoring in the 1960s led to the identification of pause-dependent polymorphic ventricular tachycardia as the underlying mechanism [144]. The term “torsades de pointes” was first used in 1966 to describe the peculiar appearance of a ventricular tachycardia in an elderly woman with a heart block [145]. The few ECG-documented cases of syncope or sudden death in patients with congenital LQTS have been characterized by torsades de pointes, although the pause dependence typical of the drug-related form is not always present [146]. Although torsades de pointes can occur in many settings, such as heart block or intracranial disease such as subarachnoid hemorrhage, it is usually seen in patients with one of the congenital LQTS or in association with drug therapy [147]. The list of drugs that may cause torsades de pointes includes several class III antiarrhythmics which are KvLQT1 blockers, such as dofetilide, ibutilide, sotalol, and amiodarone; class Ia antiarrhythmics such as quinidine, procainamide, or disopyramide; calcium channel blockers such as bepridil or lidoflazine; and a wide variety of hERG blockers including macrolide antibiotics (clarithromycin, erythromycin), antiemetic agents, and motility regulators such as cisapride, domperidone, and droperidol and antipsychotic agents such as chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide, and methadone. Other drugs that may block KvLQT1 are the widely used diuretic agent indapamide, the benzodiazepine L7, chromanol 293B, which produces a voltage-dependent open channel block and is less prone to proarrhythmic effects, and the class III antiarrhythmic drug azimilide, a blocker of both IKr and IKs with rate-independent effects maintained under ischemic or hypoxic conditions [115]. Risk factors for drug-induced torsades de pointes include female sex, hypokalemia, severe hypomagnesemia, bradycardia, baseline QT prolongation or subclinical LQTS, ion channel polymorphisms, congestive heart failure, digitalis therapy, recent conversion from atrial fibrillation, especially with a QT-prolonging drug, high drug concentrations, and rapid rate of intravenous infusion with a QT-prolonging drug [147]. Clinical management of LQT-1 and LQT-5 includes β-adrenergic blockade with propranolol [148], sympathetic denervation of the heart [149], left stellate ganglion block or ablation [150], continuous isoproterenol infusion [151], or automatic implantable defibrillators/ permanent pacemakers, sometimes placed very early during lifetime, e.g., at 19 days after birth, and set at high pacing rates, over 110 beats/min [152]. In such a case, rapid rate pacing resulted in progressive left ventricular dilation and diffuse hypokinesia, requiring orthotopic heart transplantation at age 12. In a study on six patients with known KvLQT1 mutations, of whom four had documented episodes of torsades de pointes, Shimizu et al. showed that co-infusion of nicorandil alleviated early afterdepolarization phenomena,
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however without any clear benefit over conventional β-blocker therapy [153]. A retrospective study found that patients carrying mutations in the KCNQ1 gene responded better to β-adrenergic blocking agents than did those with mutations in the KCNH2 gene (12 of 13 vs. 1 of 5, p = 0.0077, Fisher’s exact test) [154]. The Jervell and Lange-Nielsen syndrome type 1 (JLNS1) is caused by homozygous or compound heterozygous mutations in the KCNQ1 gene, located on chromosome 11p15. A molecular genetics study detected homozygosity for a deletioninsertion mutation (1,244, −7 +8) in the C-terminal domain of KCNQ1 in three affected children of two families with JLNS [155]. Another report identified two deaf siblings in a small Amish family, both homozygous for a 2-bp deletion in KCNQ1 [123]. A study on ten JLNS families in Great Britain and Norway identified nine different mutations in the KCNQ1 gene, with truncation of the protein proximal to the C-terminal assembly domain, expected to preclude assembly of KCNQ1 monomers into tetramers, thus explaining the recessive inheritance of JLNS [156]. This hypothesis was strengthened by a report that identified a small domain between residues 589 and 620 in the KCNQ1 C-terminus that may function as an assembly domain for KCNQ1 [157]. The deletion-insertion mutation at KCNQ1 residue 540 described by Neyroud et al. [155] eliminated important parts of this C-terminal assembly domain. These results provided a molecular basis for the clinical observation that heterozygous JLN carriers show slight cardiac dysfunction and that the severe JLNS phenotype is characterized by the absence of the KvLQT1 channel. A study of 252 probands with LQTS identified 4 cases with compound heterozygous and 2 with homozygous mutations in KCNQ1, none of whom were deaf [158]. The carriers of biallelic KCNQ1 mutations had a severe cardiac phenotype but were not deaf because the KvLQT1 channel retained some function. Thus, in JLNS1 deafness occurs because KvLQT1 plays an important role in hearing via control of endolymph homeostasis being expressed in the stria vascularis of the inner ear, as shown by in situ hybridization. Another variant of the Jervell and Lange-Nielsen syndrome (JLNS2) is caused by homozygous or compound heterozygous mutations in the KCNE1 gene on chromosome 21q22. The finding is based on a study in a small consanguineous British family with JLNS, where affected children were homozygous by descent for markers on chromosome 21, in a region containing the KCNE1 gene [159]. Another study found compound heterozygosity for KCNE1 mutations in affected members of a Lebanese family with JLNS [160]. An interesting case was a young girl with JLNS via homozygous KCNE1 mutation, her heterozygous first-degree relatives presenting a milder phenotype with partial hearing loss and QT prolongation [161]. Whereas LQT-1 and LQT-5 syndromes are caused by mutations in the KCNQ1 and KCNE1 gene, respectively, resulting in KvLQT1 loss of function, KCNQ1 gain-of-function
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mutations lead to the opposite phenotype, short QT syndrome (SQTS). Defects in KCNQ1 are the cause of short QT syndrome type 2 (SQT-2), characterized by idiopathic persistently and uniformly short QT intervals on ECG in the absence of structural heart disease in affected individuals, causing syncope and sudden death. The first reported case was a 70-year-old man, lacking any physical or physiologic abnormalities and with a negative family history, who was successfully resuscitated after an episode of ventricular fibrillation. Subsequent 3-year ECG follow-up showed consistent QT interval shortening (290 ms) [162]. Analysis of candidate genes identified a g919c substitution in KCNQ1, leading to the V307L mutant, characterized by a pronounced negative shift of the half-activation potential and an acceleration of the activation kinetics. Another gain-of-function mutation, familial atrial fibrillation type 3 (ATFB3) was first reported by a study on a four-generation Chinese family from Shandong province, presenting autosomal dominant hereditary atrial fibrillation [163], based on a proband identified in 1970 at age 22. The study found linkage of the disorder to chromosome 11p15.5, related to a S140G mutation in KCNQ1.
Fast Delayed Rectifier K+ Current (IKr) The marked differences between the native IKr current and hERG currents in heterologous expression systems in terms of gating, regulation by external K+, and sensitivity to antiarrhythmics suggest the presence of accessory modulating subunits. The β-subunit MiRP1, encoded by KCNE2, causes a +5 → 10 mV depolarizing shift in steady-state activation when co-expressed with hERG, accelerates the rate of deactivation, and causes a decrease in single-channel conductance from 13 to 8 pS [164]. However, many other factors may contribute to these differences, including heteromultimers with ERG2 and 3, several ERG1 splice variants identified in the heart [165, 166], and posttranslational modification of hERG proteins [105, 167]. More than 200 mutations in KCNH2 cause a loss-of-function phenotype resulting in the proarrhythmic type 2 long QT syndrome (LQT-2), with missense single-residue substitutions being predominant (~67 % frequency). The LQT-2 phenotype can result via multiple mechanisms, including abnormalities in Kv11.1 synthesis (class 1 mechanism), defects in intracellular transport (protein trafficking) to the cell membrane (class 2 mechanism), channel gating (class 3 mechanism), or permeation (class 4 mechanism) [168]. A study on 34 missense Kv11.1 LQT-2 mutant channels expressed in HEK293 cells revealed that 28 of them resulted via a class 2 mechanism (Fig. 9.3), which could be corrected when the cells were incubated for 24 h at reduced temperature (27 °C) or with the drugs E4031 or thapsigargin [169]. Pore mutations may also result in a loss
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of function, sometimes due to a trafficking defect [170], they may or may not coassemble with wild type hERG subunits to exert dominant-negative effects [117, 171], or may give rise to altered channel kinetics leading to decreased repolarizing currents [172, 173]. Other mutations altering deactivation kinetics are those located in the Per-Arnt-Sim (PAS) domain, in the N-terminal region of hERG, which normally interacts with the channel and reduces the rate of deactivation. A particularly interesting mutation, N629D, leading to loss of C-type inactivation coupled with loss of K+ selectivity, results in a gain of function. The mutation from GFGN to GFGD in the selectivity filter sequence results in a loss of K+ vs. Na+ selectivity, allowing for nonspecific passage of monovalent cations. Mutations in hERG account for LQT-2, the second most common form of LQTS, a disease affecting approximately 1 in 5,000 individuals. Almost all hERG mutations characterized to date are loss-of-function mutations, via haploinsufficiency or dominant-negative suppression of wild type channels. The first study indicating that mutations in the hERG gene are responsible for LQT-2 [174] included a single-strand conformation polymorphism and DNA sequence analysis, detecting hERG mutations in six LQT families, including two intragenic deletions, one splicedonor mutation, three missense mutations, and a de novo mutation in one kindred. Although inheritance of LQTS is autosomal dominant, female predominance has often been observed, sometimes being attributed to increased susceptibility to cardiac arrhythmias in women. A recent study demonstrated distortion in the transmission of the mutant alleles in both LQT-1 and LQT-2 [175]. Classic Mendelian inheritance ratios were not observed in the offspring of either female carriers of LQT-1 or male and female carriers of LQT-2. Among 1,534 descendants, 870 (57 %) were carriers of a mutation and 664 (43 %) were non-carriers (p < 0.001). Among the 870 carriers, the alleles for LQTS were transmitted more often to female offspring (55 %) than to male offspring (45 %) (p = 0.005). Increased maternal transmission of LQTS mutations to daughters was also observed, possibly contributing to the excess of female patients with autosomal dominant LQTS. Rajamani et al. studied the electrophysiological consequences of mutant hERG blockade by pharmacological agents, finding one compound, fexofenadine, that was able to rescue the electrophysiology defect without complete channel blockade, suggesting that this might be a useful treatment for some LQT-2 patients [176]. Beyond hereditary LQT-2, hERG channels are particularly promiscuous from a pharmacological point of view, being easily blocked by a wide array of drugs with diverse chemical structures, due to the lack of two essential proline residues (the Pro-X-Pro sequence, replaced in hERG by IlePhe-Gly) [177] in the carboxyl end of the S6 domain,
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Channelopathies and Heart Disease
107 Sequence varient Trafficking deficient WT-like trafficking
34 LqT2 “mutations” P596R I593R Extracelluar
G572S I571L
T436M
S1
S2
S3
G601S
N629D/S V630A/L F640V
N
S5
S4
G Selectivity F Filter (GFG) G
S6 F G
D456Y A422T T421M
N N-linked glycosylation
Y611H V612L A614V
G628S T623I
A561T/V
Cytosol H562P T474I P347S
N470D
R762W F805C
R534C S818L V822M R823W
R328C
R922W COOH
NH2
I31S
Fig. 9.3 The Kv11.1 α-subunit transmembrane topology and several sites of point mutations, most of them resulting in trafficking defects (Reprinted from Anderson et al. [169], ©2006 with permission from Wolters Kluwer Health)
rendering this region more flexible and allowing relatively large molecules to enter the pore inner vestibule and access a putative binding site [178]. Advances in molecular biology over the past decade led to the discovery that hERG inhibition is a central factor of arrhythmogenesis in acquired LQTS (aLQTS). Shah and Hondeghem [179] incorporated hERG blockade in a more refined indicator for drug-induced proarrhythmia in individuals with reduced repolarization reserve: the TRIaD factors (triangulation, reverse usedependence, instability of the action potential, and dispersion). They suggest that drug-induced QT interval prolongation is likely to be proarrhythmic when associated with the presence or augmentation of TRIaD, whereas it is not likely to induce arrhythmias in the absence of TRIaD factors. Not all compounds known to induce aLQTS act via acute inhibition of hERG channels. Two notable exceptions are pentamidine and arsenic trioxide, which suppress intracellular hERG protein trafficking. hERG is the primary target of methanesulfonanilides (e.g., dofetilide, E4031,
ibutilide, MK499), a group of potent and specific class III anti-arrhythmic agents. An elegant homology modeling study based on the crystal structure of Kcsa [180] identified Phe656 and other four S6 residues located in the pore (Tyr652, Gly648, Val625, Thr623) crucial for high-affinity binding by methanesulfonanilides. The aromatic rings of hERG-blocking drugs are likely to interact with the aromatic rings of Tyr652 and Phe656, as confirmed in studies with cisapride and terfenadine, while the other three residues were found to be more specific for methanesulfonanilides. hERG mutations that result in loss of inactivation (S620T, S631A) reduce the affinity for methanesulfonanilides and certain (e.g., haloperidol) but not all other hERG-blocking drugs, indicating that allosteric changes during inactivation may be required for high-affinity drug binding. Similarly, the SQTS-associated hERG N588K mutation, which causes loss of inactivation, reduces methanesulfonanilide sensitivity [181]. Using mutant hERG S631C channels, Ulens and Tytgat proved that drug affinity and C-type
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inactivation can be actively controlled by altering the redox state of the residue at position 631 [182]. An analysis of cases of torsades de pointes induced by the hERG blocker dofetilide suggested that a coding hERG single nucleotide polymorphism (SNP), leading to the mutation R1047L, could predispose to acquired LQTS (aLQTS) and torsades de pointes by changing channel activation and deactivation, thus reducing current and lengthening cardiac AP, without altering dofetilide blocking affinity. Following the identification of the MiRP1 T8A polymorphism, associated with drug-induced LQTS, Sesti et al. found that hERG currents were slightly reduced when co-expressed with MiRP1 T8A compared with MiRP1 wild type, and hERG/MiRP1 T8A heteromers displayed markedly increased affinity to block by sulfamethoxazole, which caused aLQTS in the index patient [183]. This polymorphism was shown to cause lack of N-glycosylation at position N6, by destroying the respective glycosylation site in MiRP1, leading to fourfold increase in the affinity to sulfamethoxazole, an example of aLQTS due to SNP-induced facilitated drug binding to hERG channels. There is evidence that mutation in the KCR1 (an EAG channel regulatory protein) gene (equivalent of S. cerevisiae ALG10, an α-1,2 glucosyltransferase involved in the terminal glycosylation step of the lipidlinked Glc(2)Man(9)GlcNAc(2) oligosaccharide) on chromosome 12p11 confers reduced susceptibility to acquired LQT-2. In patients with drug-induced cardiac repolarization defects, sequencing of the KCR1 gene revealed the I447V substitution, that occurred at a reduced frequency (0.1 %) relative to a matched control population (7.0 %), suggesting that I447V may confer reduced susceptibility to aLQTS [184]. The clinical result was supported by in vitro studies of sensitivity of hERG to dofetilide, via co-expression with wild type and I447V KCR1. Another inherited form of LQTS, LQT-6, is caused by mutations in KCNE2, the gene encoding the accessory β-subunit of hERG channels, MiRP1. The first case, reported in 1999, was a healthy 38-year-old Caucasian female with an episode of ventricular fibrillation while jogging, requiring defibrillation. Subsequent ECGs showed an atypical response to exercise, with markedly prolonged QTc intervals, ranging from 390 to 500 ms. Heterozygous missense mutations in KCNE2 were identified in this case and other two healthy females with LQTS, one of them associated with clarithromycin-induced arrhythmia via increased channel blockade by the antibiotic [164]. Another study identified biallelic digenic mutations, an F60L mutation in KCNE2 and an R1623Q mutation in SCN5A, in a 1-month-old male infant with syncope, torsades de pointes, cardiac arrest, and a QTc of 460 ms [185]. Gain-of-function mutations in KCNE2 may result in familial atrial fibrillation type 4 (ATFB4). A study on 28 unrelated Han Chinese families with atrial fibrillation found the R27C mutation in two
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probands [186]. The mutation was present in all affected members in the 2 kindreds and was absent in 462 healthy unrelated Chinese subjects. On the other hand, gain-of-function mutations in KCNH2 itself cause short QT syndrome type 1 (SQT-1). The first reported cases were of a brother, sister, and mother with QT intervals of less than 80 % of predicted value (280, 272, and 260 ms, respectively), associated in the 17-year-old sister with several episodes of paroxysmal atrial fibrillation requiring cardioversion [187]. All three affected family members received implantable cardioverter defibrillators, and treatment with propafenone maintained them free of atrial fibrillation. A further study identified in this family the N588K mutation in the KCNH2 gene, concluding that codon 588 is a hotspot for SQT-1 [188]. Using a candidate gene approach in two previously reported families with SQT [189], Brugada et al. directly sequenced several ion channel genes involved in ventricular AP repolarization, identifying two different missense mutations in the KCNH2 gene leading to the same N588K substitution [181]. The occurrence of sudden cardiac death in the first 12 months of life in two patients suggested the possibility of a link between KCNH2 gain-of-function mutations and sudden infant death syndrome. From a cohort of 2,008 healthy individuals, an analysis of 200 cases with the shortest QTc and 198 with the longest QTc, comparing the allele, genotype, and haplotype frequencies of polymorphisms in cardiac ion channel genes (10 SNPs in KCNQ1, 2 in KCNE1, 4 in SCN5A, and 1 in KCNH2) between these two groups, suggested that genetic determinants located in these genes influence QTc length in healthy individuals and may represent risk factors for arrhythmias and sudden cardiac death in patients with cardiovascular disease [190]. Beyond mutations in other cardiac ion channel genes (e.g., KCNQ1, SCN5A) resulting in sudden infant death syndrome (SIDS), one study reported an hERG mutation (K101E) in an infant with sudden death [191]. A putative pharmacological treatment of SQT-1 could be quinidine in selected cases, even without defibrillator implantation, whereas sotalol or flecainide failed to prolong the QT interval in affected patients, due to reduced sensitivity of mutant hERG channels to these blockers.
Fast and Slow Transient Outward K+ Current (Ito) Another important early repolarization current that shapes the cardiac AP is the transient outward current Ito. This current contributes, together with a Ca2+-activated Cl- current (sometimes dubbed Ito2), to the phase 1 notch and the spikeand-dome appearance of ventricular cardiomyocyte AP in larger mammals. Nerbonne found two K+ Ito components which differ in activation and inactivation kinetics [106, 192].
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Both currents are blocked by 4-aminopyridine (4-AP) in the millimolar range, and Ito fast is also sensitive to block by heteropodatoxin 2 and 3 [193]. The Ito fast main subunit has been identified as Kv4.2 (KCND2 gene) and Kv4.3 (KCND3 gene) [194, 195], while Ito slow has been attributed to Kv1.4 (KCNA4 gene) [193, 196]. Homo- or heterotetrameric Kv4.2/Kv4.3 channels interact with several regulatory subunits, such as K+ channels interacting proteins KChIP1 to KChIP4, forming octameric assemblies, dipeptidyl peptidase-like protein-6 (DPP6) and DPP10, disks large homolog 1 (DLG1), also known as synapse-associated protein 97 (SAP97), DLG4, and filamins A and C (FLNA, FLNC). KChIPs bind to the cytoplasmic N-termini of Kv4 α-subunits and act as chaperones, enhancing cell-surface expression and modulating their inactivation kinetics and rate of recovery from inactivation. The KChIPs have four EF-hand-like Ca2+ binding domains. Thus, although Kv4.x are intrinsically Ca2+ insensitive, they can be modulated by intracellular Ca2+ signals via interaction with KChIPs [197]. DPP subunits also regulate the activation and inactivation properties of Kv4 channels [198, 199]. In cardiomyocytes, Kv4 channels form a tripartite complex with the anchoring protein SAP97, belonging to the MAGUK family (membraneassociated guanylate kinase) and several protein kinases, e.g., Ca2+/calmodulin kinase II (CaMKII). SAP97 is abundantly expressed in myocardium and also interacts with Shaker (Kv1.x) and Kir channels, regulating their targeting to the sarcolemma. Suppression of SAP97 by using short hairpin RNA inhibited Ito in cardiac myocytes, whereas its overexpression by using an adenovirus increased Ito. The interaction of Kv4 with SAP97 occurs via consensus residue sequences of the type xS/TxV/L interacting with the PDZ domains of these MAGUK proteins. Deletion of the PDZ domain-binding motif Ser-Ala-Leu (SAL) in the C-terminus of Kv4.2 and 4.3 led to a lack of regulation of Kv4.3 by CaMKII inhibitors, while in wild-type Kv4.3 and not in Kv4.2 channels CaMKII inhibition accelerates Ito inactivation, resulting in an enhanced fast transient component of the outward current [200]. MiRP3, the single-span membrane protein encoded by KCNE4, was found to colocalize with Kv 4.2 subunits, leading to the hypothesis that regional heterogeneity in cardiac expression of MiRP3, Kv4.2, and KChIP2 in health and disease may establish the local attributes and magnitude of cardiac Ito [201]. In heterologous expression systems, MiRP3 shifts the half-activation potential of Kv4.2 approximately 20 mV, slows time to peak and inactivation approximately 100 %, and speeds recovery from inactivation approximately 30 %. KChIP2 increases peak Kv4.2 current, shifts the half-activation potential 5 mV, slows time to peak approximately 10 %, inactivation 100 %, and speeds recovery from inactivation 250 %. Simultaneous expression of all 3 subunits yields a different biophysical profile and abolishes the MiRP3-induced overshoot. Similar
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effects on gating properties of Kv4.3 are exerted by accessory subunits KChIP2, MiRP1, and DPP6 [202]. Kv4.3 interaction with MiRP1 removes voltage dependence of block by flecainide (IC50 ~ 10 μM), presumably via an interaction with conserved Kv4.3 residues V399 and V401 (V402 and V404 in Kv4.2), located in the carboxy-terminal end of transmembrane helix S6, at the intracellular mouth of the channel, preventing flecainide interaction with these residues. It has been reported that Kv4.2 channels with an N-terminal deletion, Δ2-40, cannot interact functionally with KChIP2 isoforms [203, 204]. However, a recent study proved that KChIP2b can alter several Kv4.2 Δ2-39-gating characteristics; therefore these effects are not necessarily dependent upon an intact N-terminus [205]. Downregulation of Ito contributes to AP shape alteration in myocardial infarction (MI) and other diseases. A recent study investigated the possible role of high-mobility group box 1 (HMGB1), a proinflammatory cytokine reported to increase dramatically in the serum of patients with MI, participating in ischemia-reperfusion injury and recovery of post-infarction failing heart, in regulating cardiac Ito and electrical stability [206]. HMGB1 treatment for 24 h significantly inhibited native Ito in neonatal rat ventricular myocytes, decreasing the mRNA and protein levels of Ito α-subunits Kv4.2 and Kv4.3 but not the β-subunits KChIP2 and KCNE2, with a slight prolongation in APD. The receptor binding domain (residues 150–186) of the receptor for advanced glycation end product (RAGE) similarly inhibited Ito, while treatment with soluble RAGE, which blocks binding of ligands to cell-surface RAGE, partially restored Ito current density and Kv4 protein expression. Important insights concerning the role of Ito fast and Ito slow in pathology have been gained from mutagenesis experiments on the corresponding genes in mice. Thus, ventricular myocytes of transgenic mice expressing a dominant-negative pore mutant of Kv4.2 (Kv4.2 W362F), which leads to selective elimination of Ito fast, present prolonged APs and QT intervals, but the animals are phenotypically normal, due to overexpression of Kv1.4 (Ito slow). In contrast, Kv4.2W362F/ Kv1.4−/− mice lack both Ito fast and Ito slow, their APs and QT intervals are markedly prolonged, and they present ventricular arrhythmias and AV block, which may result either from loss of atrial Ito fast or electrical remodeling in the conducting system [192]. Another mutant mouse model, Kv4.2N, expressing a truncated Kv4.2 α-subunit that also functions as a dominant negative, presents phenotypic alterations, such as hypertrophy, chamber dilation, and interstitial fibrosis, and develops congestive heart failure with increased incidence of sudden death at the age of 10–12 weeks. In the normal ventricular myocardium, there is a transmural gradient of the predominant transient outward current component, Ito fast, and of Kv4.2 expression, as well as slighter variations in Ito slow, Kv 1.4, and Kv4.3 expression
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Table 9.3 Classification of J wave syndromes J wave syndrome Inherited ERS type 1
Anatomic location
Leads with J wave
Anterolateral left ventricle
I, V4–V6
Normalization of J-point elevation and inhibition of VT/VF
ERS type 2
Inferior left ventricle
II, III, aVF
Normalization of J-point elevation and inhibition of VT/VF
ERS type 3
Left and right ventricles
Global
Brugada syndrome
Right ventricle V1–V3
Limited data Normalization of J-point elevation and inhibition of VT/VF Normalization of J-point elevation and inhibition of VT/VF
Acquired Ischemiamediated VT /VF Hypothermiamediated VT /VF
Left and right ventricles Left and right ventricles
Response to isoproterenol
Response to quinidine
Any of the 12 Limited data standard leads Any of the 12 Inhibition of VT/VF standard leads
Normalization of J-point elevation and inhibition of VT/VF Normalization of J-point elevation and inhibition of VT/VF Limited data
Gene mutations CACNA1C CACNB2B
KCNJ8 CACNA1C CACNB2B CACNA1C
Normalization of J-point elevation and inhibition of VT/VF
SCN5A CACNA1C CACNB2B GPD1-L SCN1B KCNE3 SCN3B KCNJ8
NA
SCN5A
NA
NA
Adapted from Antzelevitch and Yan [221]
[113, 195, 207, 208], leading to faster inactivation (and recovery from inactivation) in epicardium vs. endocardium. The expression of the two Ito fast subunits is also higher in the right free ventricular wall compared to the interventricular septum [209]. These epi-endocardial gradients tend to decrease in ventricular hypertrophy and heart failure [210–214] and myocardial infarction [215], due to a degree of Kv4.2/4.3 and KChIP2 downregulation and Kv1.4 upregulation, a phenomenon called electrical remodeling. Thus, the ventricular epicardium, but not endocardium, commonly displays APs with a prominent Ito-mediated notch or spike and dome. This difference may lead to a transmural voltage gradient during early ventricular repolarization, recorded as a J wave or J-point elevation on surface ECG, as suggested by experiments on arterially perfused canine ventricular wedge preparations [216]. The J wave, first described by Tomaszewski in 1938 in an accidentally frozen man [217] and considered long time a benign phenomenon, was recognized as an arrhythmia-prone condition in 1984, with the presentation of three cases of ventricular fibrillation occurred during sleep in young male Southeast Asian refugees with structurally normal hearts [218]. In 1992, Pedro and Josep Brugada published a landmark study describing eight sudden cardiac death cases in patients with “right bundle branch block” and ST-segment elevation in precordial leads V1–V3, without obvious structural heart disease [219], a condition defined in 1996 as “Brugada syndrome” [216, 220]. It was later understood that J-wave augmentation or ST-segment elevation found in Brugada syndromes may occur in the absence of
myocardial ischemia, due to an increased ventricular transmural Ito gradient, resulting in partial or complete loss of the AP dome or a coved dome due to a markedly accentuated AP notch. A modern view of the so-called “J wave syndromes” groups these pathological entities, which may be inherited or acquired, into Brugada syndromes, early repolarization syndromes, and “idiopathic” ventricular fibrillation, as well as acquired ischemia- or hypothermia-mediated ST-segment elevation with ventricular tachycardia/ventricular fibrillation [221]. Early repolarization syndromes (ERS) are in turn classified into three distinct subtypes, according to the heart region expressing the most pronounced changes in repolarization: anterolateral left ventricle (ERS type 1), inferior left ventricle (ERS type 2), or global (ERS type 3) (Table 9.3). Our own modeling studies on two-dimensional strips of ventricular cardiomyocytes suggest a new physiological role for the ventricular transmural Ito gradient, namely, to compensate the subendocardial notch and subepicardial elevation during phase 1 resulting from intercellular current flow via gap junctions [222].
Inward Rectifier K+ Current (IK1) The first functional description of the cardiac inward rectifier current IK1 is the result of the pioneering studies of Silvio Weidmann in the early 1950s, using the two-microelectrode technique in sheep Purkinje fibers. Weidmann identified an inwardly rectifying conductance [223] similar to that
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originally described by Bernard Katz in 1949 in skeletal muscle [224]. IK1 currents perform a variety of functions, such as establishing AP waveform and excitability in neuronal and muscle tissues, maintaining the resting potential in working (mainly ventricular) cardiomyocytes, preventing repeated discharge and pacemaker activity, maintaining the AP plateau with relatively small inward currents, and shortening of AP duration at high [K+]o concentrations. IK1 currents are generated by homo- or heterotetrameric Kir α-assemblies composed of subunits with two transmembrane domains encoded by genes belonging to the Kir2.x subfamily (Kir2.1, 2.2, and 2.3). IK1 is a highly K+-selective current, and its I-V plot features a region of negative slope conductance, accounting for the unusual dependence on [K+]o via a “crossover” effect, such that beyond the crossover potential the conductance decreases upon increasing [K+]o. IK1 density is higher in ventricular myocytes, associated with a faster phase 3 repolarization, and lower in atrial myocytes and Purkinje cells. The rectification properties of IK1 are also different in ventricle and atrium, the negative slope conductance region being virtually absent in atrial cells but prominent in ventricular myocytes. This peculiar I-V profile has been attributed to a voltage-dependent block of outward K+ flow by intracellular Mg2+ or organic cationic polyamines. Of the polyamines, spermine and spermidine cause considerably steeper block than putrescine or Mg2+, and they are active at micromolar concentrations; therefore the total cellular polyamine levels (10 μM to 10 mM) are clearly sufficient to account for inward rectification. Polyamine block depends critically on two negatively charged residues, D172 in the TM2 domain and E224 in the C-terminal domain [225, 226]. Charge neutralization mutations at these positions reduce polyamine and Mg2+ sensitivity close to those of the weakly rectifying Kir1.1. Another study found a threonine residue immediately preceding the TM1 domain, critically regulating the rates of polyamine and Mg2+ unbinding [227]. Other mutagenesis studies proved the importance of a disulfide bridge between Cys residues 122 and 154 for proper channel folding, although disruption of the bond with reducing agents once the channel has been correctly assembled does not impede its function. The stability of the selectivity filter is dependent on a salt bridge formed between E138 and R148. Individual mutation of either of these two residues leads to loss of channel function, while the double mutation E138R/ R148E restores channel activity, although with loss of K+ over Na+ selectivity and a dramatically reduced conductance. Kir2.x channels interact via PDZ-recognition domains with several scaffolding proteins, such as LIN7A, LIN7B, LIN7C, DLG1, CASK, and APBA1, which play an important role in their membrane localization and trafficking. Kir2.x channels are modulated by several factors, such as phosphorylation and intracellular pH. Although the pHi sensitivity is lower compared to that of Kir1.1, where a charge neutralizing
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mutation of K80 leads to loss of this property, introduction of a lysine in the corresponding position (M84K) converts Kir2.1 in a pHi-sensitive channel. In Kir2.3 channels, the corresponding residue is M58, but T53 appears to be critical in conferring pH sensitivity [228]. Kir2.1 channels can be regulated by PKA-mediated phosphorylation. While in heterologous expression systems the effects have been controversial, native IK1 channels from guinea pig or human ventricular myocytes were inhibited by exposure to the purified PKA catalytic subunit applied on the intracellular side [229, 230], and a point mutation close to the end of the C-terminus (S425N) abolished this inhibition [231]. The downregulating action of tyrosine kinases on Kir2.1 has been targeted to the Y242 residue in the C-terminus [232]. Kir2.x interaction with PIP2 also modulates their activity, the channel-lipid interaction being required for channel function. Thus, IK1 changes can occur subsequent to agonistmediated depletion of the membrane phospholipid pool by Gq-coupled PLC activators [233], but the physiological importance of this process is probably limited by the fact that depleted PIP2 is rapidly resynthesized via PI- and PIP1-kinases. The majority of KCNJ2 mutations cause loss of function when expressed alone and variable degrees of dominantnegative suppression of wild-type Kir 2.1, 2.2, and 2.3 channel function [234]. The Kir2.1 D71V mutant exerts a strong dominant-negative effect on all Kir2.x family members, consistent with the idea that one or more mutant subunits within the Kir2.x tetramer are sufficient to eliminate channel function [235]. Mice with a targeted deletion of the coding region of Kir2.1 (Kir2.1−/−) present a cleft palate, similar to Andersen syndrome patients, and die shortly after birth due to respiratory complications and the inability to suckle. Although ventricular myocytes isolated from these newborn mice completely lacked IK1, fired APs spontaneously, and contracted to a greater extent than wild-type cells, in the intact animals the functional consequences of this cellular phenotype are not evident, the only abnormality present on ECG recordings being pronounced bradycardia [192]. The explanation of this mild phenotype may reside in the presence of a small, slowly activating inward rectifier current, distinct from IK1, evident in Kir2.1−/− myocytes. The pathological consequences of KCNJ2 mutations in humans are LQT syndrome type 7 (LQT-7), also called Andersen or Andersen-Tawil syndrome or Andersen cardiodysrhythmic periodic paralysis, short QT syndrome type 3 (SQT-3), and familial atrial fibrillation type 9 (ATFB9). Andersen-Tawil syndrome (ATS) is an autosomal dominant disorder of ventricular repolarization manifested by mild QT interval prolongation but prominent U waves and marked QU interval prolongation, leading to frequent premature ventricular contractions, bigeminy, and nonsustained polymorphic and bidirectional ventricular
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tachycardia [236]. Although tachycardia is often frequent in these patients, degeneration into lethal ventricular arrhythmias is relatively uncommon. ATS is associated with periodic skeletal muscle paralysis and dysmorphic skeletal features. Similar to other LQTS, some carriers display little or no phenotype. As in the Kir2.1−/− mouse, the cardiac phenotype of ATS patients is mild, in spite of the fact that the Kir2.1 mutations suppress IK1 markedly [192]. The first ATS case, reported in 1971, was an 8-year-old boy with short stature, hypertelorism, broad nasal root, mandibular hypoplasia, scaphocephaly, clinodactyly V, and a defect of the soft and hard palate [237]. Subsequent studies reported a 31-year-old housewife with bidirectional ventricular tachycardia whose mother died of “heart failure” at age 37 [238], a 19-year-old man with episodes of cardiac dysfunction associated with tetraparesis whose brother had died at age 16 of a heart condition, and another brother had a similar disease, while their father experienced attacks of muscle weakness that decreased in frequency with advancing age [239]. Tawil et al. showed that the Andersen syndrome is distinct from other forms of potassium-sensitive periodic paralysis, demonstrating lack of genetic linkage [240]. Another study [241] reported 11 patients from 5 kindreds with the classical triad of potassium-sensitive periodic paralysis, ventricular arrhythmia, and an unusual facial appearance, combined with a long QTc interval, deemed as a minimal diagnostic sign. Canún et al. suggested that recognition of the characteristic face in ATS patients permits an early diagnosis, although the severity of the facial involvement is not correlated with the severity of heart or muscle involvement [242]. Tristani-Firouzi et al. performed extensive clinical and electrophysiology studies on 17 ATS kindreds with ten different mutations [236]. At least two dysmorphic features were present in 28 of 36 (78 %) KCNJ2 mutation carriers: 39 % had low-implanted ears, 36 % hypertelorism, 44 % small mandibles, 64 % clinodactyly, 11 % syndactyly, 8 % cleft palate, and 11 % scoliosis. LQT was present in 71 % and ventricular arrhythmias in 64 %. A heterozygous missense mutation (R67W) in the KCNJ2 gene was identified in 41 members of a kindred with ventricular arrhythmias and periodic paralysis [243]. Other features seen in this kindred included unilateral dysplastic kidney and cardiovascular malformations (bicuspid aortic valve, bicuspid aortic valve with coarctation of the aorta, or valvular pulmonary stenosis). A study identified 8 different mutations in 17 unrelated probands with ATS, of which 6 novel mutations of residues involved in PIP2 binding [244]. Other two recent studies identified each two different heterozygous missense mutations in the KCNJ2 gene, in affected members of two Korean families [245], or in two unrelated probands with periodic paralysis and cardiac dysrhythmias [246]. Chan et al. reported a 3-generation Taiwanese family with ATS, including a
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35-year-old female with periodic paralysis, characteristic facial features, and LQTS, presenting major depression with suicide ideation, hyperreflexia with extensor plantar responses, evidence of demyelination with periventricular and subcortical white matter lesions on brain MRI, and an 8-year-old affected son with borderline decreased executive function and learning disability [247]. The authors suggest that neuropsychiatric involvement in ATS may be underestimated, postulating a role for KCNJ2 in proper myelination and neuronal function. A treatment tried with success in a young woman with ATS due to a R218W mutation was a combination of amiodarone and acetazolamide, resulting in marked and long-lasting improvement in cardiac and muscular function [248]. In contrast, SQTS are characterized by idiopathic persistently and uniformly short QT interval in the absence of structural heart disease, causing syncope and sudden death. SQT-3 has a unique ECG phenotype characterized by asymmetrical T waves. ATFB9 was described within a study of a 4-generation Chinese family segregating autosomal dominant atrial fibrillation [249]. The proband was a 59-year-old man diagnosed with atrial fibrillation at 54 years of age, with paroxysmal attacks two to three times a month. His father and an older sister were diagnosed with the same condition at ages 58 and 50, respectively. A younger sister, diagnosed at age 50, presented paroxysmal attacks once or twice a week, and a 57-year-old niece presented paroxysmal atrial fibrillation on a 24-h ECG monitoring. All affected members had normal QT intervals, experienced no episode of muscle weakness or syncope, did not have frequent premature ventricular beats or ventricular tachycardia on a 24-h ECG monitoring, presented no dysmorphic features, and serum K+ levels were normal. A heterozygous missense gain-offunction mutation in the KCNJ2 gene (V93I) was identified. An interesting finding is the reduction in IK1 exerted by elevated diastolic intracellular Ca2+ levels in heart failure, via PKC-dependent and PKC-independent mechanisms [250]. Since Ca2+ release from sarcoplasmic reticulum stores also reduces IK1, this paradigm may be relevant for arrhythmias related to acquired or inherited ryanodine receptor type 2 (RyR2) dysfunction. Mutations in the RyR2 gene can also cause arrhythmias and sudden death [251]. A study performed by Ackerman’s group on selected RyR coding regions from a large series of LQTS patients referred to the Mayo Clinic found that 17 (6.3 %) of 269 genotype-negative LQTS patients featured a RyR2 mutation [252]. This study identified 15 distinct RyR2 mutations in the 23 analyzed exons, of which 12 novel mutations, 14 missense mutations, 1 duplication/insertion, and two mutations localized to the calstabin-2 (FKBP12.6) binding domain. Typically, RyR2 mutations cause type 1 catecholaminergic polymorphic ventricular tachycardia (CPVT1), a condition phenotypically mimicking LQTS.
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Acetylcholine-Activated Inward Rectifier K+ Current (IK(ACh))
ATP-Inhibited Inward Rectifier K+ Current (IK(ATP))
Vagal stimulation, resulting in ACh release from nerve endings, exerts cardiac actions mediated by muscarinic receptors mainly via opening of a peculiar type of inwardly rectifying K+ channels, dubbed K(ACh) channels [253] or G-protein-coupled inward rectifier (GIRK) channels, beyond reducing voltage-gated ICa and If. GIRK channels have been grouped in the Kir3.x subfamily, comprising four members [254]. Channel activation is due to an effect of the dissociated βγ-subunit of the pertussis-sensitive G-protein Gi/o [255]. In chronic atrial fibrillation, constitutive agonistindependent IK(ACh) results from abnormal PKC activity, whereas the M2-muscarinic receptor-mediated IK(ACh) activation does not require the contribution of protein kinases [256]. Similarly, atrial tachycardia-induced remodeling increases agonist-independent constitutive IK(ACh) by enhancing spontaneous channel opening, thus enhancing a current which plays a significant role in remodeling-associated atrial fibrillation promotion and APD abbreviation [257]. Recordings in atrial myocytes from mice with a targeted deletion of the Kir3.4 gene (Kir3.4−/−) revealed the absence of the GTPγS-activated IK(ACh), prominent in wild-type atrial cells. Although resting heart rates in Kir3.4 double knockout mice are normal, heart rate variability in response to vagal stimulation is reduced by approximately one half, and the remaining response appears with a longer latency [258]. In addition, atrial fibrillation does not arise in Kir3.4−/− animals challenged with carbachol [259]. Mutations in the Kir3.4 gene KCNJ5 may result in a specific form of LQTS (LQT-13), as well as in familial hyperaldosteronism type 3 (FH3). LQT-13 was described in a large, 4-generation Chinese family segregating autosomal dominant LQTS [260]. The proband was a 62-year-old woman with a 40-year history of syncopal episodes. Nine other patients of 49 family members presented similar clinical features, including a markedly prolonged QT interval (QTc 520 ms) but no structural cardiac abnormalities. The proband and three affected relatives developed persistent atrial fibrillation. A heterozygous missense mutation (G387R) was identified in the KCNJ5 gene. FH3 is a novel familial form of hyperaldosteronism reported in a father and two daughters diagnosed with severe secondary hypertension refractory to medical treatment by age 7 [261]. All three subjects underwent bilateral adrenalectomy, the adrenal glands showing dramatic enlargement and massive hyperplasia and cellular hypertrophy of a single cortical compartment with features of fasciculate zone, with an atrophic glomerular zone on histopathology examination. A subsequent study identified a missense mutation in the KCNJ5 gene at codon 158, causing increased Na+ conductance and cell depolarization in adrenal glomerulosa cells, leading to secondary Ca2+ entry and aldosterone production [262].
KATP channels function as metabolic sensors in a wide variety of cell types, coupling energy metabolism to cellular excitability. They mediate insulin release from pancreatic beta cells, control the firing rate of glucose-responsive neurons in the ventromedial hypothalamus, protect neurons during hypoxia, and participate in the maintenance of the coronary vascular tone. They are also called ADPactivated K+ channels, because their open probability is proportional to the [ADP]/[ATP] ratio and they are distributed abundantly in all regions of the heart, coupling the AP shape to the metabolic state of the cell. During ischemia or ischemic preconditioning, the increased [ADP]/[ATP] ratio activates IK(ATP) and abbreviates the AP, resulting in a reduction in contractile force generation that may be cardioprotective. At normal ionic concentrations, activation of approximately 0.6 % of KATP channels should account for a 50 % reduction in APD [263, 264], while under conditions of high extracellular K+, such as those found in early ischemia, the activation of only 0.4 % of KATP channels could account for 50 % reduction in APD [265]. The minimum requirement for the formation of a functional KATP channel appears to be the presence of two types of subunits: a pore-forming subunit (Kir6.x) and a sulfonylurea receptor (SUR) regulatory subunit, a member of the ABC proteins (ATP-binding cassette). The KATP channel protein complex may include other metabolically active protein subunits, such as adenylate kinase, creatine kinase, and lactate dehydrogenase [266–268]. Kir6.2 subunits interact via their C-termini with glyceraldehyde-3-phosphate dehydrogenase, triose-phosphate isomerase, and pyruvate kinase, and thus the activity of these enzymes causes channel closure, possibly due to ATP formation in the immediate intracellular microenvironment of this macromolecular KATP channel complex [269]. Although mutations in the genes encoding both subunits may lead to pathological phenotypes, cardiac involvement is negligible, possibly due to the minor role of these channels in repolarization in normal conditions and activation only during ischemia or pre/post-conditioning. Thus, mutations in KCNJ11, the gene encoding Kir6.2 subunits, result in familial hyperinsulinemic hypoglycemia type 2 (HHF2), permanent neonatal diabetes mellitus (PNDM), and transient neonatal diabetes mellitus type 3 (TNDM3) and may contribute to non-insulin-dependent diabetes mellitus (NIDDM), also known as diabetes mellitus type 2, while mutations in ABCC8, the gene encoding SUR1 subunits, may result in leucine-induced hypoglycemia (LIH), familial hyperinsulinemic hypoglycemia type 1 (HHF1), permanent neonatal diabetes mellitus (PNDM), and transient neonatal diabetes mellitus type 2 (TNDM2).
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Mutations in Funny (Hyperpolarization-Activated) Channels (If) If is perhaps most widely known for its role in the generation of spontaneous pacemaker activity in the heart [270], a result of phase 4 diastolic depolarization in pacemaker cells. Actually several other current components contribute to this process: the voltage-dependent K+ currents activated during the preceding AP, the background Na+ current, the Na+/Ca2+ exchangers, and the L- and T-type Ca2+ channels, but If plays the major role due to its unique properties: a Na+/K+ permeability ratio between 0.2 and 0.4 [271] rendering a reversal potential of −10 to −20 mV, an activation threshold around −40 to −45 mV, a half-activating potential of −65 to −70 mV, and slightly more negative in Purkinje fibers. Its modulation by cyclic adenosine monophosphate (cAMP) levels [272] explains its role in cardiac rhythm regulation by autonomic neurotransmitters. Thus, adrenergic agonists facilitate If activation by shifting its mid-activation potential to more positive values, in the range of potentials reached during pacemaker activity: −40 to −60 mV in sinoatrial node cells and −80 to −100 mV in Purkinje fibers. Due to its peculiar properties, this current received various names over time: Ih (hyperpolarization-activated), If (funny), IQ (queer), and IAR (anomalous rectifier). Four genes encoding If channels have been cloned and sequenced, receiving the names HCN1–HCN4 (hyperpolarization-activated cyclic nucleotide-gated); they share about 60 % sequence similarity with Kv channels. Of these, HCN4 and, to a lesser extent, HCN2, are expressed at myocardial level. Expression is both developmentally and regionally regulated. Neonatal ventricular myocytes with pacemaker activity predominantly express HCN2, but its level of expression declines in adulthood. HCN4, encoding the subunit with the slowest gating kinetics, is the primarily expressed subtype in the SA node, AV node, and ventricular conducting system. Knockout of the HCN4 gene is embryonically lethal. HCN channels are tetramers, formed by the assembly of four α-subunits, each of them composed of six transmembrane domains (S1–S6). cAMP binds to the cyclic nucleotide-binding domain (CNBD) located within the C-terminus. A unique mutation in human HCN4, 573X, abolishes the cAMP-dependent regulation, resulting in a decreased pacemaking rate of SA node cells and marked reduction in heart rate at rest and during exercise in a heterologous targeted inducible expression murine model [273], revealing the pathophysiologic mechanism of hHCN4-573Xlinked SA node dysfunction in humans. Another singleresidue substitution in the HCN4 CNBD (S672R) results in a negative voltage shift of about 5 mV of the activation curve, without affecting cAMP-induced activation. The functional consequences of this leftward shift mimic the effects of a mild vagal stimulation, resulting in bradycardia. Fifteen
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individuals carrying this missense point mutation in exon 7 of HCN4, belonging to a large (27-member) Italian family, presented a hereditary form of asymptomatic sinus bradycardia, featuring resting heart rates in the range 43–60 bpm, with a mean of 52 bpm, compared to resting heart rates in the range 64–81 bpm, with a mean of 73 bpm, in a control group composed of 12 wild-type individuals [274]. Bradycardia and the HCN4 mutation cosegregated tightly, with a two-point limit of detection (LOD) score of 5.07–5.66, corresponding to penetrance values ranging from 0.7 to 1. HCN channels interact with several proteins. Thus, KCNE2 may act as auxiliary β-subunits. Co-expression of KCNE2 and HCN4 increases conductance but slows channel kinetics and shifts the activation curve to more negative voltages. HCN4 channels membrane localization involves interaction with caveolin-rich membrane microdomains (caveolae). Experimental evidence indicates that adrenergic modulation of If is better performed by β2 than β1 receptor stimulation, due to colocalization of β2 receptors and If channels in caveolar spaces. Beyond modulation of If activity by extracellular protons, which shift its activation to more hyperpolarized potentials, slowing pacemaker activity, a number of pharmacological compounds which act as HCNspecific blockers exert heart rate-reducing effects useful in chronic stable angina. These substances include alinidine (the N-alyl derivative of clonidine), zatebradine (UL-FS49), cilobradine (DK-AH26) and falipamil (originally derived from the L-type Ca2+ channel blocker verapamil), ZD7288, and ivabradine (S16257). A recent HCN gating model with transitions between two modes with shifted voltage dependence explains the voltage hysteresis and “memory” of HCN channels during different phases in the pacemaker cycle, which decreases the risk of arrhythmia in pacemaker cells, according to computer simulations [275]. Mutations in the HCN4 gene are a cause of sick sinus syndrome type 2 (SSS2), also known as atrial fibrillation with bradyarrhythmia or familial sinus bradycardia, and of Brugada syndrome type 8 (BrS8). The first clinical description of SSS2 was provided by a study of a family in which nine members belonging to three generations presented nodal rhythm with bradycardia and tended to develop paroxysms of atrial fibrillation in the fourth decade of life [276, 277]. Individuals in subsequent generations suffered from more symptomatic bradycardia at a younger age than their parents, requiring, in some cases, pacemaker implantation, and developed intermittent atrial fibrillation requiring chronic treatment. In a large family with SSS2 spanning three generations as an autosomal dominant trait, there was an association between the grade of mental retardation and the severity of the sinoatrial disorder in some cases [278]. In another family, SSS2 was associated with brachydactyly type C in the so-called Spanish type of heart-hand syndrome [279]. Beyond the S672R HCN4 mutation identified by
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Milanesi et al. [274], other studies described heterozygosity for HCN4 mutation D553N, leading to severe bradycardia (39 bpm average) and syncope in a 43-year-old woman, with cardiac arrest for 40 s followed by polymorphic ventricular tachycardia and torsades de pointes [280], or the G480R substitution in eight affected members of a four-generation family with asymptomatic sinus bradycardia [281]. The Brugada syndrome type 8 was described in a 41-year-old man with recurrent episodes of syncope at rest, whose ECG showed saddleback ST-segment elevation in right precordial leads, incomplete right bundle branch block, and QT intervals in the upper limit of normal [282]. A 24-h ECG monitoring revealed polymorphic ventricular tachycardia during sleep, and ventricular fibrillation could be reproducibly induced by programmed ventricular stimulation without drug provocation, requiring an internal cardioverter defibrillator. Heterozygosity for a splice site mutation in the HCN4 gene was identified. Beyond mutagenesis mechanisms, pathological alterations in cardiac function may lead to modifications of If expression. Thus, in spontaneously hypertensive rats (SHR), ventricular levels of HCN2 and HCN4 expression are increased [283]. The properties of If in myocytes isolated from explanted human hearts with dilated or ischemic cardiomyopathy were similar to those of If in SHR [284–286]. Along with a reduced IK1 expression in failing human hearts, HCN overexpression may increase electrical instability, especially under the elevated β-adrenergic signaling typical of these pathological conditions, and may contribute to triggering fatal arrhythmias. Genetic or cellular approaches based on in situ delivery of HCN genes were adopted in the pursuit of strategies to develop “biological pacemakers,” eventually able to replace the electronic devices used today [287]. To date, different strategies have been used to generate an HCN-based “biological pacemaker”: (1) adenoviral-mediated HCN2 infection, (2) implant of mesenchymal stem cells overexpressing HCN2 channels, and (3) implant of spontaneously beating human embryonic stem cell-derived cardiomyocytes (hESC-CMs). A recent study proved that the spontaneous electrical activity of hESC-CMs and induced pluripotent stem cells-derived cardiomyocytes (iPSC-CMs) exhibits beat rate variability (BRV) and power-law behavior comparable to those of human SA node cells, raising the possibility to create biological pacemakers using iPSC-CMs obtained starting from the patient’s own hair follicles, via keratinocytes-derived iPSC, thus eliminating the critical need for immunosuppression [288].
Mutations in Gap Junction Channels (Ij) Gap junctions form a low resistance connection between cardiac cells. In normal adult ventricular myocardium, gap junctions are confined almost exclusively to the intercalated
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disks [289], one myocyte being connected to 11 or 12 similar cells. The channels responsible for the large conductance of a gap junction consist of two hemichannels or connexons in two apposing cells, each of them composed of six polypeptide subunits or connexins [290]. Connexins are designated according to the species from which they were derived and their theoretical molecular mass, expressed in KDa. Three connexins have been identified in cardiomyocytes: connexin 43 (Cx43), the most abundant, connexin 45 (Cx45), and connexin 40 (Cx40). Cx40 is preferentially expressed in atria, nodal tissue, and the Purkinje network. Each connexin is composed of four α-helical transmembrane segments, M1 to M4. M3 is amphipathic and probably part of the pore structure. Connexin subunits interact with various intracellular proteins, involved in their membrane trafficking (KIAA1432/ CIP150, CNST), phosphorylation (SRC, CIP150, CSNK1D), assembly or disassembly (TJP1), and degradation (SGSM3). Cx43 channels have main conductance states of 90–115 pS and are relatively insensitive to changes in transjunctional voltage compared to channels composed of Cx40 or Cx45. Cx40 form channels with larger conductance (150–160 pS). In contrast, Cx45 channels exhibit a much lower main state conductance of 25 pS and are highly sensitive to transjunctional voltage [291]. Gap junction conductance and permeability is regulated by connexin phosphorylation. During the course of ischemia, decreased ATP levels, increased intracellular Ca2+, and acidosis determine gap junction closure through Cx43 dephosphorylation and internalization into the cytosol. Connexin expression and coupling are enhanced during initial phases of hypertrophic growth, while in chronic heart disease (ischemic cardiomyopathy, end-stage aortic stenosis, etc.) connexin expression is downregulated. Mutations in cardiac connexin genes are associated with a variety of genetic syndromes, some of them featuring cardiovascular involvement, consisting in either developmental abnormalities or arrhythmogenic conditions. Thus, defects in the Cx43 gene GJA1 are the cause of autosomal dominant oculodentodigital dysplasia (ODDD), autosomal recessive ODDD, syndactyly type 3 (SDTY3, an autosomal dominant trait), hypoplastic left heart syndrome (HLHS), HallermannStreiff syndrome (HSS), and atrioventricular septal defect type 3 (AVSD3). ODDD, also known as oculodentoosseous dysplasia, is a highly penetrant syndrome associated with craniofacial (ocular, nasal, dental) and limb dysmorphisms, spastic paraplegia, and neurodegeneration. Craniofacial abnormalities include a narrow, pinched nose with hypoplastic alae nasi, small anteverted nares, prominent columnella, and microcephaly. Ocular defects include microphthalmia, microcornea, cataracts, glaucoma, and optic atrophy. Hypotrichosis and brittle nails are present, while type 3 syndactyly and conductive deafness may occur in some cases. Cardiac abnormalities are observed in rare instances. A study described a 2-generation family with ODDD and progressive
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paraplegia associated with leukodystrophic changes documented by MRI, suggesting that the phenotype of the disorder should include spastic paraparesis [292]. Neurologic symptoms are frequent in ODDD and include dysarthria, neurogenic bladder disturbances, spastic paraparesis, ataxia, anterior tibial muscle weakness, and seizures, while mild mental retardation occurs infrequently [293]. Sequencing of the GJA1 gene in 17 ODDD families led to identification of 16 different missense mutations and 1 codon duplication [294], resulting in channel disassembly or altered conduction properties. A study of a 5-generation Danish family with ODDD identified the GJA1 V96M substitution in all cases [295]. Studies in Dutch individuals with palmoplantar keratoderma and ODDD identified 2-bp deletions in the GJA1 gene, affecting the C-terminal loop of Cx43 [296, 297]. In a mouse model of ODDD heterozygous for the GJA1 I130T mutation, associated with increased incidence of cardiac arrhythmias in human ODDD patients [294], impaired posttranslational processing of Cx43 resulted in diminished cellcell coupling, slowing of cardiac impulse propagation, and a proarrhythmic substrate [298]. Ninety-three percent of the heterozygous Cx43 I130T mice displayed hind-limb syndactyly, a characteristic phenotypic feature observed in human ODDD patients. However, morphological heart abnormalities were absent in these animals, in contrast to Cx43+/− germ-line knockout mice or Cx43Jrt/+ G60S mutant mice, which present right ventricular outflow obstruction, atrial septal defect, or patent foramen ovale. A subsequent study [299] examined the ocular phenotype of GJA1 Jrt/+ G60S mutant mice, evidencing diffuse and intracellular Cx43 immunofluorescence in ciliary bodies, different from the gap junction plaques prevalent in wild-type mice, lower intraocular pressure at 21 weeks of age, microphthalmia, enophthalmia, anterior angle closure, and reduced pupil diameter. All these changes are important in understanding the causal links between GJA1 mutations and glaucoma in individuals with ODDD. The hypoplastic left heart syndrome (HLHS) refers to the abnormal development of the left-sided cardiac structures, resulting in obstruction to blood flow from the left ventricular outflow tract. In addition, the syndrome includes underdevelopment of the left ventricle, aorta, and aortic arch, as well as mitral atresia or stenosis [300]. In eight pediatric heart transplant recipients with HLHS, two missense mutations and two silent polymorphisms were identified in the GJA1 gene. Atrioventricular septal defect type 3 (AVSD3) is a congenital heart malformation characterized by a common atrioventricular junction coexisting with deficient atrioventricular septation. The complete form involves underdevelopment of the lower part of the atrial septum and the upper part of the ventricular septum. A less severe form, known as ostium primum atrial septal defect, has a deficiency of the atrial septum [300]. Mutations in the GJA5 gene cause familial atrial standstill (FAS) and familial atrial fibrillation type
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11 (ATFB11). FAS is an extremely rare arrhythmia, characterized by the absence of electrical and mechanical activity in the atria. The ECG features bradycardia, the absence of P waves, and a junctional narrow complex escape rhythm [301]. Atrial standstill can be caused by a mutation in the SCN5A gene in combination with a rare GJA5 phenotype [302]. ATFB11 can be caused by a heterozygous mutation or a somatic mutation in the GJA5 gene [301]. Prolonged episodes of atrial fibrillation result in electrical and structural remodeling, favoring its recurrence or perpetuation and involving changes in Cx40 expression and distribution both in the atrial myocardium and in the thoracic veins (superior vena cava and pulmonary veins) [303]. Abnormal Cx40 expression correlated with both trigger formation from the thoracic veins, a mechanism recently confirmed by computerized modeling studies [304], as well as enhanced vulnerability of the atrial myocardium to fibrillation.
TRP Channels and Heart Disease Transient receptor potential (TRP) channels form a superfamily of cation channels divided into various subfamilies: classical or canonical (TRPC), vanilloid (TRPV), melastatinrelated (TRPM), polycystins (TRPP), mucolipins (TRPML), ankyrin-bound (TRPA), and NO-mechanopotential (TRPN). These channels are gated by diverse physical (voltage, stretch, temperature, etc.) and chemical stimuli. They are found in a variety of excitable and non-excitable cells where they are involved in different physiological functions, including ion transport, osmoregulation, stretch sensing, and temperature sensing. In 1986, Putney first postulated the existence of storeoperated Ca2+ channels (SOCC), starting from the observation that depletion of intracellular Ca2+ stores caused subsequent Ca2+ influx into the cells [305, 306]. Hoth and Penner described a calcium current in mast cells, activated by depletion of intracellular calcium stores, ICRAC (calcium release-activated calcium current) [307]. The current is carried by very low conductance highly Ca2+-selective channels named ORAI1, the opening of which is regulated by STIM1, a protein located probably in the endoplasmic reticulum and signaling Ca2+ concentration within this intracellular store. Recent studies [308] propose that store-operated calcium entry (SOCE) channels may be heteromeric complexes of TRPC and ORAI subunits, based on experiments showing that the expression of ORAI1 in cells stably overexpressing TRPC3 or TRPC6 increased SOCE and that SOCEenhancing levels of ORAI1 “silence” spontaneous activity of stably overexpressed TRPC3. In contrast to SOCE and ICRAC, Gd3+-sensitive receptor-operated calcium entry (ROCE), mediated by TRPC3, TRPC6, or TRPC7, represents Ca2+ entry through TRPCs as well as SOCE/ICRAC channels
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activated secondary to the stimulation of a receptor-Gq/11phospholipase C (PLC) signaling pathway, by generated diacylglycerol (DAG), a molecule that activates TRPC3/6/7 but not TRPC1/4/5. Yuan et al. have shown that, in contrast to ORAI, several TRPC channels (1,2,4, and 5) are regulated by STIM1 via an electrostatic interaction involving residues 672–685, which explains the role of TRPC1/4 subunits within heteromeric channels in regulating STIM1independent TRPC3/6 subunits. When expressed at high level, these channels can also function in a STIM1independent mode [309]. Several studies have linked increased TRPC channel activity to cardiac hypertrophy and heart failure. Seth et al. have shown that cardiac pressure overload by transverse aortic constriction or chronic angiotensin infusion upregulates a TRPC-like nonselective cation current in cardiomyocytes [310], while protection to hemodynamic stress and neurohormonal excess is conferred in TRPC1−/− mice or upon using the selective TRPC3 inhibitor Pyr3 [311] by altered mechanosensitive signaling through calcineurin/NFAT, mTOR and Akt. Overexpression of TRPC3 or 6 was shown to induce cardiac hypertrophy through calcineurin/NFAT signaling in transgenic mice [312, 313]. Moreover, Wu et al. used myocytes from hypertrophied hearts of TRPC3/4/6 dominant-negative (dn) mice to show that they lack a unique store-depletion-operated Ca2+ influx, which is normally present in cells from wild-type animals. TRPC4 dn inhibited the activity of TRPC3/6/7 in the heart, suggesting that these two types of TRPCs function in coordinated complexes. By double immunofluorescent staining they demonstrated a colocalization of TRPC3 with the Na+/Ca2+ exchanger NCX1 in dnTRPC3 cardiomyocytes [314]. Another study performed on cardiomyocytes from insulin-resistant obese ob/ob mice [315] showed that insulin fails to potentiate TRPC3 currents in this setting, in contrast to the situation in normal animals. Equally intriguing and complex are the effects of TRP channels in the generation of heart rhythm and various arrhythmias. Ju and Allen demonstrated SOCC activity in toad sinoatrial node (SAN) pacemaker cells, as well as the presence of TRPC1/3/4/6 in single SAN, atrial, and ventricular myocytes, using antibodies [316]. They also demonstrated expression of all TRPC genes except TRPC5 in myocardium by RT-PCR, resuming previous expression studies of Freichel et al. [317]. This indicates an important role of SOCC/TRPC in heart rate modulation by changes in the content of sarcoplasmic reticulum, especially in embryonic pacemaker cells, before expression of functional pacemaker ion channels. In higher vertebrates, TRPM4 may play an important role in pacemaking [318], accounting for the Ca2+-activated 25 pS nonselective cation channel which is permeable to Na+ and K+ but not to Ca2+. This channel was discovered in human atrial myocytes [319]. It is inhibited by
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flufenamic acid and glibenclamide, sensitive to PIP2, and shows higher levels of expression in atrial than in ventricular myocardium [320]. The channel is also a likely candidate for the delayed afterdepolarizations observed under conditions of Ca2+ overload, which may lead to various types of arrhythmia. Moreover, these channels are mechanosensitive (stretchactivated nonselective cation channels or SACs), explaining the long-known increase in heart rate produced by stretch of the atria. In 1994, Gannier et al. discovered that streptomycin (40 μM) reverses large stretch-induced increases in [Ca]i in isolated guinea pig ventricular myocytes. Gd3+ and GsMTx-4, which block SACs, also inhibit atrial fibrillation [321]. Using electrophysiology methods, we have identified a Mg2+-inhibited cation (MIC) current in cardiomyocytes [322, 323]. The biophysical properties of the underlying channels, as well as their regulation by membrane phospholipids and by pharmacological agents, led to their identification as TRPM7. The channels can be detected in ventricular myocytes by immunofluorescence or RT-PCR (own unpublished data). Aarts et al. have shown that TRPM7 plays an important role in neuronal cell death by late Ca2+ entry during prolonged oxygen-glucose deprivation (OGD) upon activation by free oxygen/nitrogen radicals via the nitric oxide pathway. Neuron pretreatment with TRPM7 siRNA to induce silencing of its mRNA increases survival in OGD conditions [324]. Recent studies have completed these findings. Thus, Wei et al. have shown that transient periods of brain ischemia are characterized by substantial decreases in extracellular [Ca2+] and [Mg2+], leading to TRPM7 activation and cell death [325]. Jiang et al. have shown a neuroprotective effect of NGF in vivo and in vitro on hippocampal neurons via TrkA activation and subsequent regulation of TRPM7 expression [326]. It is also worth mentioning TRPM7 upregulation in human atria fibroblasts in atrial fibrillation [327]. Although previous studies on isolated cells or animal models have demonstrated the role of TRPCs in store-operated Ca2+ entry and consequent cardiac hypertrophy upon activation by mechanical stretch or insulin-like signals, as well as the deleterious role of TRPM7 during prolonged neuronal ischemia, the extent to which these results are relevant for human pathology is largely unknown.
Concluding Remarks As we have seen within this brief presentation, although the frequency of channelopathies in the general population is very low, they are important from a theoretical point of view, by emphasizing the relationships between ion channel structural, functional and regulation properties, and their physiological roles. Within a comprehensive monograph entitled “Ion Channels and Disease,” Prof. Frances M. Ashcroft identified at least five distinct mechanisms involved in
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channelopathies: (1) mutations in the promoter region of an ion channel gene causing underexpression or overexpression, (2) mutations in the coding region resulting in gain or loss of channel function, (3) defective regulation of channel activity by ligands or modulators, (4) autoantibodies to channel proteins, and (5) cell death triggered by excess of ion channel function [328]. We should never forget the genetic heterogeneity of channelopathies. Thus, the same clinical phenotype (e.g., a LQT syndrome) can be caused by mutations in different genes, while different mutations in the same gene may result in very different clinical phenotypes. In this context it is worth mentioning the different significance of mutations for a molecular biologist and a geneticist: while for the former a mutation is any change in the natural sequence of a gene, the latter would take it into account only if it results in phenotype changes leading to clinical disease. Since most cardiac channelopathies result in arrhythmias, it is important to emphasize that, in the light shed by recent experimental and modeling studies, arrhythmogenic conditions, such as early afterdepolarizations (EADs), represent emergent properties at cellular level and result from a complex imbalance involving several molecular factors, e.g., a mismatch between the time constants of activation and inactivation of the Ca2+ current and the time constant of activation of the K+ current [329, 330]. This is in contrast to the simplistic but currently prevailing view that establishes a direct and straightforward causal connection between ion channel gene mutation and arrhythmia. We hope that further research will clarify all the intricate details of the complex relationship leading from gene mutation to clinical syndrome and that novel high-throughput diagnostic and therapeutic approaches, such as the “cardiovascular risk assessment microarray chips” or use of cardiac tissue grown in vitro starting from induced pluripotent stem cells to tailor antiarrhythmic pharmacotherapy for each patient, will gradually transform the terra incognita of cardiac channelopathies into a well-established field of current day practice.
Abbreviations 4-AP ABC ADP Akt
aLQTS AMPA AP APBA APD
4-aminopyridine ATP binding cassette Adenosine diphosphate Protein kinase B, human analogue of Ak (mouse strain) t (thymoma) retrovirus Akt-8 oncogene v-Akt Acquired long QT syndrome 2-amino-3-(5-methyl-3-oxo-1,2- oxazol-4-yl) propanoic acid Action potential Amyloid beta (A4) precursor protein-binding family A Action potential duration
ATFB ATP ATS AV AVSD BrS BRV CaM CaMKII cAMP CAPON CASK CAV3 CDI cDNA CHO-K1 CL CMD1E CNBD CNST CPVT CRAC CSNK1D Cx DLG DMD dn DPP EAD EAG ECG eNOS ERS ET-1 FAS FH3 FHF1B FKBP FLNA FLNC GIRK GJA1 GLO GsMTx4 GTPγS HCN hERG
Familial atrial fibrillation Adenosine triphosphate Andersen-Tawil syndrome Atrio-ventricular Atrio-ventricular septal defect Brugada syndrome Beat rate variability Calmodulin Ca2+/calmodulin kinase II Cyclic adenosine monophosphate Carboxyl-terminal PDZ ligand of nNOS Ca2+/calmodulin-dependent serine protein kinase Caveolin 3 Calcium-dependent inactivation Complementary deoxyribonucleic acid A cell line derived from the original Chinese hamster ovary (CHO) cell line Cycle length Dilated cardiomyopathy type 1E Cyclic nucleotide binding domain Consortin, connexin sorting protein Catecholaminergic polymorphic ventricular tachycardia Ca2+ release-activated Ca2+ current Casein kinase 1 delta Connexin Disks large homolog Duchenne muscular dystrophy Dominant negative Dipeptidyl peptidase-like protein Early afterdepolarization Ether-à-go-go Electrocardiography Or NOS3 – endothelial nitric oxide synthase Early repolarization syndrome Endothelin 1 Familial atrial standstill Familial hyperaldosteronism type 3 Fibroblast growth factor homologous factor 1B FK506-binding protein Filamin A Filamin C G-protein-coupled inward rectifier K+ (channel) Gap junction protein alpha 1 Glyoxalase 1 gene linked to HLA loci, localized to 6p21.3 – p21.1 Grammostola spatulata mechanotoxin-4 Guanosine 5'[gamma-thio]triphosphate Hyperpolarization-activated cyclic nucleotidegated (channel) Human ether-à-go-go (eag)-related gene
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hESC-CMs
Human embryonic stem cell-derived cardiomyocytes HHF Familial hyperinsulinemic hypoglycemia HLA Human leukocyte antigen HLA DR D-related HLA locus HLHS Hypoplastic left heart syndrome HMGB1 High-mobility group box 1 HSS Hallermann-Streiff syndrome HVA High voltage activated I123-MIBG m-iodobenzyl guanethidine ICCD Isolated cardiac conduction disease IGF-1 Insulin-like growth factor 1 iNOS Or NOS2 – inducible nitric oxide synthase iPSC-CMs Induced pluripotent stem cell-derived cardiomyocytes JLNS Jervell and Lange-Nielsen syndrome KChAP K+ channel associated protein KChIP K+ channel interacting protein KCR1 K+ channel regulator 1 KDa kilodaltons KIAA1432/CIP150 Connexin 43-interacting protein of 150 KDa LIH Leucine-induced hypoglycemia LIN Cell lineage fate determination genes in C. elegans LOD Limit of detection LQT Long QT syndrome LVA Low voltage activated MAGUK Membrane-associated guanylate kinase MI Myocardial infarction MIC Magnesium-inhibited cation (current) MIDAS Metal ion-dependent adhesion site MinK Minimal K+ channel subunit (ancillary subunit associated to KvLQT1) MiRP MinK-related peptide (ancillary subunit associated to hERG and KvLQT1 channels) mRNA Messenger ribonucleic acid mTOR Mammalian target of rapamycin NCX Na+/Ca2+ exchanger Nedd4 Neural precursor cell expressed developmentally down-regulated protein 4 NFAT Nuclear factor of activated T cells NGF Nerve growth factor NIDDM Non-insulin dependent diabetes mellitus NMR Nuclear magnetic resonance nNOS Or NOS1 – neuronal nitric oxide synthase NOS1AP Nitric oxide synthase 1 adaptor protein ODDD Oculodentodigital dysplasia
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OGD PAS PCCD PDZ
PFHB1A PI PIP2 PKA PKC PLC PMCA4b PNDM PP1 QTc RAGE ROCE RT-PCR RWS RyR SA SAC SAP SDTY3 SGSM3 SHR SIDS siRNA SNP SNTA1 SOCC SOCE SPECT SQT SRC SSS STIM1 SUR TASK-1 TJP1 TM TNDM3 TRIaD TrkA TRP TRPA TRPC TRPM TRPML
Oxygen-glucose deprivation Per-Arnt-Sim domain Progressive cardiac conduction defect Postsynaptic density protein (PSD95), Drosophila discs large tumor suppressor (Dlg1), zonula occludens-1 protein (zo-1) Progressive familial heart block type 1A Phosphatidylinositol Phosphatidylinositol 4,5 bisphosphate Protein kinase A Protein kinase C Phospholipase C Plasma membrane Ca2+ ATPase 4b Permanent neonatal diabetes mellitus Protein phosphatase 1 Corrected QT interval Receptor for advanced glycation end product Receptor-operated calcium entry Reverse transcription - polymerase chain reaction Romano-Ward syndrome Ryanodine receptor Sino-atrial Stretch-activated channel Synapse-associated protein Syndactyly type 3 Small G protein signaling modulator 3 Spontaneously hypertensive rats Sudden infant death syndrome Small interfering RNA Single nucleotide polymorphism α1-syntrophin Store-operated Ca2+ channels Store-operated calcium entry Single-photon emission computed tomography Short QT syndrome Rous sarcoma protooncogene (tyrosine kinase pp60c-src) Sick sinus syndrome Stromal interaction molecule 1 Sulfonylurea receptor TWIK-related acid-sensitive (tandem pore domain) K+ channel-1 Tight junction protein 1 Transmembrane domain Transient neonatal diabetes mellitus type 3 Triangulation, reverse use dependence, instability of the action potential, and dispersion Tyrosine-kinase A Transient receptor potential (channels) Ankyrin-bound TRP Classical (canonical) TRP Melastatin-related TRP Mucolipins
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TRPN TRPP TRPV TWIK-1/2 VDI VF VT VWFA
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NO-mechanopotential TRP Polycystins Vanilloid TRP Two-pore-domain weak inward rectifier K+ channels 1/2 Voltage-dependent inactivation Ventricular fibrillation Ventricular tachycardia von Willebrand factor type A domain
References 1. Armstrong CM, Hille B. Voltage-gated ion channels and electrical excitability. Neuron. 1998;20(3):371–80. 2. FitzHugh R. Thresholds and plateaus in the Hodgkin-Huxley nerve equations. J Gen Physiol. 1960;43:867–96. 3. Hall AE, Hutter OF, Noble D. Current–voltage relations of Purkinje fibres in sodium-deficient solutions. J Physiol. 1963;166:225–40. 4. Hutter OF, Noble D. Rectifying properties of heart muscle. Nature. 1960;188:495. 5. Weidmann S. Effect of current flow on the membrane potential of cardiac muscle. J Physiol. 1951;115(2):227–36. 6. Deck KA, Trautwein W. Ionic currents in cardiac excitation. Pflugers Arch Gesamte Physiol Menschen Tiere. 1964;280:63–80. 7. Reuter H. The dependence of slow inward current in Purkinje fibres on the extracellular calcium-concentration. J Physiol. 1967;192(2):479–92. 8. Noble D, Tsien RW. The kinetics and rectifier properties of the slow potassium current in cardiac Purkinje fibres. J Physiol. 1968;195(1):185–214. 9. Noble D,Tsien RW. Outward membrane currents activated in the plateau range of potentials in cardiac Purkinje fibres. J Physiol. 1969;200(1):205–31. 10. McAllister RE, Noble D, Tsien RW. Reconstruction of the electrical activity of cardiac Purkinje fibres. J Physiol. 1975;251(1):1–59. 11. Reuter H, Seitz N. The dependence of calcium efflux from cardiac muscle on temperature and external ion composition. J Physiol. 1968;195(2):451–70. 12. DiFrancesco D, Noble D. A model of cardiac electrical activity incorporating ionic pumps and concentration changes. Philos Trans R Soc Lond B Biol Sci. 1985;307(1133):353–98. 13. DiFrancesco D. A new interpretation of the pace-maker current in calf Purkinje fibres. J Physiol. 1981;314:359–76. 14. Hamill OP, Marty A, Neher E, Sakmann B, Sigworth FJ. Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pflugers Arch. 1981;391(2):85–100. 15. Neher E, Sakmann B. Single-channel currents recorded from membrane of denervated frog muscle fibres. Nature. 1976;260(5554):799–802. 16. Amuzescu B, Mubagwa K. Cardiac ion channels and transporters. In: Georgescu A, Antohe F, editors. From vascular cell biology to cardiovascular medicine. Trivandrum: Transworld Research Network; 2011. p. 51–98. 17. Bers DM. Excitation-contraction coupling and cardiac contractile force. 2nd ed. Dordrecht: Kluwer Academic Publishers; 2001. 452 p. 18. Roden DM, George Jr AL. Structure and function of cardiac sodium and potassium channels. Am J Physiol. 1997;273(2 Pt 2):H511–25. 19. Abriel H, Kass RS. Regulation of the voltage-gated cardiac sodium channel Nav1.5 By interacting proteins. Trends Cardiovasc Med. 2005;15(1):35–40.
20. Kontis KJ, Goldin AL. Sodium channel inactivation is altered by substitution of voltage sensor positive charges. J Gen Physiol. 1997;110(4):403–13. 21. Stühmer W, Conti F, Suzuki H, Wang XD, Noda M, Yahagi N, Kubo H, Numa S. Structural parts involved in activation and inactivation of the sodium channel. Nature. 1989;339(6226):597–603. 22. Rohl CA, Boeckman FA, Baker C, Scheuer T, Catterall WA, Klevit RE. Solution structure of the sodium channel inactivation gate. Biochemistry. 1999;38(3):855–61. 23. Cormier JW, Rivolta I, Tateyama M, Yang AS, Kass RS. Secondary structure of the human cardiac Na + channel C terminus: evidence for a role of helical structures in modulation of channel inactivation. J Biol Chem. 2002;277(11):9233–41. Epub 2001 Dec 10. 24. Albrecht DE, Froehner SC. Syntrophins and dystrobrevins: defining the dystrophin scaffold at synapses. Neurosignals. 2002;11(3):123–9. 25. Finsterer J, Stöllberger C. The heart in human dystrophinopathies. Cardiology. 2003;99(1):1–19. 26. Ueda K, Valdivia C, Medeiros-Domingo A, Tester DJ, Vatta M, Farrugia G, Ackerman MJ, Makielski JC. Syntrophin mutation associated with long QT syndrome through activation of the nNOSSCN5A macromolecular complex. Proc Natl Acad Sci U S A. 2008;105(27):9355–60. Epub 2008 Jun 30. 27. Aarnoudse AJ, Newton-Cheh C, de Bakker PI, Straus SM, Kors JA, Hofman A, Uitterlinden AG, Witteman JC, Stricker BH. Common NOS1AP variants are associated with a prolonged QTc interval in the Rotterdam Study. Circulation. 2007;116(1):10–6. Epub 2007 Jun 18. 28. Arking DE, Pfeufer A, Post W, Kao WH, Newton-Cheh C, Ikeda M, West K, Kashuk C, Akyol M, Perz S, Jalilzadeh S, Illig T, Gieger C, Guo CY, Larson MG, Wichmann HE, Marbán E, O’Donnell CJ, Hirschhorn JN, Kääb S, Spooner PM, Meitinger T, Chakravarti A. A common genetic variant in the NOS1 regulator NOS1AP modulates cardiac repolarization. Nat Genet. 2006;38(6):644–51. Epub 2006 Apr 30. 29. Cronk LB, Ye B, Kaku T, Tester DJ, Vatta M, Makielski JC, Ackerman MJ. Novel mechanism for sudden infant death syndrome: persistent late sodium current secondary to mutations in caveolin-3. Heart Rhythm. 2007;4(2):161–6. Epub 2006 Dec 6. 30. Medeiros-Domingo A, Kaku T, Tester DJ, Iturralde-Torres P, Itty A, Ye B, Valdivia C, Ueda K, Canizales-Quinteros S, Tusié-Luna MT, Makielski JC, Ackerman MJ. SCN4B-encoded sodium channel beta4 subunit in congenital long-QT syndrome. Circulation. 2007;116(2):134–42. Epub 2007 Jun 25. 31. Tan HL, Kupershmidt S, Zhang R, Stepanovic S, Roden DM, Wilde AA, Anderson ME, Balser JR. A calcium sensor in the sodium channel modulates cardiac excitability. Nature. 2002;415(6870):442–7. 32. Kim J, Ghosh S, Liu H, Tateyama M, Kass RS, Pitt GS. Calmodulin mediates Ca2+ sensitivity of sodium channels. J Biol Chem. 2004;279(43):45004–12. Epub 2004 Aug 16. 33. Priori SG, Napolitano C, Gasparini M, Pappone C, Della Bella P, Brignole M, Giordano U, Giovannini T, Menozzi C, Bloise R, Crotti L, Terreni L, Schwartz PJ. Clinical and genetic heterogeneity of right bundle branch block and ST-segment elevation syndrome: a prospective evaluation of 52 families. Circulation. 2000;102(20):2509–15. 34. Mohler PJ, Rivolta I, Napolitano C, LeMaillet G, Lambert S, Priori SG, Bennett V. Nav1.5 E1053K mutation causing Brugada syndrome blocks binding to ankyrin-G and expression of Nav1.5 on the surface of cardiomyocytes. Proc Natl Acad Sci U S A. 2004;101(50):17533–8. Epub 2004 Dec 3. 35. Mohler PJ, Schott JJ, Gramolini AO, Dilly KW, Guatimosim S, duBell WH, Song LS, Haurogné K, Kyndt F, Ali ME, Rogers TB, Lederer WJ, Escande D, Le Marec H, Bennett V. Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death. Nature. 2003;421(6923):634–9.
9
Channelopathies and Heart Disease 36. Mohler PJ, Splawski I, Napolitano C, Bottelli G, Sharpe L, Timothy K, Priori SG, Keating MT, Bennett V. A cardiac arrhythmia syndrome caused by loss of ankyrin-B function. Proc Natl Acad Sci U S A. 2004;101(24):9137–42. Epub 2004 Jun 3. 37. Grant AO. Cardiac ion channels. Circ Arrhythm Electrophysiol. 2009;2(2):185–94. 38. Lerche H, Jurkat-Rott K, Lehmann-Horn F. Ion channels and epilepsy. Am J Med Genet. 2001;106(2):146–59. 39. Steinlein OK. Genes and mutations in idiopathic epilepsy. Am J Med Genet. 2001;106(2):139–45. 40. Bennett PB, Yazawa K, Makita N, George Jr AL. Molecular mechanism for an inherited cardiac arrhythmia. Nature. 1995;376(6542):683–5. 41. Chandra R, Starmer CF, Grant AO. Multiple effects of KPQ deletion mutation on gating of human cardiac Na + channels expressed in mammalian cells. Am J Physiol. 1998;274(5 Pt 2):H1643–54. 42. Clancy CE, Rudy Y. Linking a genetic defect to its cellular phenotype in a cardiac arrhythmia. Nature. 1999;400(6744):566–9. 43. Antzelevitch C, Yan G, Shimizu W, Burashnikov A. Electrical heterogeneity, the ECG, and cardiac arrhythmias. In: Zipes DP, Jalife J, editors. Cardiac electrophysiology: from cell to bedside. Philadelphia: Saunders; 2000. p. 222–38. 44. Carmeliet E, Fozzard HA, Hiraoka M, Janse MJ, Ogawa S, Roden DM, Rosen MR, Rudy Y, Schwartz PJ, Matteo PS, Antzelevitch C, Boyden PA, Catterall WA, Fishman GI, George AL, Izumo S, Jalife J, January CT, Kléber AG, Marbán E, Marks AR, Spooner PM, Waldo AL, Weiss JM, Zipes DLP. New approaches to antiarrhythmic therapy. Part I : emerging therapeutic applications of the cell biology of cardiac arrhythmias. Circulation. 2001;104(23):2865–73. 45. Clancy CE, Tateyama M, Liu H, Wehrens XH, Kass RS. Nonequilibrium gating in cardiac Na + channels: an original mechanism of arrhythmia. Circulation. 2003;107(17):2233–7. Epub 2003 Apr 14. 46. Brugada J, Brugada R, Brugada P. Right bundle-branch block and ST-segment elevation in leads V1 through V3: a marker for sudden death in patients without demonstrable structural heart disease. Circulation. 1998;97(5):457–60. 47. An RH, Wang XL, Kerem B, Benhorin J, Medina A, Goldmit M, Kass RS. Novel LQT-3 mutation affects Na + channel activity through interactions between alpha- and beta1-subunits. Circ Res. 1998;83(2):141–6. 48. Rivolta I, Abriel H, Tateyama M, Liu H, Memmi M, Vardas P, Napolitano C, Priori SG, Kass RS. Inherited Brugada and long QT-3 syndrome mutations of a single residue of the cardiac sodium channel confer distinct channel and clinical phenotypes. J Biol Chem. 2001;276(33):30623–30. Epub 2001 Jun 15. 49. Veldkamp MW, Viswanathan PC, Bezzina C, Baartscheer A, Wilde AA, Balser JR. Two distinct congenital arrhythmias evoked by a multidysfunctional Na(+) channel. Circ Res. 2000;86(9):E91–7. 50. Clancy CE, Rudy Y. Na(+) channel mutation that causes both Brugada and long-QT syndrome phenotypes: a simulation study of mechanism. Circulation. 2002;105(10):1208–13. 51. Kyndt F, Probst V, Potet F, Demolombe S, Chevallier JC, Baro I, Moisan JP, Boisseau P, Schott JJ, Escande D, Le Marec H. Novel SCN5A mutation leading either to isolated cardiac conduction defect or Brugada syndrome in a large French family. Circulation. 2001;104(25):3081–6. 52. Grant AO, Carboni MP, Neplioueva V, Starmer CF, Memmi M, Napolitano C, Priori S. Long QT syndrome, Brugada syndrome, and conduction system disease are linked to a single sodium channel mutation. J Clin Invest. 2002;110(8):1201–9. 53. Liu H, Tateyama M, Clancy CE, Abriel H, Kass RS. Channel openings are necessary but not sufficient for use-dependent block of cardiac Na(+) channels by flecainide: evidence from the analysis of disease-linked mutations. J Gen Physiol. 2002;120(1):39–51.
121 54. Splawski I, Timothy KW, Tateyama M, Clancy CE, Malhotra A, Beggs AH, Cappuccio FP, Sagnella GA, Kass RS, Keating MT. Variant of SCN5A sodium channel implicated in risk of cardiac arrhythmia. Science. 2002;297(5585):1333–6. 55. Brugada R, Brugada J, Antzelevitch C, Kirsch GE, Potenza D, Towbin JA, Brugada P. Sodium channel blockers identify risk for sudden death in patients with ST-segment elevation and right bundle branch block but structurally normal hearts. Circulation. 2000;101(5):510–5. 56. Priori SG, Napolitano C, Schwartz PJ, Bloise R, Crotti L, Ronchetti E. The elusive link between LQT3 and Brugada syndrome: the role of flecainide challenge. Circulation. 2000;102(9):945–7. 57. Abriel H, Wehrens XH, Benhorin J, Kerem B, Kass RS. Molecular pharmacology of the sodium channel mutation D1790G linked to the long-QT syndrome. Circulation. 2000;102(8):921–5. 58. Grant AO, Chandra R, Keller C, Carboni M, Starmer CF. Block of wild-type and inactivation-deficient cardiac sodium channels IFM/QQQ stably expressed in mammalian cells. Biophys J. 2000;79(6):3019–35. 59. Viswanathan PC, Bezzina CR, George Jr AL, Roden DM, Wilde AA, Balser JR. Gating-dependent mechanisms for flecainide action in SCN5A-linked arrhythmia syndromes. Circulation. 2001;104(10):1200–5. 60. Nagatomo T, January CT, Makielski JC. Preferential block of late sodium current in the LQT3 DeltaKPQ mutant by the class I(C) antiarrhythmic flecainide. Mol Pharmacol. 2000;57(1):101–7. 61. Abriel H, Cabo C, Wehrens XH, Rivolta I, Motoike HK, Memmi M, Napolitano C, Priori SG, Kass RS. Novel arrhythmogenic mechanism revealed by a long-QT syndrome mutation in the cardiac Na(+) channel. Circ Res. 2001;88(7):740–5. 62. Wang DW, Yazawa K, Makita N, George Jr AL, Bennett PB. Pharmacological targeting of long QT mutant sodium channels. J Clin Invest. 1997;99(7):1714–20. 63. Ahern CA, Zhang JF, Wookalis MJ, Horn R. Modulation of the cardiac sodium channel NaV1.5 by Fyn, a Src family tyrosine kinase. Circ Res. 2005;96(9):991–8. Epub 2005 Apr 14. 64. Jespersen T, Gavillet B, van Bemmelen MX, Cordonier S, Thomas MA, Staub O, Abriel H. Cardiac sodium channel Na(v)1.5 interacts with and is regulated by the protein tyrosine phosphatase PTPH1. Biochem Biophys Res Commun. 2006;348(4):1455–62. Epub 2006 Aug 10. 65. Liu H, Sun HY, Lau CP, Li GR. Regulation of voltage-gated cardiac sodium current by epidermal growth factor receptor kinase in guinea pig ventricular myocytes. J Mol Cell Cardiol. 2007;42(4):760–8. Epub 2006 Dec 22. 66. London B, Michalec M, Mehdi H, Zhu X, Kerchner L, Sanyal S, Viswanathan PC, Pfahnl AE, Shang LL, Madhusudanan M, Baty CJ, Lagana S, Aleong R, Gutmann R, Ackerman MJ, McNamara DM, Weiss R, Dudley Jr SC. Mutation in glycerol-3-phosphate dehydrogenase 1 like gene (GPD1-L) decreases cardiac Na + current and causes inherited arrhythmias. Circulation. 2007;116(20):2260–8. Epub 2007 Oct 29. 67. Perez-Reyes E. Molecular physiology of low-voltage-activated t-type calcium channels. Physiol Rev. 2003;83(1):117–61. 68. Bean BP. Two kinds of calcium channels in canine atrial cells. Differences in kinetics, selectivity, and pharmacology. J Gen Physiol. 1985;86(1):1–30. 69. Nilius B, Hess P, Lansman JB, Tsien RW. A novel type of cardiac calcium channel in ventricular cells. Nature. 1985;316(6027):443–6. 70. Hagiwara N, Irisawa H, Kameyama M. Contribution of two types of calcium currents to the pacemaker potentials of rabbit sinoatrial node cells. J Physiol. 1988;395:233–53. 71. Zhou Z, Lipsius SL. T-type calcium current in latent pacemaker cells isolated from cat right atrium. J Mol Cell Cardiol. 1994;26(9):1211–9.
122 72. Zamponi GW, Lory P, Perez-Reyes E. Role of voltage-gated calcium channels in epilepsy. Pflugers Arch. 2009;460(2):395–403. 73. Collin T, Wang JJ, Nargeot J, Schwartz A. Molecular cloning of three isoforms of the L-type voltage-dependent calcium channel beta subunit from normal human heart. Circ Res. 1993;72(6):1337–44. 74. Brust PF, Simerson S, McCue AF, Deal CR, Schoonmaker S, Williams ME, Veliçelebi G, Johnson EC, Harpold MM, Ellis SB. Human neuronal voltage-dependent calcium channels: studies on subunit structure and role in channel assembly. Neuropharmacology. 1993;32(11):1089–102. 75. Heinemann SH, Terlau H, Stühmer W, Imoto K, Numa S. Calcium channel characteristics conferred on the sodium channel by single mutations. Nature. 1992;356(6368):441–3. 76. Faber GM, Silva J, Livshitz L, Rudy Y. Kinetic properties of the cardiac L-type Ca2+ channel and its role in myocyte electrophysiology: a theoretical investigation. Biophys J. 2007;92(5):1522–43. Epub 2006 Dec 8. 77. Zühlke RD, Pitt GS, Deisseroth K, Tsien RW, Reuter H. Calmodulin supports both inactivation and facilitation of L-type calcium channels. Nature. 1999;399(6732):159–62. 78. Zühlke RD, Pitt GS, Tsien RW, Reuter H. Ca2 + −sensitive inactivation and facilitation of L-type Ca2+ channels both depend on specific amino acid residues in a consensus calmodulin-binding motif in the(alpha)1C subunit. J Biol Chem. 2000;275(28):21121–9. 79. Alseikhan BA, DeMaria CD, Colecraft HM, Yue DT. Engineered calmodulins reveal the unexpected eminence of Ca2+ channel inactivation in controlling heart excitation. Proc Natl Acad Sci U S A. 2002;99(26):17185–90. Epub 2002 Dec 16. 80. Peterson BZ, DeMaria CD, Adelman JP, Yue DT. Calmodulin is the Ca2+ sensor for Ca2+ − dependent inactivation of L-type calcium channels. Neuron. 1999;22(3):549–58. 81. Marks ML, Trippel DL, Keating MT. Long QT syndrome associated with syndactyly identified in females. Am J Cardiol. 1995;76(10):744–5. 82. Reichenbach H, Meister EM, Theile H. The heart-hand syndrome. A new variant of disorders of heart conduction and syndactylia including osseous changes in hands and feet. Kinderarztl Prax. 1992;60(2):54–6. 83. Splawski I, Timothy KW, Sharpe LM, Decher N, Kumar P, Bloise R, Napolitano C, Schwartz PJ, Joseph RM, Condouris K, TagerFlusberg H, Priori SG, Sanguinetti MC, Keating MT. Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell. 2004;119(1):19–31. 84. Splawski I, Timothy KW, Decher N, Kumar P, Sachse FB, Beggs AH, Sanguinetti MC, Keating MT. Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations. Proc Natl Acad Sci U S A. 2005;102(23):8089–96. discussion 8086–8. Epub 2005 Apr 29. 85. Yazawa M, Hsueh B, Jia X, Pasca AM, Bernstein JA, Hallmayer J, Dolmetsch RE. Using induced pluripotent stem cells to investigate cardiac phenotypes in Timothy syndrome. Nature. 2011;471(7337):230–4. Epub 2011 Feb 9. 86. Antzelevitch C, Pollevick GD, Cordeiro JM, Casis O, Sanguinetti MC, Aizawa Y, Guerchicoff A, Pfeiffer R, Oliva A, Wollnik B, Gelber P, Bonaros Jr EP, Burashnikov E, Wu Y, Sargent JD, Schickel S, Oberheiden R, Bhatia A, Hsu LF, Haissaguerre M, Schimpf R, Borggrefe M, Wolpert C. Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death. Circulation. 2007;115(4):442–9. Epub 2007 Jan 15. 87. Vassort G, Talavera K, Alvarez JL. Role of T-type Ca2+ channels in the heart. Cell Calcium. 2006;40(2):205–20. 88. Niwa N, Yasui K, Opthof T, Takemura H, Shimizu A, Horiba M, Lee JK, Honjo H, Kamiya K, Kodama I. Cav3.2 subunit underlies
B. Amuzescu et al.
89.
90.
91.
92.
93.
94.
95.
96.
97. 98.
99.
100.
101.
102.
103.
104.
105.
the functional T-type Ca2+ channel in murine hearts during the embryonic period. Am J Physiol Heart Circ Physiol. 2004;286(6):H2257–63. Epub 2004 Feb 26. Huang B, Qin D, El-Sherif N. Early down-regulation of K + channel genes and currents in the postinfarction heart. J Cardiovasc Electrophysiol. 2000;11(11):1252–61. Izumi T, Kihara Y, Sarai N, Yoneda T, Iwanaga Y, Inagaki K, Onozawa Y, Takenaka H, Kita T, Noma A. Reinduction of T-type calcium channels by endothelin-1 in failing hearts in vivo and in adult rat ventricular myocytes in vitro. Circulation. 2003;108(20):2530–5. Epub 2003 Oct 27. Martínez ML, Heredia MP, Delgado C. Expression of T-type Ca(2+) channels in ventricular cells from hypertrophied rat hearts. J Mol Cell Cardiol. 1999;31(9):1617–25. Nuss HB, Houser SR. T-type Ca2+ current is expressed in hypertrophied adult feline left ventricular myocytes. Circ Res. 1993;73(4):777–82. Yue L, Feng J, Gaspo R, Li GR, Wang Z, Nattel S. Ionic remodeling underlying action potential changes in a canine model of atrial fibrillation. Circ Res. 1997;81(4):512–25. Levine TB, Bernink PJ, Caspi A, Elkayam U, Geltman EM, Greenberg B, McKenna WJ, Ghali JK, Giles TD, Marmor A, Reisin LH, Ammon S, Lindberg E. Effect of mibefradil, a T-type calcium channel blocker, on morbidity and mortality in moderate to severe congestive heart failure: the MACH-1 study. Mortality Assessment in Congestive Heart Failure Trial. Circulation. 2000;101(7):758–64. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999;341(10):709–17. Cittadini A, Monti MG, Isgaard J, Casaburi C, Strömer H, Di Gianni A, Serpico R, Saldamarco L, Vanasia M, Saccà L. Aldosterone receptor blockade improves left ventricular remodeling and increases ventricular fibrillation threshold in experimental heart failure. Cardiovasc Res. 2003;58(3):555–64. Noble D. Modelling the heart: insights, failures and progress. Bioessays. 2002;24(12):1155–63. Sanguinetti MC, Jurkiewicz NK. Two components of cardiac delayed rectifier K + current. Differential sensitivity to block by class III antiarrhythmic agents. J Gen Physiol. 1990;96(1): 195–215. Sanguinetti MC, Jurkiewicz NK. Delayed rectifier outward K + current is composed of two currents in guinea pig atrial cells. Am J Physiol. 1991;260(2 Pt 2):H393–9. Busch AE, Malloy K, Groh WJ, Varnum MD, Adelman JP, Maylie J. The novel class III antiarrhythmics NE-10064 and NE-10133 inhibit IsK channels expressed in Xenopus oocytes and IKs in guinea pig cardiac myocytes. Biochem Biophys Res Commun. 1994;202(1):265–70. Carmeliet E. Use-dependent block and use-dependent unblock of the delayed rectifier K + current by almokalant in rabbit ventricular myocytes. Circ Res. 1993;73(5):857–68. Lerche C, Seebohm G, Wagner CI, Scherer CR, Dehmelt L, Abitbol I, Gerlach U, Brendel J, Attali B, Busch AE. Molecular impact of MinK on the enantiospecific block of I(Ks) by chromanols. Br J Pharmacol. 2000;131(8):1503–6. Anumonwo JM, Freeman LC, Kwok WM, Kass RS. Delayed rectification in single cells isolated from guinea pig sinoatrial node. Am J Physiol. 1992;262(3 Pt 2):H921–5. Follmer CH, Colatsky TJ. Block of delayed rectifier potassium current, IK, by flecainide and E-4031 in cat ventricular myocytes. Circulation. 1990;82(1):289–93. Pond AL, Scheve BK, Benedict AT, Petrecca K, Van Wagoner DR, Shrier A, Nerbonne JM. Expression of distinct ERG proteins in
9
Channelopathies and Heart Disease
106.
107.
108.
109.
110.
111.
112.
113.
114.
115.
116.
117.
118.
119.
120.
121.
rat, mouse, and human heart. Relation to functional I(Kr) channels. J Biol Chem. 2000;275(8):5997–6006. Nerbonne JM. Molecular basis of functional voltage-gated K + channel diversity in the mammalian myocardium. J Physiol. 2000;525(Pt 2):285–98. Boyle WA, Nerbonne JM. A novel type of depolarization-activated K + current in isolated adult rat atrial myocytes. Am J Physiol. 1991;260(4 Pt 2):H1236–47. Wang Z, Fermini B, Nattel S. Sustained depolarization-induced outward current in human atrial myocytes. Evidence for a novel delayed rectifier K + current similar to Kv1.5 cloned channel currents. Circ Res. 1993;73(6):1061–76. Backx PH, Marbán E. Background potassium current active during the plateau of the action potential in guinea pig ventricular myocytes. Circ Res. 1993;72(4):890–900. Liu DW, Antzelevitch C. Characteristics of the delayed rectifier current (IKr and IKs) in canine ventricular epicardial, midmyocardial, and endocardial myocytes. A weaker IKs contributes to the longer action potential of the M cell. Circ Res. 1995;76(3):351–65. Bryant SM, Wan X, Shipsey SJ, Hart G. Regional differences in the delayed rectifier current (IKr and IKs) contribute to the differences in action potential duration in basal left ventricular myocytes in guinea-pig. Cardiovasc Res. 1998;40(2):322–31. Main MC, Bryant SM, Hart G. Regional differences in action potential characteristics and membrane currents of guinea-pig left ventricular myocytes. Exp Physiol. 1998;83(6):747–61. Näbauer M, Beuckelmann DJ, Uberfuhr P, Steinbeck G. Regional differences in current density and rate-dependent properties of the transient outward current in subepicardial and subendocardial myocytes of human left ventricle. Circulation. 1996;93(1):168–77. Liu DW, Gintant GA, Antzelevitch C. Ionic bases for electrophysiological distinctions among epicardial, midmyocardial, and endocardial myocytes from the free wall of the canine left ventricle. Circ Res. 1993;72(3):671–87. Clancy CE, Kass RS. Inherited and acquired vulnerability to ventricular arrhythmias: cardiac Na + and K + channels. Physiol Rev. 2005;85(1):33–47. Marx SO, Kurokawa J, Reiken S, Motoike H, D’Armiento J, Marks AR, Kass RS. Requirement of a macromolecular signaling complex for beta adrenergic receptor modulation of the KCNQ1-KCNE1 potassium channel. Science. 2002;295(5554): 496–9. Splawski I, Shen J, Timothy KW, Lehmann MH, Priori S, Robinson JL, Moss AJ, Schwartz PJ, Towbin JA, Vincent GM, Keating MT. Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Circulation. 2000;102(10):1178–85. Bianchi L, Priori SG, Napolitano C, Surewicz KA, Dennis AT, Memmi M, Schwartz PJ, Brown AM. Mechanisms of I(Ks) suppression in LQT1 mutants. Am J Physiol Heart Circ Physiol. 2000;279(6):H3003–11. Bianchi L, Shen Z, Dennis AT, Priori SG, Napolitano C, Ronchetti E, Bryskin R, Schwartz PJ, Brown AM. Cellular dysfunction of LQT5-minK mutants: abnormalities of IKs, IKr and trafficking in long QT syndrome. Hum Mol Genet. 1999;8(8): 1499–507. Shalaby FY, Levesque PC, Yang WP, Little WA, Conder ML, Jenkins-West T, Blanar MA. Dominant-negative KvLQT1 mutations underlie the LQT1 form of long QT syndrome. Circulation. 1997;96(6):1733–6. Abbott GW, Goldstein SA. Disease-associated mutations in KCNE potassium channel subunits (MiRPs) reveal promiscuous disruption of multiple currents and conservation of mechanism. FASEB J. 2002;16(3):390–400.
123 122. Kurokawa J, Chen L, Kass RS. Requirement of subunit expression for cAMP-mediated regulation of a heart potassium channel. Proc Natl Acad Sci U S A. 2003;100(4):2122–7. Epub 2003 Feb 3. 123. Chen Q, Zhang D, Gingell RL, Moss AJ, Napolitano C, Priori SG, Schwartz PJ, Kehoe E, Robinson JL, Schulze-Bahr E, Wang Q, Towbin JA. Homozygous deletion in KVLQT1 associated with Jervell and Lange-Nielsen syndrome. Circulation. 1999;99(10):1344–7. 124. Roden DM, Lazzara R, Rosen M, Schwartz PJ, Towbin J, Vincent GM. Multiple mechanisms in the long-QT syndrome. Current knowledge, gaps, and future directions. The SADS Foundation Task Force on LQTS. Circulation. 1996;94(8):1996–2012. 125. Wollnik B, Schroeder BC, Kubisch C, Esperer HD, Wieacker P, Jentsch TJ. Pathophysiological mechanisms of dominant and recessive KVLQT1 K + channel mutations found in inherited cardiac arrhythmias. Hum Mol Genet. 1997;6(11):1943–9. 126. Donger C, Denjoy I, Berthet M, Neyroud N, Cruaud C, Bennaceur M, Chivoret G, Schwartz K, Coumel P, Guicheney P. KVLQT1 C-terminal missense mutation causes a forme fruste long-QT syndrome. Circulation. 1997;96(9):2778–81. 127. Mohammad-Panah R, Demolombe S, Neyroud N, Guicheney P, Kyndt F, van den Hoff M, Baró I, Escande D. Mutations in a dominant-negative isoform correlate with phenotype in inherited cardiac arrhythmias. Am J Hum Genet. 1999;64(4):1015–23. 128. Chouabe C, Neyroud N, Richard P, Denjoy I, Hainque B, Romey G, Drici MD, Guicheney P, Barhanin J. Novel mutations in KvLQT1 that affect Iks activation through interactions with Isk. Cardiovasc Res. 2000;45(4):971–80. 129. Chouabe C, Neyroud N, Guicheney P, Lazdunski M, Romey G, Barhanin J. Properties of KvLQT1 K + channel mutations in Romano-Ward and Jervell and Lange-Nielsen inherited cardiac arrhythmias. EMBO J. 1997;16(17):5472–9. 130. Splawski I, Tristani-Firouzi M, Lehmann MH, Sanguinetti MC, Keating MT. Mutations in the hminK gene cause long QT syndrome and suppress IKs function. Nat Genet. 1997;17(3):338–40. 131. Franqueza L, Lin M, Shen J, Splawski I, Keating MT, Sanguinetti MC. Long QT syndrome-associated mutations in the S4-S5 linker of KvLQT1 potassium channels modify gating and interaction with minK subunits. J Biol Chem. 1999;274(30): 21063–70. 132. Gibor G, Yakubovich D, Rosenhouse-Dantsker A, Peretz A, Schottelndreier H, Seebohm G, Dascal N, Logothetis DE, Paas Y, Attali B. An inactivation gate in the selectivity filter of KCNQ1 potassium channels. Biophys J. 2007;93(12):4159–72. Epub 2007 Aug 17. 133. Ward OC. A new familial cardiac syndrome in children. J Ir Med Assoc. 1964;54:103–6. 134. Jervell A, Lange-Nielsen F. Congenital deaf-mutism, functional heart disease with prolongation of the Q-T interval and sudden death. Am Heart J. 1957;54(1):59–68. 135. Romano C, Gemme G, Pongiglione R. Rare cardiac arrythmias of the pediatric age. Ii. Syncopal attacks due to paroxysmal ventricular fibrillation. (Presentation of 1st case in Italian pediatric literature). Clin Pediatr (Bologna). 1963;45:656–83. 136. Hashiba K. Hereditary QT, prolongation syndrome in Japan: genetic analysis and pathological findings of the conducting system. Jpn Circ J. 1978;42(10):1133–50. 137. Gamstorp I, Nilsen R, Westling H. Congenital cardiac arrhythmia. Lancet. 1964;2(7366):965. 138. Vincent GM. The heart rate of Romano-Ward syndrome patients. Am Heart J. 1986;112(1):61–4. 139. Göhl K, Feistel H, Weikl A, Bachmann K, Wolf F. Congenital myocardial sympathetic dysinnervation (CMSD)–a structural defect of idiopathic long QT syndrome. Pacing Clin Electrophysiol. 1991;14(10):1544–53.
124 140. Tester DJ, Will ML, Haglund CM, Ackerman MJ. Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing. Heart Rhythm. 2005;2(5):507–17. 141. Weitkamp LR, Moss AJ. The long QT (Romano-Ward) syndrome locus, LQT, is probably linked to the HLA loci. Cytogenet Cell Genet. 1985;40:775. 142. Itoh S, Munemura S, Satoh H. A study of the inheritance pattern of Romano-Ward syndrome. Prolonged Q-T interval, syncope, and sudden death. Clin Pediatr (Phila). 1982;21(1):20–4. 143. Weitkamp LR, Moss AJ, Lewis RA, Hall WJ, MacCluer JW, Schwartz PJ, Locati EH, Tzivoni D, Vincent GM, Robinson JL, Guttormsen SA. Analysis of HLA and disease susceptibility: chromosome 6 genes and sex influence long-QT phenotype. Am J Hum Genet. 1994;55(6):1230–41. 144. Selzer A, Wray HW. Quinidine syncope. Paroxysmal ventricular fibrillation occurring during treatment of chronic atrial arrhythmias. Circulation. 1964;30:17–26. 145. Dessertenne F. La tachycardie ventriculaire à deux foyers opposés variables [ventricular tachycardia with 2 variable opposing foci]. Arch Mal Coeur Vaiss. 1966;59(2):263–72. 146. Viskin S, Fish R, Zeltser D, Belhassen B, Heller K, Brosh D, Laniado S, Barron HV. Arrhythmias in the congenital long QT syndrome: how often is torsade de pointes pause dependent? Heart. 2000;83(6):661–6. 147. Roden DM. Drug-induced prolongation of the QT interval. N Engl J Med. 2004;350(10):1013–22. 148. Gale GE, Bosman CK, Tucker RB, Barlow JB. Hereditary prolongation of QT interval. Study of two families. Br Heart J. 1970;32(4):505–9. 149. Moss AJ, McDonald J. Unilateral cervicothoracic sympathetic ganglionectomy for the treatment of long QT interval syndrome. N Engl J Med. 1971;285(16):903–4. 150. Moss AJ, Schwartz PJ. Sudden death and the idiopathic long Q-T syndrome. Am J Med. 1979;66(1):6–7. 151. Di Segni E, David D, Katzenstein M, Klein HO, Kaplinsky E, Levy MJ. Permanent overdrive pacing for the suppression of recurrent ventricular tachycardia in a newborn with long QT syndrome. J Electrocardiol. 1980;13(2):189–92. 152. Klein HO, Levi A, Kaplinsky E, Di Segni E, David D. Congenital long-QT syndrome: deleterious effect of long-term high-rate ventricular pacing and definitive treatment by cardiac transplantation. Am Heart J. 1996;132(5):1079–81. 153. Shimizu W, Kurita T, Matsuo K, Suyama K, Aihara N, Kamakura S, Towbin JA, Shimomura K. Improvement of repolarization abnormalities by a K + channel opener in the LQT1 form of congenital long-QT syndrome. Circulation. 1998;97(16):1581–8. 154. Itoh T, Kikuchi K, Odagawa Y, Takata S, Yano K, Okada S, Haneda N, Ogawa S, Nakano O, Kawahara Y, Kasai H, Nakayama T, Fukutomi T, Sakurada H, Shimizu A, Yazaki Y, Nagai R, Nakamura Y, Tanaka T. Correlation of genetic etiology with response to beta-adrenergic blockade among symptomatic patients with familial long-QT syndrome. J Hum Genet. 2001;46(1):38–40. 155. Neyroud N, Tesson F, Denjoy I, Leibovici M, Donger C, Barhanin J, Faure S, Gary F, Coumel P, Petit C, Schwartz K, Guicheney P. A novel mutation in the potassium channel gene KVLQT1 causes the Jervell and Lange-Nielsen cardioauditory syndrome. Nat Genet. 1997;15(2):186–9. 156. Tyson J, Tranebjaerg L, McEntagart M, Larsen LA, Christiansen M, Whiteford ML, Bathen J, Aslaksen B, Sorland SJ, Lund O, Pembrey ME, Malcolm S, Bitner-Glindzicz M. Mutational spectrum in the cardioauditory syndrome of Jervell and Lange-Nielsen. Hum Genet. 2000;107(5):499–503. 157. Schmitt N, Schwarz M, Peretz A, Abitbol I, Attali B, Pongs O. A recessive C-terminal Jervell and Lange-Nielsen mutation of the
B. Amuzescu et al.
158.
159.
160.
161.
162.
163.
164.
165.
166.
167.
168.
169.
170.
171.
172.
173.
KCNQ1 channel impairs subunit assembly. EMBO J. 2000;19(3):332–40. Westenskow P, Splawski I, Timothy KW, Keating MT, Sanguinetti MC. Compound mutations: a common cause of severe long-QT syndrome. Circulation. 2004;109(15):1834–41. Epub 2004 Mar 29. Tyson J, Tranebjaerg L, Bellman S, Wren C, Taylor J, Bathen J, Aslaksen B, Sorland SJ, Lund O, Malcolm S, Pembrey M, Bhattacharya S, Bitner-Glindzicz M. IsK and KvLQT1: mutation in either of the two components of the delayed rectifier potassium channel can cause the Jervell and Lange-Nielsen syndrome. Am J Hum Genet. 1997;61:A349. Schulze-Bahr E, Haverkamp W, Wedekind H, Rubie C, Hördt M, Borggrefe M, Assmann G, Breithardt G, Funke H. Autosomal recessive long-QT syndrome (Jervell Lange-Nielsen syndrome) is genetically heterogeneous. Hum Genet. 1997;100(5–6): 573–6. Duggal P, Vesely MR, Wattanasirichaigoon D, Villafane J, Kaushik V, Beggs AH. Mutation of the gene for IsK associated with both Jervell and Lange-Nielsen and Romano-Ward forms of Long-QT syndrome. Circulation. 1998;97(2):142–6. Bellocq C, van Ginneken AC, Bezzina CR, Alders M, Escande D, Mannens MM, Baro I, Wilde AA. Mutation in the KCNQ1 gene leading to the short QT-interval syndrome. Circulation. 2004;109(20):2394–7. Chen YH, Xu SJ, Bendahhou S, Wang XL, Wang Y, Xu WY, Jin HW, Sun H, Su XY, Zhuang QN, Yang YQ, Li YB, Liu Y, Xu HJ, Li XF, Ma N, Mou CP, Chen Z, Barhanin J, Huang W. KCNQ1 gain-of-function mutation in familial atrial fibrillation. Science. 2003;299(5604):251–4. Abbott GW, Sesti F, Splawski I, Buck ME, Lehmann MH, Timothy KW, Keating MT, Goldstein SA. MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia. Cell. 1999;97(2):175–87. Lees-Miller JP, Kondo C, Wang L, Duff HJ. Electrophysiological characterization of an alternatively processed ERG K + channel in mouse and human hearts. Circ Res. 1997;81(5):719–26. London B, Trudeau MC, Newton KP, Beyer AK, Copeland NG, Gilbert DJ, Jenkins NA, Satler CA, Robertson GA. Two isoforms of the mouse ether-a-go-go-related gene coassemble to form channels with properties similar to the rapidly activating component of the cardiac delayed rectifier K + current. Circ Res. 1997;81(5):870–8. Pond AL, Nerbonne JM. ERG proteins and functional cardiac I(Kr) channels in rat, mouse, and human heart. Trends Cardiovasc Med. 2001;11(7):286–94. Zhou Z, Gong Q, Epstein ML, January CT. HERG channel dysfunction in human long QT syndrome. Intracellular transport and functional defects. J Biol Chem. 1998;273(33):21061–6. Anderson CL, Delisle BP, Anson BD, Kilby JA, Will ML, Tester DJ, Gong Q, Zhou Z, Ackerman MJ, January CT. Most LQT2 mutations reduce Kv11.1 (hERG) current by a class 2 (trafficking-deficient) mechanism. Circulation. 2006;113(3): 365–73. Petrecca K, Atanasiu R, Akhavan A, Shrier A. N-linked glycosylation sites determine HERG channel surface membrane expression. J Physiol. 1999;515(Pt 1):41–8. Sanguinetti MC, Curran ME, Spector PS, Keating MT. Spectrum of HERG K + −channel dysfunction in an inherited cardiac arrhythmia. Proc Natl Acad Sci U S A. 1996;93(5):2208–12. Ficker E, Jarolimek W, Kiehn J, Baumann A, Brown AM. Molecular determinants of dofetilide block of HERG K + channels. Circ Res. 1998;82(3):386–95. Smith PL, Baukrowitz T, Yellen G. The inward rectification mechanism of the HERG cardiac potassium channel. Nature. 1996;379(6568):833–6.
9
Channelopathies and Heart Disease
174. Curran ME, Splawski I, Timothy KW, Vincent GM, Green ED, Keating MT. A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell. 1995;80(5):795–803. 175. Imboden M, Swan H, Denjoy I, Van Langen IM, Latinen-Forsblom PJ, Napolitano C, Fressart V, Breithardt G, Berthet M, Priori S, Hainque B, Wilde AA, Schulze-Bahr E, Feingold J, Guicheney P. Female predominance and transmission distortion in the long-QT syndrome. N Engl J Med. 2006;355(26):2744–51. 176. Rajamani S, Anderson CL, Anson BD, January CT. Pharmacological rescue of human K(+) channel long-QT2 mutations: human ether-a-go-go-related gene rescue without block. Circulation. 2002;105(24):2830–5. 177. del Camino D, Holmgren M, Liu Y, Yellen G. Blocker protection in the pore of a voltage-gated K + channel and its structural implications. Nature. 2000;403(6767):321–5. 178. Thomas D, Karle CA, Kiehn J. The cardiac hERG/IKr potassium channel as pharmacological target: structure, function, regulation, and clinical applications. Curr Pharm Des. 2006;12(18): 2271–83. 179. Shah RR, Hondeghem LM. Refining detection of drug-induced proarrhythmia: QT interval and TRIaD. Heart Rhythm. 2005;2(7):758–72. 180. Mitcheson JS, Chen J, Lin M, Culberson C, Sanguinetti MC. A structural basis for drug-induced long QT syndrome. Proc Natl Acad Sci U S A. 2000;97(22):12329–33. 181. Brugada R, Hong K, Dumaine R, Cordeiro J, Gaita F, Borggrefe M, Menendez TM, Brugada J, Pollevick GD, Wolpert C, Burashnikov E, Matsuo K, Wu YS, Guerchicoff A, Bianchi F, Giustetto C, Schimpf R, Brugada P, Antzelevitch C. Sudden death associated with short-QT syndrome linked to mutations in HERG. Circulation. 2004;109(1):30–5. Epub 2003 Dec 15. 182. Ulens C, Tytgat J. Redox state dependency of HERGS631C channel pharmacology: relation to C-type inactivation. FEBS Lett. 2000;474(1):111–5. 183. Sesti F, Abbott GW, Wei J, Murray KT, Saksena S, Schwartz PJ, Priori SG, Roden DM, George Jr AL, Goldstein SA. A common polymorphism associated with antibiotic-induced cardiac arrhythmia. Proc Natl Acad Sci U S A. 2000;97(19):10613–8. 184. Petersen CI, McFarland TR, Stepanovic SZ, Yang P, Reiner DJ, Hayashi K, George AL, Roden DM, Thomas JH, Balser JR. In vivo identification of genes that modify ether-a-go-go-related gene activity in Caenorhabditis elegans may also affect human cardiac arrhythmia. Proc Natl Acad Sci U S A. 2004;101(32):11773– 8. Epub 2004 Jul 27. 185. Millat G, Chevalier P, Restier-Miron L, Da Costa A, Bouvagnet P, Kugener B, Fayol L, Gonzalez Armengod C, Oddou B, Chanavat V, Froidefond E, Perraudin R, Rousson R, Rodriguez-Lafrasse C. Spectrum of pathogenic mutations and associated polymorphisms in a cohort of 44 unrelated patients with long QT syndrome. Clin Genet. 2006;70(3):214–27. 186. Yang Y, Xia M, Jin Q, Bendahhou S, Shi J, Chen Y, Liang B, Lin J, Liu Y, Liu B, Zhou Q, Zhang D, Wang R, Ma N, Su X, Niu K, Pei Y, Xu W, Chen Z, Wan H, Cui J, Barhanin J, Chen Y. Identification of a KCNE2 gain-of-function mutation in patients with familial atrial fibrillation. Am J Hum Genet. 2004;75(5):899– 905. Epub 2004 Sep 13. 187. Gussak I, Brugada P, Brugada J, Wright RS, Kopecky SL, Chaitman BR, Bjerregaard P. Idiopathic short QT interval: a new clinical syndrome? Cardiology. 2000;94(2):99–102. 188. Hong K, Bjerregaard P, Gussak I, Brugada R. Short QT syndrome and atrial fibrillation caused by mutation in KCNH2. J Cardiovasc Electrophysiol. 2005;16(4):394–6. 189. Gaita F, Giustetto C, Bianchi F, Wolpert C, Schimpf R, Riccardi R, Grossi S, Richiardi E, Borggrefe M. Short QT syndrome: a familial cause of sudden death. Circulation. 2003;108(8):965–70. Epub 2003 Aug 18.
125 190. Gouas L, Nicaud V, Berthet M, Forhan A, Tiret L, Balkau B, Guicheney P. Association of KCNQ1, KCNE1, KCNH2 and SCN5A polymorphisms with QTc interval length in a healthy population. Eur J Hum Genet. 2005;13(11):1213–22. 191. Christiansen M, Tønder N, Larsen LA, Andersen PS, Simonsen H, Oyen N, Kanters JK, Jacobsen JR, Fosdal I, Wettrell G, Kjeldsen K. Mutations in the HERG K + −ion channel: a novel link between long QT syndrome and sudden infant death syndrome. Am J Cardiol. 2005;95(3):433–4. 192. Nerbonne JM, Nichols CG, Schwarz TL, Escande D. Genetic manipulation of cardiac K(+) channel function in mice: what have we learned, and where do we go from here? Circ Res. 2001;89(11):944–56. 193. Xu H, Guo W, Nerbonne JM. Four kinetically distinct depolarization-activated K + currents in adult mouse ventricular myocytes. J Gen Physiol. 1999;113(5):661–78. 194. Barry DM, Trimmer JS, Merlie JP, Nerbonne JM. Differential expression of voltage-gated K + channel subunits in adult rat heart. Relation to functional K + channels? Circ Res. 1995;77(2):361–9. 195. Dixon JE, Shi W, Wang HS, McDonald C, Yu H, Wymore RS, Cohen IS, McKinnon D. Role of the Kv4.3 K + channel in ventricular muscle. A molecular correlate for the transient outward current. Circ Res. 1996;79(4):659–68. 196. Bou-Abboud E, Nerbonne JM. Molecular correlates of the calcium-independent, depolarization-activated K + currents in rat atrial myocytes. J Physiol. 1999;517(Pt 2):407–20. 197. An WF, Bowlby MR, Betty M, Cao J, Ling HP, Mendoza G, Hinson JW, Mattsson KI, Strassle BW, Trimmer JS, Rhodes KJ. Modulation of A-type potassium channels by a family of calcium sensors. Nature. 2000;403(6769):553–6. 198. Nadal MS, Ozaita A, Amarillo Y, Vega-Saenz de Miera E, Ma Y, Mo W, Goldberg EM, Misumi Y, Ikehara Y, Neubert TA, Rudy B. The CD26-related dipeptidyl aminopeptidase-like protein DPPX is a critical component of neuronal A-type K + channels. Neuron. 2003;37(3):449–61. 199. Radicke S, Cotella D, Graf EM, Ravens U, Wettwer E. Expression and function of dipeptidyl-aminopeptidase-like protein 6 as a putative beta-subunit of human cardiac transient outward current encoded by Kv4.3. J Physiol. 2005;565(Pt 3):751–6. Epub 2005 May 12. 200. El-Haou S, Balse E, Neyroud N, Dilanian G, Gavillet B, Abriel H, Coulombe A, Jeromin A, Hatem SN. Kv4 potassium channels form a tripartite complex with the anchoring protein SAP97 and CaMKII in cardiac myocytes. Circ Res. 2009;104(6):758–69. Epub 2009 Feb 12. 201. Levy DI, Cepaitis E, Wanderling S, Toth PT, Archer SL, Goldstein SA. The membrane protein MiRP3 regulates Kv4.2 channels in a KChIP-dependent manner. J Physiol. 2010;588(Pt 14):2657–68. Epub 2010 May 24. 202. Radicke S, Vaquero M, Caballero R, Gomez R, Nunez L, Tamargo J, Ravens U, Wettwer E, Delpon E. Effects of MiRP1 and DPP6 beta-subunits on the blockade induced by flecainide of Kv4.3/ KChIP2 channels. Br J Pharmacol. 2008;154(4):774–86. Epub 2008 Apr 21. 203. Bähring R, Dannenberg J, Peters HC, Leicher T, Pongs O, Isbrandt D. Conserved Kv4 N-terminal domain critical for effects of Kv channel-interacting protein 2.2 on channel expression and gating. J Biol Chem. 2001;276(26):23888–94. Epub 2001 Apr 3. 204. Barghaan J, Tozakidou M, Ehmke H, Bähring R. Role of N-terminal domain and accessory subunits in controlling deactivation-inactivation coupling of Kv4.2 channels. Biophys J. 2008;94(4):1276–94. Epub 2007 Nov 2. 205. Hovind LJ, Skerritt MR, Campbell DL. K(V)4.3 N-terminal deletion mutant Delta2-39: effects on inactivation and recovery characteristics in both the absence and presence of KChIP2b. Channels. 2011;5(1):43–55. Epub 2011 Jan 1.
126 206. Liu W, Deng J, Xu J, Wang H, Yuan M, Liu N, Jiang Y, Liu J. High-mobility group box 1 (HMGB1) downregulates cardiac transient outward potassium current (Ito) through downregulation of Kv4.2 and Kv4.3 channel transcripts and proteins. J Mol Cell Cardiol. 2010;49(3):438–48. Epub 2010 May 17. 207. Brahmajothi MV, Campbell DL, Rasmusson RL, Morales MJ, Trimmer JS, Nerbonne JM, Strauss HC. Distinct transient outward potassium current (Ito) phenotypes and distribution of fastinactivating potassium channel alpha subunits in ferret left ventricular myocytes. J Gen Physiol. 1999;113(4):581–600. 208. Dixon JE, McKinnon D. Quantitative analysis of potassium channel mRNA expression in atrial and ventricular muscle of rats. Circ Res. 1994;75(2):252–60. 209. Wickenden AD, Jegla TJ, Kaprielian R, Backx PH. Regional contributions of Kv1.4, Kv4.2, and Kv4.3 to transient outward K + current in rat ventricle. Am J Physiol. 1999;276(5 Pt 2):H1599–607. 210. Bénitah JP, Gomez AM, Bailly P, Da Ponte JP, Berson G, Delgado C, Lorente P. Heterogeneity of the early outward current in ventricular cells isolated from normal and hypertrophied rat hearts. J Physiol. 1993;469:111–38. 211. Beuckelmann DJ, Näbauer M, Erdmann E. Alterations of K + currents in isolated human ventricular myocytes from patients with terminal heart failure. Circ Res. 1993;73(2):379–85. 212. Näbauer M, Kääb S. Potassium channel down-regulation in heart failure. Cardiovasc Res. 1998;37(2):324–34. 213. Tomita F, Bassett AL, Myerburg RJ, Kimura S. Diminished transient outward currents in rat hypertrophied ventricular myocytes. Circ Res. 1994;75(2):296–303. 214. Wang Y, Cheng J, Chen G, Rob F, Naseem RH, Nguyen L, Johnstone JL, Hill JA. Remodeling of outward K + currents in pressure-overload heart failure. J Cardiovasc Electrophysiol. 2007;18(8):869–75. Epub 2007 May 30. 215. Kaprielian R, Sah R, Nguyen T, Wickenden AD, Backx PH. Myocardial infarction in rat eliminates regional heterogeneity of AP profiles, I(to) K(+) currents, and [Ca(2+)](i) transients. Am J Physiol Heart Circ Physiol. 2002;283(3):H1157–68. 216. Yan GX, Antzelevitch C. Cellular basis for the electrocardiographic J wave. Circulation. 1996;93(2):372–9. 217. Tomaszewski W. Changements electrocardiographiques observés chez un homme mort de froid. Arch Mal Coeur Vaiss. 1938;31:525–8. 218. Otto CM, Tauxe RV, Cobb LA, Greene HL, Gross BW, Werner JA, Burroughs RW, Samson WE, Weaver WD, Trobaugh GB. Ventricular fibrillation causes sudden death in Southeast Asian immigrants. Ann Intern Med. 1984;101(1):45–7. 219. Brugada P, Brugada J. Right bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome. A multicenter report. J Am Coll Cardiol. 1992;20(6):1391–6. 220. Miyazaki T, Mitamura H, Miyoshi S, Soejima K, Aizawa Y, Ogawa S. Autonomic and antiarrhythmic drug modulation of ST segment elevation in patients with Brugada syndrome. J Am Coll Cardiol. 1996;27(5):1061–70. 221. Antzelevitch C, Yan GX. J wave syndromes. Heart Rhythm. 2009;7(4):549–58. 222. Corlan AD, Amuzescu B, Milicin I, Iordachescu V, Poenaru E, Corlan I, De Ambroggi L. Intercellular conductance variability influences early repolarization potentials in a model of the myocardial tissue with stochastic architecture. In: 7th international symposium on Advanced Topics in Electrical Engineering (ATEE). 2011. Bucharest. p. 1–4. http://ieeexplore.ieee.org/xpl/ freeabs_all.jsp?arnumber=5952183. 223. Weidmann S. Rectifier properties of Purkinje fibers. Am J Physiol. 1955;183(3):761. 224. Katz B. Les constantes électriques de la membrane du muscle. Arch Sci Physiol. 1949;2:285–99.
B. Amuzescu et al. 225. Stanfield PR, Davies NW, Shelton PA, Sutcliffe MJ, Khan IA, Brammar WJ, Conley EC. A single aspartate residue is involved in both intrinsic gating and blockage by Mg2+ of the inward rectifier, IRK1. J Physiol. 1994;478(Pt 1):1–6. 226. Yang J, Jan YN, Jan LY. Control of rectification and permeation by residues in two distinct domains in an inward rectifier K + channel. Neuron. 1995;14(5):1047–54. 227. Ruppersberg JP, Fakler B, Brandle U, Zenner H-P, Schultz JH. An N-terminal site controls blocker-release in Kir2.1 channels. Biophys J. 1996;70:A361. 228. Qu Z, Yang Z, Cui N, Zhu G, Liu C, Xu H, Chanchevalap S, Shen W, Wu J, Li Y, Jiang C. Gating of inward rectifier K + channels by proton-mediated interactions of N- and C-terminal domains. J Biol Chem. 2000;275(41):31573–80. 229. Koumi S, Backer CL, Arentzen CE, Sato R. Beta-adrenergic modulation of the inwardly rectifying potassium channel in isolated human ventricular myocytes. Alteration in channel response to beta-adrenergic stimulation in failing human hearts. J Clin Invest. 1995;96(6):2870–81. 230. Koumi S, Wasserstrom JA, Ten Eick RE. Beta-adrenergic and cholinergic modulation of inward rectifier K + channel function and phosphorylation in guinea-pig ventricle. J Physiol. 1995;486(Pt 3):661–78. 231. Wischmeyer E, Karschin A. Receptor stimulation causes slow inhibition of IRK1 inwardly rectifying K + channels by direct protein kinase A-mediated phosphorylation. Proc Natl Acad Sci U S A. 1996;93(12):5819–23. 232. Wischmeyer E, Döring F, Karschin A. Acute suppression of inwardly rectifying Kir2.1 channels by direct tyrosine kinase phosphorylation. J Biol Chem. 1998;273(51):34063–8. 233. Cho H, Lee D, Lee SH, Ho WK. Receptor-induced depletion of phosphatidylinositol 4,5-bisphosphate inhibits inwardly rectifying K + channels in a receptor-specific manner. Proc Natl Acad Sci U S A. 2005;102(12):4643–8. Epub 2005 Mar 14. 234. Preisig-Müller R, Schlichthorl G, Goerge T, Heinen S, Brüggemann A, Rajan S, Derst C, Veh RW, Daut J. Heteromerization of Kir2.x potassium channels contributes to the phenotype of Andersen’s syndrome. Proc Natl Acad Sci U S A. 2002;99(11):7774–9. 235. Plaster NM, Tawil R, Tristani-Firouzi M, Canún S, Bendahhou S, Tsunoda A, Donaldson MR, Iannaccone ST, Brunt E, Barohn R, Clark J, Deymeer F, George Jr AL, Fish FA, Hahn A, Nitu A, Ozdemir C, Serdaroglu P, Subramony SH, Wolfe G, Fu YH, Ptáček LJ. Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen’s syndrome. Cell. 2001;105(4):511–9. 236. Tristani-Firouzi M, Jensen JL, Donaldson MR, Sansone V, Meola G, Hahn A, Bendahhou S, Kwiecinski H, Fidzianska A, Plaster N, Fu YH, Ptáček LJ, Tawil R. Functional and clinical characterization of KCNJ2 mutations associated with LQT7 (Andersen syndrome). J Clin Invest. 2002;110(3):381–8. 237. Andersen ED, Krasilnikoff PA, Overvad H. Intermittent muscular weakness, extrasystoles, and multiple developmental anomalies. A new syndrome? Acta Paediatr Scand. 1971;60(5): 559–64. 238. Stubbs WA. Bidirectional ventricular tachycardia in familial hypokalaemic periodic paralysis. Proc R Soc Med. 1976;69(3):223–4. 239. Kramer LD, Cole JP, Messenger JC, Ellestad MH. Cardiac dysfunction in a patient with familial hypokalemic periodic paralysis. Chest. 1979;75(2):189–92. 240. Tawil R, Ptacek LJ, Pavlakis SG, DeVivo DC, Penn AS, Ozdemir C, Griggs RC. Andersen’s syndrome: potassium-sensitive periodic paralysis, ventricular ectopy, and dysmorphic features. Ann Neurol. 1994;35(3):326–30. 241. Sansone V, Griggs RC, Meola G, Ptacek LJ, Barohn R, Iannaccone S, Bryan W, Baker N, Janas SJ, Scott W, Ririe D, Tawil R.
9
Channelopathies and Heart Disease
242.
243.
244.
245.
246.
247.
248.
249.
250.
251.
252.
253.
254. 255.
256.
257.
Andersen’s syndrome: a distinct periodic paralysis. Ann Neurol. 1997;42(3):305–12. Canún S, Pérez N, Beirana LG. Andersen syndrome autosomal dominant in three generations. Am J Med Genet. 1999;85(2):147–56. Andelfinger G, Tapper AR, Welch RC, Vanoye CG, George Jr AL, Benson DW. KCNJ2 mutation results in Andersen syndrome with sex-specific cardiac and skeletal muscle phenotypes. Am J Hum Genet. 2002;71(3):663–8. Epub 2002 Jul 29. Donaldson MR, Jensen JL, Tristani-Firouzi M, Tawil R, Bendahhou S, Suarez WA, Cobo AM, Poza JJ, Behr E, Wagstaff J, Szepetowski P, Pereira S, Mozaffar T, Escolar DM, Fu YH, Ptacek LJ. PIP2 binding residues of Kir2.1 are common targets of mutations causing Andersen syndrome. Neurology. 2003;60(11):1811–6. Choi BO, Kim J, Suh BC, Yu JS, Sunwoo IN, Kim SJ, Kim GH, Chung KW. Mutations of KCNJ2 gene associated with AndersenTawil syndrome in Korean families. J Hum Genet. 2007;52(3):280– 3. Epub 2007 Jan 9. Bendahhou S, Fournier E, Gallet S, Menard D, Larroque MM, Barhanin J. Corticosteroid-exacerbated symptoms in an Andersen’s syndrome kindred. Hum Mol Genet. 2007;16(8):900– 6. Epub 2007 Feb 26. Chan HF, Chen ML, Su JJ, Ko LC, Lin CH, Wu RM. A novel neuropsychiatric phenotype of KCNJ2 mutation in one Taiwanese family with Andersen-Tawil syndrome. J Hum Genet. 2010;55(3):186–8. Epub 2010 Jan 29. Junker J, Haverkamp W, Schulze-Bahr E, Eckardt L, Paulus W, Kiefer R. Amiodarone and acetazolamide for the treatment of genetically confirmed severe Andersen syndrome. Neurology. 2002;59(3):466. Xia M, Jin Q, Bendahhou S, He Y, Larroque MM, Chen Y, Zhou Q, Yang Y, Liu Y, Liu B, Zhu Q, Zhou Y, Lin J, Liang B, Li L, Dong X, Pan Z, Wang R, Wan H, Qiu W, Xu W, Eurlings P, Barhanin J, Chen Y. A Kir2.1 gain-of-function mutation underlies familial atrial fibrillation. Biochem Biophys Res Commun. 2005;332(4):1012–9. Fauconnier J, Lacampagne A, Rauzier JM, Vassort G, Richard S. Ca2 + −dependent reduction of IK1 in rat ventricular cells: a novel paradigm for arrhythmia in heart failure? Cardiovasc Res. 2005;68(2):204–12. Epub 2005 Aug 3. Laitinen PJ, Brown KM, Piippo K, Swan H, Devaney JM, Brahmbhatt B, Donarum EA, Marino M, Tiso N, Viitasalo M, Toivonen L, Stephan DA, Kontula K. Mutations of the cardiac ryanodine receptor (RyR2) gene in familial polymorphic ventricular tachycardia. Circulation. 2001;103(4):485–90. Tester DJ, Kopplin LJ, Will ML, Ackerman MJ. Spectrum and prevalence of cardiac ryanodine receptor (RyR2) mutations in a cohort of unrelated patients referred explicitly for long QT syndrome genetic testing. Heart Rhythm. 2005;2(10):1099–105. Sakmann B, Noma A, Trautwein W. Acetylcholine activation of single muscarinic K + channels in isolated pacemaker cells of the mammalian heart. Nature. 1983;303(5914):250–3. Chandy KG, Gutman GA. Nomenclature for mammalian potassium channel genes. Trends Pharmacol Sci. 1993;14(12):434. Logothetis DE, Kurachi Y, Galper J, Neer EJ, Clapham DE. The beta gamma subunits of GTP-binding proteins activate the muscarinic K + channel in heart. Nature. 1987;325(6102):321–6. Voigt N, Friedrich A, Bock M, Wettwer E, Christ T, Knaut M, Strasser RH, Ravens U, Dobrev D. Differential phosphorylationdependent regulation of constitutively active and muscarinic receptor-activated IK, ACh channels in patients with chronic atrial fibrillation. Cardiovasc Res. 2007;74(3):426–37. Epub 2007 Feb 12. Yeh YH, Ehrlich JR, Qi X, Hébert TE, Chartier D, Nattel S. Adrenergic control of a constitutively active acetylcholine-regu-
127
258.
259.
260.
261.
262.
263.
264.
265.
266.
267.
268.
269.
270.
271.
272.
273.
lated potassium current in canine atrial cardiomyocytes. Cardiovasc Res. 2007;74(3):406–15. Epub 2007 Feb 12. Wickman K, Nemec J, Gendler SJ, Clapham DE. Abnormal heart rate regulation in GIRK4 knockout mice. Neuron. 1998;20(1):103–14. Kovoor P, Wickman K, Maguire CT, Pu W, Gehrmann J, Berul CI, Clapham DE. Evaluation of the role of I(KACh) in atrial fibrillation using a mouse knockout model. J Am Coll Cardiol. 2001;37(8):2136–43. Yang Y, Yang Y, Liang B, Liu J, Li J, Grunnet M, Olesen SP, Rasmussen HB, Ellinor PT, Gao L, Lin X, Li L, Wang L, Xiao J, Liu Y, Liu Y, Zhang S, Liang D, Peng L, Jespersen T, Chen YH. Identification of a Kir3.4 mutation in congenital long QT syndrome. Am J Hum Genet. 2010;86(6):872–80. Geller DS, Zhang J, Wisgerhof MV, Shackleton C, Kashgarian M, Lifton RP. A novel form of human mendelian hypertension featuring nonglucocorticoid-remediable aldosteronism. J Clin Endocrinol Metab. 2008;93(8):3117–23. Epub 2008 May 27. Choi M, Scholl UI, Yue P, Björklund P, Zhao B, Nelson-Williams C, Ji W, Cho Y, Patel A, Men CJ, Lolis E, Wisgerhof MV, Geller DS, Mane S, Hellman P, Westin G, Åkerström G, Wang W, Carling T, Lifton RP. K + channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension. Science. 2011;331(6018):768–72. Nichols CG, Lederer WJ, Cannell MB. ATP dependence of KATP channel kinetics in isolated membrane patches from rat ventricle. Biophys J. 1991;60(5):1164–77. Weiss JN, Venkatesh N, Lamp ST. ATP-sensitive K + channels and cellular K + loss in hypoxic and ischaemic mammalian ventricle. J Physiol. 1992;447:649–73. Ferrero Jr JM, Saiz J, Ferrero JM, Thakor NV. Simulation of action potentials from metabolically impaired cardiac myocytes. Role of ATP-sensitive K + current. Circ Res. 1996;79(2):208–21. Carrasco AJ, Dzeja PP, Alekseev AE, Pucar D, Zingman LV, Abraham MR, Hodgson D, Bienengraeber M, Puceat M, Janssen E, Wieringa B, Terzic A. Adenylate kinase phosphotransfer communicates cellular energetic signals to ATP-sensitive potassium channels. Proc Natl Acad Sci U S A. 2001;98(13):7623–8. Epub 2001 Jun 5. Crawford RM, Budas GR, Jovanovic S, Ranki HJ, Wilson TJ, Davies AM, Jovanovic A. M-LDH serves as a sarcolemmal K(ATP) channel subunit essential for cell protection against ischemia. EMBO J. 2002;21(15):3936–48. Crawford RM, Ranki HJ, Botting CH, Budas GR, Jovanovic A. Creatine kinase is physically associated with the cardiac ATPsensitive K + channel in vivo. FASEB J. 2002;16(1):102–4. Epub 2001 Nov 29. Dhar-Chowdhury P, Harrell MD, Han SY, Jankowska D, Parachuru L, Morrissey A, Srivastava S, Liu W, Malester B, Yoshida H, Coetzee WA. The glycolytic enzymes, glyceraldehyde-3-phosphate dehydrogenase, triose-phosphate isomerase, and pyruvate kinase are components of the K(ATP) channel macromolecular complex and regulate its function. J Biol Chem. 2005;280(46):38464–70. Epub 2005 Sep 16. DiFrancesco D, Ojeda C. Properties of the current if in the sinoatrial node of the rabbit compared with those of the current iK, in Purkinje fibres. J Physiol. 1980;308:353–67. Pape HC. Queer current and pacemaker: the hyperpolarizationactivated cation current in neurons. Annu Rev Physiol. 1996;58:299–327. Wainger BJ, DeGennaro M, Santoro B, Siegelbaum SA, Tibbs GR. Molecular mechanism of cAMP modulation of HCN pacemaker channels. Nature. 2001;411(6839):805–10. Alig J, Marger L, Mesirca P, Ehmke H, Mangoni ME, Isbrandt D. Control of heart rate by cAMP sensitivity of HCN channels. Proc Natl Acad Sci U S A. 2009;106(29):12189–94. Epub 2009 Jul 1.
128 274. Milanesi R, Baruscotti M, Gnecchi-Ruscone T, DiFrancesco D. Familial sinus bradycardia associated with a mutation in the cardiac pacemaker channel. N Engl J Med. 2006;354(2):151–7. 275. Männikkö R, Pandey S, Larsson HP, Elinder F. Hysteresis in the voltage dependence of HCN channels: conversion between two modes affects pacemaker properties. J Gen Physiol. 2005;125(3):305–26. Epub 2005 Feb 14. 276. Bacos JM, Eagan JT, Orgain ES. Congenital familial nodal rhythm. Circulation. 1960;22:887–95. 277. Surawicz B, Hariman RJ. Follow-up of the family with congenital absence of sinus rhythm. Am J Cardiol. 1988;61(6):467–9. 278. Lehmann H, Klein UE. Familial sinus node dysfunction with autosomal dominant inheritance. Br Heart J. 1978;40(11):1314–6. 279. Ruiz de la Fuente S, Prieto F. Heart-hand syndrome. III. A new syndrome in three generations. Hum Genet. 1980;55(1):43–7. 280. Ueda K, Nakamura K, Hayashi T, Inagaki N, Takahashi M, Arimura T, Morita H, Higashiuesato Y, Hirano Y, Yasunami M, Takishita S, Yamashina A, Ohe T, Sunamori M, Hiraoka M, Kimura A. Functional characterization of a trafficking-defective HCN4 mutation, D553N, associated with cardiac arrhythmia. J Biol Chem. 2004;279(26):27194–8. Epub 2004 Apr 30. 281. Nof E, Luria D, Brass D, Marek D, Lahat H, Reznik-Wolf H, Pras E, Dascal N, Eldar M, Glikson M. Point mutation in the HCN4 cardiac ion channel pore affecting synthesis, trafficking, and functional expression is associated with familial asymptomatic sinus bradycardia. Circulation. 2007;116(5):463–70. Epub 2007 Jul 23. 282. Ueda K, Hirano Y, Higashiuesato Y, Aizawa Y, Hayashi T, Inagaki N, Tana T, Ohya Y, Takishita S, Muratani H, Hiraoka M, Kimura A. Role of HCN4 channel in preventing ventricular arrhythmia. J Hum Genet. 2009;54(2):115–21. Epub 2009 Jan 23. 283. Fernández-Velasco M, Goren N, Benito G, Blanco-Rivero J, Boscá L, Delgado C. Regional distribution of hyperpolarizationactivated current (If) and hyperpolarization-activated cyclic nucleotide-gated channel mRNA expression in ventricular cells from control and hypertrophied rat hearts. J Physiol. 2003;553(Pt 2):395–405. Epub 2003 Sep 26. 284. Cerbai E, Pino R, Porciatti F, Sani G, Toscano M, Maccherini M, Giunti G, Mugelli A. Characterization of the hyperpolarizationactivated current, I(f), in ventricular myocytes from human failing heart. Circulation. 1997;95(3):568–71. 285. Cerbai E, Sartiani L, DePaoli P, Pino R, Maccherini M, Bizzarri F, DiCiolla F, Davoli G, Sani G, Mugelli A. The properties of the pacemaker current I(F)in human ventricular myocytes are modulated by cardiac disease. J Mol Cell Cardiol. 2001;33(3): 441–8. 286. Hoppe UC, Jansen E, Südkamp M, Beuckelmann DJ. Hyperpolarization-activated inward current in ventricular myocytes from normal and failing human hearts. Circulation. 1998;97(1):55–65. 287. Barbuti A, Baruscotti M, DiFrancesco D. The pacemaker current: from basics to the clinics. J Cardiovasc Electrophysiol. 2007;18(3):342–7. Epub 2007 Jan 30. 288. Mandel Y, Weissman A, Schick R, Barad L, Novak A, Meiry G, Goldberg S, Lorber A, Rosen MR, Itskovitz-Eldor J, Binah O. Human embryonic and induced pluripotent stem cells-derived cardiomyocytes exhibit beat rate variability and power-law behavior. Circulation. 2012;125(7):883–93. 289. Peters NS, Wit AL. Myocardial architecture and ventricular arrhythmogenesis. Circulation. 1998;97(17):1746–54. 290. Spray DC, Burt JM. Structure-activity relations of the cardiac gap junction channel. Am J Physiol. 1990;258(2 Pt 1):C195–205. 291. Kanno S, Saffitz JE. The role of myocardial gap junctions in electrical conduction and arrhythmogenesis. Cardiovasc Pathol. 2001;10(4):169–77.
B. Amuzescu et al. 292. Norton KK, Carey JC, Gutmann DH. Oculodentodigital dysplasia with cerebral white matter abnormalities in a two-generation family. Am J Med Genet. 1995;57(3):458–61. 293. Loddenkemper T, Grote K, Evers S, Oelerich M, Stögbauer F. Neurological manifestations of the oculodentodigital dysplasia syndrome. J Neurol. 2002;249(5):584–95. 294. Paznekas WA, Boyadjiev SA, Shapiro RE, Daniels O, Wollnik B, Keegan CE, Innis JW, Dinulos MB, Christian C, Hannibal MC, Jabs EW. Connexin 43 (GJA1) mutations cause the pleiotropic phenotype of oculodentodigital dysplasia. Am J Hum Genet. 2003;72(2):408–18. Epub 2002 Nov 27. 295. Kjaer KW, Hansen L, Eiberg H, Leicht P, Opitz JM, Tommerup N. Novel Connexin 43 (GJA1) mutation causes oculo-dento-digital dysplasia with curly hair. Am J Med Genet A. 2004;127A(2):152–7. 296. van Steensel MA, Spruijt L, van der Burgt I, Bladergroen RS, Vermeer M, Steijlen PM, van Geel M. A 2-bp deletion in the GJA1 gene is associated with oculo-dento-digital dysplasia with palmoplantar keratoderma. Am J Med Genet A. 2005;132A(2):171–4. 297. Vreeburg M, de Zwart-Storm EA, Schouten MI, Nellen RG, Marcus-Soekarman D, Devies M, van Geel M, van Steensel MA. Skin changes in oculo-dento-digital dysplasia are correlated with C-terminal truncations of connexin 43. Am J Med Genet A. 2007;143(4):360–3. 298. Kalcheva N, Qu J, Sandeep N, Garcia L, Zhang J, Wang Z, Lampe PD, Suadicani SO, Spray DC, Fishman GI. Gap junction remodeling and cardiac arrhythmogenesis in a murine model of oculodentodigital dysplasia. Proc Natl Acad Sci U S A. 2007;104(51):20512–6. Epub 2007 Dec 11. 299. Tsui E, Hill KA, Laliberte AM, Paluzzi D, Kisilevsky I, Shao Q, Heathcote JG, Laird DW, Kidder GM, Hutnik CM. Ocular pathology relevant to glaucoma in a Gja1(Jrt/+) mouse model of human oculodentodigital dysplasia. Invest Ophthalmol Vis Sci. 2011;52(6):3539–47. Print 2011 May. 300. Dasgupta C, Martinez AM, Zuppan CW, Shah MM, Bailey LL, Fletcher WH. Identification of connexin43 (alpha1) gap junction gene mutations in patients with hypoplastic left heart syndrome by denaturing gradient gel electrophoresis (DGGE). Mutat Res. 2001;479(1–2):173–86. 301. Gollob MH, Jones DL, Krahn AD, Danis L, Gong XQ, Shao Q, Liu X, Veinot JP, Tang AS, Stewart AF, Tesson F, Klein GJ, Yee R, Skanes AC, Guiraudon GM, Ebihara L, Bai D. Somatic mutations in the connexin 40 gene (GJA5) in atrial fibrillation. N Engl J Med. 2006;354(25):2677–88. 302. Groenewegen WA, Firouzi M, Bezzina CR, Vliex S, van Langen IM, Sandkuijl L, Smits JP, Hulsbeek M, Rook MB, Jongsma HJ, Wilde AA. A cardiac sodium channel mutation cosegregates with a rare connexin40 genotype in familial atrial standstill. Circ Res. 2003;92(1):14–22. 303. Chaldoupi SM, Loh P, Hauer RN, de Bakker JM, van Rijen HV. The role of connexin40 in atrial fibrillation. Cardiovasc Res. 2009;84(1):15–23. Epub 2009 Jun 17. 304. Zemlin CW, Mitrea BG, Pertsov AM. Spontaneous onset of atrial fibrillation. Physica D. 2009;238(11–12):969–75. 305. Putney Jr JW. A model for receptor-regulated calcium entry. Cell Calcium. 1986;7(1):1–12. 306. Putney JW. Origins of the concept of store-operated calcium entry. Front Biosci (Schol Ed). 2011;3:980–4. 307. Hoth M, Penner R. Depletion of intracellular calcium stores activates a calcium current in mast cells. Nature. 1992;355(6358):353–6. 308. Liao Y, Erxleben C, Abramowitz J, Flockerzi V, Zhu MX, Armstrong DL, Birnbaumer L. Functional interactions among Orai1, TRPCs, and STIM1 suggest a STIM-regulated heteromeric Orai/TRPC model for SOCE/Icrac channels. Proc Natl Acad Sci U S A. 2008;105(8):2895–900. Epub 2008 Feb 19.
9
Channelopathies and Heart Disease
309. Yuan JP, Kim MS, Zeng W, Shin DM, Huang G, Worley PF, Muallem S. TRPC channels as STIM1-regulated SOCs. Channels (Austin). 2009;3(4):221–5. Epub 2009 Jul 15. 310. Seth M, Zhang ZS, Mao L, Graham V, Burch J, Stiber J, Tsiokas L, Winn M, Abramowitz J, Rockman HA, Birnbaumer L, Rosenberg P. TRPC1 channels are critical for hypertrophic signaling in the heart. Circ Res. 2009;105(10):1023–30. Epub 2009 Sep 24. 311. Kiyonaka S, Kato K, Nishida M, Mio K, Numaga T, Sawaguchi Y, Yoshida T, Wakamori M, Mori E, Numata T, Ishii M, Takemoto H, Ojida A, Watanabe K, Uemura A, Kurose H, Morii T, Kobayashi T, Sato Y, Sato C, Hamachi I, Mori Y. Selective and direct inhibition of TRPC3 channels underlies biological activities of a pyrazole compound. Proc Natl Acad Sci U S A. 2009;106(13):5400–5. Epub 2009 Mar 16. 312. Bush EW, Hood DB, Papst PJ, Chapo JA, Minobe W, Bristow MR, Olson EN, McKinsey TA. Canonical transient receptor potential channels promote cardiomyocyte hypertrophy through activation of calcineurin signaling. J Biol Chem. 2006;281(44):33487–96. Epub 2006 Sep 1. 313. Nakayama H, Wilkin BJ, Bodi I, Molkentin JD. Calcineurindependent cardiomyopathy is activated by TRPC in the adult mouse heart. FASEB J. 2006;20(10):1660–70. 314. Wu X, Eder P, Chang B, Molkentin JD. TRPC channels are necessary mediators of pathologic cardiac hypertrophy. Proc Natl Acad Sci U S A. 2010;107(15):7000–5. Epub 2010 Mar 29. 315. Fauconnier J, Lanner JT, Sultan A, Zhang SJ, Katz A, Bruton JD, Westerblad H. Insulin potentiates TRPC3-mediated cation currents in normal but not in insulin-resistant mouse cardiomyocytes. Cardiovasc Res. 2007;73(2):376–85. Epub 2006 Oct 27. 316. Ju YK, Allen DG. Store-operated Ca2+ entry and TRPC expression; possible roles in cardiac pacemaker tissue. Heart Lung Circ. 2007;16(5):349–55. Epub 2007 Sep 5. 317. Freichel M, Schweig U, Stauffenberger S, Freise D, Schorb W, Flockerzi V. Store-operated cation channels in the heart and cells of the cardiovascular system. Cell Physiol Biochem. 1999;9(4–5):270–83. 318. Vassort G, Alvarez J. Transient receptor potential: a large family of new channels of which several are involved in cardiac arrhythmia. Can J Physiol Pharmacol. 2009;87(2):100–7. 319. Colquhoun D, Neher E, Reuter H, Stevens CF. Inward current channels activated by intracellular Ca in cultured cardiac cells. Nature. 1981;294(5843):752–4.
129 320. Nilius B, Vennekens R. From cardiac cation channels to the molecular dissection of the transient receptor potential channel TRPM4. Pflugers Arch. 2006;453(3):313–21. Epub 2006 May 6. 321. Gannier F, White E, Lacampagne A, Garnier D, Le Guennec JY. Streptomycin reverses a large stretch induced increases in [Ca2+] i in isolated guinea pig ventricular myocytes. Cardiovasc Res. 1994;28(8):1193–8. 322. Gwanyanya A, Amuzescu B, Zakharov SI, Macianskiene R, Sipido KR, Bolotina VM, Vereecke J, Mubagwa K. Magnesiuminhibited, TRPM6/7-like channel in cardiac myocytes: permeation of divalent cations and pH-mediated regulation. J Physiol. 2004;559(Pt 3):761–76. Epub 2004 Jul 22. 323. Mubagwa K, Stengl M, Flameng W. Extracellular divalent cations block a cation non-selective conductance unrelated to calcium channels in rat cardiac muscle. J Physiol. 1997;502(Pt 2):235–47. 324. Aarts M, Iihara K, Wei WL, Xiong ZG, Arundine M, Cerwinski W, MacDonald JF, Tymianski M. A key role for TRPM7 channels in anoxic neuronal death. Cell. 2003;115(7):863–77. 325. Wei WL, Sun HS, Olah ME, Sun X, Czerwinska E, Czerwinski W, Mori Y, Orser BA, Xiong ZG, Jackson MF, Tymianski M, MacDonald JF. TRPM7 channels in hippocampal neurons detect levels of extracellular divalent cations. Proc Natl Acad Sci U S A. 2007;104(41):16323–8. Epub 2007 Oct 3. 326. Jiang H, Tian SL, Zeng Y, Li LL, Shi J. TrkA pathway(s) is involved in regulation of TRPM7 expression in hippocampal neurons subjected to ischemic-reperfusion and oxygen-glucose deprivation. Brain Res Bull. 2008;76(1–2):124–30. Epub 2008 Feb 12. 327. Du J, Xie J, Zhang Z, Tsujikawa H, Fusco D, Silverman D, Liang B, Yue L. TRPM7-mediated Ca2+ signals confer fibrogenesis in human atrial fibrillation. Circ Res. 2010;106(5):992–1003. 328. Ashcroft FM. Ion channels and disease. Channelopathies. San Diego: Academic; 2000. 481 p. 329. Amuzescu B, Georgescu A, Nistor G, Popescu M, Svab I, Flonta ML, Corlan AD. Stability and sustained oscillations in a ventricular cardiomyocyte model. Interdiscip Sci Comput Life Sci. 2012;4(1):1–18. 330. Tran DX, Sato D, Yochelis A, Weiss JN, Garfinkel A, Qu Z. Bifurcation and chaos in a model of cardiac early afterdepolarizations. Phys Rev Lett. 2009;102(25):258103. Epub 2009 Jun 25. 331. Herbert E, Chahine M. Clinical aspects and physiopathology of Brugada syndrome: review of current concepts. Can J Physiol Pharmacol. 2006;84(8–9):795–802.
Late Open Artery Hypothesis and Cardiac Electrical Stability
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Craig Steven McLachlan, Brett Hambly, and Mark McGuire
Abstract
The concept that late reperfusion resulting in a patent infarct artery causes benefit beyond myocardial salvage (also referred to as the open artery hypothesis) remains somewhat controversial. The seminal animal studies are reviewed in this chapter that lead to two decades of inquiry into the open artery hypothesis. In the rat, Hochman and Choo showed that late reperfusion independent of myocardial infarct size may still improve healing of the infarct, resulting in a thicker infarct wall, less infarct expansion, less LV dilation, and improved cardiac function. Translational evidence for late reperfusion having a benefit on ventricular cavity size during chronic post-infarct healing is reviewed in association with cardiac electrical stability. Consistent with that idea, randomized clinical trials have clearly shown that reperfusion within 6 h reduces mortality and reduces the incidence of induced ventricular tachycardia. Although, the 6-h cutoff for reperfusion in acute MI patients is based primarily on old thrombolytic data. More recent trials with longer time to reperfusion cutoff levels have been performed with percutaneous transluminal coronary angioplasty (PTCA) with or without stents. Notably, the benefits of late reperfusion do not depend on the amount of salvaged myocardium at risk in these clinical studies, and reperfusion as late as 12-h and possibly up to 24-h post-MI exert a beneficial effect on ventricular remodeling. Beyond 24 h, however, the data are less encouraging. The results of more recent clinical trials further diminish the enthusiasm for late reperfusion and do not support the concept that late reperfusion improves cardiac electrical stability. In fact some evidence suggests it may be worse. Keywords
Late reperfusion • Cardiac electrical stability • Open artery hypothesis • Cardiac remodeling
C.S. McLachlan, PhD (*) Rural Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia e-mail:
[email protected] B. Hambly, MBBS, PhD, DipAnt Department of Pathology, University of Sydney, Darlington, NSW 2050, Australia M. McGuire, MBBS, PhD, FRACP Department of Cardiology, Royal Prince Alfred Hospital, Missenden Rd, Camperdown, NSW 2050, Australia A.S. Kibos et al. (eds.), Cardiac Arrhythmias, DOI 10.1007/978-1-4471-5316-0_10, © Springer-Verlag London 2014
During the last three decades, researchers have developed a clearer understanding of the pathophysiology of a nonreperfused acute and evolving myocardial infarct scar. The question as to whether reperfusion modifies electrical instability within the infarct zone or border region remains a topic of interest, as imaging and cardiac electrical mapping capabilities have continued to evolve both clinically and experimentally. Decreased cardiac electrical stability in both animals and humans has been documented during either infarct scar healing or following complete healing of the infarct [1, 2]. In particular, electrophysiological substrates appear to be well developed by the first week of a developing 131
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infarct scar. The infarct scar at 1–2 weeks post-MI remains a mechanistic risk for development of ventricular tachycardia (VT). Sustained monomorphic VT affects up to 5 % of patients with a history of prior myocardial infarction, reentry being the most frequent mechanism [2]. Ventricular arrhythmic events are responsible for the majority of sudden cardiac deaths after myocardial infarction. Treatments aimed at preventing or reducing post-infarction cardiac electrical instability are therefore important [1]. Mechanisms responsible for post-infarction decreased electrical stability are not fully understood (certainly the core of an infarct is now attracting attention). It has long been hypothesized that reperfusion of the infarct-related artery will reduce the incidence of postinfarction VT. There is evidence that thrombotic occlusion of a coronary artery results in a wave front of irreversible myocardial cell injury extending from the subendocardium to the subepicardium in a time-dependent fashion. Early sustained patency of the infarct-related artery induces myocardial salvage, which both preserves left ventricular function and promotes cardiac electrical stability. The open artery hypothesis concerns late reperfusion, where reperfusion does not salvage myocardium. The open artery hypothesis also suggests that if late reperfusion is achieved, this would be associated with a survival advantage [3]. Several mechanisms have been proposed to mediate suggested mortality benefits of late reperfusion; these include a limitation of infarct expansion, improved LV function, salvage of the peri-infarct hibernating myocardium, and collateral flow preventing infarction in other areas [3]. The open artery hypothesis also suggests that late reperfusion may improve cardiac electrical stability although evidence for this remains elusive. This chapter examines the evidence for the effects of late reperfusion on cardiac remodeling and ultimately its effects on cardiac electrical stability. The open artery hypothesis as proposed by Kim and Braunwald [4] suggest that late reperfusion will inhibit ventricular remodeling and promote electrical stability and thereby can prevent sudden death. At the end of the last century, the benefits of late opening of the infarct-related artery had remained to be substantiated by further animal studies and large randomized clinical trials [5]. During the last 10 years, a number of studies have addressed the open artery hypothesis to suggest that late opening of an infarct-related artery has no effect on cardiac electrical stability and in some cases may make it even worse. Indeed as of April 2007, it was advised that in the foreseeable future, stable patients with persistent occlusion of the infarct artery late after myocardial infarction, and without severe ischemia or uncontrollable angina, should be managed initially with optimal medical treatment alone, and not with percutaneous coronary intervention. For example, the Occluded Artery Trial (OAT) failed to show a clinical
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benefit over a 2.9-year mean follow-up, with routine mechanical recanalization of the occluded infarct-related artery (IRA) in stable patients enrolled 3–28 calendar days following an index myocardial infarction (MI) on the clinical endpoints of death, MI, and class IV congestive heart failure (CHF) [6]. Failure of the OAT to demonstrate benefit attributable to a strategy of PCI was against previous experimental and observational data. On one hand, negative OAT results may disprove the broadly accepted hypothesis that late infarct-artery patency is causally related to improved outcomes. Below, we review the open artery hypothesis with respect to the timing of infarct in relation to reperfusion, infarct remodeling, and how late reperfusion has been examined to date with respect to cardiac electrical stability.
An Evolving Myocardial Infarction A regional myocardial infarct is an area of tissue necrosis caused by obstruction of the coronary artery blood supply to that region. According to Crawford [7], for an infarct to form, the cessation of the blood supply must occur abruptly and must be complete. In 1912, James Herrick [8] attributed obstruction to the coronary blood flow to coronary artery thrombosis. However, it was not until 68 years after the initial observation by Herrick [8] that DeWood and associates [9] were able to confirm these findings. It was reported that in 87 % of patients with a Q-wave acute infarction undergoing coronary artery bypass surgery, thrombosis could be found in the infarct-related arteries within the first 4 h of the initial symptoms [9]. In contrast to acute thrombus formation, gradual reduction in blood supply, caused by progressive and slow narrowing of a sclerotic artery, leads to piecemeal cell death and replacement with fibrous tissue, which is a different pathological entity from infarction [7]. Towards the end of the 1960s, the question emerged of whether it is possible to halt the progression of an evolving infarct.
The Wave Front of Cellular Necrosis In the late 1970s at a conference in Copenhagen, Goldstein and Kent [10] opened their presentation with the statement, “The possibility that therapeutic intervention might reduce the extent of acute myocardial infarction remains one of the most exciting and challenging prospects in contemporary medicine....” This statement was based on the fact that not all myocardial cells within a defined ischemic area die at the same time. Reimer and associates [11, 12] examined the relationship between time and infarct progression, in what has become a classic study. It was shown that ligation of the canine left circumflex coronary artery with or without reperfusion results in a transmural wave of progression of cell
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death beginning in the subendocardium and progressing towards the subepicardium. These studies provided the initial evidence that viable myocardium is available for salvage in the subepicardium for at least 3 h and perhaps 6 h following occlusion of a major coronary artery in dogs [11]. Subsequent animal studies in several species have confirmed the existence of an infarct-related time-dependent wave front of cellular necrosis [13, 14]. However, interspecies differences in the rate of progression of the wave front have been observed, due primarily to differences in coronary anatomy and the availability of collateral circulation. In pigs, transmural infarction is complete within 2 h and in rabbits within 60 min [13, 15]. While the rate of progression may differ across species, the early appearance of irreversible damage in the subendocardium and its subsequent progression is constant. Four mechanisms have been proposed to account for the direction of the wave front: a transmural gradient in collateral flow, a gradient in wall stress, differences in intrinsic regional metabolic properties, and unique cell-tocell interactions [14].
Segments of Non-infarcted Myocardium and Ventricular Remodeling
Infarct Expansion: In Acute and Chronic Myocardial Infarction
Thrombolytic Therapy
Pathological and clinical studies in humans with an evolving myocardial infarct have demonstrated that 30 % of these patients are at risk of infarct expansion [16]. Infarct expansion has been defined as thinning and dilatation of the infarct area that may continue to progress and develop over a number of weeks. Continuing expansion of the infarct may be associated with increased mortality rates, progressive ventricular chamber remodeling accompanied by a decrease in diastolic function, myocardial aneurysm formation, electrical instability, and/or ventricular rupture [17]. As the more stable infarct scar ages, this is associated with progressive activation delays in the scar and with isolated potentials separated by isoelectric intervals as determined by endocardial electrogram recordings [18]. Direct change in the cellular architecture both within and at the infarct border zone has been proposed as a mechanism for the initiation and progression of infarct expansion. Four separate and independent cellular hypotheses have been generated to explain the mechanism of this alteration in cardiac shape, i.e., dilation and thinning of the infarct zone: 1. Lengthening or stretching of myocytes [19] 2. Reduction in cellular space via a collapse of the intramyocardial vascular compartment [19, 20] 3. Side-to-side slippage of cells and capillaries across the wall in the peri-infarcted region [19, 21] 4. Cellular death via necrosis or apoptosis (regulated cell death independent of necrosis [22]), also restricted regulation of autophagy [23]
Irrespective of the underlying mechanism for infarct expansion at the cellular level, the recognition that changes in segments of the myocardium occur as a compensatory process for infarct thinning and dilatation is also important. This process is fundamental to understand changes in the ventricular cavity and wall dimensions during infarct healing. Left ventricular function post-infarction has been found to be the most important determinant of both early (in-hospital, <2 weeks) and late mortality. Interestingly, with further developments in ultrasound imaging, more recent studies have shown that increased speckle-tracking strain dysfunction within the peri-infarct region as opposed to the infarct and remote infarct regions predict a higher incidence of inducible VT [24]. The infarct segment in the studies by Bertini and associates was defined as longitudinal strain values of greater than −5 % and peri-infarct segment defined as immediately adjacent to an infarct segment [24].
Initial attempts to investigate the benefits of thrombolytic therapy were through small clinical trials conducted between 1959 and 1979, and results were unconvincing. When a meta-analysis of these 24 trials was conducted, a 22 % reduction in mortality was demonstrated [25]. These findings spurned a number of large controlled clinical trials that have shown a definitive improvement in patient survival when thrombolytic therapy (intracoronary or intravenous) is administered early when compared with placebo [26–28]. The GISSI-1 trial was a randomized study of 11,806 patients receiving 1.5 million units of streptokinase over 1 h or standard medical therapy (GISSI, 1986). Patients enrolled in the study had electrocardiographically documented ST segment elevation or depression and symptoms lasting less than 12 h. At 21 days, an overall 18 % reduction in in-hospital mortality was observed in those patients treated with streptokinase. The benefit derived from treatment encompassed time as a dependent factor. For example, those patients treated within 3 and 6 h of symptom onset demonstrated a reduction in mortality of 23 and 17 %, respectively. However, a significant mortality benefit was not observed if treatment was delayed to 6–9 h after symptom onset. The Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) trial [26] examined the effectiveness of a dose of tissue plasminogen activator (t-PA) with intravenous heparin when administered in an accelerated manner. For example, over a period of 90 min, 66 % of the t-PA dose was
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administered within 30 min rather than the usual 3 h period. This dosage regimen for t-PA with adjunctive heparin was found superior to streptokinase or the combination of t-PA and streptokinase in reducing mortality [26]. It was further reported that at 24 h, the mortality rate was reduced by 19 % with accelerated t-PA as compared with other thrombolytic regimens. Likely, the beneficial mortality outcomes reflected target vessel patency. For example, accelerated t-PA led to a 90-min patency rate of 81 % compared to 60 % for streptokinase [26]. This trial further supports the hypothesis that rapid restoration of blood supply improves survival in a time-dependant fashion.
Early Reperfusion and Associated Reductions in Ventricular Remodeling While most of the mortality benefit is probably due to salvage of myocardium, the decrease in mortality with early reperfusion described above is related in part to a reduction in infarct expansion and subsequent ventricular remodeling. Myocardial tissue edema that is a feature of acute reperfused myocardial infarction and contributes to stunning of viable peri-infarct myocardium (the “area at risk”) undergoes regression with early reperfusion over time. Regression of edema has been reported on T2w MRI following early reperfusion and is related to improved myocardial contractility post-MI in both animal models and in humans [29] over a number of weeks. This suggests that improvement of strain in stunned myocardium closely follows the regression of myocardial edema. Additionally, clinical evidence for a reduction in infarct expansion with early thrombolytic therapy has been documented by Visser and associates [30]. For example, the incidence of infarct expansion was significantly reduced in patients receiving tissue-type plasminogen activator within 6 h of symptom onset compared to those who did not receive thrombolytic therapy (16 % versus 40 %, respectively; p < 0.01). Follow-up at 3 months further revealed that those patients who had not received therapy had significantly worse ventricular remodeling indices. A loss of contractile function at the infarcted segment results in a corresponding systolic lengthening of the infarct, the consequences of which are a decreased systolic ejection fraction and increase in end-systolic volume that is proportional to the size of the infarct [31]. Therefore, any treatment aimed at limiting infarct size should also proportionally lessen systolic volume increases. Early reperfusion that rescues non-infarcted myocardium and thereby reduces infarct size would explain the smaller left ventricular volumes in those patients that have undergone reperfusion [32, 33]. A subset of patients from the GISSI-1 trial that had undergone reperfusion underwent 2-dimensional echocardiography
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before discharge and after 6 months. At predischarge, 161 thrombolysed patients had smaller end-diastolic and endsystolic left ventricular volumes and a lower echocardiographic infarct size index compared to those that did not undergo thrombolysis. The differences that occurred during the acute phase remained significant up to the last assessment at 6 months. A linear relationship was found between end-systolic volume and measures of regional wall motion. The beneficial effect of streptokinase in this study is due to a reduction in infarct size and prevention of ventricular volume changes over time.
Does Reperfusion Independent of Myocardial Salvage (i.e., Late Reperfusion) Delay Ventricular Remodeling Post-infarction? The timing of reperfusion, or only reperfusion per se, with respect to respective influence on minimizing systolic ventricular volume increases post-infarction, has influenced the emergence of the late open artery hypothesis. Jeremy and associates [34] were the first to investigate the relationship between infarct-related artery patency and changes in end-diastolic left ventricular volume during the first 30 days of infarct healing. Their study involved 40 patients who had not received thrombolysis or any other form of interventional treatment for acute myocardial infarction. All patients underwent both angiography and radionuclide angiography within 48 h and at 30 days post-infarct to assess artery patency and left ventricular volume, respectively. At the end of the study, post-infarct ventricular dilation of ≥20 % compared to 48 h baseline occurred in 40 % of patients and a volume decrease of ≤20 % in 12.5 % patients. The degree of perfusion of the infarct-related artery was the most important predictor of change in left ventricular volume, independent of infarct size measured by creatine kinase [34]. Marino and associates [35] also demonstrated, using angiography, the importance of a patent artery in determining left ventricular volume, independent of infarct size. These investigators examined, in a group of 64 patients with acute infarction involving one vessel, the relationship between artery patency, infarct size, and end-systolic left ventricular volume. A significant difference in infarct size and ventricular volume was found when comparing those patients with a patent artery and those that did not, whereas there was no significant relationship between ejection fraction and infarct size for these two groups of patients [35]. Furthermore, spontaneous reperfusion, too late to salvage myocardial tissue, may still have an inherent clinical benefit in preventing both infarct expansion and later ventricular remodeling, i.e., ventricular dilation.
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Ejection Fraction and Reperfusion Assessment: Is Ventricular Volume or Area a More Sensitive Measure of Clinical Outcome?
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The majority of the early clinical trials, involving thrombolytic therapy, have included some measure of global left ventricular function, in particular the use of echo calculated ejection fractions. Nevertheless, these studies have not demonstrated any relationship between mortality and ejection fraction that would account for large improvements in survival [36]. For example, in the Western Washington Intracoronary Streptokinase in Myocardial Infarction trial, the 30-day mortality rates were dramatically reduced in streptokinase-treated patients within 12 h of symptom onset (3.7 %) compared to placebo (11.2 %). This reduction in mortality was documented without any significant change in left ventricular ejection fraction or in measured infarct size by quantitative single-photon tomographic imaging with thallium-201. The findings in the GISSI-1 trial also suggest that ejection fraction is a non-predictive measurement of remodeling post-reperfusion following infarction. It was concluded, in a subset of 64 patients, that there was a lack of correlation between ejection fraction and patency of the infarct-related artery, despite lower end-diastolic and endsystolic volumes in those receiving streptokinase [37]. Early on, when comparing individual early reperfusion thrombolytic trials, it became obvious that there was no clear relationship between ejection fraction and mortality [36]. However, when the results of a large number of randomized thrombolytic trials were pooled, it was demonstrated that patients receiving thrombolytic therapy compared to controls, sampled across various time points, generally show an improvement in ejection fraction [38]. It has, however, been argued that end-systolic volume is a better predictor of survival than ejection fraction [39]. In light of this knowledge, it is remarkable that the prime determinant of the utilization of implantable cardioverter-defibrillators is based on an ejection fraction of less than 35 % [40]. Both low ejection fraction and inducible tachyarrhythmias identify patients with coronary disease at increased mortality risk. Ejection fraction does not discriminate between modes of death, whereas inducible tachyarrhythmia identifies patients for whom death, if it occurs, is significantly more likely to be arrhythmic, especially if ejection fraction is >or =30 % [41]. New imaging techniques now exist to assess the myocardial infarct scar that may be implicated in the pathways that lead to post-infarction mortality. Magnetic resonance-based imaging can quantify cardiac structure and function and the presence and extent of myocardial fibrosis and ischemia. Ejection fraction indexes are mainly dependent on the relationship between preload and afterload. End-systolic volume is regarded as an index of left ventricular function,
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Fig. 10.1 Effect of the post-infarction healing process on cardiac geometry and its relation to wall stress and heart failure in a mouse model. (a) Transverse ventricular sections day 3, 7, or 28 post-MI. (b) Photomicrographs of infarct area on day 3, 7, or 28 post-MI. (c) Over time after the onset of MI, the infarct length, and left ventricular cavity become larger, whereas the infarct wall thickness becomes thinner. Wall stress is proportional to the cavity diameter and intracavitary pressure and inversely proportional to the wall thickness (Laplace’s law). Thus, wall stress and ventricular remodeling (dilatation and wall thinning) have a vicious relationship, accelerating one another and exacerbating heart failure (Reproduced from Takemura et al. [3] with permission of Oxford University Press)
which is dependent on both afterload and contractility but is independent of preload [42]. Therefore, left ventricular dilation, as measured by end-systolic volumes occurring after infarction, may be a more sensitive index of predicting mortality following reperfusion, because it accounts for the complex relationship between hyperkinesis and dilation and does not rely on load dependency [36, 43]. In summary, progressive left ventricular dilation following infarction is usually the consequence of a permanently occluded coronary artery [3]. In contrast, post-infarction inhibition of left ventricular dilation is frequently associated with an open and patent infarct-related artery. Left ventricular volume is an important predictor of survival outcome after myocardial infarction (Fig. 10.1).
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Early reperfusion salvages myocardium within the area at risk, reducing infarct size and inhibiting infarct expansion which results in smaller infarct volumes. Thus, early reperfusion reduces ventricular remodeling and improves survival. On the other hand, late reperfusion, which occurs when myocardial salvage is no longer possible, may confer a survival advantage on the basis of preserved systolic volumes. From these early suggestions that reperfusion may still be useful even after infarction is complete lead to the emergence of the “open artery hypothesis.” For example, Hirayama and associates [44] described, in detail, both infarct size and ventricular volume changes associated with early (1.8 ± 1 h), intermediate (4.2 ± 0.7 h), and late (10 ± 4.9 h) thrombolytic reperfusion therapy in 69 patients with acute infarction. They found, using single-photon emission computerized tomography (SPECT) and ventriculography, that early reperfusion decreased infarct size and preserved left ventricular function, whereas late reperfusion did not. In contrast, the end-diastolic volume did not differ significantly between early, intermediate, and late reperfused groups. These three reperfusion groups demonstrated a significantly smaller end-diastolic volume when compared to the non-reperfused group after 1 month. Ventricular volumes increased significantly during the course of myocardial infarction only in the non-reperfused group. These investigators concluded that inhibition of ventricular dilation by late reperfusion of the infarct-related artery is the probable mechanism by which late intervention reduces mortality. However, the time point at which late reperfusion took place in this study was in fact not late reperfusion, as some salvage of the myocardium would have already occurred at this time. In addition, the end point of 1 month may not have been long enough to ascertain whether ventricular dilation end points across all treatment groups would have been reached. Additionally, it is now known that tissue heterogeneity is present and quantifiable within the infarcted myocardial tissue. In patients with a prior MI and moderately reduced LV systolic function, the extent of the peri-infarct zone (border zone) characterized by cardiac MRI provides prognostic value beyond LV systolic volume index or ejection fraction for post-MI mortality [45]. Specifically, it has been shown that border zone and tissue heterogeneity correlates with increased ventricular irritability by programmed electrical stimulation. There have also been studies that have shown that reperfusion time modifies infarcted tissues. There are marked differences in electroanatomic chronic scar size and pattern (years latter) between patients with and without successful reperfusion at the time of MI. Less histological confluent electroanatomic scars match layers of surviving myocyte bundles on biopsy [46]. Early reperfusion and less confluent electroanatomic scars are associated with faster VTs (Fig. 10.2).
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Early Support for the Open Artery Hypothesis: Evidence from Retrospective Clinical Trial Data Cigarroa and associates [47] examined the clinical course of 179 patients at 4 weeks post-infarction. These patients had a single coronary vessel occlusion (verified by angiography) and were not given thrombolysis. Initially, left ventricular volumes and global ejection fractions were similar in both subsets of patients with either a patent or non-patent artery. What was surprising was that at the end of a mean follow-up of 47 months, none of the 64 patients with partial or complete antegrade flow had died, compared with 21 deaths among the 115 patients in whom flow in the infarctrelated artery was absent or minimal. In addition, the incidence of congestive heart failure was significantly lower in patients with a patent artery than in those with occluded infarct-related arteries, 6 % versus 17 %, respectively. Trappe and associates [48] have also identified coronary patency as a powerful predictor of survival following a myocardial infarction. Two hundred and fourteen patients were studied with single-vessel coronary disease, 75 % of whom had an acute myocardial infarction. In those patients with a patent artery when compared to patients with residual stenosis, the incidence of sudden death was 15 % versus 3 %, respectively.
GUSTO-I Trial Analysis of the GUSTO-1 trial indicates that an open artery may improve 1-year survival rates independent of myocardial salvage. This evidence was drawn from 30 day survivors in whom angiographic data was available on patency of the infarct-related artery during the initial hospital admission. In a multivariate analysis, a higher ejection fraction remained the only predictor of lower mortality [49]. These findings are limited since it is unknown what percentage of patients in the open artery group had initially closed arteries that spontaneously reopened or what proportion of patient’s arteries reoccluded. Previous studies have shown that ejection fraction may not be significantly different in patients with late myocardial salvage compared to patients that did not sustain myocardial salvage but did have an open and sustained patent artery.
TAMI Trial Whereas reperfusion and sustained patency of the infarctrelated artery improves survival, reocclusion of a previously revascularized infarct-related artery in acute myocardial infarction is associated with a much poorer prognosis. In a
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A Patient Reperfused Patchy Contiguous viable 1 Yes Yes 2
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Fig. 10.2 The relation between viable myocytes and fibrosis was characterized. Five patterns of local histological scar were identified (A through E). The presence of any of these types in the assessed core infarct region was scored and compared with the presence of reperfusion and the pattern of electroanatomic scar in the 10 patients in whom
histological assessment was performed. Three representative examples of electroanatomic maps (patients 1, 5, and 6) are shown; the assumed area that was resected by the surgeon is indicated (Reproduced from Wijnmaalen et al. [46] with permission of Wolters Kluwer Health)
review of the data obtained from the Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) study group, the importance of both sustained arterial patency and permanent reocclusion were identified as significant factors influencing mortality [50]. In patients with early and late patency of their infarct-related artery, there was an in-hospital death rate of 4.5 %, while those with late occlusion of an infarctrelated artery or an occluded artery that never opened sustained an in-hospital mortality rate of 11 and 17 %, respectively. Furthermore, when infarct-related arteries became reoccluded after thrombolytic therapy, the failure of angioplasty to restore patency was associated with a higher mortality (26.7 %) compared to patients in whom the artery could be opened (12.1 %).
Ellis and associates [51] have described the results of primary coronary angioplasty in those patients that did not receive prior thrombolytic therapy. This study classified 256 patients who received “late” angioplasty 6–48 h after the onset of chest pain and those treated with “early” angioplasty within 6 h of chest pain. Successful angioplasty was achieved in over 70 % of all patients treated. Successful angioplasty was associated with an in-hospital mortality rate of 5.5 %, whereas unsuccessful angioplasty was associated with a 43.3 % hospital mortality rate. The predictors of hospital death were cardiogenic shock, low ejection fraction, unsuccessful angioplasty, and advanced age. The time to angioplasty was not a predictor of outcome. However, a possible limitation of this study was patient selection bias. The groups
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were not randomized, and the late group had a higher incidence of diabetes, multivessel disease, and poor ejection fraction [52]. These results with reductions in mortality provided evidence that late emergency PCI may be justified when the likelihood of angioplasty (and nowadays with additional stenting) success is high.
Clinical Trials and Evaluation of Late Reperfusion Thrombolytic Trials ISIS-2 Trial The Second International Study of Infarct Survival (ISIS-2), where patients were permitted to receive intravenous streptokinase up to 24 h after a myocardial infarction, was one of the first studies to imply it might be beneficial to administer streptokinase or another thrombolytic agent after 6 h of acute myocardial infarction. More specifically, an improvement in survival was significant up to 12 h and approached significance at 24 h in the ISIS-2 study. However, ISIS-2 patients receiving late reperfusion thrombolytic therapy involved only a subset of the patient group. LATE Trial In contrast, the Late Assessment of Thrombolytic Efficacy (LATE) study specifically addressed the issue of late administration of thrombolysis in 5,711 patients presenting with acute infarction between 6 and 24 h after symptom onset. In the LATE study, it was shown that patients treated within 12 h with thrombolysis had a 25 % reduction in mortality when assessed 35 days after treatment. This benefit in mortality, however, did not extend to those treated between 12 and 24 h. EMERAS Trial In the EMERAS trial, in-hospital mortality was similar among 3,600 patients with acute myocardial infarction who presented between 6 and 24 h after the onset of symptoms whether they received streptokinase or placebo. However, among the subgroup of 2,080 patients treated between 7 and 12 h from symptom onset, it was revealed that there was a nonsignificant trend towards fewer in-hospital deaths following streptokinase (11.7 %) versus placebo (13.2 %).
Angioplasty Trials TAMI-6 Trial The Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) 6 trial was one of the first randomized trials to assess the role of angioplasty for occluded infarct-related arteries
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beyond the first 12 h of acute myocardial infarction [53]. One hundred and ninety-seven patients with ST segment elevation during the acute phase of the infarction were randomized to receive t-PA or placebo. Follow-up treatment consisted of either PTCA versus no angioplasty for those with an occluded infarct-related artery 12–48 h after the initial onset of symptoms. Patency was established in 81 % of the patients randomized to PTCA. Sixty percent of these patients were free from restenosis and continued to have a patent infarct-related artery at 6 months. In a subset of those patients that did not receive angioplasty, sustained spontaneous reperfusion of their infarct-related artery was noted in some and a patency rate of 38 % was maintained at 6-month follow-up in this group. There was no difference with respect to ventricular volumes in those patients that sustained late spontaneous reperfusion or underwent late angioplasty and had a patent artery at 6-month follow-up. Left ventricular dilatation and progression of systolic dysfunction can occur up to 3 years after initial infarction [54]. In a randomized trial by Dzavik and associates [55], the effect of late PTCA on left ventricular function (ventriculography) was determined in patients with occlusion of the infarct-related artery up to 6 weeks after a first Q-wave myocardial infarction. An upper limit of 6 weeks was chosen as a window by Dzavik et al. as a time interval when the success rate of angioplasty may still be adequate, yet extensive remodeling and ventricular dilation may not have occurred. Forty-four were randomized to PTCA or no PTCA. At 4 months, angiography revealed a patent artery in 43 % of angioplasty patients and in 19 % with no angioplasty. At follow-up, patients with a patent infarct-related vessel had a significantly greater improvement in left ventricular ejection fraction than those with a persistently occluded or reoccluded coronary artery. The investigators concluded that the efficacy of late PTCA, when assessed at 4 months, is limited by a high reocclusion rate. Pizzetti et al. [56] evaluated echocardiographic ejection fractions in patients that had percutaneous transluminal coronary angioplasty attempted within 18 days after infarction. The failure to maintain a patent artery was high as 41 % or 11/27 patients in the first 3 months. In patients with successful percutaneous transluminal coronary angioplasty, the mean left ventricular volume index at 6-month follow-up was less than half of that in the patients with failed angioplasty. Ejection fractions also showed a significant improvement. However, the major limitation of this study was its small size and the fact that patients were not randomized to PTCA or no PTCA. Horie et al. [57] investigated the effect of late PTCA over a 5-year period on clinical outcome and mortality. Eightythree patients with initial Q-wave anterior myocardial infarction greater than 24 h (24 h to 3 weeks) after the onset of symptoms were randomized into a PTCA group (n = 44)
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and a no PTCA group (n = 39). Left ventricular ejection fraction and regional wall motion at 6 months after myocardial infarction were similar in the two groups. However, left ventricular end-diastolic and end-systolic volume indexes were significantly reduced in the PTCA group. Cardiac events such as sudden death, reinfarction, and congestive heart failure when subjected to a 5-year Kaplan-Meier actuarial event-free survival analysis revealed that the no angioplasty group had a worse outcome than the PTCA group. A patency rate of 93 % was achieved with angioplasty in this study, and a 94 % patency rate was maintained at follow-up. This is the first study to document such high patency rates at follow-up. The investigators suggest the reduction in ventricular volume associated with a patent artery may be the mechanism responsible for the beneficial clinical outcomes in this study. Patients with normal epicardial flow in the IRA (thrombolysis in myocardial infarction [TIMI] grade 3) but reduced tissue-level perfusion as quantified have larger infarcts, worse global and regional LV systolic function, and increased mortality. The extent to which effective microvascular perfusion can be achieved by PCI following an acute myocardial infarction likely determines ventricular volume outcomes [58]. The Total Occlusion Study of Canada-2, an ancillary study of the 2,166-patient Occluded Artery Trial, enrolled 381 stable patients with a persistently occluded infarctrelated artery (IRA) days to weeks post-MI to PCI or medical therapy alone. Change in myocardial perfusion grade (MPG) was determined from immediate post-PCI to 1-year follow-up (157 patients), and the relationship between initial MPG and LV function and volume was assessed in 139 patients [58]. Preserved MPG was present in the majority of patients with normal epicardial flow following late PCI recanalization of the IRA. Impaired baseline MPG was associated with unfavorable LV indices, whereas preserved baseline MPG was associated with segmental and global LV recovery.
Electrical Stability A number of methods have been used to detect electrical instability. These include the signal-averaged electrocardiogram and invasive electrophysiological studies. Of these techniques, the latter is the most accurate [59]. There is significant clinical evidence that early thrombolytic therapy reduces the late incidence of ventricular fibrillation [60]. It was reported by Vermeer and associates [60] that in 533 patients, the frequency of primary ventricular fibrillation (occurring spontaneously in the first 48 h after the onset of infarct-related symptoms) was 9 % in patients receiving no thrombolytic therapy and 5 % in those allocated to thrombolytic therapy. Furthermore, the incidence of late
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ventricular fibrillation (documented after 48 h of symptom onset) was 4 % in the control group compared to an incidence of 1 % in the treated group. A small number of studies have utilized noninvasive markers of arrhythmogenesis to determine the benefit of an open artery. The detection of late potentials has been the most frequently applied noninvasive method to assess electrical stability. Late potentials are detected at the body surface by means of signal averaging and digital filtering of the electrocardiograms to indicate the presence of an electrophysiological substrate (slow conduction) that is necessary for facilitating the occurrence and maintenance of ventricular reentrant arrhythmias. As a result of delayed ventricular activation, late potentials usually occur in the terminal part of the QRS complex. The prevalence of late potentials following myocardial infarction ranges from 32 % on day 1–54 % on day 7–10 post-infarction [61]. This suggests that, during late healing of the infarct, preexisting impairments of conduction in conjunction with regional changes in activation times and refractory periods (with remodeling of the reentrant circuits) become more disparate. Thus, ventricular late potentials may indicate the degree of preexisting conduction impairment, and they should correlate with the ease of induction of ventricular tachyarrhythmias [62]. However, Gomes [63] cautions that one must understand that the presence of an arrhythmic substrate and the occurrence of late potentials should not automatically be equated with the occurrence of a sustained tachyarrhythmia, since other electrophysiologic characteristics, such as differential refractoriness, are equally important with respect to maintaining a tachycardia. Additionally, an arrhythmic substrate may remain dormant, protected by entrance or exit block. Thrombolytic therapy administered within the first 4–6 h of myocardial infarction decreases the incidence of late potentials on a signal-averaged electrocardiogram [64, 65]. Additionally, several studies have also reported on the relationship of a patent infarct-related artery and to late potentials and subsequent arrhythmic events. Zimmerman et al. [66] studied a total of 223 patients, of which 59 received t-PA (within 6 h of symptom onset) and 164 were treated conventionally. Late potentials were present in 13 % of patients with a patent infarct-related artery and in 26 % of patients with a closed artery; these differences were statistically significant. Pedretti et al. [67] reported that patients who did not receive thrombolytic therapy had a higher prevalence of late potentials compared to patients who did (34 % versus 17 %, p < 0.001). Likewise, when the patency of the infarct-related artery was assessed, 9 % of patients with a patent infarctrelated artery were found to have late potentials, compared to 39 % of patients with a closed infarct-related artery (p < 0.001). In their study, late potentials were present in
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75 % of patients with arrhythmic events and in 18 % of those without arrhythmic events (p < 0.001) during a follow-up period of 14 ± 8 months. Steinberg et al. [68] examined the effect of late thrombolytic therapy administered 6–24 h after myocardial infarction on the signal-averaged electrocardiogram. Of 310 patients studied, 160 received placebo and 150 received t-PA. They noted that t-PA was associated with fewer abnormalities compared with placebo. The prevalence of an abnormal SAECG was reduced by 32 % in those receiving t-PA. Their study, however, did not explore the relationship between late potentials and artery patency post-reperfusion. Ragosta et al. [69] hypothesized that very late reperfusion by angioplasty accomplished >24 h after onset of infarction would reduce late potentials and improve the parameters studied on the signal-averaged electrocardiogram. In this study, 41 patients with a totally occluded infarct-related artery underwent angioplasty after an average of 12 ± 8 days of chronic infarction. Angioplasty was successful in 32 patients and unsuccessful in 9. No change in the incidence of late potentials occurred in either the reperfused or nonreperfused cases, compared to their baseline levels recorded during late healing before the angioplasty. Furthermore, there were no differences between the reperfused and nonreperfused groups or when these groups were compared to their original baseline signal-averaged electrocardiogram. The general finding being that late reperfusion after acute infarction has little effect on the signal-averaged electrocardiogram, even among patients in whom late reperfusion caused an improvement in regional wall motion. It was, however, observed that in patients with successful reperfusion, and in whom an absence of late potentials had been identified, there was improvement in wall motion, as assessed by echocardiography. Presumably the absence of late potentials prior to reperfusion was due to hibernating myocardium. It was further suggested that one of the determinants for late potentials after acute myocardial infarction is the absence of viable myocardium in the infarct zone. However, a limitation of this study was that a small sample size population was studied and that no effort was made to reassess the patency of the reperfused infarct-related artery over 30 days of clinical assessment that followed the initial reperfusion procedure. In contrast, Lomama et al. [70] showed that very late coronary angioplasty (12 ± 8 days) was associated with a significant decrease in late potentials, in 9 out of 58 patients (15 %) versus 23 out of 65 patients (30 %). However, this study suffers from the fact that signal-averaged electrocardiograms were not assessed at baseline time points. Therefore, the incidence of late potentials pre-angioplasty could not be assessed, and intraindividual comparison of ventricular late potentials before and after coronary balloon dilatation was not possible. In summary, these two findings suggest that late but not very late reperfusion may have a positive effect on
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electrical stability, while very late reperfusion of the infarctrelated artery based on these results (of signal-averaged electrocardiography and late potentials) does not affect electrical stability. More recently, an ancillary study of the Occluded Artery Trial evaluated the effects of late opening and stenting of an occluded infarct artery on several noninvasive measures of electrophysiological stability during the first year after myocardial infarction [71]. This was one of the first studies to evaluate cardiac electrical stability with respect to late reperfusion with PCI combined with stents. Heart rate variability was the primary measure. Major secondary measures evaluated repolarization (dynamic changes in T-wave morphology (T-wave variability) and delayed myocardial conduction (filtered QRS duration on the signal-averaged ECG). Compared with medical therapy alone, late reperfusion and stenting of a persistently occluded infarct-related artery did not change heart rate variability, filtered QRS, or T-wave variability during the first year after myocardial infarction [71]. These results are consistent with the lack of clinical benefit, including no reduction in sudden death, with PCI for stable patients with persistently occluded infarct-related arteries after myocardial infarction in the main Occluded Artery Trial.
An Open Infarct-Related Artery on Spontaneous and Induced Arrhythmias Several investigators have attempted to demonstrate that an open infarct-related artery has favorable effects on both spontaneous and induced ventricular arrhythmias. Vermeer et al. [60] reported a reduction in the incidence of spontaneous ventricular fibrillation after 48 h in 533 patients divided into those that received streptokinase therapy and those that did not. Kersschot et al. [72] examined the effects of early reperfusion in acute myocardial infarction on arrhythmias induced by programmed electrical stimulation in 62 patients randomized to either combined intravenous and intracoronary streptokinase or to standard coronary care medical management (control group). An electrophysiological study was performed 26 ± 14 days from the time of infarct onset. Sustained monomorphic ventricular tachycardia was induced in 2 of 17 patients in the early reperfusion group and in 14 of 19 patients in the no-reperfusion group (p < 0.001). Bourke et al. [73], demonstrated that early reperfusion with streptokinase prevented both the induction of ventricular tachycardia and spontaneous episodes of ventricular fibrillation. In summary, these studies demonstrated that sustained ventricular tachycardia is significantly less commonly induced in patients administered with early thrombolysis. Reperfusion does not protect against recurrent ventricular arrhythmias. Link et al. [74] found no association between coronary revascularization and prevention of tachycardia
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recurrence in survivors of ventricular fibrillation. In this study, 29 patients presented with ventricular fibrillation and underwent coronary revascularization. Nineteen patients had implantable cardioverter-defibrillator therapy. These patients were followed for 36 ± 21 months. Eight deaths occurred, three of which were sudden. In those patients receiving implantable defibrillators, intracardiac electrograms documented that sustained ventricular tachycardia was present in three patients and ventricular fibrillation in four. Therefore, in patients presenting with ventricular fibrillation, coronary revascularization alone does not provide adequate protection against recurrent ventricular arrhythmias, whereas an implantable defibrillator did. Indeed, a number of studies have identified patients whose ventricular arrhythmias are aggravated by coronary artery bypass grafting. There are also documented cases where patients with no previous history of ventricular arrhythmias develop malignant ventricular tachycardia following bypass grafting [53, 75, 76]. Topol et al. [53] studied 12 patients out of 1,675, who underwent coronary artery bypass grafting. Ten of the twelve patients had had a prior infarct, and all were observed to have a recurrent, sustained ventricular tachycardia, with episodes lasting greater than 3 weeks. These patients did not have suppressed ventricular function preoperatively (mean ejection fraction 39 %). In three patients, ventricular tachycardia was associated with graft thrombosis. However, in the other nine patients, the mechanism appeared to be different. It was suggested that ten patients underwent complete revascularization to a region likely to be no longer viable but instead replaced with scar tissue. Reperfusion in these particular regions may lead to altered dispersion of repolarization, favoring the initiation of reentrant circuits. Steinberg et al. [75] identified a previous myocardial infarct as a significant risk factor for the subsequent development of post-reperfusion ventricular tachycardia. The placement of a coronary artery bypass graft across an area of non-collateralized infarct has been shown to be independently associated with the development of ventricular tachycardia [76]. The risk of ventricular tachycardia in those with a prior myocardial infarct was calculated to be 7 %. However, the risk was 30 % if patients had an ejection fraction less than 40 % and combined congestive heart failure. Brugada et al. [77] made the observation that an arrhythmogenic area requires a specific blood supply to preserve the electrical activity of the myocardial cells involved in that arrhythmogenic circuit. Support for the idea that blood supply preserves an arrhythmic area is founded on the observation that it is both possible to cause transcoronary chemical ablation of ventricular tachycardia or temporarily suppress it by the use of ice cold isotonic saline. Via the use of selective coronary angiography and ice cold isotonic saline, it is possible to localize the arterial blood supply to the site of origin
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of ventricular tachycardia, by selective coronary artery injections [77, 78]. Therefore, in patients with both chronic infarction and an arrhythmogenic substrate, it is possible that when blood flow is interrupted, ventricular tachycardia can be rendered noninducible. Conversely, when blood flow resumes, ventricular tachycardia can recur. Thus this may explain, why coronary artery bypass grafting across an occluded vessel may reverse a dormant arrhythmogenic tissue: in essence, a state of electrical hibernation [75]. Furthermore, a patent IRA may prove beneficial by providing capacity for collateral blood flow to another coronary territory should subsequent coronary artery occlusion occur in a different coronary bed. Collateral flow in both subacute and chronic MIs has the potential to influence late clinical outcomes through preserved function of viable cardiac myocytes, altered ventricular geometry, or via electrical stability. Moreover, it is conceivable that the degree of collateralization modulates the ability to achieve reperfusion outcomes [79]. On the other hand, a sub-study of OAT demonstrated that late reperfusion in the presence or absence of collaterals did not influence death, reinfarction, or class IV heart failure [79]. It was concluded that decisions about revascularization in patients with recent MI and occluded IRAs should not be made on the presence or grade of angiographic collaterals [79]. In summary, the Occluded Artery Trial (OAT) and followon sub-studies demonstrated that late reperfusion with PCI and stenting does not produce a reduction in the composite of death, reinfarction, and class IV heart failure over a 2.9year mean follow-up [6]. At present the open artery hypothesis is not recommended over medical therapy to reduce the incidence of sudden death or death related to the pathological process of post-infarction remodeling.
References 1. Stevenson WG. Ventricular scars and ventricular tachycardia. Trans Am Clin Climatol Assoc. 2009;120:403–12. 2. Segal OR, Chow AW, Peters NS, Davies DW. Mechanisms that initiate ventricular tachycardia in the infarcted human heart. Heart Rhythm. 2010;7(1):57–64. 3. Takemura G, Nakagawa M, Kanamori H, Minatoguchi S, Fujiwara H. Benefits of reperfusion beyond infarct size limitation. Cardiovasc Res. 2009;83(2):269–76. 4. Kim CB, Braunwald E. Potential benefits of late reperfusion of infarcted myocardium. The open artery hypothesis. Circulation. 1993;88(5 Pt 1):2426–36. 5. Carnendran L, Steinberg JS. Does an open infarct-related artery after myocardial infarction improve electrical stability? Prog Cardiovasc Dis. 2000;42(6):439–54. 6. Hochman JS, Reynolds HR, Dzavík V, Buller CE, Ruzyllo W, Sadowski ZP, Maggioni AP, Carvalho AC, Rankin JM, White HD, Goldberg S, Forman SA, Mark DB, Lamas GA, Occluded Artery Trial Investigators. Long-term effects of percutaneous coronary intervention of the totally occluded infarct-related artery in the subacute phase after myocardial infarction. Circulation. 2011;124(21):2320–8.
142 7. Crawford T. Pathology of ischaemic heart disease. London: Butterworths; 1977. 8. Herrick JB. Clinical features of sudden obstruction of the coronary arteries. JAMA. 1912;59:2015–20. 9. DeWood MA, Spores J, Notske R, Mouser LT, Burroughs R, Golden MS, Lang HT. Prevalence of total coronary occlusion during the early hours of transmural infarction. N Engl J Med. 1980;303:897–902. 10. Goldstein RE, Kent KM. Influence of heart rate, arterial pressure, and treatment with nitroglycerin on acute myocardial ischemia and infarction. In: Wilhelmsen L, Hjalmarson A, editors. Acute and long-term medical management of myocardial ischemia. Goteborg: ASTRA Pharmaceuticals; 1977. 11. Reimer K, Lowe JE, Rasmussen MM, Jennings RB. The wavefront phenomenon of ischemic cell death. 1. Myocardial infarct size vs duration of coronary occlusion in dogs. Circulation. 1977;56:786–94. 12. Reimer KA, Jennings RB. The wavefront phenomenon of myocardial ischemic cell death, II: transmural progression of necrosis within the framework of ischemic bed size (myocardium at risk) and collateral flow. Lab Invest. 1979;40:633–44. 13. Sage MD, Gavin JB. The development and progression of myocyte injury at the margins of experimental myocardial infarcts. Pathology. 1985;17:617–22. 14. Garcia-Dorado D, Theroux P, Desco M, Solares J, Elizaga J, Fernandez-Aviles F, Alonso J, Soriano J. Cell-to-cell interaction: a mechanism to explain wave-front progression of myocardial necrosis. Am J Physiol. 1989;256:H1266–73. 15. Fujiwara H, Ashraf M, Sato S, Millard RW. Transmural cellular damage and blood flow distribution in early ischemia in pig hearts. Circ Res. 1982;51:683–93. 16. Hutchins GM, Bulkley BH. Infarct expansion versus extension: two different complications of acute myocardial infarction. Am J Cardiol. 1978;41:1127–32. 17. Schuster EH, Bulkley BH. Expansion of transmural myocardial infarction: a pathophysiologic factor in cardiac rupture. Circulation. 1979;60:1532–8. 18. Bogun F, Krishnan S, Siddiqui M, Good E, Marine JE, Schuger C, Oral H, Chugh A, Pelosi F, Morady F. Electrogram characteristics in postinfarction ventricular tachycardia: effect of infarct age. J Am Coll Cardiol. 2005;46(4):667–74. 19. Weisman HF, Bush DE, Mannisi JA, Weisfeldt ML, Healy B. Cellular mechanisms of myocardial infarct expansion. Circulation. 1988;78:186–201. 20. Vogel WM, Apstein CS, Briggs LL, Gaasch WH, Ahn J. Acute alterations in left ventricular diastolic chamber stiffness. Role of the “erectile” effect of coronary arterial pressure and flow in normal and damaged hearts. Circ Res. 1982;51:465–78. 21. Olivetti G, Capasso JM, Sonnenblick EH, Anversa P. Side-to-side slippage of myocytes participates in ventricular wall remodeling acutely after myocardial infarction in rats. Circ Res. 1990;67:23–34. 22. Anversa P, Cheng W, Liu Y, Leri A, Redaelli G, Kajstura J. Apoptosis and myocardial infarction. Basic Res Cardiol. 1998;93:8–12. 23. Kanamori H, Takemura G, Goto K, Maruyama R, Tsujimoto A, Ogino A, Takeyama T, Kawaguchi T, Watanabe T, Fujiwara T, Fujiwara H, Seishima M, Minatoguchi S. The role of autophagy emerging in postinfarction cardiac remodelling. Cardiovasc Res. 2011;91(2):330–9. 24. Bertini M, Ng AC, Borleffs CJ, Delgado V, Wijnmaalen AP, Nucifora G, Ewe SH, Shanks M, Thijssen J, Zeppenfeld K, Biffi M, Leung DY, Schalij MJ, Bax JJ. Longitudinal mechanics of the periinfarct zone and ventricular tachycardia inducibility in patients with chronic ischemic cardiomyopathy. Am Heart J. 2010;160(4):729–36. 25. Yusuf S, Collins R, Peto R. Intravenous and intracoronary fibrinolytic therapy in acute myocardial infarction: overview of results on
C.S. McLachlan et al.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38. 39.
40.
41.
42.
mortality, reinfarction and side-effects from 33 randomised controlled trials. Eur Heart J. 1985;6:556–85. GUSTO. An international randomised trail comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med. 1993;329:673–82. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. SIS-2: randomized trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. J Am Coll Cardiol. 1988;12(6 Suppl A):3A–13. Hennekens CH, O'Donnell CJ, Ridker PM, Marder VJ. Current issues concerning thrombolytic therapy for acute myocardial infarction. J Am Coll Cardiol. 1995;25(7 Suppl):18S–2222. Kidambi A, Mather AN, Swoboda P, Motwani M, Fairbairn T, Greenwood JP, Plein S. Recovery of regional myocardial function and myocardial oedema following reperfused acute myocardial infarction. J Cardiovasc Magn Reson. 2012;14 Suppl 1:O64. Visser CA, Delemarre BJ, Peels K. Left ventricular remodelling following anterior wall myocardial infarction. Am J Cardiac Imaging. 1992;6:127–33. McKay RG, Pfeffer MA, Pasternak RC, Markis JE, Come PC, Nakao S, Alderman JD, Ferguson JJ, Safiam RD, Grossman W. Left ventricular remodelling after myocardial infarction: a corollary to infarct expansion. Circulation. 1986;74:693–702. White HD, Norris RM, Brown MA, Takayama M, Maslowsky A, Bass NM, Ormiston JA, Whitlock T. Effect of intravenous streptokinase on left ventricular function and early survival after acute myocardial infarction. N Engl J Med. 1987;317:850–5. Serruys PW, Simoons ML, Suryapranata H, Vermeer F, Wijns W, Van der Brand M, Bar F, Zwaan C, Kraus XH, Remme WJ, Res J, Verheugt FWA, van Domburg R, Lubsen J, Hugenholtz PG. Preservation of global and regional left ventricular function after early thrombolysis in acute myocardial infarction. J Am Coll Cardiol. 1986;7:729–42. Jeremy RW, Hackworthy RA, Bautovich GB, Hutton B, Harris PJ. Infarct artery perfusion and changes in left ventricular volume in the month after acute myocardial infarction. J Am Coll Cardiol. 1987;9:989–95. Marino P, Destro G, Barbieri E, Bicego D. Reperfusion of the infarct related coronary artery prevents left ventricular expansion above and beyond myocardial salvage. Am Heart J. 1992;123:1157–65. Califf RM, Harrelson-Woodlief L, Topol EJ. Left ventricular ejection fraction may not be useful as an end point of thrombolytic comparative trials. Circulation. 1990;82:1847–53. Marino P, Zanolla L, Zardini P. Effect of acute streptokinase on left ventricular modeling and function after acute myocardial infarction: the GISSI (Gruppo Italiano per Studio della Streptochinasi nell’Infarto Miocardico) trial. J Am Coll Cardiol. 1989;14:1149–58. Granger CB, Califf RM, Topol EJ. Thrombolytic therapy for acute myocardial infarction. A review. Drugs. 1992;44:293–325. Norris RM, White HD. Therapeutic trials in coronary thrombosis should measure left ventricular function as a primary end point of treatment. Lancet. 1988;1:104–6. Buxton AE, Ellison KE, Lorvidhaya P, Ziv O. Left ventricular ejection fraction for sudden death risk stratification and guiding implantable cardioverter-defibrillators implantation. J Cardiovasc Pharmacol. 2010;55(5):450–5. Buxton AE, Lee KL, Hafley GE, Wyse DG, Fisher JD, Lehmann MH, Pires LA, Gold MR, Packer DL, Josephson ME, Prystowsky EN, Talajic MR, MUSTT Investigators. Relation of ejection fraction and inducible ventricular tachycardia to mode of death in patients with coronary artery disease: an analysis of patients enrolled in the multicenter unsustained tachycardia trial. Circulation. 2002;106(19):2466–72. Zardini P, Marino P, Golia G, Anselmi M, Castelli M. Ventricular remodeling and infarct expansion. Am J Cardiol. 1993;72(19): 98G–106106.
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43. Van de Werf F. Discrepancies between the effects of coronary reperfusion on survival and left ventricular function. Lancet. 1989;1:1367–8. 44. Hirayama A, Adachi T, Asada S, Mishima M, Nanto S, Kusuoka H, Yamamoto K, Matsumura Y, Hori M, Inoue M, Kodama K. Late reperfusion for acute myocardial infarction limits the dilatation of left ventricle without the reduction of infarct size. Circulation. 1993;88:2565–74. 45. Heidary S, Patel H, Chung J, Yokota H, Gupta SN, Bennett MV, Katikireddy C, Nguyen P, Pauly JM, Terashima M, McConnell MV, Yang PC. Quantitative tissue characterization of infarct core and border zone in patients with ischemic cardiomyopathy by magnetic resonance is associated with future cardiovascular events. J Am Coll Cardiol. 2010;55(24):2762–8. 46. Wijnmaalen AP, Schalij MJ, von der Thüsen JH, Klautz RJ, Zeppenfeld K. Early reperfusion during acute myocardial infarction affects ventricular tachycardia characteristics and the chronic electroanatomic and histological substrate. Circulation. 2010;121(17):1887–95. 47. Cigarroa RG, Lange RA, Hillis LD. Prognosis after acute myocardial infarction in patients with and without residual anterograde coronary blood flow. Am J Cardiol. 1989;64:155–60. 48. Trappe HJ, Lichtlen PR, Klein H, Wenzlaff P, Hartwig CA. Natural history of single vessel disease: risk of sudden coronary death in relation to coronary anatomy and arrhythmia profile. Eur Heart J. 1989;10:514–24. 49. Puma JA, Sketch Jr MA, Thompson TD, Simes JR, Morris DC, White HD, Topol EJ, Califf RM. Support for the open-artery hypothesis in survivors of acute myocardial infarction: analysis of 11,228 patients treated with thrombolytic therapy. Am J Cardiol. 1999;83:482–7. 50. Ohman EM, Califf RM, Topol EJ, Candela R, Abbottsmith C, Ellis S, Sigmon KN, Kereiakes D, George B, Stack R. Consequences of reocclusion after successful reperfusion therapy in acute myocardial infarction. Circulation. 1990;82:781–91. 51. Ellis SG, O’Neill WW, Bates ER, Walton JA, Nabel EG, Topol EJ. Coronary angioplasty as primary therapy for acute myocardial infarction 6 to 48 hours after symptom onset: report of an initial experience. J Am Coll Cardiol. 1989;13:1122–6. 52. Hutter AM. Coronary angioplasty in acute myocardial infarction: should it be done? To whom? When? J Am Coll Cardiol. 1989;13:1127–9. 53. Topol EJ, Lerman BB, Baughman KL, Platia EV, Griffith LSC. De Novo refractory ventricular tachyarrhythmias after coronary revascularisation. Am J Cardiol. 1986;57:57–9. 54. Gaudron P, Eilles C, Kugler I, Ertl G. Progressive left ventricular remodelling after myocardial infarction. Circulation. 1993;87:755–63. 55. Dzavik V, Beanlands DS, Davies RF, Leddy D, Marquis J, Teo KK, Ruddy TD, Burton JR, Humen DP. Effects of late percutaneous transluminal coronary angioplasty of an occluded infarct-related coronary artery on left ventricular function in patients with a recent (<6 weeks) Q wave acute myocardial infarction (total Occlusion post-Myocardial Infarction Intervention Study [TOMIIS] – a pilot study). Am J Cardiol. 1994;73:856–61. 56. Pizzetti G, Belotti G, Margonato A, Cappelleti A, Chierchia SL. Coronary recanalization by elective angioplasty prevents ventricular dilation after anterior myocardial infarction. J Am Coll Cardiol. 1996;28:837–45. 57. Horie H, Takahashi M, Minai K, Izumi M, Takaoka A, Nozawa M, Yokohama H, Fujita T, Sakamoto T, Kito O, Okamura H, Kinoshita M. Long-term effect of late reperfusion for acute anterior myocardial infarction with percutaneous transluminal coronary angioplasty. Circulation. 1998;98:2377–82. 58. Steigen TK, Buller CE, Mancini GB, Jorapur V, Cantor WJ, Rankin JM, Thomas B, Webb JG, Kronsberg SS, Atchison DJ, Lamas GA,
143
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70. 71.
72.
73.
74.
Hochman JS, Džavík V. Myocardial perfusion grade after late infarct artery recanalization is associated with global and regional left ventricular function at one year: analysis from the Total Occlusion Study of Canada-2. Circ Cardiovasc Interv. 2010;3(6):549–55. Richards DA, Byth K, Ross DL, Uther JB. What is the best predictor of spontaneous ventricular tachycardia and sudden death after myocardial infarction? Circulation. 1991;83:756–63. Vermeer F, Simoons ML, Lubsen J. Reduced frequency of ventricular fibrillation after early thrombolysis in myocardial infarction. Lancet. 1986;1:1147–8. McGuire M, Kuchar DL, Ganes J, Sammel N. Natural history of late potentials in the first ten days after acute myocardial infarction and relation to early ventricular arrhythmias. Am J Cardiol. 1988;61:1187–90. Shenasa M, Fetsch T, Martinez-Rubio A, Borggrefe M, Breithardt G. Signal averaging in patients with coronary artery disease: how helpful is it? J Cardiovasc Electrophysiol. 1993;4:609–26. Gomes JA. The prognostic significance of the signal averaged electrocardiogram in the infarct survivor. In: Gersh BJ, Rahimtoola SH, editors. Acute myocardial infarction. 2nd ed. New York: Chapman and Hall; 1997. Gang ES, Lew AS, Hong M, Wang FZ, Siebert CA, Peter T. Decreased incidence of ventricular late potentials after successful thrombolytic therapy for acute myocardial infarction. N Engl J Med. 1989;321:712–6. Eldar M, Leor J, Hod H, Rotsein Z, Truman S, Kaplinisky E, Abboud S. Effect of thrombolysis on the evolution of late potentials within 10 days of infarction. Br Heart J. 1990;63:273–6. Zimmerman M, Adamee R, Ciaroni S, Malbois F, Tieche R. Reduction in the frequency of ventricular late potentials after acute myocardial infarction by early thrombolytic therapy. Am J Cardiol. 1991;67:697–703. Pedretti R, Laporata A, Erto MD, Gementi A, Bonelli R, Anza C, Colombo E, Maslowsky F, Santoro F, Cara B. Influence of thrombolysis on signal averaged electrocardiography and late arrhythmic events after acute myocardial infarction. Am J Cardiol. 1992;69:866–72. Steinberg JS, Hachman JS, Morgan CD, Dorian P, Naylor CD, Theroux P, Topol EJ, Armstrong PW. Effects of thrombolytic therapy administration 6 to 24 hours after myocardial infarction on signal averaged ECG. Results of a Multicenter Randomized Trial. Circulation. 1994;90:746–52. Ragosta M, Sabia PJ, Kaul S, DiMarco JP, Sarembock IJ, Powers ER. Effects of late (1 to 30 days) reperfusion after myocardial infarction on the signal averaged electrocardiogram. Am J Cardiol. 1993;71:19–23. Lomama E, Heft G, Persoz A, Vacheron A. Late coronary angioplasty and ventricular late potentials. Am J Cardiol. 1998;82:985–7. Rashba EJ, Lamas GA, Couderc JP, Hollist SM, Dzavik V, Ruzyllo W, Fridrich V, Buller CE, Forman SA, Kufera JA, Carvalho AC, Hochman JS, OAT-EP Investigators. Electrophysiological effects of late percutaneous coronary intervention for infarct-related coronary artery occlusion: the Occluded Artery Trial-Electrophysiological Mechanisms (OAT-EP). Circulation. 2009;119(6):779–87. Kersschot IE, Brugada P, Ramentol M, Zehender M, Waldecker B, Stevenson WG, Geibel A, De Zwann C, Wellens HJJ. Effects of early reperfusion in acute myocardial infarction on arrhythmias induced by programmed stimulation: a prospective, randomized study. J Am Coll Cardiol. 1986;7:1234–42. Bourke JP, Young AA, Richards DA, Uther JB. Reduction in incidence of inducible ventricular tachycardia after myocardial infarction by treatment with streptokinase during infarct evolution. J Am Coll Cardiol. 1990;16:1703–10. Link MS, Cesarz CA, Griffith JL, Estes MNA, Wang PJ. Evaluation of coronary revascularization to prevent tachycardia recurrences in survivors of ventricular fibrillation. Am J Cardiol. 1999;83:960–2.
144 75. Steinberg JS, Gaur A, Sciacca R, Tan E. New-onset sustained ventricular tachycardia after cardiac surgery. Circulation. 1999;99:903–8. 76. Rubin DA, Nieminski K, Monteferrante JC, Magee T, Reed GE, Herman MV. Ventricular arrhythmias after coronary artery bypass graft surgery: incidence, risk factors and long term prognosis. J Am Coll Cardiol. 1985;6:307–10. 77. Brugada P, De Swart H, Smeets JLRM, Wellens HJJ. Transcoronary chemical ablation of ventricular tachycardia. Circulation. 1989;79: 475–82.
C.S. McLachlan et al. 78. Brugada P, De Swart H, Smeets JLRM, Wellens HJJ. Termination of tachycardias by interrupting blood supply to the arrhythmogenic area. Am J Cardiol. 1988;62:387–92. 79. Steg PG, Kerner A, Mancini GB, Reynolds HR, Carvalho AC, Fridrich V, White HD, Forman SA, Lamas GA, Hochman JS, Buller CE, OAT Investigators. Impact of collateral flow to the occluded infarct-related artery on clinical outcomes in patients with recent myocardial infarction: a report from the randomized occluded artery trial. Circulation. 2010;121(25):2724–30.
The Clinical Utility of 12-Lead Resting ECG in the Era of Ablation Strategies
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Jang-Ho Bae, Taek-Geun Kwon, and Ki-Hong Kim
Abstract
Since Einthoven invented the string galvanometer for registering electrical activity of the heart in 1903, electrocardiography (ECG) became the most common and important medical examination. With this 12-lead surface ECG, we can diagnose arrhythmia, ischemic heart disease, or other heart disease. Electrophysiologic study (EPS) has increased our understanding about the mechanism of arrhythmias, including atrioventricular nodal reentry tachycardia (AVNRT), atrioventricular reentry tachycardia (AVRT), atrial tachycardia (AT), and ventricular tachycardia (VT). Catheter ablation using radiofrequency energy has become the treatment of choice for most supraventricular tachycardia (SVT) and VT. Precise review of 12-lead surface ECG can give us the cause of SVT and location of accessory pathway (AP) and focal site of monomorphic VT. So we can plan the ablation technique and reduce the procedure time. We are going to see the usefulness of 12-lead surface ECG for EPS, especially in the era of radiofrequency catheter ablation. Keywords
Electrocardiography • SVT • Accessory pathway • WPWsyndrome • VT
Atrioventricular Nodal Reentry Tachycardia Among the SVT, AVNRT is the most common (56 %), followed by AVRT (27 %) and AT (17 %). Presumptive diagnosis of SVT before EPS and radiofrequency catheter ablation (RFCA) would be very useful in order to increase success rate and decrease complication rate [1]. There are many ECG criteria to differentiate PSVT, whether it is AVNRT or AVRT. Because retrograde atrial activation and antegrade ventricular activation occur almost simultaneously in typical AVNRT, P wave usually buried within or fused with the QRS complex and RP interval is less than 70 ms (Fig. 11.1), whereas it is more than 70 ms in
J.-H. Bae, MD, PhD, FACC (*) • T.-G. Kwon, MD, PhD K.-H. Kim, MD Department of Internal Medicine, Heart Center, Konyang University Hospital, Daejeon, South Korea e-mail:
[email protected] A.S. Kibos et al. (eds.), Cardiac Arrhythmias, DOI 10.1007/978-1-4471-5316-0_11, © Springer-Verlag London 2014
AVRT [2]. Other findings of AVNRT are pseudo r’ wave in V1, pseudo S wave in inferior lead, or absence of positive ECG findings [3]. Visible retrograde P wave and QRS alternans are observed more frequently in AVRT [4].
Atrioventricular Reentry Tachycardia Concealed Accessory Pathway ECG of AVRT will show P waves inscribed within the ST-T wave segment with an RP interval that is usually less than one-half the tachycardia RR interval and more than 70 ms. ST segment depression or T wave inversion also can occur, even in patients without coronary artery disease. Patterns of repolarization changes may vary with the location of the AP: ST segment depression in V3 to V6 is almost invariably seen with a left lateral AP; ST segment depression and a negative T wave in the inferior leads are associated with a posterosep145
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Fig. 11.1 (a) 12-lead ECG shows a regular SVT recorded at an ECG paper speed of 25 mm/s. (b) After conversion to sinus rhythm, the 12-lead ECG shows sinus rhythm. In (a), note the pseudo r′ in V1 (arrowhead) and accentuated S waves (pseudo S wave) in II, III, and aVF (arrow)
tal or posterior AP; A negative or notched T wave in V2 or V3 with a positive retrograde P wave in at least two inferior leads suggests an anteroseptal AP [5, 6]. Recently, Rostock et al. suggested an algorithm for concealed AP localization using retrograde P wave polarity during orthodromic AVRT [7]. Four leads of the 12-lead surface ECG were identified to localize the AP: I, aVR, aVL, and V1. Lead V1 was used to differentiate right (negative or isoelectric) from left (solely positive) APs.
Retrograde P wave in lead I was exclusively negative in left posterior APs and became more positive with an AP location shifting towards right anterior. If the polarity of P wave is positive in V1 and negative in lead I, AP locates at left posterior (Figs. 11.2 and 11.3). On the other hand, if the polarity of P wave is negative in V1 and positive in lead I, AP locates at right anterior (Figs. 11.2 and 11.4). P wave polarity in lead aVR demonstrated a shift from a positive polarity in left APs to isoelectric in right APs. The opposite
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The Clinical Utility of 12-Lead Resting ECG in the Era of Ablation Strategies
Fig. 11.2 Localization of accessory pathway. Stepwise algorithm to predict AP location using T-wave-subtracted retrograde P wave polarity during orthodromic AVRT
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Fig. 11.3 12-lead ECG during orthodromic AVRT. The polarity of retrograde P wave is positive in V1 and negative in lead I, localizing the AP to the left posterior
direction was observed for lead aVL. Stepwise algorithm was illustrated at Fig. 11.2. Bundle branch block that results in an increase in the tachycardia cycle length is consistent with AVRT utilizing an
ipsilateral AP. This is result from the extra time required to traverse a circuit with conduction proceeding down the opposite bundle branch and then across the septum (Fig. 11.5).
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Fig. 11.4 12-lead ECG during orthodromic AVRT. The polarity of retrograde P wave is negative in V1 and positive in lead I, localizing the AP to the right anterior
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a Fig. 11.5 Effects of bundle branch block (BBB) during orthodromic AVRT. Ventriculoatrial conduction time is prolonged when BBB developed during orthodromic AVRT sustained by AP located in the same or
b ipsilateral ventricle as the bundle branch that is blocked. In AVRT with left lateral AP, tachycardia cycle length is 263 ms when RBBB developed (a) and 283 ms when LBBB developed (b)
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The Clinical Utility of 12-Lead Resting ECG in the Era of Ablation Strategies
Preexcitation RFCA is the treatment of choice in patients with WolffParkinson-White (WPW) syndrome. Precise localization of the AP is essential for successful ablation and reducing the procedure time. If accurate localization of the AP is available before the procedure, RFCA can be easier with shorter procedure time. Several criteria have been proposed for localization of AP from the surface ECG. Recently, three algorithms (Chern-En Chiang’s, Fitzpatrick’s, and Xie’s algorithm) have offered great accuracy for predicting AP location (86, 88, and 93 %, respectively), using different electrocardiographic criteria. Chiang’s algorithm was based on the polarity of delta wave and the R/S ratio in the frontal and precordial leads [8]. Fitzpatrick’s algorithm was based on the R/S ratio in the frontal and precordial leads and the delta wave frontal axis, the delta wave amplitude, or the sum of the delta wave amplitude in frontal leads [9]. Xie’s algorithm was based mainly on the polarity and morphology of the QRS complex [10]. However, the degree of accordance of three algorithms for localization of APs was lower than the expected one, although there are some limitations in the study [11]. An algorithm developed by Arruda et al. using the polarity of the delta wave within the initial 20 ms of the preexcitation has an overall sensitivity of 90 % and specificity of 99 % [12]. AP can be localized using the following steps: Step 1 (Left free-wall APs): If either the delta wave in lead I is negative or isoelectric or the R wave is greater in amplitude than the S wave in lead V1, a left free-wall AP is present. If this criterion is fulfilled, lead aVF is examined. If the delta
wave in lead aVF is positive, a left lateral/anterolateral (LL/ LAL) AP is identified. If a delta wave in lead aVF is isoelectric or negative, the AP is located at the left posterior/posterolateral (LP/LPL) region (Figs. 11.6 and 11.7). If the criteria in leads I and V1 are not fulfilled, a septal or right free-wall accessory AV pathway is identified. Proceed to step 2. Step 2 (Subepicardial APs): Lead II is examined. A negative delta wave in lead II identifies the subepicardial posteroseptal AP. If the delta wave in lead II is isoelectric or positive, proceed to step 3. Step 3 (Septal APs): Lead V1 is examined. A negative or isoelectric delta wave in lead V1 identifies a septal AP. If this criterion is fulfilled, lead aVF is examined. If the delta wave in lead aVF is negative, an AP is identified, which is located at the posteroseptal tricuspid annulus or at the coronary sinus ostium and surrounding region (PSTA/CSOs). If the delta wave is isoelectric in lead aVF, the AP may be located close to either the posteroseptal tricuspid annulus (PSTA) or the posteroseptal mitral annulus (PSMA) as shown in Figs. 11.6 and 11.8. A positive delta wave in aVF identifies a pathway located within the anteroseptal/right anterior paraseptal (AS/RAPS) or mid-septal tricuspid annulus (MSTA) regions. These two regions are differentiated by examining the R/S ratio in lead III: R > S identifies AS/RAPS AP, and R < S identifies an AP located along the MSTA, as illustrated Fig. 11.6. If the delta wave in lead V1 is positive (after having excluded patients with a left freewall AP in step 1), a right free-wall accessory AV pathway is identified. Proceed to step 4.
Step 1 left free wall APs
Step 2 subepicardial APs
Step 3 septal APs
Lead I (± or −) or V1 R≥S
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Fig. 11.6 Stepwise ECG algorithm for predicting accessory pathway location
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Fig. 11.7 The delta wave is negative in lead I and R > S in lead V1. The polarity of delta wave in lead aVF is positive. Accessory pathway locates at left lateral/anterolateral
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Fig. 11.8 The delta wave is isoelectrical in lead V1 and lead aVF, localizing the pathway to the posteroseptal region. The positive delta wave in lead II and in the lateral leads, I, aVL, and V6, localizes the pathway to the right side
Step 4 (Right free-wall APs): In patients with right free-wall APs, examine lead aVF. A positive delta wave in lead aVF identifies a right anterior/anterolateral AP (RA/RAL) as shown in Figs. 11.6 and 11.9. If the delta wave in aVF is iso-
electric or negative, examine lead II. A positive delta wave in lead II identifies a right lateral AP (RL), and an isoelectric delta wave in lead II identifies a right posterior/posterolateral AP (RP/RPL), as illustrated in Figs. 11.6 and 11.10.
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The Clinical Utility of 12-Lead Resting ECG in the Era of Ablation Strategies
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aVL
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Fig. 11.9 The delta wave is positive in lead V1 and in aVF, localizing the pathway to the right anterior/anterolateral (RA/RAL) region I
aVR
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Fig. 11.10 The delta wave is positive in lead V1, isoelectrical in lead aVF and lead II, localizing the pathway to the right posterior/posterolateral (RP/RPL) region
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Fig. 11.11 12-lead ECG shows atrial tachycardia with variable degree of atrioventricular block. The polarity of P wave is positive in V1 and positive in inferior leads (II, III, and aVF), localizing the focal AT to the left superior
Atrial Tachycardia
Ventricular Tachycardia
Atrial tachycardia (AT) is the least among the SVT; however, it does not respond to pharmacological therapy well and generally needs RFCA for cure. RFCA for AT is complex and needs a 3D mapping. So if we suppose the location of AT focus, the procedure could be less complex. P wave morphology in focal atrial tachycardia is useful for distinguishing atrial origin. Kistler et al. suggest that lead V1 is the most useful in distinguishing a right from a left atrial focus [13]. A negative or biphasic (positive, then negative) P wave in lead V1 is associated with a tachycardia arising from the RA. A positive or biphasic (negative, then positive) P wave in lead V1 is associated with a tachycardia originating in the LA as shown in Fig. 11.11. Because of the posterior location of pulmonary veins, the P wave in V1 is universally positive for tachycardias originating at the pulmonary veins.
The surface ECG is probably the most important initial mapping technique in determining the site of origin of ventricular tachycardia (VT). In addition to confirming the diagnosis of VT, the 12-lead morphology of VT can help in its location. The QRS complex during VT is generated from a distinct site of origin for focal VTs or from the exit site of a constrained diastolic isthmus during reentrant VT. There are some general principles: First, left ventricular free-wall VT shows RBBB morphology, while VT exiting from the interventricular septum or right ventricle displays LBBB morphology. Second, septal exits are associated with narrower QRS complexes consisted with synchronous rather than sequential ventricular activation. Third, basal sites show positive precordial concordance, while negative concordance is seen in apical sites of origin [14].
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Fig. 11.12 12-lead ECG shows wide QRS tachycardia and LBBB morphology with inferior axis, late precordial transition after V3, and notching in the inferior leads. These mean an idiopathic VT arising from the posterior aspect of the free wall of the RVOT
Usually, outflow tract VT has LBBB morphology with inferior axis and deeply negative QS complexes in leads aVL and aVR. Septal site of right ventricular outflow tract (RVOT) tends to have narrower LBBB QRS complexes with earlier precordial transition (positive QRS by V3 or earlier) and larger amplitudes in the inferior leads. On the other hand, free-wall sites in the RVOT have later precordial transition, with broader QRS complexes and notching in the inferior leads [15]. Posterior sites in the RVOT have positive QRS complex in limb lead I because of leftward initial vector [16], as illustrated in Fig. 11.12. Precordial R wave transitions earlier than V2 are suggestive of a left ventricular outflow tract (LVOT) of VT [17]. Anterolateral mitral annulus sites show positive precordial concordance with an RBBB morphology in V1 and usually
with late notching in the inferior leads as shown in Fig. 11.13. Septal sites of parahisian region have LBBB morphology with left inferior axis and dominant R in lead I. VT arising from aortomitral continuity (basal LVOT) displays a qR pattern in V1 as a result of the left fibrous trigone deflecting initial electrical activation leftward or a RBBB morphology with positive concordance [18] (Fig. 11.13). Fascicular VT, also known as left septal VT or verapamilsensitive VT, is due to reentry involving altered Purkinje fibers on the left ventricular aspect of the septum. Reentry involving left posterior fascicle with an exit at the inferoapical LV septum shows an RBBB morphology with left superior axis and RS complexes in V5 and V6, as illustrated in Fig. 11.14. Reentry involving the left anterior fascicle shows RBBB morphology with right axis deviation.
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Fig. 11.13 12-lead ECG shows a positive precordial concordance with RBBB morphology in V1, inferior axis, relatively wide QRS complex, and negative in lead I. These mean an idiopathic VT arising from the anterolateral mitral annulus of LVOT
Fig. 11.14 The surface ECG shows the relatively narrow QRS complex and AV dissociation in lead V3. There is a right bundle branch block and left superior axis. This is a typical example of fascicular VT due to reentry involving the left posterior fascicle
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The Clinical Utility of 12-Lead Resting ECG in the Era of Ablation Strategies
References 1. Porter MJ, Morton JB, Denman R, et al. Influence of age and gender on the mechanism of supraventricular tachycardia. Heart Rhythm. 2004;1:397–8. 2. ACC/AHA/ESC guidelines for the management of patients with supraventricular arrhythmias-executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Supraventricular Arrhythmias). Circulation. 2003;108: 1871–909. 3. Gonz´alez-Torrecilla E, Almendral J, Arenal A, et al. Independent predictive accuracy of classical electrocardiographic criteria in the diagnosis of paroxysmal atrioventricular reciprocating tachycardias in patients without preexcitation. Europace. 2008;10:624–8. 4. Kalbfleisch SJ, El-Atassi R, Calkins H, et al. Differentiation of paroxysmal narrow QRS complex tachycardias using the 12-lead electrocardiogram. J Am Coll Cardiol. 1993;21:85–9. 5. Riva SI, Della Bella P, Fassini G, Carbucicchio C, Tondo C. Value of analysis of ST segment changes during tachycardia in determining type of narrow QRS complex tachycardia. J Am Coll Cardiol. 1996;27(6):1480. 6. Scheinman MM, Wang YS, Van Hare GF, Lesh MD. Electrocardiographic and electrophysiologic characteristics of anterior, midseptal and right anterior free wall accessory pathways. J Am Coll Cardiol. 1992;20(5):1220. 7. Rostock T, Sydow K, Steven D, Lutomsky B, Servatius H, Drewitz I, Falke V, Müllerleile K, Ventura R, Meinertz T, Willems S. A new algorithm for concealed accessory pathway localization using T-wave-subtracted retrograde P-wave polarity during orthodromic atrioventricular reentrant tachycardia. J Interv Card Electrophysiol. 2008;22(1):55–63. 8. Chiang CE, Chen SA, Teo WS, Tsai DS, Wu TJ, Cheng CC, Chiou CW, Tai CT, Lee SH, Chen CY, et al. An accurate stepwise electrocardiographic algorithm for localization of accessory pathways in patients with Wolff-Parkinson-White syndrome from a comprehensive analysis of delta waves and R/S ratio during sinus rhythm. Am J Cardiol. 1995;76(1):40–6. 9. Fitzpatrick AP, Gonzales RP, Lesh MD, Modin GW, Lee RJ, Scheinman MM. New algorithm for the localization of accessory
10.
11.
12.
13.
14.
15.
16.
17.
18.
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atrioventricular connections using a baseline electrocardiogram. J Am Coll Cardiol. 1994;23(1):107–16. Xie B, Heald SC, Bashir Y, Katritsis D, Murgatroyd FD, Camm AJ, Rowland E, Ward DE. Localization of accessory pathways from the 12-lead electrocardiogram using a new algorithm. Am J Cardiol. 1994;74(2):161–5. Katsouras CS, Greakas GF, Goudevenos JA, Michalis LK, Kolettis T, Economides C, Argyri U, Pappas S, Sideris DA. Localization of accessory pathways by the electrocardiogram: which is the degree of accordance of three algorithms in use? Pacing Clin Electrophysiol. 2004;27(2):189–93. Arruda MS, McClelland JH, Wang X, et al. Development and validation of an ECG algorithm for identifying accessory pathway ablation site in Wolff-Parkinson-White syndrome. J Cardiovasc Electrophysiol 1998;9:2–12. Kistler PM, Roberts-Thomson KC, Haqqani HM, Fynn SP, Singarayar S, Vohra JK, Morton JB, Sparks PB, Kalman JM. P-wave morphology in focal atrial tachycardia: development of an algorithm to predict the anatomic site of origin. J Am Coll Cardiol. 2006;48(5):1010. Haqqani HM, Morton JB, Kalman JM. Using the 12-lead ECG to localize the origin of atrial and ventricular tachycardias: part 2– ventricular tachycardia. J Cardiovasc Electrophysiol. 2009;20(7): 825–32. Dixit S, Gerstenfeld EP, Callans DJ, Marchlinski FE. Electrocardiographic patterns of superior right ventricular outflow tract tachycardias: distinguishing septal and free-wall sites of origin. J Cardiovasc Electrophysiol. 2003;14(1):1–7. Jadonath RL, Schwartzman DS, Preminger MW, Gottlieb CD, Marchlinski FE. Utility of the 12-lead electrocardiogram in localizing the origin of right ventricular outflow tract tachycardia. Am Heart J. 1995;130(5):1107–13. Callans DJ, Menz V, Schwartzman D, Gottlieb CD, Marchlinski FE. Repetitive monomorphic tachycardia from the left ventricular outflow tract: electrocardiographic patterns consistent with a left ventricular site of origin. J Am Coll Cardiol. 1997;29(5): 1023–7. Dixit S, Gerstenfeld EP, Lin D, Callans DJ, Hsia HH, Nayak HM, Zado E, Marchlinski FE. Identification of distinct electrocardiographic patterns from the basal left ventricle: distinguishing medial and lateral sites of origin in patients with idiopathic ventricular tachycardia. Heart Rhythm. 2005;2(5):485–91.
Long-Term ECG (Holter) Monitoring and Head-Up Tilt Test
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Santosh Kumar Dora
Abstract
Long term electrocardiogram monitoring is a very useful investigation to diagnose, assess prognosis and assess response to drug therapy in cardiac arrhythmic and ischemic disorders. Commonly it is used for the diagnosis of undiagnosed palpitation or syncope. Holter monitoring is used over one or two days where as event recorder and external loop recorder can be used for several days to weeks. Implantable loop recorder has the highest diagnostic value and can be used for several years to pick up very rare episodes. Head up tilt test is commonly performed to diagnose vasovagal syncope in clinically indicated cases of undiagnosed syncope. To increase diagnostic yield and reduce procedure time, various pharmacological provocations have been introduced. The commonest positive response is type-1, where the syncope is associated with a fall in blood pressure and heart rate but not leading to asystole for more than 3 seconds. The risk of procedure is low, but in rare instances there can be prolonged period of asystole requiring cardiac resuscitation. Keywords
Electrocardiogram • Holter • Telemetry • Head-up-tilt vasovagal • syncope
Long-Term ECG (Holter) Monitoring Santosh Kumar Dora
eters during real-life activities. It is especially helpful in detecting the changes which occur transiently, otherwise difficult to pick up during routine examination in the office setting. However unlike a 12 lead electrocardiogram, Holter test records only two or three channels.
Introduction Long-term electrocardiogram monitoring is a valuable investigation in the recording of an episode of arrhythmia or ischemia as well as monitoring the effectiveness of therapeutic measures [1, 2]. Its ability to examine the electrocardiogram over an extended period during ambulatory period gives an opportunity to examine various electrocardiographic param-
S.K. Dora, MD, DM Cardiac Electrophysiology and Pacing, Asian Heart Institute and Research Center, Mumbai, MH 400051, India e-mail:
[email protected] A.S. Kibos et al. (eds.), Cardiac Arrhythmias, DOI 10.1007/978-1-4471-5316-0_12, © Springer-Verlag London 2014
Types of Long-Term Electrocardiograph Monitoring Long-term electrocardiograph monitoring is of two types: external or implantable. Conventional long-term electrocardiograph monitor is the traditional Holter monitor which is an external device and records two or three channel electrocardiogram in an analog tape or digital card over 24 h [3]. Currently there are many more external devices such as event recorder, external loop recorder, and mobile outpatient telemetry. The event recorder is a handheld patient-operated electrocardiograph system and has been shown to improve the diagnosis of transient arrhythmias significantly [4, 5]. 157
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This device needs patient participation in terms of activating the device on the occurrence of the symptoms. In contrast the external loop recorder and mobile cardiac outpatient telemetry can detect and record even the asymptomatic clinical significant arrhythmias automatically in addition to patientactivated events [6, 7]. These devices are also capable of immediate wireless transmission of the recorded electrocardiogram to a central monitoring station via mobile telephone or Internet. The central monitoring station in turn sends the data to the concerned physician. This enables the physician to get quick access to the relevant arrhythmic data and take an appropriate corrective measure. The implantable device is a small device the size of a flash drive which is generally implanted subcutaneously in the left side by the side of the sternum. These devices can be implanted for a prolonged period and are very useful in recording rare episodes. Following is a brief outline of various types of long-term electrocardiograph monitoring devices being used now.
Holter Monitor This is an external recorder connected to the patient’s chest by skin electrodes. It records electrocardiogram continuously and does beat to beat analysis. It normally records for 24 or 48 h. The usage cost is low and it is simple to use. The disadvantage is if the arrhythmic episodes are rare, then it may not detect during the 24- or 48-h wear-in period. Event Recorder This is a small device applied on to the patient’s chest whenever the symptom is experienced. It records one channel electrocardiogram for few seconds. The advantage of this device is it is used over the chest only when it is required and can be retained by the patients for few days to weeks. The disadvantage is it may not be suitable for syncope evaluation as patient loses consciousness during the episode and thus cannot apply the device on the chest to record the possible arrhythmic episode. External Loop Recorder This device is connected to the patient by skin electrodes. It has a memory loop, and when activated by the patient, it records the event few minutes before to few minutes after the activation point.
Mobile Cardiac Outpatient Telemetry In this device there is a portable receiver which is capable of transmitting the data recorded by an external loop recorder manually or automatically over the telephone network or Internet. Implantable Loop Recorder This is an implantable device similar to the size of a pacemaker and implanted to the patient’s chest by the side of the sternum on the left side. It records the arrhythmic episodes
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spontaneously or as activated by the patient for a period of few minutes before to few minutes after the activation point. The advantage is it can be used for a very long time up to 3 years in some device enabling recording very rare episodes. The utility of long-term electrocardiogram is as follows: 1. Diagnosis of rhythm disorder 2. Assessment of risk in certain cardiac conditions 3. Assessment of effectiveness of therapies
Diagnosis Ambulatory electrocardiogram can detect intermittent episodes of malignant arrhythmia which leads to symptom (Fig. 12.1). Ambulatory electrocardiogram is considered diagnostic only when there is a correlation between symptom and simultaneous electrocardiogram monitoring showing arrhythmia [1, 2]. If symptoms are rare, then a standard Holter monitor, which records electrocardiogram over only 24 h period, may fail to detect any abnormal electrocardiogram, thus significantly reducing the sensitivity. Holter monitoring has a sensitivity value of only 22 % in diagnosing syncope and/or palpitation of unknown origin [8]. The sensitivity depends on many factors like monitoring techniques, duration of monitoring, patient compliance, and frequency of arrhythmic episodes. The specificity of ambulatory electrocardiogram monitoring in diagnosing arrhythmic or nonarrhythmic palpitation is optimal. The external loop recorder has much higher diagnostic value of 66–83 % and are cost effective compared to Holter device in diagnosing frequent episodes of symptoms [4, 9]. The mobile cardiac outpatient telemetry exhibits the highest diagnostic value compared to all other external devices [10]. The implantable loop recorders have much higher diagnostic value and cost-effectiveness than the conventional tests and can be used for a very long period and especially useful in very infrequent episodes of symptoms [11]. However it is an invasive method, and with availability of high-quality noninvasive external recorders, it may not be preferred by many patients. The RUP (recurrent unexplained palpitations study) demonstrated a higher diagnostic value (73 % vs. 21 %) and a better cost-effectiveness ratio compared to Holter, event recorder, and electrophysiology study in patients with infrequent palpitation [12]. Not all rhythm disorders recorded in a Holter monitor are significant. Sinus bradycardia, sinus pauses, and type I second-degree AV block may be recorded during sleep in normal healthy persons. However a significant rhythm disturbance is uncommon in healthy young persons. The indications of ambulatory monitoring are given in Table 12.1.
Risk Assessment Myocardial infarction survivors are at increased risk of sudden death, and the major cause of this is ventricu-
12 Long-Term ECG (Holter) Monitoring and Head-Up Tilt Test
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Fig. 12.1 Holter recording shows high-grade AV block without any ventricular escape beat Table 12.1 Indication for ambulatory electrocardiogram monitoring Class 1 1. Patients with unexplained syncope, near syncope, or episodic dizziness in whom the cause is not obvious 2. Patients with unexplained recurrent palpitations Class 2b 1. Patients with episodic shortness of breath, chest pain, or fatigue that is not otherwise explained 2. Patients with neurological events when transient atrial fibrillation or atrial flutter is suspected 3. Patients with symptoms such as syncope, near syncope, episodic dizziness, or palpitation in whom a probable cause other than an arrhythmia has been identified but in whom symptoms persists despite treatment of this other cause Class 3 1. Patients with symptoms such as syncope, near syncope, episodic dizziness, or palpitation in whom other causes have been identified by history, physical examination, and laboratory tests 2. Patients with cerebrovascular accidents, without other evidences of arrhythmia The indication is as per ACC/AHA guidelines Crawford et al. [1]
lar tachycardia or ventricular fibrillation. The goal of risk stratifying such patients is to identify a group of patients at high risk of development of an arrhythmic event and to reduce such events by an intervention. Ambulatory electro-
cardiogram monitoring may be helpful in such patients and usually performed over a 24 h period before hospital discharge. Frequent (>10/h) and high-grade ventricular ectopy (repetitive premature ventricular complexes, multiform premature ventricular complexes, ventricular tachycardia) after myocardial infarction have been associated with risk of sudden cardiac death. However the positive predictive value of premature ventricular complexes for an arrhythmic event remains low ranging from 5 to 15 %. Evidence from cardiac arrhythmia suppression trial (CAST) shows possibility of premature ventricular complex as a marker rather than a causal relationship with sudden cardiac death because premature ventricular complex suppression with class IC drugs was associated with increased mortality compared to placebo [13]. The positive predictive value increases from 15 to 34 % for an arrhythmic event if ambulatory electrocardiogram monitoring is combined with an assessment of left ventricular function. Later trials showed decreased left ventricular function as the single most important predictor of sudden cardiac death due to arrhythmia and the necessity of automatic implantable cardioverter defibrillator for mortality benefits [14–16]. Ambulatory electrocardiogram is not needed in asymptomatic post-myocardial infarction patients who have an ejection fraction of more than 40 % because
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malignant arrhythmia occurs infrequently in such patients. The other group of patients where Holter may be useful for risk stratification is congestive heart failure and idiopathic hypertrophic cardiomyopathy [1]. Studies in congestive heart failure have shown that ventricular arrhythmia is sensitive but not a specific marker of sudden cardiac death. Ambulatory electrocardiogram monitoring adds to the prognostic information provided by known risk factor for patients with hypertrophic cardiomyopathy. The presence of sustained or nonsustained ventricular tachycardia puts a patient with hypertrophic cardiomyopathy in a high-risk category.
S.K. Dora
Head-Up Tilt Test Santosh Kumar Dora
Introduction
Heart rate variability is used to evaluate vagal and sympathetic influences on the sinus node and to identify patients at risk for sudden cardiac death. It predicts all causes of mortality and has been put as class IIb in predicting mortality in patients with post-myocardial infarction left ventricular dysfunction. Frequency domain analysis is considered to be superior to the time domain analysis for determining heart rate variability [17].
Head-up tilt test (HUTT) is a diagnostic procedure commonly done to study adaptation of heart rate and blood pressure to changes in position and is helpful in identifying patients suffering from vasovagal syncope. Kenny and colleagues first reported the diagnostic utility of this test [22]. In the beginning only head-up tilt was used to provoke vasovagal syncope, but later various pharmacological provocations were introduced to increase the diagnostic yield. Vasovagal syncope is also known as neurocardiogenic syncope. It occurs due to sudden hypotension with or without associated bradycardia. The triggers which lead to vasovagal syncope either lead to decrease in ventricular filling or increase in catecholamine secretion [23–25]. These triggers include sight of blood, pain, prolonged standing, a warm environment, hot shower, and stressful situations. The patient feels severe light-headedness often resulting in syncope.
Efficacy of Antiarrhythmic Therapy
Pathophysiology of Vasovagal Syncope
Long-term electrocardiogram has been widely used to assess antiarrhythmic efficacy as well as therapies directed at ischemia [18]. CAST study used ambulatory electrocardiogram monitor to test the antiarrhythmic drug efficacy. Despite the suppression of frequent ventricular ectopic by class IC drugs, it showed increase in cardiac arrhythmia-related mortality [13]. However, use of class III drugs, i.e., amiodarone and sotalol, has shown to suppress ventricular arrhythmia in specific cardiac subpopulations without increase in all cause mortality [19, 20]. Although amiodarone decreases arrhythmia, it has not shown to be better than placebo in terms of overall survival in a population with coronary artery disease, left ventricular dysfunction, and unsustained ventricular arrhythmia [21]. Automatic implantable cardioverter defibrillator has been consistently shown to have survival benefit in this group of patient population when used as secondary as well as primary prophylaxis [14–16]. One of the common indications of long-term electrocardiogram monitoring is assessment of atrial fibrillation recurrence following pharmacological or catheter intervention treatment for atrial fibrillation. As asymptomatic atrial fibrillation is not rare, long-term electrocardiogram monitor gives an ample opportunity to record such events to plan out the management strategy, especially the anticoagulation therapy in specific group of patients based on CHADS2 score.
Vasovagal syncope commonly occurs in upright posture. Upright posture along with the abovementioned triggering factor leads to venous pooling in the lower part of body by approximately 500–1,000 ml. Subsequently an additional 700 ml of protein-free fluid is filtered into the interstitial spaces in the next 10 min [26]. The decrease in venous return and thus the resulting stroke volume lead to stimulation of baroreceptors which in turn lead to increase in catecholamine secretion. This leads to increase in heart rate, vigorous ventricular contraction, and constriction of resistance and capacitance vessels to maintain minimum blood pressure to maintain adequate cerebral blood flow. The vigorous contraction of ventricles stimulates the vagal C fibers, consisting of nonmyelinated fibers found in the atria, ventricles, and pulmonary artery. These afferent C fibers activate centrally located dorsal vagal nucleus in the medulla, leading to a paradoxical withdrawal of peripheral sympathetic tone and increase in vagal tone which in turn leads to vasodilation and bradycardia. This leads to a significant fall in blood pressure and severe inadequacy in maintaining cerebral blood flow and results into syncope. Vasovagal syncope also can occur at the sight of blood and extreme emotional stress situations. This suggests involvement of higher neural centers in the pathophysiology of vasovagal syncope. A schematic diagram of pathophysiology of vasovagal syndrome is depicted in Fig. 12.2.
Heart Rate Variability
12 Long-Term ECG (Holter) Monitoring and Head-Up Tilt Test Fig. 12.2 Pathophysiology of vasovagal syncope
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Venous pooling
Central triggers i.e. sight of blood, emotions
Activation of baroreceptors and increased catecholamine secretion
Increase in heart rate increase ventricular contraction vasoconstriction
Increased ventricular contraction leads to stimulation of vagal C fibers stimulates dorsal vagal nucleus in medulla
Stimulates higher centers in cortex
Reflex vasodilation and bradycardia leading to syncope
Protocols of HUTT
Tilt Test with Pharmacological Provocation
Patient should fast 2–3 h before the test and is allowed to take their usual medications. However if the patient has been already prescribed some drugs for vasovagal syncope including beta-adrenergic blocker, then he should stop five half-lives prior to the test. The patient lies down on a tilt capable table with a footboard support. For extra safety to prevent a fall, patient is normally strapped lightly. Intravenous cannulation is placed for rapid access to any intravenous drug if needed. The room ambience should be dimly lit, calm, and quite.
Pharmacologic provocation was introduced in 1989 to increase the diagnostic yield [30]. After 10 min of nondrug tilt if there is no response, then the patient is returned to supine position and isoprenaline infusion is started at initial dose of 1 μg/min and tilt was performed. If there is no response, the dose was gradually increased up to 3 μg/min without any intervening supine position. With this protocol the positive response was 61 % with a specificity of 93 % [31]. Subsequently various workers used sublingual nitroglycerine in view of increase in isoprenaline-related side effects. Raviele and coworkers showed that in cases of syncope with unknown origin after 45 min of baseline tilting if 0.3 mg of sublingual nitrate is administered, then there is 51 % of positive response with 94 % of specificity [32]. A comparison of nitrate and isoprenaline showed similar sensitivity and specificity [33]. Subsequent studies showed use of 400 μg nitroglycerine spray after 20 min of baseline tilt yielded a positive response of 69 % [34, 35]. Different kind of response to tilt testing is depicted in Table 12.2 [36].
Tilt Test Without Pharmacologic Provocation The table is tilted to 60°. The average time taken for onset of syncope is 24 ±10 min. Based on this report Fitzpatrik and colleague had proposed a minimum of 45 min [27]. The test is terminated before that if the patient develops syncope before that time. With this protocol the positive response in patients with syncope of unknown origin is 75 % and the specificity is 93 %. Various workers have suggested better sensitivity at a tilt of 70–80° [28, 29].
162 Table 12.2 Response to tilt testing Type 1 (mixed response) Patient develops syncope associated with fall in blood pressure The heart rate falls after the fall in blood pressure. Usually the heart rate does not decrease below 40/min; if it does then it is for less than 10 s or asystole of less than 3 s Type 2a (cardioinhibiton without asystole) Patient develops syncope associated with fall in blood pressure The heart rate falls after the fall in blood pressure. The heart rate decreases below 40/min and remains so for more than 10 s. Cardiac systole if present, it is for less than 3 s Type 2b (cardioinhibiton with asystole) Patient develops syncope associated with fall in blood pressure The heart rate falls at the same time or after the fall in blood pressure. The cardiac systole is for more than 3 s Type 3 (nonsignificant fall in heart rate) Patient develops syncope associated with fall in blood pressure The fall in heart rate is less than 10 % of the peak heart rate during tilt test
Risk of Head-Up Tilt Study By and large the tilt study is safe. A rapid return to supine position as soon as syncope occurs should be attempted to avoid syncope of prolonged duration. Occasionally there is extended period of asystole requiring cardiopulmonary resuscitation. Occasionally atrial fibrillation may result, but it is usually self-terminating.
References 1. Crawford MH, Bernstein SJ, Deedwania PC, et al. ACC/AHA guidelines for ambulatory electrocardiography – Executive summary and recommendations: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the Guidelines for Ambulatory Electrocardiography). Circulation. 1999;100:886–93. 2. Kadish AH, Buxton AE, Kennedy HL, et al. ACC/AHA clinical competence statement on electrocardiography and ambulatory electrocardiogram: a report of the ACC/AHA/ACP-ASIM Task Force on Clinical Competence (ACC/AHA committee to develop a clinical competence statement on electrocardiogram and ambulatory electrocardiogram), endorsed by the international society for Holter and noninvasive electrocardiogram. J Am Coll Cardiol. 2001;38:2091–100. 3. Kennedy HL. Use of long-term (Holter) electrocardiogram recordings. In: Zipes DP, Jalife J, editors. Cardiac electrophysiology: from cell to bedside. 3rd ed. Philadelphia: WB Saunders; 1999. p. 716–29. 4. Schert D, Dala D, Henrickson CA, et al. Prospective comparison of the diagnostic utility of a standard event monitor versus a ‘leadless’ portable electrocardiogram monitor in the evaluation of patient with palpitations. J Interv Card Electrophysiol. 2008;22:39–44. 5. Kaleschke G, Hoffman B, Drewitz J, et al. Prospective multicenter validation of a simple, patient operated electrocardiograph system for the detection of arrhythmias and electrocardiogram changes. Europace. 2009;11:1362–8.
S.K. Dora 6. Olson JA, Fouts AM, Padelinam BJ, et al. Utility of mobile outpatient telemetry for the diagnosis of palpitations, presyncope, syncope and assessment of therapy efficacy. J Cardiovasc Electrophysiol. 2007;18:473–7. 7. Rotham SA, Laughlin JC, Seltzer J, et al. The diagnosis of cardiac arrhythmias: a prospective multi-center randomized study comprising mobile cardiac outpatient telemetry versus standard loop event monitoring. J Cardiovasc Electrophysiol. 2007;18:248–9. 8. Di Marco JP, Philbrick JT. Use of ambulatory electrocardiogram (Holter) monitoring. Ann Intern Med. 1990;113:53–68. 9. Zimetbaum PJ, Kim KY, Josephson ME, et al. Diagnostic yield and optimal duration of continuous-loop event monitoring for the diagnosis of palpitations. Ann Intern Med. 1998;28:890–5. 10. Joshi AK, Kowey PF, Prystowsky EN. First experience with a Mobile Cardiac Outpatient Telemetry (MOCT) system for the diagnosis and management of cardiac arrhythmias. Am J Cardiol. 2005;95:878–81. 11. Krahn AD, Klein GJ, Yee R, et al. Randomized assessment of syncope trial: conventional diagnostic testing versus a prolonged monitoring strategy. Circulation. 2001;104:46–56. 12. Giada F, Gulizia M, Francese M, et al. Recurrent unexplained palpitations (RUP) study: comparison of implantable loop recorders versus conventional diagnostic strategy. J Am Coll Cardiol. 2007;49:1951–6. 13. Investigator TC. Preliminary report: effect of encainide and flecainide on mortality in a randomized trial on arrhythmia suppression after myocardial infarction. N Engl J Med. 1989;321:406–12. 14. Moss AJ, Zareba W, Hall J, et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Eng J Med. 2002;346:877–83. 15. Brady GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Eng J Med. 2005;352:225–37. 16. Epstein AE, Di Marco JP, Ellenbogen KA, et al. ACC/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: A report of the American College of Cardiology/American Heart Association Task Force on Practice guidelines (Writing Committee to revise the ACC/AHA/NASPE 2202 Guideline Update for Implantation of Cardiac Pacemakers and antiarrhythmic devices): developed in collaboration with the American Association for Thoracic Surgery and Society of Thoracic surgeons. Circulation. 2008;117:e350–408. 17. Stein PK. Assessing heart rate variability from real world Holter reports. Card Electrophysiol Rev. 2002;6:239–44. 18. Pepine CJ, Sharef B, Andrews TC, et al. Relation between clinical, angiographic and ischemic findings at baseline and ischemia related adverse outcomes at 1 year in the asymptomatic cardiac ischemia pilot study. J Am Coll Cardiol. 1997;29:1483–9. 19. Doval HC, Nul DR, Grancelli HO, et al., for the GESICA-GEMA Investigators. Non-sustained ventricular tachycardia in severe heart failure. Circulation. 1996;94:3198–203. 20. Cairns JA, Connolly SJ, Roberts R, et al. Randomized trial of outcome after myocardial infarction in patients with frequent or repetitive ventricular depolarization: CAMIAT. Lancet. 1997;349:675–82. 21. Buxton AE, Lee KL, Fisher JD, et al. A randomized study of the prevention of sudden death in patients with coronary artery disease. N Engl J Med. 1994;341:1882–90. 22. Kenny RA, Ingram A, Bayliss J, et al. Head up tilt: a useful test for investigating unexplained syncope. Lancet. 1986;1:1352–5. 23. Grubb BP, Karas B. Clinical disorders of autonomic nervous system associated with orthostatic intolerance: an overview of classification, clinical evaluation and management. Pacing Clin Electrophysiol. 1999;22:798. 24. The Consensus Committee on American Autonomic Society and the American Academy of Neurology. Consensus statement on the
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25. 26. 27.
28.
29.
30.
Long-Term ECG (Holter) Monitoring and Head-Up Tilt Test definition of orthostatic hypotension, pure autonomic failure and multiple system atrophy. Neurology. 1996;46:1470. Goldstein DS, Holmes C, Frank SM, et al. Sympathoadrenal imbalance before neurocardiogenic syncope. Am J Cardiol. 2003;91:53–8. Smith AA, Hallisill JR, Low PA, et al. Pathophysiological basis of orthostatic hypotension in autonomic failure. J Physiol. 1999;519:1–10. Fitzpatrick AP, Theodorakis G, Vardas P, et al. Methodology of head up tilt test testing in patients with unexplained syncope. J Am Coll Cardiol. 1991;17:125–30. Almquist A, Goldenberg IF, Milstein S, et al. Provocation of bradycardia and hypotension by isoproterenol and upright posture in patients with unexplained syncope. N Engl J Med. 1989;320:346–51. Natale A, Akhtar M, Jazayeri M, et al. Provocation of hypotension during head-up tilt testing in subjects with no history of syncope or presyncope. Circulation. 1995;92:54–8. Waxman MB, Yao L, Cameron DA, et al. Isoproterenol introduction of vasopressor type reaction in vasopressor prone persons. Am J Cardiol. 1989;63:58–65.
163 31. Morilli CA, Klein GJ, Zandri S, et al. Diagnostic accuracy of a low dose isoproterenol head-up test protocol. Am Heart J. 1995;129:901–6. 32. Raviele A, Menozzi C, Brignoli M, et al. Value of head up tilt test potentiated by sublingual nitroglycerine to assess the origin of unexplained syncope. Am J Cardiol. 1995;76:267–72. 33. Oraii S, Maleki M, Minooii M, et al. Comparing two different protocols for tilt table testing: sublingual glyceryl trinitrate versus isoprenaline infusion. Heart. 1999;81:603–5. 34. Del Rosso A, Bartoli P, Bartoletti A, et al. Shortened head up tilt testing potentiated with sublingual nitroglycerine in patients with unexplained syncope. Am Heart J. 1998;135:564–70. 35. Del Rosso A, Bartoletti A, Bartoli P, et al. Methodology of head up tilt test potentiated with sublingual nitroglycerine in unexplained syncope. Am J Cardiol. 2000;85:1007–11. 36. Benditt DG, Ermis C, Fei L. Head up tilt testing. In: Zipes DP, Jalife J, editors. Cardiac electrophysiology: from cell to bedside. 4th ed. Philadelphia: WB Saunders; 2004. p. 812–22.
Echocardiography in Arrhythmias
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Ioan Tiberiu Nanea
Abstract
Simultaneous assessment of electrical activity with anatomical and functional cardiac changes by echocardiographic examination provides criteria for the diagnosis of arrhythmias and their hemodynamic consequences. Structural echocardiography views the kinetics of the atrial and ventricular walls and the behavior of the valve apparatus during the cardiac cycle, establishing morphological and functional parameters which may identify atrial and ventricular arrhythmias. Changes of the transvalvular systolic and diastolic flow velocities or tissue velocities and concomitant analysis of the temporal relationship between atrial and ventricular activity provide criteria for positive and differential diagnosis of arrhythmias. In the same context provided by arrhythmias, echocardiography can quantify the hemodynamic parameters of the ventricular function. Interesting is the attempt to identify the origin of the ventricular ectopic beats from the left or the right ventricle. Comparison of the values of the electromechanical interval assessed at the mitral and tricuspid annulus could provide information on this. At the end of every section, we synthesized the morphological and functional echocardiographic changes useful for the diagnosis of arrhythmias. Keywords
Arrhythmias • Transvalvular Doppler flow • Tissue Doppler velocities
Diagnosis of Atrial and Ventricular Premature Beats Diagnosis of atrial and ventricular premature beats is achieved through temporal relationship between atrial contraction (identified by echocardiography) and QRS complex (by electrocardiography). Pulsed tissue Doppler echocardiography at the level of the (left) atrial wall detects atrial contraction velocity. If the tissue
I.T. Nanea, MD, PhD, FESC Department of Cardiology, Prof Dr Th. Burghele University Hospital, University of Medicine and Pharmacy Carol Davila, Bucharest, Romania e-mail:
[email protected] A.S. Kibos et al. (eds.), Cardiac Arrhythmias, DOI 10.1007/978-1-4471-5316-0_13, © Springer-Verlag London 2014
velocity of the atrial contraction precedes the QRS complex, then the premature beat is atrial or atrial with aberrancy. When atrial tissue activity is seen after the QRS complex, the diagnosis of ventricular premature beat is required (Fig. 13.1, the arrows show atrial contraction – CA) [1]. The red arrow indicates that the velocity of atrial contraction is placed after the QRS complex, suggesting the diagnosis of ventricular premature beat.
Identification of Ventricular Premature Beats Origin The prolonged QRS duration results in an intraventricular asynchronism and in an increased electromechanical interval (QRS onset – onset of systolic velocity of longitudinal fibers) 165
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Fig. 13.1 Pulsed tissue Doppler of the left atrial wall from the apical 4 chamber view [4]
during premature beats [2]. In a premature beat originating in the left ventricle (for example), the electromechanical interval will have a lower value in the left ventricle and prolonged in the right one (right ventricle is activated later, after the left ventricle). Comparison between the values of the electromechanical interval can determine premature beat’s origin. The velocity of isovolumetric contraction of the longitudinal fibers is an easier parameter to measure because it is more clearly expressed on the pulsed tissue Doppler image (Fig. 13.2a, b, red arrows). So, if the interval between the onset of QRS complex and the onset of the isovolumetric contraction velocity is inferior at the mitral annulus (80 ms; Fig. 13.2) compared to the same interval, measured at the tricuspid annulus (150 ms; Fig. 13.2b), the premature beat originates in the left ventricle. If the interval between the onset of QRS complex and the onset of the isovolumetric contraction velocity is inferior at the tricuspid annulus (80 ms; Fig. 13.3a) compared to the same interval measured at mitral annulus (120 ms; Fig. 13.3b), premature beat originates in the right ventricle (see above).
The electromechanical interval in a patient with VVI pacemaker helps to establish the origin of ventricular premature beats. The lead of the VVI pacemaker being placed in the right ventricle, the time between the onset of QRS complex, and the isovolumetric contraction of longitudinal fibers at the tricuspid annulus will be shorter than the one at the mitral annulus. This finding certifies the value of the electromechanical interval in the assessment of the origin of ventricular premature beats [3, 4]. Concluding, the values of the electromechanical interval measured at tricuspid versus mitral annulus may appreciate the place of origin of the ventricular premature beats.
Sinus Tachycardia and Supraventricular Paroxistic Tachycardia In sinus tachycardia and supraventricular paroxistic tachycardia, the changes are not specific. The diastolic filling is limited, confirmed by overlapping of early and late diastolic transvalvular mitral Doppler flow velocities (E + A, Fig. 13.4a). Also, one might observe the fusion of tissue velocities of the longitudinal fibers E′ and A′ (Fig. 13.4b).
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Fig. 13.2 (a) Pulsed tissue Doppler of lateral mitral annulus. (b) Pulsed tissue Doppler of tricuspid annulus
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Fig. 13.4 (a) Mitral inflow spectral Doppler [4]. (b) Pulsed tissue Doppler of tricuspid annulus [4]
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Junctional Rhythm On the electrocardiogram seen in Fig. 13.5a, b, the QRS complex has normal duration, with 35/min rate, and the absence of P waves is observed. This is the junctional rhythm. Atrial activity in junctional rhythm depends on the location of the pacemaker in the atrioventricular node and, at the same time, on the status of retrograde conduction system. The A wave absence suggests a junction-atrium retrograde block, medium junctional rhythm, or sinus arrest with junctional rhythm (Fig. 13.5a). White thin arrow indicates mitral regurgitation. Figure 13.5b shows the absence of right atrium wall contraction. White arrows indicate the passive movement of the wall of the right atrium produced by ventricular contraction. For the diagnosis of junctional rhythm, it is essential to identify left and right atrial contraction and its functional consequences, in connection with P wave and QRS complex.
Atrial Fibrillation Atrium kinetics has an essential role in identifying atrial rhythms. One cannot distinguish the atrium contraction in atrial fibrillation. In Fig. 13.6a the white thin arrows show passive movements of the right atrium transmitted by the ventricular contraction, in contrast to the waving movements of interatrial septum induced by atrial fibrillation (thick arrows).
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Fig. 13.5 (a) Mitral inflow spectral Doppler [4]; the white arrow suggests mitral regurgitation. (b) M mode of the right atrial wall from the subcostal view [4]
The magnitude of the tissue Doppler systolic (white arrows) and diastolic velocities (red arrows) depends on the length of the R-R intervals (Fig. 13.6b). Atrial contraction is not effective in atrial fibrillation; mitral valves are not opened in late diastole (Fig. 13.6c). Only the early diastolic opening of mitral valves (white arrows) is noticed (Fig. 13.6c). At the same time, one cannot observe the late diastolic component on mitral or tricuspid flow (Fig. 13.6d; arrows indicate the early diastolic filling). Mitral valve late diastolic opening (Fig. 13.6c; red arrow) is not given by atrial contraction; it is produced because of a prolonged diastole. Aortic flow in atrial fibrillation has different velocities induced by variable diastoles and by FrankStarling phenomenon (Fig. 13.6e). In conclusion, echocardiographic changes in atrial fibrillation have the following consequences: 1. The magnitude of mitral and aortic spectral flow velocities and of systolic and diastolic tissue velocities is variable, depending on the R-R intervals. 2. Tissue and spectral Doppler diastolic velocities induced by atrial activity are absent. 3. In atrial fibrillation the repetitive diastolic mitral or tricuspid valvular opening is not noticed (atrial mechanical activity is ineffective). 4. Right atrium wall contraction is not identified. 5. Waving movements of interatrial septum might be seen.
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Fig. 13.5 (continued)
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Fig. 13.6 (a) M mode from the subcostal view [4]. (b) Pulsed tissue Doppler of lateral mitral annulus [4]. (c) M mode of the mitral valve from the apical 4 chamber view [4]. (d) Mitral inflow spectral Doppler [4]. (e) Spectral Doppler recording aortic flow [4]
172 Fig. 13.6 (continued)
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Fig. 13.6 (continued)
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Atrial Flutter In atrial flutter atrial contractions are effective. In Fig. 13.7a, b, one can notice additional opening of tricuspid and mitral valve by each atrial contraction (white arrows). In Fig. 13.7c, the efficiency of atrial contraction is demonstrated by tissue Doppler velocity of right atrial wall of 5.1 cm/s (normal 9 ± 2.6 cm/s in sinus rhythm) (arrows). NB: The echocardiographic images are achieved during carotid sinus compression.
Hemodynamics in Atrial Flutter In Fig. 13.8a, in atrial flutter at M mode, color Doppler exam is distinguished repetitive anterograde flow in left ventricle during atrial contractions (red color) and repetitive mitral regurgitation during atrial relaxations (blue color). Another example, Fig. 13.8b, identifies the same aspects of anterograde spectral Doppler flow in left ventricle (red arrows) and retrograde flow in left atrium (blue arrows) during atrial contractions and relaxations. These hemodynamic aspects show the atrial contractions’ efficiency in atrial flutter. NB: The echocardiographic exams are achieved during carotid sinus compression in a patient with mitral regurgitation and atrial flutter.
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Fig. 13.7 (a) M mode of the tricuspid valve from the apical 4 chamber view [4]. (b) M mode of the mitral valve from the short axis view [4]. (c) Pulsed tissue Doppler of the right atrial wall from the apical 4 chamber view [4]
To conclude, the echocardiographic diagnosis in atrial flutter is based on detecting morphological and functional consequences of effective atrial contractions and on the degree of atrioventricular block: • Repetitive diastolic opening of mitral and tricuspid valves. • Repetitive mitral and tricuspid diastolic flows. • Repetitive diastolic tissue Doppler waves of the left ventricle’s longitudinal fibers. • Tissue Doppler velocities with significant amplitude of left or right atrial contractions. • In atrial flutter with 2:1 atrioventricular block with the rate of atrial flutter waves over 250/min, one notices a unique opening of atrioventricular valves, a unique diastolic flow, and also a single tissue Doppler diastolic velocity of the left ventricle longitudinal fibers.
Left Atrial Appendage Doppler Flow in Atrial Rhythms Identification Hemodynamic aspects of left atrial appendage may appreciate changes in atrial rhythm. In sinus rhythm one can identify a draining velocity (contraction) (Fig. 13.9, red arrow) of 0.48 m/s and a filling velocity of 0.68 m/s (white arrows). In atrial fibrillation or atrial flutter, draining or filling velocities of left atrial appendage are absent or reduced.
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Fig. 13.7 (continued)
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Fig. 13.9 Left atrial appendage spectral Doppler recorded during transesophageal echocardiography [4]
Sinus Arrest In Fig. 13.10a, the contraction of right atrium is not observed (green arrow indicates the place where the waves should have been) (previously the contraction of atrium wall was visible (red arrow)). Also one cannot distinguish the mitral valve opening induced by atrial contraction (Fig. 13.10b; green arrow). In Fig. 13.10c, d, A and A′ waves are not noticed using spectral and pulsed tissue Doppler (arrows). So, the echocardiographic exam in sinus arrest is characterized by the absence of anatomical and functional consequences of atrial contractions. The disappearance of inferior movement of right atrium wall, atrioventricular valves late diastolic opening, and also the absence of late diastolic spectral and tissue Doppler A and A′ waves are remarked.
The echocardiographic remark in first-degree atrioventricular block is the fusion of the transvalvular atrioventricular waves at spectral Doppler examination. However, pulsed tissue Doppler identifies the early and late diastolic velocities. These echocardiographic functional aspects described above are variable and depend on the duration of the P-R interval and therefore on the early diastole. Sometimes in first-degree atrioventricular block with very long P-R interval, diastolic mitral regurgitation can be identified. Figure 13.12 confirms the diastolic mitral regurgitation (thick white arrow) and the systolic mitral regurgitation (thin white arrow, mosaic flow) at M mode color Doppler.
Second-Degree Atrioventricular Block First-Degree Atrioventricular Block First-degree atrioventricular block significantly reduces the early diastole. In Fig. 13.11a, no individualized spectral Doppler diastolic E and A waves can be observed. However, tissue Doppler velocities E′ and A′ are distinct (Fig. 13.11b, recording in the same patient). Clear presence of tissue Doppler velocity E′ (Fig. 13.11b) certifies the early diastolic filling, although it is not distinct (E wave) at the spectral Doppler examination.
During second-degree atrioventricular Mobitz II block 2:1, the ventricle receives three diastolic flows, initially atrial filling associated with early diastolic filling A + E waves and then followed by A wave atrial contraction (Fig. 13.13a). Figure 13.13b shows diastolic tissue velocities, expression of the hemodynamic changes described above: A′ + E′ velocities induced by the atrial contraction and early diastolic filling and A′ velocity produced by the second atrial contraction.
178 Fig. 13.10 (a) M mode of the right atrial wall from the subcostal view. (b) M mode of the mitral valve from the parasternal long axis view. (c) Mitral inflow spectral Doppler. (d) Pulsed tissue Doppler of lateral mitral annulus
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Fig. 13.10 (continued)
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Fig. 13.12 M mode color Doppler of the mitral valve [4]
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Fig. 13.13 (a) Mitral inflow spectral Doppler from the apical 2 chamber view [4]. (b) Pulsed tissue Doppler of lateral mitral annulus [4]
182 Fig. 13.13 (continued)
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In conclusion, in this case, although during diastole in second-degree atrioventricular Mobitz II block, the ventricle receives three blood flows, through the atrial contraction, early diastolic filling, and second atrial contraction; spectral Doppler echocardiography identifies only two diastolic flows. The first is caused by atrial contraction fused with the early diastolic filling, and the second is produced by the next atrial contraction. Also at pulsed tissue Doppler exam, the first wave is represented by the fusion of longitudinal fibers velocity induced by atrial contraction and early diastolic tissue velocity, and the second tissue wave is determined by the next atrial contraction. NB: The high or very low rate of the atrial contractions associated with second-degree atrioventricular Mobitz II block may damage the functional aspects at echocardiography described above. In second-degree atrioventricular Mobitz II block, probably we do not correctly assess diastolic function of the ventricles.
Total Atrioventricular Block In total atrioventricular block atrioventricular dissociation is recognized by the absence of ventricular conduction of an impulse from the sinus node (when atria are controlled by the sinus rhythm). In Fig. 13.14 atrial contraction is observed (identified on ECG by the P wave indicated by the arrow) which is not followed by a transvalvular mitral diastolic flow. Atrial contraction occurs with closed mitral valves during the ventricular systole, which results in the absence of the A wave. When atrial contraction occurs in the context of opened mitral valve, the diastolic appearance is A + E wave (early + late diastolic filling) or only A wave (filling from atrial contraction). In Fig. 13.14b, one can distinguish the diastolic tissue Doppler velocities, expression of the hemodynamic alterations presented above: E′ wave, isolated A′ waves, or A′ plus E′
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Fig. 13.14 (a) Mitral inflow spectral Doppler [4]. (b) Pulsed tissue Doppler of lateral mitral annulus [4]
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Fig. 13.15 Mitral inflow spectral Doppler [4]
tissue waves. Depending on the participation of atrial contraction to ventricular filling (contractions with the atrioventricular valve opened or closed), the transaortic or pulmonary flow will have different velocities (different values of S wave velocity). Echocardiographic features in complete atrioventricular block could be summarized as follows: • Transpulmonary or transaortic Doppler spectral flow has different magnitudes, as well as tissue systolic velocities of longitudinal fibers. This is a result of the possibilities of atrial participation to ventricular filling. • Diastolic filling is also printed out by the atrial contraction (when sinus rhythm is controlling the atrial activity). Therefore during the same diastolic cycle, on spectral Doppler, one can distinguish A waves, E + A waves, or A + E waves. During the overlap of atrial with ventricular systole, no A wave is seen (ECG – echocardiography nonconcordance: P wave − A wave). Diastolic tissue Doppler velocities being the expression of the same hemodynamic alterations, A′ waves, A′ + E′ waves, and E′ + A′ waves or
absence of A′ wave are recorded in the same diastolic cycle (during atrial with ventricular systole overlap, respectively). • Presence of diastolic mitral regurgitation (see Fig. 13.15). In prolonged diastoles one can identify a regurgitant flow (framed by white arrows, Fig. 13.15) which signifies diastolic mitral regurgitation. During ventricular systole one can observe in this case systolic mitral regurgitation too (Fig. 13.15, red arrow).
Ventricular Tachycardia: Echocardiographic Aspects Right atrial contraction produces an inferior movement of its wall (Fig. 13.16, thick white arrows). The electrocardiography suggests ventricular tachyarrhythmia (thin white arrows). Combining ECG and echocardiography, we demonstrate the atrioventricular dissociation, ECG – echocardiography nonconcordance.
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Fig. 13.16 M mode of the right atrial wall from the subcostal view [4]
Conclusions
The key of the echo exam for arrhythmias’ diagnosis is atrial contraction identification and its consequences, atrioventricular and ventriculovascular flow changes, and finally systolic or diastolic spectral tissue Doppler velocities [2]. Detection of atrial activity is essential and primordial and it is done by identifying [5, 6]: • Right atrial wall contraction • Late diastolic atrioventricular transvalvular flow • Late diastolic tissue Doppler velocity • Tissue Doppler velocity of right or left atrial wall contraction One can distinguish atrial premature beats with aberrancy versus ventricular premature beats by anatomical and sometimes functional consequences of atrial contraction, which is temporally placed before QRS complexes. This is especially visualized using M mode of the right atrial wall from the subcostal view [4, 7, 8]. Atrioventricular dissociation in ventricular tachycardia or total atrioventricular block may be indicated by the anatomical and functional effects of atrial contraction too,
in connection with QRS complexes [9]. Also atrial flutter makes echocardiographic temporal relationship between atrial contraction and its consequences on the ventricular function [7]. Sinus arrest or atrial fibrillation is distinguished by the temporary or permanent absence of the activity produced by the atrial contraction. Variations of the amplitude of systolic transvalvular spectral and tissue Doppler velocities provide relations about the degree of the ventricles’ filling (when Frank-Starling’s law is operational) [10]. The degree of filling of the ventricles is variable depending on the type of arrhythmia or conduction disturbance: atrioventricular block, atrioventricular dissociation, successive atrial contractions, or prolonged diastole. Morphological and functional echocardiographic changes induced by arrhythmias or conduction disturbances may confirm an uncertain electrocardiographic diagnosis and even specify per primam the arrhythmia’s diagnosis (atrial premature beats with aberrancy, origin of ventricular premature beats, junctional rhythm, sinus arrest).
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References 1. Nanea T, Gheorghe GS, Cristea A, Ilieşiu AM, Nicolae C, Păun N. Identificarea rezervei diastolice prin studii ecocardiografice. Lucrare de Grant. Foaie de informare medicala 19. 2010. Romanian. 2. Marwick HT, et al. Myocardial imaging tissue Doppler and speckle tracking. Malden/Oxford: Wiley-Blackwell; 2007. 3. Nanea IT, Gheorghe GS, Cristea A, Ilieşiu AM, Nicolae C, Păun N. Evaluarea viabilităţii miocardice în cardiomiopatia ischemică utilizând modificările morfo-funcţionale cardiace induse de aritmiile ce realizează umplere ventriculară variabilă. Identificarea rezervei diastolice. Ed. Univ. Carol Davila Bucureşti. 2012. Romanian 4. Nanea IT. Ecocardiografia în aritmii. Diagnostic si hemodinamica. Atlas. Ed. Univ. Carol Davila Bucureşti. 2011. Romanian. 5. Sutherland GR, et al. Doppler myocardial imaging. Hasselt: BSWKbvba; 2006.
I.T. Nanea 6. Drinkovic N. Subcostal M-mode echo of the right atrial wall in the diagnosis of cardiac arrhythmias. Am J Cardiol. 1982;50:1104–8. 7. De Maria AN, et al. Hemodynamic effects of cardiac arrhythmias. Angiology. 1977;28:427–43. 8. Eder V, et al. Localization of the ventricular preexcitation site in WPW syndrome with Doppler tissue imaging. J Am Soc Echocardiogr. 2000;13:11. 9. D’Andrea A, Ducceschi V, Caso P, Galdersi M, Mercurio B, Liccardo B, et al. Usefulness of Doppler tissue imaging for the assessment of right and left ventricular myocardial function in patients with dual-chamber pacing. Int J Cardiol. 2001;81(1): 75–83. 10. McDonald IG, et al. Analysis of left ventricular wall motion by reflected ultrasound: application to assessment of myocardial function. Circulation. 1972;46:14.
Electrophysiologic Testing and Cardiac Mapping
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Mitsunori Maruyama and Teppei Yamamoto
Abstract
Electrophysiologic testing refers to a catheter procedure that involves the recording of intracardiac electrical signals and programmed electrical stimulation. Electrophysiologic testing provides clinically valuable information in the management of patients with known or suspected cardiac arrhythmias and is useful to determine the mechanisms and physiological characteristics of the cardiac arrhythmia or the future risks of cardiac adverse events. Electrophysiologic testing either may be performed for diagnostic purposes only or may be part of a combined diagnostic and therapeutic (e.g., catheter ablation) procedure. In this chapter, clinical indications, practical diagnostic procedures for various types of cardiac arrhythmia, and an overview of cardiac mapping are reviewed. Keywords
Electrophysiologic test • Mapping • Indication • Diagnosis
Electrophysiologic Testing An electrophysiologic testing (EP test or EP study) is an invasive procedure using electrode catheters for recording intracardiac electrograms and cardiac pacing. EP test is a valuable tool in the management of patients with documented or suspected cardiac arrhythmias of various etiologies.
Clinical Indications EP test allows us to induce cardiac arrhythmias in the catheter laboratory with programmed cardiac stimulation and/ or pharmacological intervention, whereby we may be able to make a diagnosis in patients with unexplained palpitations or syncope despite clinical work-ups with noninvasive tests or predict future risks of an adverse cardiac event in M. Maruyama, MD, PhD (*) • T. Yamamoto, MD Cardiovascular Center, Chiba-Hokuso Hospital, Nippon Medical School, 1715 Kamakari, 2701694 Inzai, Chiba, Japan e-mail:
[email protected] A.S. Kibos et al. (eds.), Cardiac Arrhythmias, DOI 10.1007/978-1-4471-5316-0_14, © Springer-Verlag London 2014
possible candidates for implantable device therapy. In recent years, a wide variety of cardiac tachyarrhythmias can be treated by radiofrequency catheter ablation (RFCA). EP test is essential in performing RFCA which requires a definite diagnosis of the cardiac arrhythmias. Absolute contraindications to EP test are few but include unstable angina, bacteremia, acute decompensated congestive heart failure not caused by the arrhythmia, major bleeding diathesis, and acute lower extremity venous thrombosis, if femoral vein cannulation is desired. Specific indications for EP test are as follows: Sick sinus syndrome (SSS): This is caused by sinus node dysfunction presents with sinus bradycardia, sinoatrial block, or sinus arrest which sometimes follow the cessation of supraventricular tachycardia such as atrial fibrillation/ flutter (i.e., tachycardia-bradycardia syndrome). Because treatment (principally pacemaker implantation) is necessary only for symptomatic patients, correlation of symptoms (paroxysmal dizziness, near-syncope, or syncope) with sinus node dysfunction is a critical part of patient’s management. EP test is of value in symptomatic patients in whom SSS is suspected but cannot be documented in association with symptoms. 187
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Atrioventricular block (AV block): AV block with associated symptoms (easy fatigability, dyspnea on exertion, angina, dizziness, near-syncope, or syncope) documented by ECG does not require EP test for deciding subsequent treatment. Also, ECG diagnosis of complete AV block or type II second-degree AV block with bundle branch block usually obviates the need for further invasive studies regardless of the presence of symptoms. EP test is indicated in symptomatic patients with suspected AV block but unproved or asymptomatic patients with type I second-degree AV block possibly at intra- or infra-His levels (i.e., concomitant bundle branch block, exercise-induced AV block). EP test is also recommended in a patient with type II seconddegree AV block with narrow QRS complex because pseudo-AV block is possible [1]. In addition, EP test is useful for AV block patients with indication of pacemaker implantation in case concomitant sinus node dysfunction is possible, which may affect a selection of the pacemaker mode. Narrow QRS complex tachycardia: It is a tachyarrhythmia of supraventricular origin including inappropriate sinus tachycardia, sinoatrial nodal reentry, atrial tachycardia (AT), atrial fibrillation (AF), atrial flutter (AFL), junctional ectopic tachycardia (JT), atrioventricular nodal reentrant tachycardia (AVNRT), and orthodromic atrioventricular reciprocating tachycardia (AVRT). Clinical and electrocardiographic features help the differential diagnosis for sinus tachycardia, AF, and AFL, but EP test is often necessary to distinguish AT, AVNRT, and orthodromic AVRT which are the most common causes of narrow QRS complex tachycardia with a regular rhythm. Since RFCA has become an established procedure to cure most types of narrow QRS complex tachycardia, diagnostic EP test with consideration of RFCA therapy is indicated in a patient who has drug-resistant tachycardias or does not prefer long-term drug therapy. Wide QRS complex tachycardia: This includes ventricular tachycardia (VT), supraventricular tachycardia with aberrant conduction or bystander preexcitation, and antidromic AVRT. Accurate diagnosis is essential for the management of patients with wide QRS complex tachycardia. Thus diagnostic EP test is indicated if definite diagnosis cannot be made from surface ECG, or RFCA therapy is considered. Further, EP test is of use in guiding drug therapy for VT in patients with a structural heart disease by assessing the inducibility of VT. Wolff-Parkinson-White syndrome (WPW syndrome): This is characterized by a short PR interval and the delta wave on surface ECG caused by ventricular preexcitation with accessory AV bypass tracts. AVRT and AF are common in patients with WPW syndrome, and rarely, rapid ventricu-
M. Maruyama and T. Yamamoto
lar responses during AF can lead to ventricular fibrillation (VF) and sudden cardiac death. Therefore, EP test is indicated if a patient with preexcitation has associated symptoms (palpitation, chest pain, dyspnea, pre-syncope, syncope, or cardiac arrest) and RFCA therapy is considered. Unexplained syncope: EP test is indicated in patients with unexplained syncope in whom initial evaluation suggests an arrhythmic cause of syncope. These patients include those with ECG abnormalities, structural heart disease, and syncope associated with palpitation. Evaluation of future risks of cardiac adverse events: EP test is useful in predicting a future risk of sudden cardiac death and helps to determine a treatment strategy in patients with coronary artery disease with a reduced left ventricular function (ejection fraction less than 30–35 %) by evaluating VT/VF inducibility [2]. Other groups of patients who are considered a high risk of sudden cardiac death (e.g., nonischemic cardiomyopathy, Brugada syndrome) may benefit from EP test in the management of the patients, although the value of EP test for risk stratification in these patient populations remains to be established [2].
Requirement for EP Test To perform EP test, the necessary equipment is single- or biplane cineangiographic fluoroscopy, EP recording system, and cardiac stimulator. ECG polygraph that is not specially made for EP test can be utilized for recording, but it is desirable to use a recording system dedicated to EP test that has more ECG channels and better ECG processing capability. The current EP workstation (e.g., EP WorkMate System, EP MedSystems Inc., BARD LabSystem PRO, Bard Inc.) integrates EP recording system, programmed cardiac stimulator, fluoroscopic and electroanatomical imaging parameters, hemodynamic monitor, and RF ablation system, which is quite useful in EP test especially when RFCA is also carried out. A medical doctor engaged in EP test should have expertise including the ability to safely perform the catheterization procedure for intracardiac recording and stimulation, thorough understanding of the basic and clinical electrophysiology, and knowledge of pharmacologic effects of medication used during EP test. We think the minimal staff requirement is one EP doctor, one to two medical equipment technicians, and one registered nurse for EP test and one to two EP doctors and two to three medical equipment technicians and one registered nurse for RFCA procedure. During EP test, a functioning cardioverter-defibrillator must be available at the patient’s side because intentional or inadvertent induction of a lifethreatening arrhythmia can occur.
14 Electrophysiologic Testing and Cardiac Mapping
Patient Preparation for EP Test Preoperative evaluation is important to lower the complication rate of EP test. Induction of sustained tachyarrhythmias or catheter placement in a certain approach may be at high risk of complication in patients with left main or severe three-vessel coronary artery disease, decompensated heart failure, severe hypertrophic cardiomyopathy, critical aortic stenosis, aortic aneurysm or dissection, or intracardiac thrombus. Antiarrhythmic drugs should be stopped for at least five half-lives prior to EP test unless evaluating the effect or side effect of antiarrhythmic drugs is the purpose of the study. Because EP test is an invasive procedure, a patient must be informed about the value of the EP test, its risks, and expected outcomes. Automated cuff blood pressure devices are useful in hemodynamic monitoring during EP test, but invasive blood pressure monitoring is preferred in unstable patients or when transseptal access to the left atrium is planned. In general, intravenous conscious sedation (e.g., midazolam, propofol, dexmedetomidine) is used especially for longer procedures. Conscious sedation is usually achieved safely without anesthesiologists. The use of oxygen saturation monitor, respiratory monitoring with such as capnography, and bispectral analysis of brain electrical activity (BIS monitor) will help to maintain an adequate sedation. Sedation should not be given when symptoms need to be confirmed during EP test or arrhythmias of interest seem to be attributable to automatic or triggered activity mechanism that can be suppressed with sedation. Foley catheter should be inserted into the bladder particularly when a patient is sedated in order to avoid urinary retention and monitor urination.
Placement of Electrode Catheters Electrode catheters are used during EP test for recording and pacing. These days, a variety of electrode catheters in different sizes (2–8 Fr), curves, numbers of electrode, interelectrode distances are available. Electrode catheters have a fixed or deflectable tip. Since electrode catheters are much stiffer than catheters used in other cardiac catheterization, procedures and most types of electrode catheters do not have an inside lumen, which makes it impossible to advance the catheter in the vessels along with a guidewire; caution should be exercised in manipulating the catheter to avoid injury of the heart and vessels. If an operator feels some resistance during the advancement of the catheter, pull and re-advancement at a different angle should be tried rather than applying an additional force. Typically, the placement of the electrode catheters at the right atrium (RA), His bundle (HB) region, and right ventricle (RV) are introduced via the femoral vein. The coronary sinus (CS) is more easily reached through the right internal jugular or subclavian vein, although the femoral
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approach is also possible in most cases. The left ventricle (LV) or mitral annulus can be accessed by retrograde aortic approach with the catheter introduced via the femoral artery. When mapping of the left atrium (LA) is required, the catheter is introduced via the femoral vein, and then reached to the LA by transseptal approach through a patent foramen ovale or interatrial septal puncture with the Brockenbrough technique.
Programmed Cardiac Stimulation Cardiac stimulation is carried out by delivering a pulse of electrical current through the electrode catheter from an external cardiac stimulator. The cardiac stimulator has a constant current source and delivers pacing at a wide range of cycle lengths (CLs) and variable current strengths and pulse widths. A typical stimulator is capable of pacing in predetermined patterns at precise timed intervals, which is called a programmed stimulation. The stimulation is usually performed with an output at twice diastolic pacing threshold. Burst pacing is pacing at a constant CL for a certain duration. After burst pacing at a given CL, the CL is shortened in a series of steps (stepwise incremental burst pacing). Extrastimulus technique consists of basic constant pacing (S1) at a specified duration (typically 600, 500, and 400 ms for 6–8 beats), followed by a premature extrastimulus (S2, S3,…, Sn) at progressively shortened coupling intervals in 10–20 ms steps. For a single extrastimulus, the S1–S2 coupling interval is shortened from the basic CL until it fails to capture. The effective refractory period (ERP) is defined as the longest S1–S2 coupling interval that results in the pacing failure. When more extrastimuli (S3,…, Sn) are introduced, the common pacing method is that the S2–S3 (Sn–Sn + 1) interval is progressively shortened while the S1–S2 (Sn–1– Sn) interval 10–20 ms longer than the S2 (Sn) ERP is held constant.
Clinical Practice in EP Test SSS: To evaluate the sinus node function, electrode catheter is positioned in the high RA at a site near the sinus node. Another electrode catheter is usually placed in the HB region to also assess the function of AV conduction. Since correlation of symptoms with ECG evidence of sinus node dysfunction is important to decide subsequent treatment, a patient should not be sedated. The advantage of EP test for SSS is that we can examine the sinus node function in several methods, a role of autonomic nervous function in SSS, and confirm symptoms during induced sinus arrest in the EP laboratory. Normal automaticity in the sinus node is characterized by spontaneous diastolic depolarization that can be
190 Fig. 14.1 Evaluation of sinus node function. A transient suppression of sinus node automaticity was induced by overdrive atrial pacing (cycle length 330 ms for 30 s). The maximal prolongation of the sinus cycle length (sinus node recovery time (SNRT)) was seen following the first beat after cessation of the pacing (secondary pause). Near-syncope was accompanied during this pause period, which revealed the cause of syncope in this case
M. Maruyama and T. Yamamoto
SNRT 5.03 s
1s
suppressed by overdrive pacing, followed by a gradual recovery to the baseline sinus CL. Therefore, the sinus node recovery time (SNRT) after cessation of overdrive pacing at the high RA at various heart rates (90–200 bpm, 10–20 bpm step) for 30–60 s reflects the automatic function of the sinus node (Fig. 14.1). SNRT is defined as the longest pause from the last paced beat to the first sinus return beat. Normally, the initial pause immediately after cessation of pacing is the longest and the sinus CL is gradually shortened thereafter. However, the second beat after the last paced beat occasionally shows an unexpected lengthening of the sinus CL, resulting in the longer pause than the first pause (i.e., secondary pause). In that case, the secondary pause should be taken for the measurement of SNRT. Since the baseline sinus CL influences SNRT, corrected SNRT can be calculated by subtracting the baseline sinus CL from SNRT. Normal values of SNRT and corrected SNRT are less than 1,500 ms and 500 ms, respectively. If the SNRT or corrected SNRT does not exceed the normal value, a longer duration (90–120 s) of overdrive pacing at the CL at which the longest SNRT is obtained should also be tested. Complete autonomic blockade with propranolol (0.2 mg/kg) and atropine (0.04 mg/kg) provides the intrinsic heart rate that is the sinus rate independent of autonomic influence. The normal intrinsic heart rate is age-dependent and can be predicted using the following equation: 118 − (0.57 × age); normal values are ±14 % for age ≤45 years and ±18 % for age > 45 years. Autonomic blockade not only reveals that SSS is associated with intrinsic or extrinsic (i.e., abnormal autonomic regulation) problem in the sinus node, but may also make SNRT lengthen in case compensatory autonomic action or sinus entrance block obscures the true SNRT at baseline. The measurement of sinoatrial conduction time is also somewhat helpful, which can be indirectly obtained by Strauss and Narula methods or by direct recording of the sinus node electrogram [3]. AV block: Three electrode catheters are placed at the RA, HB region, and RV apex in the standard EP test for the assessment of the AV and VA conduction, although the RV catheter can be spared by placing the RA catheter into the RV when ventricular pacing is needed. The HB region is
located at the junction of the RA and RV; therefore, a local electrogram in this region displays activation of the adjacent atrial, HB, and ventricular tissues. It is important to record the most proximal HB potential in order to properly measure the AH and HV intervals and not to overlook intra-Hisian block (split HB electrograms). At baseline, the normal range of the AH and HV intervals are 50–120 ms and 35–55 ms, respectively. The HV interval >100 ms is associated with a high incidence of progression to complete AV block, suggesting a clinical indication of permanent pacing. When AV block greater than second degree is observed spontaneously or during atrial constant pacing, localization of the site of AV block provides information for subsequent decision-making (Fig. 14.2). The site of AV block at intra- or infra-His levels (H–H′ or H–V block) indicates a high risk for complete AV block and the need for a permanent pacemaker unless it occurs during atrial pacing at a very short CL (<350 ms) or a sudden increase in atrial pacing rate. A rapid ventricular pacing for a long duration may transiently exacerbate the AV conduction thereby inducing a higher degree of AV block in patients with abnormal AV conduction below the AV node level (i.e., fatigue phenomenon). Rarely, pseudo-AV block can occur by concealed AV junctional or ventricular extrasystole, which can be revealed by EP test [1]. Narrow QRS complex tachycardia: Four electrode catheters placed at the high RA (or RA appendage), HB region, CS, and RV apex/base are generally used to diagnose the mechanism of narrow QRS complex tachycardia. Because the CS lies along the mitral annulus, a multielectrode catheter in the CS records both LA and LV electrograms, although the amplitude and sharpness of each CS electrogram depend on the anatomical relationship of the CS to the LA and LV. The most proximal CS electrode is usually positioned at the CS ostium for the diagnostic EP study. The tachycardia of interest can usually be induced in the EP laboratory by programmed cardiac stimulation and/or isoproterenol infusion. The diagnosis of AF/AFL is readily made by their characteristic features in electrical activities. AF demonstrates rapid (100–200 ms) and irregular atrial electrograms with beat-to-beat variability in morphology, amplitude, and
14 Electrophysiologic Testing and Cardiac Mapping Fig. 14.2 The site of AV block. Examples of surface ECG and intracardiac recordings during complete AV block at a supra-His level (a) and infra-His level (b)
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atrial activation sequence. AFL has rapid (190–250 ms, or slower on medication with antiarrhythmic agents) and regular atrial activation which is usually accompanied by 2:1 or variable AV conduction. Narrow QRS complex tachycardia with a 1:1 AV relationship needs some maneuvers for the differential diagnosis. A wide variety of diagnostic techniques have been reported for narrow QRS complex tachycardia, but an individual technique rarely provides a diagnosis, and multiple maneuvers are often required to reach the correct diagnosis [4]. Nevertheless, recent efforts to develop more accurate technique have much improved the diagnostic process of narrow QRS complex tachycardia in the EP laboratory, which help us to make a definite diagnosis. Figure 14.3 shows an algorithm for the diagnosis of the mechanism of narrow QRS complex tachycardia incorporating the newer methods that have been reported to be diagnostic. If the pattern of atrial activation is eccentric (i.e., the earliest activation site (EAS) does not reside near the Koch’s triangle) during ventricular pacing and the atrial activation pattern during tachycardia is the same as that during ventricular pacing, orthodromic AVRT is diagnosed. Overdrive ventricular pacing during tachycardia at a CL 10–40 ms shorter than tachycardia CL (TCL) gives us much information for diagnosis. Regarding the pacing site, RV base is a better site for differential diagnosis than RV apex [5], although care must be taken for inadvertent atrial or His-right bundle branch capture that makes the
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technique invalid [6]. If the atrial CL is accelerated to the pacing CL, the following parameters can be assessed. (1) The activation sequence following the cessation of ventricular pacing. The atrial-atrial-ventricular (A-A-V) activation sequence from the last captured atrial electrogram is diagnostic for AT. (When the His electrogram is clearly recorded, A-A-His sequence is more accurate particularly when HV interval is long [7].) (2) The presence of constant QRS fusion during ventricular pacing is diagnostic for orthodromic AVRT. (3) Perturbation (advanced or delayed) of atrial timing or tachycardia termination during a transitional QRS fusion period after initiation of ventricular pacing is diagnostic for orthodromic AVRT because atrium cannot be affected without the presence of accessory pathways [8]. (4) SA-VA interval is measured as a difference between the interval from the last stimulus to the earliest atrial electrogram (SA) and ventriculoatrial conduction time (VA). PPI-TCL is measured as a difference between the post-pacing interval (PPI) and TCL. PPI-TCL is corrected by subtraction of AV nodal conduction delay (a difference of AH interval immediately before and after pacing) from PPI-TCL (corrected PPI-TCL). Orthodromic AVRT shows SA-VA < 85 ms and corrected PPITCL < 110 ms, while AVNRT shows SA-VA ≥ 85 ms and corrected PPI-TCL ≥ 110 ms. [5, 9] If discrepant results are seen between SA-VA and corrected PPI-TCL, other additional techniques including para-Hisian entrainment [10],
192 Fig. 14.3 Diagnostic algorithm of narrow QRS complex tachycardia in the EP laboratory. See text for details. *“Eccentric” is defined here as EAS far enough from the AVN region, excluding variants of retrograde AVN conduction. **Inadvertent atrial or His-RBB capture must be ruled out. ***Discordant result between SA-VA and corrected PPI-TCL needs further examination (see text)
M. Maruyama and T. Yamamoto Atrial activation pattern during ventricular pacing and tachycardia
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delta HA values during entrainment and tachycardia, [11, 12] and positional differences in SA-VA [13] and corrected PPITCL [14] are useful for correct diagnosis. If the atrial CL cannot be accelerated to the pacing CL during overdrive ventricular pacing, overdrive pacing from multiple atrial sites (typically high RA, proximal and/or distal CS) during tachycardia discriminates AT from AVNRT as the tachycardia mechanism. If the difference in the post-pacing VA intervals (interval from the last entrained ventricular electrogram to the earliest atrial electrogram) among different atrial pacing sites is ≥15 ms, AT is diagnosed, whereas the delta VA is < 15 ms in patients with AVNRT [15]. The limitation of this algorithm is that most maneuvers necessitate a tachycardia to be sustained, and some interval criteria may not be useful when a variation in TCL is very large. If non-sustained tachycardia is induced by ventricular extrastimuli, the A-A-V(His) criterion can be used during the induction of the tachycardia to make the diagnosis of AT. Also, SA-VA and corrected PPI-TCI criteria is applicable during the tachycardia induction with ventricular extrastimuli to distinguish AVNRT from orthodromic AVRT [16]. Wide QRS complex tachycardia: Three electrode catheters positioned at the high RA, HB region, and RV apex are commonly used for the diagnosis of wide QRS complex tachycardia. Once the tachycardia of interest is induced by cardiac programmed stimulation with or without isoproterenol infusion, the ventricular rate faster than the atrial rate generally implies VT as the tachycardia’s mechanism, although a rare case of JT or AVNRT with aberrant conduction and VA block in the upper common pathway is possible. Ventricular entrainment by atrial overdrive pacing during tachycardia is useful to determine the mechanism of wide QRS complex tachycardia, especially when the AV relationship is 1:1 (Fig. 14.4). If narrowing or changing of the QRS morphology is observed during entrainment, VT
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is diagnosed. If no changes in the QRS morphology is seen during entrainment, supraventricular tachycardia with aberrant conduction is likely, but bundle branch reentrant VT (BBR-VT) [17] and antidromic AVRT need to be distinguished. If the activation sequence after termination of pacing is ventricular-ventricular-atrial (V-V-A) from the last captured ventricular electrogram, BBR-VT is the responsible mechanism. [17, 18] If preexcitation is exhibited during atrial burst pacing, or the tachycardia is reset with a latecoupled atrial extrastimulus when the AV junctional atrium is refractory, the diagnosis of antidromic AVRT is made. In case atrial overdrive pacing cannot accelerate the ventricular CL to the pacing CL, entrainment pacing from the RV apex is helpful. If PPI-TCL is less than 30 ms, BBR-VT is likely [19]. The PPI-TCL >30 ms indicates VT as the tachycardia mechanism; however, JT or AVNRT with aberrant conduction should also be considered if the PPI-TCL is long (>100 ms) [19]. Unexplained syncope: As noted above, sinus node function and AV conduction can be assessed to determine if SSS and AV block are responsible for the unexplained syncope, respectively. If rapid supraventricular tachycardia or sustained monomorphic VT is induced by programmed cardiac stimulation with or without isoproterenol infusion, cardiac origin of syncope is very likely and RFCA or implantable cardioverter-defibrillator (ICD) may be indicated. Induction of polymorphic VT or VF is less diagnostic, and subsequent treatment should be considered according to underlying heart disease, type of symptom, familial history of sudden cardiac death, pacing protocol by which the polymorphic VT/VF is induced, and patient’s preference. If a bundle branch block is present despite negative results on EP test, trial of a class I antiarrhythmic agent may induce an infranodal AV block which is the possible mechanism of the unexplained syncope [1].
14 Electrophysiologic Testing and Cardiac Mapping Fig. 14.4 Diagnostic algorithm of wide QRS complex tachycardia in the EP laboratory. See text for details. *If PPI-TCL > 100 ms, a rare case of JT or ANVRT with aberrancy needs to be excluded
193 Atrial overdrive pacing during tachycardia
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Cardiac Mapping Cardiac mapping refers to the procedure of clarifying the temporal and spatial distribution of myocardial activation during a certain heart rhythm. Cardiac mapping during tachyarrhythmia seeks its mechanism, the site of origin, or a critical site of the tachycardia circuit which serve as a target for RFCA therapy. In recent years, various mapping techniques have evolved, which allow us to determine the arrhythmia mechanisms in detail and to treat a broad spectrum of cardiac arrhythmias including more complex arrhythmias.
Activation Mapping Roving catheter technique: The simplest method of mapping is achieved by moving the mapping catheter sequentially to sample multiple points of electrogram to measure the local activation. To determine the local activation, the maximum negative slope of unipolar electrogram coincides best with the arrival of the activation wavefront directly beneath the mapping electrode. However, unipolar recordings have substantial far-field signals and poor signal-tonoise ratio, which can make it difficult to separate a local activity from a distant activity. For that reason, bipolar recordings are commonly used for activation mapping, although unipolar recordings provide additional information about the direction of the activation wavefront. (Positive
PPI-TCL < 30 ms
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possible BBR-VT
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deflection (R waves) and negative deflection (QS pattern) imply an activation wavefront toward and away from the recording electrode, respectively. The latter help to recognize a mapping catheter at near the site of the activation origin.) The initial peak of a filtered (typically 30–40 to 400–500 Hz) bipolar electrogram generally coincides with local activation beneath the recording electrode pair despite an inherent limitation in determination of local activation in the case of complex multicomponent bipolar electrograms. With the roving catheter technique, the local activation time can be defined, relative to the consistent fiducial time marker such as the onset of the P wave or QRS complex on surface ECG or reference intracardiac electrogram. For mapping a tachycardia of the focal mechanism, the earliest presystolic activity preceding the onset of the P waves during AT or the QRS complex during VT by an average of 10–40 ms indicates that the mapping catheter is near the site of the tachycardia origin. For a macro-reentrant tachycardia, it is important to identify the critical isthmus of the reentrant circuit, as indicated by finding the site with a continuous activity spanning the diastole or with an isolated mid-diastolic activity. Multisite recording technique: Disadvantage of the roving catheter technique is time-consuming and a tachycardia of interest must be stable and sustained long enough to obtain the whole picture of intracardiac activation during the tachycardia. Currently, a wide variety of specially designed multipolar electrode catheters are available to map the specific regions in the heart (e.g., Halo catheter, Lasso catheter,
194 Fig. 14.5 Cardiac mapping of the left atrium during atrial tachycardia using the Ensite noncontact mapping system. Multielectrode array catheter is positioned near the site of origin through a transseptal approach. A centrifugal activation pattern suggests a focal mechanism of the tachycardia. Inset shows a virtual unipolar electrogram at the site of origin with a QS morphology pattern. LAA left atrial appendage, LSPV left superior pulmonary vein, RSPV right superior pulmonary vein, CS coronary sinus
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basket catheter). Recording intracardiac electrograms simultaneously from as many sites as possible using these multielectrode catheters greatly enhances the mapping process. Even if the recording electrodes do not cover the site of the tachycardia origin, multisite recording helps to determine which cardiac chamber should be mapped in detail (e.g., RA versus LA). Electroanatomical mapping system: Newer mapping systems have revolutionized the clinical electrophysiology to overcome the limitation of conventional mapping, which allow for reconstruction of high-resolution, threedimensional cardiac chambers and color-coded display of cardiac activation on their constructed geometry of the chamber. The CARTO mapping system (Biosense Webster, Diamond Bar, CA) uses magnetic technology to determine the location and orientation of a mapping catheter with a magnetic sensor while simultaneously recording local electrograms from the same catheter. The EnSiteNavX system (St. Jude Medical, Austin, TX) collects anatomical data using a conventional electrode catheter by LocaLisa technology which utilizes externally applied electrical currents from three pairs of skin patches with slightly different
frequencies. The EnSite noncontact mapping system can acquire more than 3,000 virtual unipolar electrograms calculated from the field voltage using a catheter-mounted multielectrode array. This system can identify the site of origin or a pattern of wavefront propagation accurately even from one beat (Fig. 14.5) as long as the array catheter is positioned near the endocardial area of interest (<4 cm). These sophisticated mapping systems can visualize cardiac activation during cardiac arrhythmias, which offer insights into the arrhythmia mechanism (focal or macro-reentry (Fig. 14.6), and provide information about RFCA target. The visualized pattern of activation may also contribute to the diagnosis of tachycardia (e.g., AT originating from near the sinus node can be distinguished from inappropriate sinus tachycardia by comparing the activation of AT with that during sinus rhythm), although the correct diagnosis is usually made by several electrophysiological maneuvers mentioned above, not by the newer mapping technologies (e.g., a focal activation arising from near the Koch’s triangle or AV annulus requires appropriate diagnostic procedures to distinguish AT from AVNRT or orthodromic AVRT).
14 Electrophysiologic Testing and Cardiac Mapping
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Fig. 14.6 Cardiac mapping of the left ventricle during ventricular tachycardia in a patient with prior inferior myocardial infarction using the CARTO electroanatomical mapping system. Activation mapping reveals macro-reentry revolving around the sites with double potentials (blue tags). A linear RFCA lesion bridging between the mitral annulus (MA) and double potential sites terminated the tachycardia
Pace Mapping Pace mapping is performed by pacing during sinus rhythm at different endocardial sites to reproduce the ECG morphology of a tachycardia of interest. The principle of pace mapping is that pacing from the site of origin for a focal tachycardia at a pacing CL similar to the TCL will result in the same activation sequence during the tachycardia. Because it is challenging to precisely characterize the P wave morphology, pace mapping is generally used to locate a ventricular source of cardiac arrhythmias (i.e., ventricular premature beats or VT). In macro-reentrant VT, pace mapping at the exit site is expected to produce a QRS configuration similar to that of VT. Pace mapping at sites more proximally located in the critical isthmus of the reentrant circuit may also produce a similar QRS complex, but in that case, an interval from the stimulus to the QRS onset is long. Pace maps with identical or near-identical matches of the QRS morphology in all 12 surface ECG leads indicate that the pacing site is located near the site of the tachycardia origin. Comparison of the QRS morphology between VT and paced beats is subjective, but recently, a quantitative analysis
of averaged correlation coefficient in 12 lead ECGs has become commercially available, which enhances the utility of pace mapping.
Entrainment Mapping Overdrive pacing during a tachycardia at a pacing CL shorter than the TCL (typically by 10–40 ms) can reset the tachycardia continuously as long as the pacing stimuli do not terminate the tachycardia. When the tachycardia mechanism is reentry, this continuous resetting of the tachycardia is termed entrainment which is demonstrated by acceleration of all electrograms responsible for maintaining the tachycardia to the pacing CL, with the resumption of the same tachycardia after cessation of pacing. During entrainment, each pacing impulse creates two activation wavefronts, one in the orthodromic direction (the same direction as the spontaneous tachycardia wavefront) and the other in the antidromic direction (the different direction from the spontaneous tachycardia wavefront). The orthodromic wavefront is conducted through the critical part of the reentrant circuit and emerges through
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the exit site, and then collides with the antidromic wavefront from the next paced stimulus. The antidromic wavefront produces a different activation from that of the spontaneous tachycardia, resulting in fusion which exhibits a mixed ECG morphology during tachycardia and pacing. Fusion can be observed on surface ECG, intracardiac electrograms, or both. If the degree of fusion is constant (constant fusion) or alters as the constant pacing CL is shortened (progressive fusion), the mechanism can be defined as macro-reentry because these phenomena are not possible in the focal mechanism (automaticity, triggered activity, or micro-reentry) [20]. If the pacing site is in the protected region (e.g., surviving myocardium within the scar region), the antidromic wavefront activates only a small portion of myocardium, whereby fusion does not become manifest (concealed fusion). The concealed fusion will help to identify the protected isthmus that is a potential target for RFCA. The PPI is the time interval from the last pacing stimulus that entrained the tachycardia to the first electrogram of the tachycardia recorded at the pacing site. The PPI consists of the intervals during which the orthodromic wavefront travels from the pacing site to the reentrant circuit and returns to the pacing site following the same path as the circulating reentrant wavefront. Therefore, the PPI at a site within the reentrant circuit should be equal to the TCL if conduction velocities and the reentrant path did not change during pacing. In a clinical practice, the pacing site is considered within the reentrant circuit if the PPI-TCL is ≤30 ms. This technique is useful in finding the critical isthmus of the reentrant circuit especially in case the activation mapping shows multiple circulating activities, in which entrainment mapping helps to determine which circulating activity is critical. Unlike macro-reentrant tachycardia, there is a limitation in application of PPI measurements to mapping a focal tachycardia. According to the mechanism of the focal tachycardia, overdrive pacing can result in suppression (automatic) or acceleration (triggered activity) of the tachycardia, leading to unstable return cycles after cessation of pacing. Nevertheless, overdrive pacing during a focal tachycardia may be helpful to estimate how far the pacing site is from the site of origin if the postpacing return cycle is reproducible and there is an abnormal conduction in the mapped chamber. If the conduction time of the focal tachycardia exceeds the TCL, a site with delayed activation can be mistakenly considered as an early site in the activation map [21]. The PPI measurements may be able to exclude such a pseudo-early activation.
References 1. Barold SS, Hayes DL. Second-degree atrioventricular block: a reappraisal. Mayo Clin Proc. 2001;76:44–57. 2. Thomas KE, Josephson ME. The role of electrophysiology study in risk stratification of sudden cardiac death. Prog Cardiovasc Dis. 2008;51:97–105.
M. Maruyama and T. Yamamoto 3. Josephson ME. Clinical cardiac electrophysiology: techniques and interpretation. Philadelphia: Lea & Febiger; 1993. 4. Knight BP, Ebinger M, Oral H, Kim MH, Sticherling C, Pelosi F, Michaud GF, Strickberger SA, Morady F. Diagnostic value of tachycardia features and pacing maneuvers during paroxysmal supraventricular tachycardia. J Am Coll Cardiol. 2000;36:574–82. 5. Veenhuyzen GD, Coverett K, Quinn FR, Sapp JL, Gillis AM, Sheldon R, Exner DV, Mitchell LB. Single diagnostic pacing maneuver for supraventricular tachycardia. Heart Rhythm. 2008;5:1152–8. 6. Perez-Rodon J, Bazan V, Bruguera-Cortada J, Mojal-Garcia S, Manresa-Dominguez JM, Marti-Almor J. Entrainment from the para-hisian region for differentiating atrioventricular node reentrant tachycardia from orthodromic atrioventricular reentrant tachycardia. Europace. 2008;10:1205–11. 7. Vijayaraman P, Lee BP, Kalahasty G, Wood MA, Ellenbogen KA. Reanalysis of the “pseudo A-A-V” response to ventricular entrainment of supraventricular tachycardia: importance of his-bundle timing. J Cardiovasc Electrophysiol. 2006;17:25–8. 8. AlMahameed ST, Buxton AE, Michaud GF. New criteria during right ventricular pacing to determine the mechanism of supraventricular tachycardia. Circ Arrhythm Electrophysiol. 2010;3:578–84. 9. Michaud GF, Tada H, Chough S, Baker R, Wasmer K, Sticherling C, Oral H, Pelosi Jr F, Knight BP, Strickberger SA, Morady F. Differentiation of atypical atrioventricular node re-entrant tachycardia from orthodromic reciprocating tachycardia using a septal accessory pathway by the response to ventricular pacing. J Am Coll Cardiol. 2001;38:1163–7. 10. Reddy VY, Jongnarangsin K, Albert CM, Sabbour H, Keane D, Mela T, McGovern B, Ruskin JN. Para-hisian entrainment: a novel pacing maneuver to differentiate orthodromic atrioventricular reentrant tachycardia from atrioventricular nodal reentrant tachycardia. J Cardiovasc Electrophysiol. 2003;14:1321–8. 11. Ho RT, Mark GE, Rhim ES, Pavri BB, Greenspon AJ. Differentiating atrioventricular nodal reentrant tachycardia from atrioventricular reentrant tachycardia by delta HA values during entrainment from the ventricle. Heart Rhythm. 2008;5:83–8. 12. Rhim ES, Hillis MB, Mark GE, Ho RT. The delta HA value during entrainment of a long RP tachycardia: another useful criterion for diagnosis of supraventricular tachycardia. J Cardiovasc Electrophysiol. 2008;19:559–61. 13. Khan AH, Khadem A, Basta MN, Gardner MJ, Parkash R, Gula LJ, Sapp JL. Differential entrainment distinguishes atrioventricular nodal reentry tachycardia from atrioventricular reentrant tachycardia. Pacing Clin Electrophysiol. 2010;33:1335–41. 14. Segal OR, Gula LJ, Skanes AC, Krahn AD, Yee R, Klein GJ. Differential ventricular entrainment: a maneuver to differentiate AV node reentrant tachycardia from orthodromic reciprocating tachycardia. Heart Rhythm. 2009;6:493–500. 15. Maruyama M, Kobayashi Y, Miyauchi Y, Ino T, Atarashi H, Katoh T, Mizuno K. The VA relationship after differential atrial overdrive pacing: a novel tool for the diagnosis of atrial tachycardia in the electrophysiologic laboratory. J Cardiovasc Electrophysiol. 2007;18:1127–33. 16. Obeyesekere M, Gula LJ, Modi S, Leong-Sit P, Angaran P, Mechulan A, Skanes AC, Krahn AD, Yee R, Klein GJ. Tachycardia induction with ventricular extrastimuli differentiates atypical atrioventricular nodal reentrant tachycardia from orthodromic reciprocating tachycardia. Heart Rhythm. 2012;9(3):335–41. 17. Merino JL, Peinado R, Fernandez-Lozano I, Sobrino N, Sobrino JA. Transient entrainment of bundle-branch reentry by atrial and ventricular stimulation: elucidation of the tachycardia mechanism through analysis of the surface ECG. Circulation. 1999;100:1784–90. 18. Abdelwahab A, Gardner MJ, Basta MN, Parkash R, Khan A, Sapp JL. A technique for the rapid diagnosis of wide complex tachycar-
14 Electrophysiologic Testing and Cardiac Mapping dia with 1:1 AV relationship in the electrophysiology laboratory. Pacing Clin Electrophysiol. 2009;32:475–83. 19. Merino JL, Peinado R, Fernandez-Lozano I, Lopez-Gil M, Arribas F, Ramirez LJ, Echeverria IJ, Sobrino JA. Bundle-branch reentry and the postpacing interval after entrainment by right ventricular apex stimulation: a new approach to elucidate the mechanism of wide-QRS-complex tachycardia with atrioventricular dissociation. Circulation. 2001;103:1102–8.
197 20. Okumura K, Henthorn RW, Epstein AE, Plumb VJ, Waldo AL. Further observations on transient entrainment: importance of pacing site and properties of the components of the reentry circuit. Circulation. 1985;72:1293–307. 21. Ikeguchi S, Peters NS. Novel use of postpacing interval mapping to guide radiofrequency ablation of focal atrial tachycardia with long intra-atrial conduction time. Heart Rhythm. 2004;1:88–93.
How to Differentiate Between AVRT, AT, AVNRT, and Junctional Tachycardia Using the Baseline ECG and Intracardiac Tracings
15
Sharon Shen and Bradley P. Knight
Abstract
Paroxysmal supraventricular tachycardia is a term that refers to a subset of supraventricular tachycardias characterized by sudden abrupt onset and termination. This group consists of atrioventricular nodal reentry tachycardia, atrioventricular reciprocating tachycardia, atrial tachycardia, and junctional ectopic tachycardia. This chapter will focus on the differentiation of these four tachycardias using electrocardiographic features and intracardiac tracings. Ultimately, the diagnosis of the tachycardia mechanism relies upon three key elements: (1) baseline observations during sinus rhythm, (2) tachycardia features, and (3) the tachycardia response to atrial and ventricular pacing maneuvers. Keywords
Supraventricular tachycardia • Differential diagnosis • Pacing maneuvers
Introduction Supraventricular tachycardias (SVT) can be categorized into two groups: tachycardias that originate in the atrium and tachycardias that depend on the atrioventricular (AV) node (Fig. 15.1). Atrial-based SVTs include sinus tachycardia, atrial tachycardia (AT), atrial flutter (AFL), atrial fibrillation (AF), and multifocal atrial tachycardia (MAT). AV node-dependent tachycardias include atrioventricular nodal reentry tachycardia (AVNRT), atrioventricular reciprocating tachycardia (AVRT), and junctional ectopic tachycardia (JET). Paroxysmal supraventricular tachycardia (PSVT) is a term that refers to SVTs with sudden abrupt onset and termination comprising of AVNRT, AVRT, AT, and JET. The S. Shen, MD Division of Cardiology, Department of Internal Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA B.P. Knight, MD, FACC, FHRS (*) Division of Cardiology, Department of Internal Medicine, Bluhm Cardiovascular Institute, Northwestern University, Feinberg School of Medicine, 251 East Huron Street, Feinberg 8-503E, Chicago, IL 60611, USA e-mail:
[email protected] A.S. Kibos et al. (eds.), Cardiac Arrhythmias, DOI 10.1007/978-1-4471-5316-0_15, © Springer-Verlag London 2014
Causes of supraventricular tachycardia
Sinus tachycardia Atrial origin
Atrial fibrillation (AF) Atrial flutter (AFL) Multifocal Atrial Tachycardia (MAT) Atrial tachycardia (AT)
AV node -dependent
AV nodal reentry tachycardia (AVNRT)
PSVT
AV reciprocating tachycardia (AVRT) Junctional ectopic tachycardia (JET)
Fig. 15.1 The differential diagnosis of SVT can be categorized into two categories: tachycardias that originate in the atrium and tachycardias that depend on the AV node. The term PSVT refers to SVTs that exhibit abrupt onset and termination, namely, AT, AVNRT, AVRT, and JET
most common of the four is AVNRT accounting for 65 % of PSVTs, while AVRT and AT account for 30 and 5 % respectively (Fig. 15.2). JET is more commonly seen in the pediatric population, namely, in infants or young children, but is not infrequently seen in adults following cardiac surgery. For the purposes of this chapter, we will focus on the differentiation of AVNRT, AVRT, AT, and JET using baseline electrocardiogram (ECG) and intracardiac tracings. The discussion of 199
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200 Mechanism of PSVT AVNRT 65 %
AVRT 30 %
AT 5%
Paroxysmal supraventricular tachycardia (PSVT) JET <1 %
RP < PR
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AVNRT * Superiorly directed P wave
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Atypical AVNRT
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Fig. 15.2 Paroxysmal supraventricular tachycardia is a term that refers to SVTs with abrupt onset and termination. AVNRT is a reentrant tachycardia that utilizes the AV node and perinodal tissues to sustain tachycardia. AVRT is a macro-reentrant tachycardia that utilizes an accessory pathway to create a circuit involving the ventricle. The mechanism behind AT can be focal or due to reentry in the atrium. The mechanism behind JET may be similar to that of AT but arises from the perinodal tissues
AVRT will focus on orthodromic reentrant tachycardia (ORT) whereby retrograde activation occurs via the accessory pathway (AP) and anterograde conduction via the AV node, resulting in a narrow QRS complex tachycardia in the absence of aberration. The diagnosis of the tachycardia mechanism relies upon three key elements: (1) baseline observations during sinus rhythm, (2) tachycardia features, and (3) the tachycardia response to atrial and ventricular pacing maneuvers.
Electrocardiographic Features Atrial Activation When evaluating PSVT, the ECG should first be assessed for P waves (atrial activity) [1]. The P waves may be easily discernible, but often comparison with a normal baseline ECG is necessary to reveal a slight alteration in the QRS, ST segment, or T wave suggesting an underlying P wave. Maneuvers to unmask the P wave include adenosine administration, carotid sinus massage, and Valsalva maneuver. When using the above maneuvers, continuation of the tachycardia with evidence of AV block suggests a diagnosis of AT. Termination of the tachycardia with a P wave that is not premature suggests the diagnosis of AVNRT or AVRT. At baseline, JET may display evidence of slower dissociated sinus P waves. However, if there is slow 1:1 retrograde conduction, then the administration of adenosine can demonstrate continuation of tachycardia with VA block confirming the diagnosis of JET.
P Wave Morphology and RP Interval When P waves are identified and the rhythm has a 1:1 AV relationship, the ECG should be evaluated for the P wave
Inferiorly directed P wave
AT
AVRT JET
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Fig. 15.3 The ECG should be assessed for P wave morphology and RP interval to aid in differentiating PSVT. *PSVT with RP <70 ms and superiorly directed P waves is highly suggestive of typical AVNRT. Caution should be exercised, however, in using the ECG findings alone to classify the tachycardia
morphology and the RP interval (Fig. 15.3). A short RP tachycardia, defined as an RP interval <50 % of the RR interval, and inferiorly directed P waves suggest a diagnosis of AT or AVRT. A short RP tachycardia with superiorly directed P waves may not be as helpful in differentiating between the four tachycardias as it can be noted with AVNRT, AVRT, JET, or AT, but a very short RP tachycardia is highly suggestive of typical (slow-fast) AVNRT. The P wave in this circumstance may appear as a pseudo r’ at the terminal portion of the QRS complex in lead V1. A long RP tachycardia with inferiorly directed P waves suggests a diagnosis of AT. A long RP tachycardia with superiorly directed P waves suggests a diagnosis of atypical (fast-slow) AVNRT, AVRT with a slowly conducting AP, or JET. Caution however should be exercised in using the ECG alone to make a diagnosis. Misclassification of PSVT by using ECG criteria alone has been reported to be as high as 20 % [2].
Baseline Observations in the EP Lab Ventricular Preexcitation Several baseline observations are useful in the EP laboratory prior to induction of SVT. These efforts provide information about the underlying substrate and may offer clues to support a specific mechanism of tachycardia. For example, evidence of ventricular preexcitation during sinus rhythm has a positive predictive value (PPV) of 86 % and negative predictive value (NPV) of 78 % that the patient will have AVRT [3]. Manifest preexcitation may be present on the baseline ECG. On intracardiac tracings, it is defined as an HV interval of
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How to Differentiate Between AVRT, AT, AVNRT, and Junctional Tachycardia Using the Baseline ECG and Intracardiac Tracings
< 35 ms. Atrial pacing can be used to unmask ventricular preexcitation by slowing AV node conduction. The presence of preexcitation, however, does not exclude other causes of SVT during which the AP is a bystander. Approximately 10 % of patients with preexcitation have inducible AVNRT. Likewise, the absence of preexcitation does not exclude the presence of an AP or the diagnosis of AVRT mediated by a slowly conducting or concealed AP.
Dual AV Node Physiology The presence of anterograde dual AV node physiology, defined by an atrial-His bundle (AH) “jump” – an increase in the A2H2 interval of more than 50 ms in response to a 10 ms decrement in the atrial extrastimulus coupling interval, is highly predictive of AVNRT (PPV 86 %). Other indicators of dual AV node physiology include an anterograde double fire, which is a two for one response with two ventricular complexes after one atrial extrastimulus where the first ventricular complex is due to conduction over the fast AV node pathway and the second is over the slow AV node pathway. Crossing over of the pacing stimulus during atrial pacing whereby the observed sustained PR interval becomes longer than the pacing, CL is another indicator of dual AV node physiology. Although highly predictive, the presence of dual AV node physiology does not exclude other diagnoses of PSVT. Approximately 14 % of patients with dual AV node physiology have either AVRT or AT. Likewise, the absence of demonstrable dual AV node physiology does not exclude the diagnosis of AVNRT, though the NPV is high at 82 %. This may in part be due to the fast and slow AV node pathways having similar effective refractory periods.
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of the largest His bundle recording with various stimulation intensities to achieve simultaneous ventricular and His bundle capture as well as ventricular capture alone. Para-Hisian pacing results in both anterograde and retrograde conduction via the His-Purkinje system (HPS). Anterograde conduction via HPS results in a relatively narrow QRS morphology. In the absence of an AP, retrograde conduction occurs over the His bundle with a stimulus to His (SH) interval of 0, followed by atrial activation where the stimulus to atrial (SA) interval equals the His to atrial (HA) interval. As the pacing output is decreased, loss of His bundle capture leads to widening of the QRS where anterograde conduction now occurs over ventricular myocardium. His activation is now delayed as it follows retrograde activation of the right bundle causing a prolongation of the SA interval. This is consistent with a typical nodal response to para-Hisian pacing (Fig. 15.4). An extranodal response is where the SA interval remains constant as atrial activation is dependent on retrograde conduction over the AP and not the AV node. During this maneuver, careful attention must be paid to the retrograde atrial activation sequence (RAAS) which should remain unchanged. A change in the RAAS suggests that retrograde conduction could be occurring over multiple pathways, either over multiple APs, fast and slow AV node pathways, or simultaneously over the AV node and AP. An extranodal response has a PPV of 83 % for AVRT, but the sensitivity of this maneuver is low at 47 % when assessed for all types of APs. The low sensitivity is likely due to the difficulty in achieving an extranodal response from APs far from the AV node.
Tachycardia Features Tachycardia CL and Septal VA Time
Ventriculoatrial Conduction Another important baseline variable to assess is ventriculoatrial (VA) conduction. Absence of VA conduction at a ventricular pacing CL >600 ms makes the diagnosis of AVRT highly unlikely. Of patients with VA block CL >600 ms, 5 % still have inducible AVRT which likely speaks to catecholamine-dependent retrograde conduction of the AP [4]. Presence of decremental VA conduction with ventricular extrastimulus pacing argues against the presence of an AP, but bear in mind that a small number of APs also have decremental conduction properties [5].
Upon initiation of tachycardia, the first two measurements should be the tachycardia CL and the septal VA time. Despite significant overlap, there are rare occasions when the tachycardia CL lends insight to the mechanism. Slow tachycardias (CL >500 ms) favor a diagnosis of AVNRT with a PPV of 83 %. The septal VA time measured from the beginning of the surface QRS complex to the earliest septal atrial electrogram of <70 ms excludes AVRT. Simultaneous atrial and ventricular activation is very suggestive of AVNRT, but does not exclude an AT with a long PR interval.
Retrograde Atrial Activation Sequence Para-Hisian Pacing Para-Hisian pacing can be performed at baseline to evaluate for the presence of a septal AP [6]. The maneuver involves incremental high-output pacing during sinus rhythm at the site
If the septal VA time is greater than 70 ms, then a coronary sinus catheter should be used to determine if the RAAS during tachycardia is concentric or eccentric. During typical AVNRT, RAAS is concentric as the earliest site of atrial activation stems from where the fast AV node pathway inserts
202 Fig. 15.4 Nodal response to para-Hisian pacing. Pacing is performed at the His position. As the output is decreased, there is loss of His capture consistent with the widening of the QRS complex. With loss of His capture, there is a concomitant increase in the stimulus to atrial electrogram interval consistent with a nodal response to para-Hisian pacing
S. Shen and B.P. Knight I aVF V1 HRA HIS p HIS m HIS d CS 9,10 CS 7,8 86 ms CS 5,6 CS 3,4 CS 1,2 52 ms
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near the His at the peak of the triangle of Koch. With atypical AVNRT, the site of earliest atrial activation occurs at the CS ostium. Rarely, AVNRT will exhibit eccentric RAAS due to leftward extension of the slow pathway into the CS or along the mitral annulus. AVRTs and ATs generally demonstrate eccentric atrial activation with the exception of paraseptal AVRT and AT.
Oscillations in Tachycardia CL Spontaneous oscillations in the tachycardia CL also known as “wobble” often afford another clue to the underlying mechanism. If changes in the A-A interval precede changes in the H-H interval where it appears that the A’s drive the V’s, then one should strongly consider the diagnosis of AT. If, however, the reverse appears true, then the tachycardia is more likely to be AVNRT, AVRT, or JET.
Tachycardia Initiation Zones of transition including initiation, aberration, AV block, and spontaneous termination provide additional insight into the tachycardia mechanism. A tachycardia
S1
induction that is reproducibly dependent on prolongation of the AH interval with atrial pacing suggests the diagnosis of AVNRT (PPV 91 %). As the atrial extrastimulus coupling interval is shortened during atrial pacing, the AV node fast pathway ERP is reached and conduction then occurs over the slow pathway appearing as a prolongation of the AH. Initiation of AVRT may also display AV delay, but that delay can occur at any point in the circuit and is not limited to the AV node. AT is independent of the AV node and thus does not require AV nodal delay for tachycardia induction.
Aberration The development of left bundle branch block (LBBB) is very suggestive of AVRT with a PPV of 92 %. The faster rate of AVRT favors the development of aberrant conduction. Likewise, the development of LBBB aberration promotes the initiation of AVRT by slowing conduction proximal to the AP, allowing it time to repolarize and thus facilitate retrograde conduction. An increase in the VA interval >20 ms with bundle branch block (BBB) is diagnostic of an ipsilateral AP-mediated ORT with a PPV of 100 % (Fig. 15.5). The increase in the VA interval is due to
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How to Differentiate Between AVRT, AT, AVNRT, and Junctional Tachycardia Using the Baseline ECG and Intracardiac Tracings
Fig. 15.5 Example of an increase in the VA interval during LBBB aberration in ORT in a patient with a concealed left lateral AP. In this example, the VA interval increases by >20 ms upon development of LBBB aberration which is diagnostic of an ipsilateral AP-mediated ORT (PPV 100 %). The increase in the VA interval is due to the slower intramyocardial conduction caused by the bundle branch block
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the slower intramyocardial conduction caused by the BBB. The increase in VA time may result in a similar increase in tachycardia CL, but the latter can be mitigated by a compensatory decrease in the AH interval.
Atrioventricular Block The presence of AV block during SVT excludes AVRT as the ventricle is integral to continuation of the macro-reentrant circuit. AV block can be seen with AT, AVNRT, and JET with block occurring in the lower common pathway in the latter two. VA block can be seen with JET, and rarely so with AVNRT due to block in the upper common pathway. The presence of VA block excludes the diagnoses of AVRT using an atrioventricular AP, and AT.
Tachycardia Termination Spontaneous termination of AVNRT and AVRT is typically caused by anterograde block in the AV node. As a result, tachycardia termination in this setting ends with a P wave that is not premature and is not followed by a QRS (Fig. 15.6). An AT with 1:1 AV conduction will generally terminate with the last atrial beat conducting to the ventricle. The simultaneous termination of AT with AV block would be an exceedingly rare phenomenon. As such, a tachycardia that terminates with a P wave excludes AT, except in the circumstance of a nonconducted premature atrial complex (PAC) terminating the AT. Tachycardia termination with a QRS does not assist in differentiating PSVT.
Diagnostic Pacing Maneuvers During Tachycardia Ventricular Overdrive Pacing After assessment of the baseline findings and tachycardia characteristics, pacing maneuvers can be used to further elucidate the tachycardia mechanism. A useful first maneuver is to entrain from the ventricle. For the purposes of this chapter, the term “entrainment” refers to acceleration of the atrial or ventricular electrograms to the pacing CL during overdrive pacing from the atrium to ventricle, with resumption of the original CL upon cessation of pacing. During this first maneuver, the ventricle is paced at a CL 10–40 ms shorter than the tachycardia CL to accelerate the atrium to the pacing CL. After confirming that the atrial CL equals the pacing CL, the RAAS can be compared. If the RAAS of the entrained complex is different from that in tachycardia, a diagnosis of AT or bystander AP is suggested. Secondly, the electrogram sequence following the last paced ventricular complex should be examined for either an “atrial-ventricular” (A-V) or “atrial-atrial-ventricular” (A-AV) response. An A-V response is consistent with either AVNRT or AVRT where the last entrained atrial beat conducts via the retrograde limb of the circuit (AV nodal pathway or AP) and then anterograde down the AV node (Fig. 15.7a). This effectively excludes AT and, as a maneuver, is particularly useful as it can be applied to 78 % of tachycardias [3]. Conversely, an A-A-V response is diagnostic of AT (Fig. 15.7b) [7]. During entrainment in AT, both retrograde and anterograde conduction occurs via the AV node. Therefore, the last entrained atrial beat finds the AV node refractory.
204 Fig. 15.6 Spontaneous termination of tachycardia ending with a P wave. Spontaneous termination of AVNRT and AVRT is typically caused by anterograde block in the AV node, resulting in tachycardia termination ending with a P wave that is not followed by a QRS. Simultaneous termination of AT with AV block and without a premature atrial beat is exceedingly rare, effectively excluding AT
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Another advantage of this maneuver is that one can also perform two calculations to differentiate between atypical AVNRT and a septal AP. The first is a post-pacing interval minus tachycardia CL (PPI-TCL) where a value >115 ms suggests atypical AVNRT (Fig. 15.8a) and alternatively, a value <115 ms suggests a septal AP-mediated AVRT (Fig. 15.8b). As the ventricle is an obligate member of the AVRT circuit, i.e., the RV pacing site is near the circuit, entrainment from the ventricle results in a shorter PPI compared to that in AVNRT. A pitfall of this calculation is that it also includes anterograde AV conduction; on the rare occasion that the first AH interval after pacing is stopped is longer than the AH during SVT, it can falsely prolong the PPI. A second calculation that only measures the differences in VA conduction is the stimulus to A interval minus VA interval during tachycardia (SA-VA). An SA-VA time >85 ms suggests atypical AVNRT (Fig. 15.8a) and, conversely, SA-VA time <85 ms suggests a septal AP-mediated AVRT (Fig. 15.8b). There are exceptions, however, to this rule when there is an AP that has significant decremental properties resulting in a very long PPI [8]. A second ventricular pacing maneuver is to burst pace the RV at a CL of 200–250 ms for 3–6 beats in an attempt to dissociate the ventricle from the atrium without terminating tachycardia. Dissociation of the ventricle from the atrium as evidence by full ventricular capture and continuation of the tachycardia excludes a diagnosis of AVRT. If attempts at ventricular pacing fail to either entrain or dissociate the ventricle, and ultimately result in termination of the tachycardia without evidence of conduction to the atrium, then AT can be excluded as termination could only have occurred by causing
block in the AV node or AP (Fig. 15.9). Similarly, a spontaneous PVC or a single ventricular extrastimulus that causes termination of tachycardia without preexcitation of the atrium also excludes the diagnosis of AT.
His Refractory Ventricular Extrastimulus Testing Another useful pacing maneuver is to deliver a ventricular extrastimulus during the His bundle refractory period and assess its effect on the atrium. The ventricular extrastimulus should be delivered at a time between the onset of the QRS complex and 30–50 ms before the expected His bundle depolarization. If a His-refractory PVC advances the atrial activation, an AP is present but may not necessarily participate in the tachycardia. If, however, the tachycardia terminates without preexcitation of the atrium, then AVRT is diagnosed (Fig. 15.10).
Atrial Overdrive Pacing Atrial pacing maneuvers can also be utilized to exclude AT. With the first maneuver, the atrium is paced at 10–40 ms shorter than the tachycardia CL to entrain the ventricle. Then the VA interval of the first return beat is compared to the VA interval during tachycardia. If the VA interval is unchanged, that suggests that atrial activation is linked to ventricular activation (VA linking) thus effectively excluding AT (Fig. 15.11). However, one should be aware that this finding is not 100 % predictive as coincidental events can rarely
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How to Differentiate Between AVRT, AT, AVNRT, and Junctional Tachycardia Using the Baseline ECG and Intracardiac Tracings
Fig. 15.7 (a) “VAV response” to entrainment pacing from the ventricle. During tachycardia, overdrive pacing of the ventricle to accelerate the atrium is performed at 10–40 ms shorter than the tachycardia CL. After confirming that the atrial CL equals the pacing CL, the electrogram response to cessation of pacing is observed to be VAV in this patient with atypical AVNRT. (b) “VAAV response” to entrainment pacing from the ventricle. After entrainment from the ventricle, the electrogram response is VAAV consistent with the patient’s diagnosis of AT. Note also the change in the atrial activation sequence during ventricular pacing consistent with an AT
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result in apparent VA linking and that 3 % of AVNRT did not exhibit VA linking. The second pacing maneuver is to pace the atrium at the longest CL that results in AV block. If the AH interval preceding termination is longer than the AH interval during tachycardia, this suggests that the tachycardia is AV node-dependent, thus excluding AT as a diagnosis. When considering the differential diagnosis of PSVT, JET by far is the least common in the adult population. It is
however often confused with AVNRT and unfortunately, catheter ablation of JET is complicated by a higher rate of complete heart block. When considering these two diagnoses, atrial pacing to entrain the His should be examined for the electrogram response after cessation of pacing. A “Hisatrial” (H-A) response suggests a diagnosis of AVNRT (Fig. 15.11), whereas a “His-His-atrial” (H-H-A) response suggests a diagnosis of JET [9].
206 Fig. 15.8 (a) PPI-TCL and SA-VA intervals in a patient with AVNRT. A PPI-TCL >115 ms is consistent with a diagnosis of AVNRT. An SA-VA time >85 ms also favors a diagnosis of AVNRT. (b) PPI-TCL and SA-VA example of a patient with a septal AP-mediated AVRT. As the ventricle is a part of the AVRT circuit, RV pacing as a result is near the circuit lending to a shorter PPI and shorter SA interval. A PPI-TCL <115 ms and an SA-VA time <85 ms are consistent with a diagnosis of septal AP-mediated AVRT
S. Shen and B.P. Knight
a
I 200 ms
aVF V1 SA = 260 ms
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How to Differentiate Between AVRT, AT, AVNRT, and Junctional Tachycardia Using the Baseline ECG and Intracardiac Tracings
Fig. 15.9 Ventricular burst pacing that causes termination of tachycardia without preexcitation of the atrium. The tachycardia terminates without preexcitation of the atrium suggesting that termination is dependent on block in the AV node or AP, thus excluding the diagnosis of AT
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208 Fig. 15.11 VA linking and AHA response to atrial pacing. This is an example of VA linking in a patient with AVNRT whereby the last entrained ventricular beat during atrial pacing has the same VA time as that in tachycardia. This also demonstrates the AHA response used to differentiate AVNRT from JET
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I II III V1 HRA HIS d
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Conclusions
Successful diagnosis of the tachycardia mechanism relies on a combination of observations and diagnostic techniques which rarely provide a diagnosis when used individually. However, a combined approach using two tachycardia observations (septal VA time and the retrograde atrial activation sequence) and one pacing maneuver (the response immediately after entrainment from the ventricle) provides a diagnosis in 65 % of tachycardias and excludes a tachycardia mechanism in an additional 27 % of cases.
References 1. Blomstrom-Lundqvist C, Scheinman MM, Aliot EM, Alpert JS, Calkins H, Camm AJ, Campbell WB, Haines DE, Kuck KH, Lerman BB, Miller DD, Shaeffer Jr CW, Stevenson WG, Tomaselli GF, Antman EM, Smith Jr SC, Faxon DP, Fuster V, Gibbons RJ, Gregoratos G, Hiratzka LF, Hunt SA, Jacobs AK, Russell Jr RO, Priori SG, Blanc JJ, Budaj A, Burgos EF, Cowie M, Deckers JW, Garcia MA, Klein WW, Lekakis J, Lindahl B, Mazzotta G, Morais JC, Oto A, Smiseth O, Trappe HJ. ACC/AHA/ESC guidelines for the management of patients with supraventricular arrhythmias – executive summary: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients with Supraventricular Arrhythmias). Circulation. 2003;108:1871–909.
2. Kalbfleisch SJ, el-Atassi R, Calkins H, Langberg JJ, Morady F. Differentiation of paroxysmal narrow QRS complex tachycardias using the 12-lead electrocardiogram. J Am Coll Cardiol. 1993;21:85–9. 3. Knight BP, Ebinger M, Oral H, Kim MH, Sticherling C, Pelosi F, Michaud GF, Strickberger SA, Morady F. Diagnostic value of tachycardia features and pacing maneuvers during paroxysmal supraventricular tachycardia. J Am Coll Cardiol. 2000;36: |574–82. 4. Yamamoto T, Yeh SJ, Lin FC, Wu DL. Effects of isoproterenol on accessory pathway conduction in intermittent or concealed WolffParkinson-White syndrome. Am J Cardiol. 1990;65:1438–42. 5. de Chillou C, Rodriguez LM, Schlapfer J, Kappos KG, Katsivas A, Baiyan X, Smeets JL, Wellens HJ. Clinical characteristics and electrophysiologic properties of atrioventricular accessory pathways: importance of the accessory pathway location. J Am Coll Cardiol. 1992;20:666–71. 6. Hirao K, Otomo K, Wang X, Beckman KJ, McClelland JH, Widman L, Gonzalez MD, Arruda M, Nakagawa H, Lazzara R, Jackman WM. Para-Hisian pacing. A new method for differentiating retrograde conduction over an accessory AV pathway from conduction over the av node. Circulation. 1996;94:1027–35. 7. Knight BP, Zivin A, Souza J, Flemming M, Pelosi F, Goyal R, Man C, Strickberger SA, Morady F. A technique for the rapid diagnosis of atrial tachycardia in the electrophysiology laboratory. J Am Coll Cardiol. 1999;33:775–81. 8. Bennett MT, Leong-Sit P, Gula LJ, Skanes AC, Yee R, Krahn AD, Hogg EC, Klein GJ. Entrainment for distinguishing atypical atrioventricular node reentrant tachycardia from atrioventricular reentrant tachycardia over septal accessory pathways with long-RP [corrected] tachycardia. Circ Arrhythm Electrophysiol. 2011;4:506–9. 9. Fan R, Tardos JG, Almasry I, Barbera S, Rashba EJ, Iwai S. Novel use of atrial overdrive pacing to rapidly differentiate junctional tachycardia from atrioventricular nodal reentrant tachycardia. Heart Rhythm. 2011;8:840–4.
Recognizing the Origin of Ventricular Premature Depolarization During Sinus Rhythm and During Non-sustained Tachycardia
16
Seow Swee-Chong
Abstract
Premature ventricular complexes (PVCs) are common and usually benign. Occasionally, intervention may be required. In these cases, localization of the origin of the PVCs or nonsustained ventricular tachycardia (NSVT) may be important in guiding therapy. A brief review is undertaken of the various methods which can be utilized to determine the site of origin of the PVCs/NSVT, ranging from the simple electrocardiogram to electrophysiological techniques to complex three-dimensional mapping systems. Case vignettes are provided to illustrate patients in whom therapy may be beneficial. Keywords
Localization • Ventricular ectopics • Non-sustained ventricular tachycardia
Introduction Premature ventricular ectopic beats (PVCs) are usually benign, especially in the absence of structural heart disease. They can be managed conservatively unless (1) the PVCs cause symptoms, (2) the PVCs are so frequent that they impair cardiac function, or (3) the PVCs are a manifestation of underlying cardiomyopathy or myocardial scarring. Symptomatic PVCs may be suppressed with betablockers, which should be first-line therapy. If these are ineffective, Class 3 antiarrhythmic drugs like sotalol or Class 1 drugs such as flecainide and propafenone may be used in the absence of underlying structural heart disease [1]. Amiodarone is generally not the first drug of choice due to its myriad side effects and long-term complications, particularly in this group of patients who tend to be young and who might therefore be on amiodarone for many years. While the iodine-free analogue of amiodarone, dronedarone, promises to be free of the same side effects, its efficacy in suppressing PVCs or ventricular tachycardia has not been systematically S. Swee-Chong, MBBS, MRCP Department of Cardiology, National University Heart Centre, Singapore, Singapore e-mail:
[email protected] A.S. Kibos et al. (eds.), Cardiac Arrhythmias, DOI 10.1007/978-1-4471-5316-0_16, © Springer-Verlag London 2014
studied in humans. Failure of medical therapy or patient’s reluctance for long-term medication is an indication for consideration of radio-frequency ablation as a therapeutic option [1]. Frequent PVCs may lead to a form of “tachycardiainduced cardiomyopathy,” with reduction in cardiac function and dilatation of heart chambers. Most of these patients are asymptomatic and as such tend to present late with impaired heart function or are picked up incidentally on screening for other conditions [2]. The burden or frequency of PVCs that is necessary to cause cardiomyopathy varies from case to case. In a study by Baman et al. [3], the cut-off value of PVC burden that separated those who developed left ventricular systolic dysfunction and those who did not was >24 %. Suppressing the PVCs with drugs may return the cardiac function to normal. Radio-frequency ablation may be preferred in patients with impaired systolic function from frequent ectopics because it results in a cure [4], thus obviating the need for long-term medications. Additionally, it avoids the difficulties of giving potentially pro-arrhythmic and negatively inotropic drugs to a patient with already impaired heart function. Occasionally, frequent PVCs may be a marker of underlying myocardial scarring due to conditions like myocarditis, right ventricular dysplasia, or coronary artery disease. 209
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Most often though, PVCs are idiopathic and arise frequently from the right ventricular outflow tract (RVOT), left ventricular outflow tract (LVOT), mitral and tricuspid annulus, and aortic cusps. These PVCs may occur singly, in salvos, or as sustained or non-sustained ventricular tachycardia (VT).
Mapping of PVCs and VT 12-Lead Electrocardiogram The humble 12-lead electrocardiogram (ECG) can be very useful in providing initial clues to the origin of PVCs and VT, albeit with limitations. A left bundle branch block pattern (LBBB) with late transition points to a right ventricular origin; while a right bundle branch block (RBBB) pattern with early transition suggests a left ventricular origin. The polarity of the QRS complexes
3
2
in the inferior leads indicates whether the origin of the VT is superior as in the RVOT or LVOT (positive) or inferior (negative). Generally, a septal origin gives rise to a narrower QRS than a lateral focus. A PVC originating from the RVOT would therefore typically have an LBBB pattern and an inferior axis. PVCs originating from the septal RVOT may be narrower, have an earlier transition, and be less likely to have a notched QRS complex in the inferior leads. PVCs from the RVOT free wall tend to have wider QRS, have a slighter later transition, and be more likely to have notched QRS complexes in the inferior leads [5, 6] (Fig. 16.1). PVCs that arise from the left ventricular outflow tract or aortic root can sometimes masquerade as an RVOT PVC. This is not surprising considering the close anatomical relationship of the two. Ouyang et al. [7] elegantly described the differences in ECG characteristics between the two entities (Fig. 16.2).
3
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aVL aVF
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V4 V4
V5 2 mV
V6 Septum
Fig. 16.1 ECG characteristics of PVCs originating from the septal versus free-wall RVOT. Twelve-lead ECG pace maps from sites 1, 2, and 3 along the septum and free wall alike right ventricular outflow tract (RVOT) showing characteristic features. Sites are labeled on the magnetic electroanatomic map in the center of the figure and over each pace map. The magnetic electroanatomic map of the RVOT is shown in a coronal projection and was acquired during sinus rhythm. The threedimensional shape of the RVOT is evident from the magnetic electroanatomic map and the illustration at the bottom of the figure. All pace maps
V5
200 ms Free wall
V6
show a left bundle branch block morphology and inferior frontal plane axis. Differences in R waves in inferior leads II, III, and aVF between the free-wall and septal pace maps are seen (broader, shorter, and notched for the free-wall sites). The precordial transition pattern for the free-wall sites is late (R to S ratio >1 by precordial leads V4) compared with the septal locations. Changes in lead I when moving from more anterior and leftward (site 3, negative QRS) to the more posterior mid rightward (site 1, positive ORS) are shown. PV pulmonic valve (Reproduced from Dixit et al. [5] with permission of John Wiley and Sons)
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Recognizing the Origin of Ventricular Premature Depolarization During Sinus Rhythm and During Non-sustained Tachycardia
Fig. 16.2 ECG characteristics of PVCs originating from the RVOT versus the aortic cusps. Anatomic location of the origin of the arrhythmia, with corresponding 12-lead electrocardiographic morphology, Note the different morphology in leads V1 and V3 with respect to the anatomic origin. L Left coronary aortic sinus, N noncoronary, aortic sinus, R mean, aortic sinus, RVOT right coronory aortic sinus, RVOT right ventricular outflow tract (Reproduced from Ouyang et al. [7] with permission of Elsevier)
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Ouyang et al. [7] reported that the r wave duration in leads V1 and V2 tended to be wider in VTs that originate from the aortic valve cusps. Thus, the r wave duration in these leads tended to be longer than 50 % of the QRS duration; and the R/S amplitude ratio was greater than 30 % for aortic cusp VTs in leads V1 and V2 (Fig. 16.3).
Electrophysiological Study Traditional electrophysiological techniques used for mapping the origin of PVCs or ventricular tachycardia include activation mapping and pace mapping. In activation mapping, a catheter positioned in the chamber of interest is used to record the local electrogram generated by the PVC/VT,
and its timing is compared to a stable reference electrogram which can be a surface lead or coronary sinus lead. The earliest point of activation delineates the likely focus of the PVC or VT. From here, pace mapping techniques can be used to further define the ablation target. A 12-lead match of the electrocardiogram generated by pacing (at the intended ablation target) with the clinical arrhythmia predicts success. Ablation therapy for PVCs and ventricular tachycardia has made great strides in recent years with the advent of electroanatomical mapping. In the past, electrophysiologists have had to rely on information gleaned from surface electrocardiograms, intracardiac multielectrode tracings, and fluoroscopy in order to identify, characterize, and localize arrhythmias. While not a replacement for traditional techniques, the evolution of three-dimensional electroanatomical mapping sys-
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aVf
C V1 B
D
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Fig. 16.4 Principle behind the CARTO electroanatomical mapping system V4
A
Fig. 16.3 Leads V1 and V2 in aortic cusp VT compared to RVOT VT. 7Example of electrocardiographic analysis of clinical arrhythmias: leads a VF, and V4 a normal sinus beat, followed by the beat of respective monomorphic ventricular tachycardia. (A) Total QRS duration, measured from the earliest onset in lead V4 to the latest activation in lead a VF (ms); (B) R-wave duration, determined in lead V1 from the QRS onset to the R-wave transaction point of the R-wave with the isoelectric line (ms); (C) R-wave amplitude, measured form the peak to the isoelectric line (mV); (D) S-wave amplitude measured from the cusp to the isoelectric line (mV) (Reproduced from Ouyang et al. [7] with permission of Elsevier)
tems and intracardiac imaging tools has made localization of ablation targets easier and arguably more accurate. The concept behind electroanatomical mapping lies in the use of catheters that collect electrical information (such as local electrogram timing in relation to a fixed stable timing reference and local voltage) together with positional information that allows localization of the point at which the electrical information was obtained in real time and space. In this way, a three-dimensional “map” of the anatomical geometry can be created, depicting either voltages of the underlying myocardium (allowing identification of areas of scarring or border zones) or activation patterns.
Types of Electroanatomical Mapping Electroanatomical mapping systems can be divided into contact or noncontact systems. In contact mapping, the mapping catheter makes direct contact with the myocardial surface (endocardial or epicardial), acquiring electrical and location data points. This can be tedious as information is collected point by point and particularly challenging for non-sustained arrhythmias. Systems that use this technique include CARTO, NavX, and MediGuide.
In noncontact mapping, there is no direct contact between the catheter and the myocardial surface. Rather, the information (far-field electrograms and location data) collected by the mapping catheter is used to extrapolate the virtual electrogram as it would/might appear on the endocardium. This provides the advantage of “acquiring” activation/voltage data of the entire chamber simultaneously and can be very useful in non-sustained rhythms. At the moment, the only system that utilizes this technique is the Ensite Array.
The Biosense Webster CARTO System The first non-fluoroscopic three-dimensional electroanatomical mapping system was marketed by Biosense Webster as the CARTO system [8, 9]. Having gone through a few incarnations, the principle behind the system remains the same: A magnetic sensor incorporated into the tip of a deflectable mapping catheter (Navistar) allows the system to calculate the catheter position relative to an external magnetic field emitted by a contraption located under the patient. This external field is generated by three coils producing overlapping spheres of magnetic field that codes the three-dimensional space around the patient’s chest with spatial and temporal information. The strength of the magnetic field measured by the catheter tip from each coil allows the system to calculate its distance from each coil, thus enabling the operator to determine the catheter tip location in six degrees of freedom, viz., x-, y-, z-axes and roll, pitch, and yaw. To correct for minor patient movement, a reference patch is positioned on the patient’s back (REFSTAR). The system factors in the location of the mapping catheter with the location of the reference patch simultaneously in real time to compensate for any patient movement (Fig. 16.4).
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Recognizing the Origin of Ventricular Premature Depolarization During Sinus Rhythm and During Non-sustained Tachycardia
The CARTOMERGE software allows for integration of CT or MRI images with the three-dimensional electroanatomical map [10] and can be highly useful for anatomically based ablation strategies such as pulmonary vein isolation. Recently, anatomical information has been augmented with the use of intracardiac echocardiograms in CARTOSOUND. In the latest CARTO 3 incarnation, impedance-based data has been hybridized with magnetic information to aid the speed and accuracy of data point acquisition. In this technology, impedance changes between the catheter tip and reference patches on the patient’s body allow the system to calculate relative catheter positions. One potential limitation of the CARTO system is the need for sequential mapping on a point-by-point, beat-by-beat basis which can be highly challenging for non-sustained or hemodynamically unstable rhythms. It is also time consuming and tedious, although the new CARTO 3 system with hybridized impedance and magnetic mapping technologies allowing quicker mapping may turn out to be a game changer. Another limitation is the CARTO system’s vulnerability to patient movement because of the location of fixed coils below the patient. Significant movement cannot be compensated for by the reference patch and can result in map inaccuracies. Needless to say, remapping is both arduous and frustrating. Lastly, the system utilizes proprietary single use catheters and does not support catheters by other manufacturers.
The Ensite NavX System Instead of magnets, the Ensite NavX system uses electrical impedance to locate the position of intracardiac catheters [11, 12]. Three orthogonal pairs of surface electrodes are attached to the patient’s body. These form orthogonal axes with the heart at its center. A low intensity oscillating electrical current is transmitted through each of the three pairs of surface electrodes, generating a transthoracic electrical field. The system then measures the potential difference between the intracardiac catheter electrodes and the surface electrodes, which allows it to determine the geographical position of the catheters and electrodes in real time. The potentials are defined in relation to a fixed reference electrode, which again can be a surface lead or intracardiac catheter. Since multiple electrode positions can be calculated simultaneously, a threedimensional electroanatomical map can be generated much more quickly by “sweeping” a mapping catheter across the endocardial surface as compared to point-by-point acquisition in the CARTO system. Another advantage of the NavX system is the fact that it does not utilize any proprietary catheter, so standard electrophysiology catheters of any
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brand can be used with the system. Map integration with CT or MRI images has also been enabled with the newer versions of the software (Fig. 16.5).
The MediGuide System The concept behind the MediGuide system is similar to the GPS (Global positioning system) satellite system used in terrestrial vehicles [13]. A tiny coil is incorporated into the tip of an intracardiac catheter or wire which allows the system to pick up signals emitted from a magnetic field generator. This generator is incorporated into the fluoroscopy detector of a standard C-arm (Siemens Axiom Artis) and emits a low intensity alternating magnetic field. This, together with a reference patch attached to the patient’s sternum, allows the system to triangulate the position of the catheter or wire tip to an accuracy of <0.5 mm. The location information thus generated is then superimposed on a static fluoroscopic image thereby allowing catheter/wire manipulation without using radiation for real time fluoroscopy. Bought over by St Jude Medical in 2008, the technology can now be integrated with electrical mapping capabilities provided through the NavX system (Fig. 16.6).
The St Jude Medical Ensite Array System Currently the only commercially available noncontact mapping system, the Ensite Array, consists of a 9 Fr catheter with a 7.6 ml (18 × 40 mm) balloon surrounded by a 64 multielectrode array (MEA) [14, 15]. The MEA is essentially an electrically insulated metallic meshwork around the ellipsoid balloon, with 0.025 in. breaks in the insulation forming the electrodes. These function as unipolar electrodes, collecting far-field electrograms from the endocardial surface within the chamber of interest without making contact with the endocardium. The raw tracings are then processed by the system to extrapolate “virtual electrograms” as they would have appeared on the endocardial surface. This data is then used to construct activation and voltage electroanatomical maps. Since electrograms are collected from many points simultaneously, there is an obvious advantage of this system for non-sustained or hemodynamically unstable arrhythmias. A potential drawback is the drop in accuracy of mapping with increasing distance (> approximately 35 mm) from the MEA balloon, which might be a practical issue in dilated ventricles in patients undergoing VT ablation. Additionally, the large caliber of the catheter and size of the MEA might limit its use in some patients. The Array can be used in conjunction with the NavX system (Fig. 16.7).
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Fig. 16.5 The NavX electroanatomical mapping system (Courtesy of St Jude Medical)
2-D / 3-D “map” and sensor position MediGuide system
MediGuide sensors in heart
Fig. 16.6 MediGuide Medical Positioning System (Courtesy of St Jude Medical)
X-ray detector with, integrated electromagnetic field emitters
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Recognizing the Origin of Ventricular Premature Depolarization During Sinus Rhythm and During Non-sustained Tachycardia
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Fig. 16.7 The Ensite multielectrode array (Courtesy of St Jude Medical)
Case Example 1: Right Ventricular Outflow Tract Tachycardia (RVOT VT)
A 26-year-old male with no previous medical history and no structural heart disease presented with palpitations. ECG showed a broad complex tachycardia with left bundle branch block pattern and inferior axis (Fig. 16.8). He failed medical therapy with beta-blockers and subsequently sotalol. Electrophysiological study and ablation guided by CARTO was performed.
During the study, the clinical arrhythmia was not inducible despite IV isoprenaline and aggressive pacing. Pace mapping was thus carried out to localize the VT focus. A good match with the clinical tachycardia was found in the RVOT septal location (Fig. 16.9), and radiofrequency energy was applied there. Post-ablation, during follow-up, there was no recurrence of palpitations (Figs. 16.10 and 16.11).
Fig. 16.8 12-lead ECG of clinical tachycardia, consistent with RVOT VT of septal origin
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Fig. 16.9 Pace map from the septal RVOT
Fig. 16.10 Left anterior oblique (LAO) view of ablation lesions (in red) in the RVOT
Fig. 16.11 Postero-anterior (PA) view of ablation lesions (in red) in the RVOT
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Recognizing the Origin of Ventricular Premature Depolarization During Sinus Rhythm and During Non-sustained Tachycardia
Case Example 2: Posterior Fascicular VT
A 20-year-old male with complaints of recurrent palpitations presents with the following ECG (Fig. 16.12). He had problems with compliance to oral verapamil, which he also claimed did not control his symptoms adequately. As such, electrophysiological study and ablation was arranged. With CARTO mapping during tachycardia, the earliest activation was in the inferior
Fig.16.12 12-lead ECG of patient with left posterior fascicular VT
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septum (red area, Fig. 16.13 and 16.14) which was consistent with the diagnosis of left posterior fascicular VT. A line of ablation was created at the junction of the middle and distal third of the ventricular septum on the left side, from the midpoint of the septum to the inferior border. Additional ablation was done at the exit point of the tachycardia. Post-ablation, there was no further inducible tachycardia.
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Fig. 16.13 Right anterior oblique (RAO) view of ablation lesions in the LV
References 1. Zipes DP, Camm AJ, Borggrefe M, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death). J Am Coll Cardiol. 2006;48(5):e247–346. 2. Yokokawa M, Kim HM, Good E, et al. Relation of symptoms and symptom duration to premature ventricular complex-induced cardiomyopathy. Heart Rhythm. 2012;9(1):92–5. 3. Baman TS, Lange DC, Ilg KJ, et al. Relationship between burden of premature ventricular complexes and left ventricular function. Heart Rhythm. 2010;7(7):865–9. 4. Takemoto M, Yoshimura H, Ohba Y, et al. Radiofrequency catheter ablation of premature ventricular complexes from right ventricular outflow tract improves left ventricular dilation and clinical status in patients without structural heart disease. J Am Coll Cardiol. 2005;45(8):1259–65.
S. Swee-Chong
Fig. 16.14 Anterior-posterior (AP) view of ablation lesions in the LV
5. Dixit S, Gerstenfeld EP, Callans DJ, Marchlinski FE. Electrocardiographic patterns of superior right ventricular outflow tract tachycardias: distinguishing septal and free-wall sites of origin. J Cardiovasc Electrophysiol. 2003;14(1):1–7. 6. Sekiguchi Y, Aonuma K, Takahashi A, et al. Electrocardiographic and electrophysiologic characteristics of ventricular tachycardia originating within the pulmonary artery. J Am Coll Cardiol. 2005;45(6):887–95. 7. Ouyang F, Fotuhi P, Ho SY, et al. Repetitive monomorphic ventricular tachycardia originating from the aortic sinus cusp: electrocardiographic characterization for guiding catheter ablation. J Am Coll Cardiol. 2002;39(3):500–8. 8. Ben-Haim SA, Osadchy D, Schuster I, Gepstein L, Hayam G, Josephson ME. Nonfluoroscopic, in vivo navigation and mapping technology. Nat Med. 1996;2(12):1393–5. 9. Nademanee K, Kosar EM. A nonfluoroscopic catheter-based mapping technique to ablate focal ventricular tachycardia. Pacing Clin Electrophysiol. 1998;21(7):1442–7. 10. Tops LF, Bax JJ, Zeppenfeld K, et al. Fusion of multislice computed tomography imaging with three-dimensional electroanatomic mapping to guide radiofrequency catheter ablation procedures. Heart Rhythm. 2005;2(10):1076–81.
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11. Krum D, Goel A, Hauck J, et al. Catheter location, tracking, cardiac chamber geometry creation, and ablation using cutaneous patches. J Interv Card Electrophysiol. 2005;12(1):17–22. 12. Earley MJ, Showkathali R, Alzetani M, et al. Radiofrequency ablation of arrhythmias guided by non-fluoroscopic catheter location: a prospective randomized trial. Eur Heart J. 2006;27(10):1223–9. 13. Jeron A, Fredersdorf S, Debl K, et al. First-in-man (FIM) experience with the Magnetic Medical Positioning System (MPS) for intracoronary navigation. EuroIntervention. 2009;5(5):552–7.
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14. Schilling RJ, Peters NS, Davies DW. Simultaneous endocardial mapping in the human left ventricle using a noncontact catheter: comparison of contact and reconstructed electrograms during sinus rhythm. Circulation. 1998;98(9):887–98. 15. Strickberger SA, Knight BP, Michaud GF, Pelosi F, Morady F. Mapping and ablation of ventricular tachycardia guided by virtual electrograms using a noncontact, computerized mapping system. J Am Coll Cardiol. 2000;35(2):414–21.
Detection and Management of Atrial Fibrillation in Patients with Stroke or TIA in Clinical Practice
17
Jerzy Krupinski, Jorge de Francisco, and Sonia Huertas
Abstract
Atrial fibrillation (AF) is the most common condition of cardioembolic stroke, and anticoagulation is the treatment generally indicated for secondary prevention and in some cases for primary prevention. The prevalence of AF is strongly associated with increasing age, rising to 5 % in people older than 65 years and to nearly 10 % in those aged 80 years. AF increases the risk of stroke four- to fivefold across all age groups, accounting for 10–15 % of all ischemic strokes and nearly 25 % of strokes in people older than 80 years. Strokeprone patients are reliably identified by a CHADS2 score >3, and they have an average risk of 5.5 strokes per 100 patient-years on aspirin. Dose-adjusted oral anticoagulation (international normalized ratio [INR], 2.0–3.0) with vitamin K antagonists is highly efficient in reducing the risk of ischemic stroke in AF patients with moderate to high risk of stroke and superior to antiplatelet agents. However, in clinical practice only about 50–70 % of AF patients with the indication receive stroke prevention with vitamin K antagonists. Moreover, even in clinical trials, warfarin-anticoagulated patients are in the therapeutic range only about 65 % of the time. Anticoagulation therapy’s associated risk of hemorrhage and cumbersome monitoring requirements have encouraged the investigation of alternative therapies for individuals with AF. Recently published data suggest that new anticoagulants including the direct thrombin inhibitor dabigatran and the direct factor Xa inhibitors rivaroxaban and apixaban are equivalent or even superior to warfarin in preventing stroke or systemic embolism in the setting of AF. There are data showing a trend toward reduction in all-cause mortality, while the most recent randomized trial demonstrated a clear reduction in the risk of death. Therefore, patients with ischemic stroke or TIA of unknown etiology should be studied for paroxysmal AF. This condition is clearly associated with subsequent stroke risk and should be treated with anticoagulants. Keywords
Stroke • Atrial fibrillation • New anticoagulants
Introduction
J. Krupinski, MD, PhD, DsC (*) • J. de Francisco, MD S. Huertas, MD Cerebrovascular Diseases Unit, Department of Neurology, Hospital Universitari Mútua Terrassa, Pl. Dr Robert, 5, 08221 Terrassa, Barcelona, Spain e-mail:
[email protected] A.S. Kibos et al. (eds.), Cardiac Arrhythmias, DOI 10.1007/978-1-4471-5316-0_17, © Springer-Verlag London 2014
Embolism of cardiac origin accounts for about 20 % of ischemic strokes. Several heart conditions enhance stroke risk. Atrial fibrillation is the most common condition of cardioembolic stroke, and anticoagulation is the treatment generally indicated for secondary prevention and in some cases for primary prevention [1]. In this chapter, we focus on atrial fibrillation as a major cardiac condition prone to cardioembolic 221
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Table 17.1 Antithrombotic therapy for Atrial Fibrillation American College and Chest Physicians guidelines 2012 Clinical situation Patients with nonrheumatic AF, including those with paroxysmal AF, who are (1) at low risk of stroke (e.g., CHADS2 [congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, prior stroke or transient ischemic attack] score of 0) At intermediate risk of stroke (e.g., CHADS2 score of 1) At high risk of stroke (e.g., CHADS2 score of ≥2)
Recommendations No therapy or aspirin
Oral anticoagulation rather than aspirin or combination therapy Oral anticoagulation rather than no therapy and aspirin or combination therapy with aspirin and clopidogrel. Where we recommend or suggest in favor of oral anticoagulation, we suggest dabigatran 150 mg bid rather than dose-adjusted vitamin K antagonist therapy
infarct and its management. To a less extent, a cardiac source of embolism as the only demonstrable etiology has been found in 4 % of lacunar infarctions [2, 3], and its role as the etiology of lacunar infarction is very rare [4, 5]. We provide a table with recent CHEST recommendations for patients with atrial fibrillation (Table 17.1). Stroke and transient ischemic attack (TIA) in terms of primary and secondary prevention should be treated in the same way. We also review antithrombotic treatment with new anticoagulants which are replacing the old J. Krupinski ones. Oral anticoagulation (OAC) is the treatment of choice for secondary prevention after a cardioembolic stroke [6, 7]. Warfarin is the commonest OAC used worldwide, although acenocoumarol, phenprocoumon, or anisindione are frequently prescribed in many countries. The mechanisms of action of these OAC are comparable, as they inhibit the vitamin K-dependent posttranslational carboxylation of glutamate residues on the N-terminal regions of coagulation factors II, VII, IX, and X by inhibiting the conversion of vitamin 2,3 epoxide to reduced vitamin K [8]. Although the benefits of OAC are supported by a high degree of evidence for stroke prevention in cardioembolic entities, such as atrial fibrillation [8], they have a narrow therapeutic index, numerous drug and dietary interactions, and a significant risk of serious bleeding, including hemorrhagic stroke [9]. Alternatives to oral anticoagulation in this setting include safer and easier to use antithrombotic drugs and definitive treatment of atrial fibrillation.
Prevalence of Atrial Fibrillation Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, resulting in a prevalence of about 1 % in the general population [10]. The prevalence of atrial fibrillation is
strongly associated with increasing age, rising to 5 % in people older than 65 years and to nearly 10 % in those aged 80 years [11]. AF is also the most frequent cardiac condition associated to the risk of ischemic stroke, although it is only weakly associated with transient ischemic attack (TIA) [12]. AF increases the risk of stroke four- to fivefold across all age groups, accounting for 10–15 % of all ischemic strokes and nearly 25 % of strokes in people older than 80 years [13, 14]. This translates to an incidence of stroke approximating 5 % a year for primary events and 12 % a year for recurrent events [15]. In AF associated with rheumatic heart disease, stroke risk is increased even more: 17-fold compared with agematched controls [16]. Patients with paroxysmal and constant AF appear to have similar risks of stroke [17].
Diagnosis of AF in Stroke Patients The 12-lead electrocardiogram (ECG) has been the “gold standard” for AF and other arrhythmia diagnosis. AF is described by the replacement of consistent P waves by rapid oscillations or fibrillatory waves that vary in size, shape, and timing associated with an irregular, frequently rapid ventricular response when atrioventricular conduction is intact. In the newest European Society of Cardiology Guidelines, AF is defined as a cardiac arrhythmia with absolutely irregular RR intervals, no distinct P waves on the surface ECG, and the atrial cycle length is usually variable and <200 ms [18, 19]. When the ventricular rate is fast, atrioventricular blockade (Valsalva maneuver, carotid massage, intravenous adenosine) can help to unmask atrial activity. The initial evaluation of a patient with AF includes characterizing the pattern of the arrhythmia as paroxysmal or persistent, determining its cause, and defining associated cardiac and extracardiac factors. Typically AF develops in the setting of and underlying heart disease (hypertensive myocardiopathy, valvular heart disease, etc.). Its common triggers include alcohol, sleep deprivation, emotional stress, large meal, caffeine, and exercise, and during a period of rest after a period of stress [18]. The presence of associated symptoms can guide us toward an underlying etiology. Dyspnea may indicate heart disease, angina points toward coronary artery disease, and syncope may be associated with AF, but ventricular arrhythmias should not be overlooked [18]. The physical examination suggests AF when irregular pulse, irregular jugular venous pulsations, or variations on the loudness of the first heart sound are detected [18]. Once AF is diagnosed with the ECG, a chest radiograph is useful to detect enlargement of the cardiac chambers and heart failure, but its best value is to determine the coexistence of pulmonary pathology. Transthoracic echocardiography should be acquired to determine left auricular and left ventricular dimensions and left ventricular wall thickness and function and to exclude valvular or pericardic or hypertrophic myocardiopathy.
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Detection and Management of Atrial Fibrillation in Patients with Stroke or TIA in Clinical Practice
Also a blood test is important in order to measure hemogram, serum electrolytes, and thyroid function. The transesophageal echocardiography (TEE) is more sensitive and specific to detect sources and potential mechanism for cardiogenic embolism; in fact, 5–15 % of patients undergoing cardioversion show a thrombus in left atrium or left atrial appendage. Several TEE features have been associated with thromboembolism including left atrium/left atrial appendage thrombus, left atrium/left atrial appendage echo contrast, reduced left atrial appendage flow velocity, and aortic atheromatous abnormalities. Finally, in patients with paroxysmal AF, an electrophysiological study may define the mechanism of the arrhythmia which is important when curative catheter ablation is considered. Also, electrophysiological studies may be helpful when sinus node dysfunction is suspected to clarify the mechanism of wide QRS complexes during AF particularly when the ventricular response is rapid [18]. Arrhythmias can be paroxysmal and asymptomatic, so a baseline ECG may be insufficient for diagnosis. AF is considered to be paroxysmal if it ends spontaneously or persistent if it lasts more than 7 days or requires termination by cardioversion. Long-standing persistent AF has lasted for at least more than 1 year when it is decided to adopt a rhythmcontrol strategy, and permanent AF exists when the presence of the arrhythmia is accepted by the patient and the physician. Patients with paroxysmal AF have the same stroke risk as patients with persistent or permanent AF [20]. In order to avoid this problem, prolonged ECG monitoring in the inpatient setting was proposed to increase the diagnostic yield. A systematic review conducted by Liao et al. compiled the data from five studies including 58 patients. Duration of monitoring ranged from 21 to 159 h increased the detection rate to 3.8–6.1 %, so increased duration on monitoring appears to be associated with increased rates of detection of AF [21]. In the 1940s, the Holter monitor has developed and thenceforth much progress in ambulatory external electrocardiogram. Hospital telemetry, Holter monitors, many types of cardiac events recorders, and mobile cardiac outpatient telemetry devices are connected by disposable electrodes, which are in turn connected to a signal processing device by lead wires [22]. A Holter monitor consists of a three to five electrode machine which yields two ECG vectors and a third derived electrocardiogram. Event recorders are carried by the patient, and loop recorders require that ECG leads be attached to the patient. When the patient activates the device, it stores a single-lead ECG before and after the activation. To overcome the limitations of the previous monitors, ambulatory telemetry has been developed. The patient is connected by three to four ECG electrodes to a batterypowered sensor for up to 30 days. In the “sensor-only” system, when the patient is near available cellular coverage,
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the stored data are transmitted directly to a central monitor. However, most of the device incorporates a second handheld machine. In this case, when this second device is near the patient, it receives the data from the sensor. Once the patient is in a location with cellular coverage, these data are transmitted to a central monitor. The handheld device permits the patient to submit information about symptoms. The information about symptomatic and asymptomatic arrhythmia permits determination of the burden of the AF [23]. Most recently a small patch device has been developed. It is placed in the left pectoral region and can store up to 14 days of a continuous single-lead ECG. A button on the patch permits the patient to mark a symptomatic episode [23]. Twenty-four hour Holter monitoring can detect an AF de novo in 1–5 % of patients with a normal basal ECG [24]. This number increases up to 9.4 % in the subgroup of stroke patients [25]. Prolonged outpatient monitoring would extend the diagnosis to another 6–8 %, with longer recordings producing greater yield [26, 27]. Ambulatory electrocardiogram recordings during 21 days permit the diagnosis of paroxysmal AF in 23 % of patients with a cryptogenic stroke or transient ischemic attack (TIA) [28].
Anticoagulants for AF OAC therapy is highly effective in reducing stroke in patients with AF. In the late 1980s and early 1990s, six trials compared OAC therapy to placebo [17, 29]. Meta-analysis showed that dose-adjusted oral anticoagulation (target international normalized ratio (INR), 2.5; range, 2.0–3.0) is highly efficacious for prevention of all strokes (both ischemic and hemorrhagic), with a risk reduction of 68 % (95 % CI, 50–70 %) as compared to placebo [13, 14, 30]. This reduction was similar for both primary and secondary prevention and for both disabling and nondisabling strokes. Aspirin showed a less consistent benefit for stroke prevention than anticoagulation therapy. Aspirin compared to placebo was evaluated in three trials, and a pooled analysis of these studies showed a mean stroke risk reduction of 21 % (95 % CI, 0–38 %) [31, 32]. Dose-adjusted OAC resulted in a relative risk reduction of 52 % (95 % CI, 37–63 %) compared to aspirin [33–37]. The ACTIVE W trial (Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events), which compared the efficacy of combined antiplatelet therapy (aspirin 75–100 mg and clopidogrel 75 mg) versus OAC in high-risk patients with AF, demonstrated clearly the superiority of OAC in the long-term prevention of major ischemic events and had a similar bleeding rate [38]. In the ACTIVE A trial, 7,554 patients with AF who were considered unsuitable to receive vitamin K antagonist therapy were randomized to receive clopidogrel (75 mg/day)
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or placebo added to aspirin. The addition of clopidogrel to aspirin reduced the rate of major vascular events from 7.6 % per year to 6.8 %, primarily due to a reduction in the rate of stroke [39]. However, the rate of major hemorrhage increased from 1.3 to 2.0 %/year. Experts conclude that warfarin therapy is indicated when the risk of stroke is high and that aspirin is preferred when the risk of stroke is low. Several attempts have been made to establish and validate risk stratification schemes to quantify the absolute risk of stroke in patients with nonvalvular atrial fibrillation [40, 41] A systematic review was conducted to identify independent risk factors for stroke in patients who have AF [42]. There are four most consistent independent factors for stroke: prior stroke or transient ischemic attack (relative risk, 2.5; 95 % CI, 1.8–3.5), hypertension (relative risk, 2.0; 95 % CI 1.6–2.5), diabetes mellitus (relative risk, 1.7; 95 % CI, 1.4–2.0), and increasing age (relative risk, 1.5; 95 % CI, 1.3–1.7). The absolute rates of stroke in patients with only one independent risk are 6–9 % per year for history of stroke/transient ischemic attack, 2–3.5 % per year for diabetes mellitus, and 1.5–3 % per year for both hypertension and age of more than 75 years. However, there is no conclusive evidence that congestive heart failure and coronary artery disease are independent risk factors for stroke. The HEMORR2HAGES scheme was developed by combining bleeding risk factors from previous schemes and validated to quantify the risk of bleeding in anticoagulated patients [43]. The scheme is calculated by adding 2 points for rebleeding and 1 point for each of the following factors: hepatic or renal disease, ethanol abuse, malignancy, old age (older than 75 years), reduced platelet counts or platelet dysfunction, uncontrolled hypertension, anemia, genetic factors, elevated fall risk, and stroke. In primary prevention studies, OAC lowered the mortality rate by 33 % (95 % CI, 9–51 %) and the combined outcome of stroke, systemic embolism, and death by 48 % (95 % CI, 34–60 %) [15]. In these studies, the reported annual incidence of major bleeding and intracranial hemorrhage was 1.3 % and 0.3 % in anticoagulated patients, compared to 1 % and 0.1 % in control patients. The risk of intracranial hemorrhage is significantly increased at INR values >4.0, with increasing age, and in patients with a history of stroke [44]. From the available information, it is clear that oral anticoagulation is more efficacious and more risky than aspirin to prevent first stroke in patients with AF [7]. Chronic oral anticoagulation therapy is indicated in patients with AF and high risk of stroke unless contraindicated [10, 45]. The optimal intensity of anticoagulation for prevention of stroke in atrial fibrillation patients appears to be an international normalized ratio of 2.0–3.0, with a target of 2.5. A case-control study found that the efficacy of warfarin declines sharply below an international normalized ratio of 2.0 [46], and the risk of
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major hemorrhage appears to increase significantly above an international normalized ratio of 3.0–4.0. Despite the encouraging results of OAC in AF, this treatment is underutilized in clinical practice as more than onethird of eligible patients in primary care practice are not receiving it [47], and subtherapeutic INR are encountered in 45 % of patients taking OAC [48]. Current guidelines (CHEST guidelines 2012 for atrial fibrillation) for antithrombotic therapy are based on the absolute risk for stroke balanced with the estimated bleeding risk [1, 10, 45]. In brief, if (1) no risk factors for stroke, aspirin therapy (81–325 mg daily); (2) one moderate risk factor for stroke (age over 75 years, high blood pressure, heart failure, impaired left ventricular systolic function with an ejection fraction of 35 % or less, or diabetes), aspirin (81–325 mg) or warfarin (international normalization ratio, 2.0–3.0; target, 2.5); and (3) more than one moderate or any high-risk factor for stroke (previous stroke, transient ischemic attack, systematic embolism, or prosthetic heart valve), warfarin (international normalization ratio, 2.0–3.0; target, 2.5; in case of a mechanical valve, target international normalization ratio is greater than 2.5) [10]. Alternative recommendations use the CHADS2 scheme for risk stratification [40, 45]. Stroke-prone patients are reliably identified by a CHADS2 score >3, and they have an average risk of 5.5 strokes per 100 patient-years on aspirin [49]. The CHADS2 scheme is comprised of five conditions: recent congestive heart failure, hypertension, age of 75 years or older, and diabetes (each of which accounts for 1 point) as well as prior stroke or transient ischemic attack, which accounts for 2 points in total score calculation. The recent variant of the score is called CHA2DS2VASc (including gender and vascular disease). To date, there are no randomized trials to determine the efficacy of anticoagulation treatment for different subtypes of stroke. However, there is a recommended treatment strategy for patients with atrial fibrillation presenting with stroke or transient ischemic attack [50]. In a large, multicenter, randomized study comparing rhythm-control with rate-control strategy in patients with atrial fibrillation and high risk of stroke or death, rhythm-control strategy offered no survival advantage. Attempted maintenance of sinus rhythm did not reduce the risk of ischemic stroke [51]. The effect of the intensity of oral anticoagulation on the severity of atrial fibrillation-related stroke was assessed [52]. Adequate anticoagulation reduced not only the frequency of ischemic stroke but also its severity and the risk of death from stroke, highlighting an important incremental benefit of anticoagulation. Despite its proven efficacy in secondary prevention of stroke, anticoagulation therapy is not initiated in a major portion of especially elderly patients with AF, mainly because of contraindications but also because of multiple patient and physician barriers [40]. There has been some concern about
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Detection and Management of Atrial Fibrillation in Patients with Stroke or TIA in Clinical Practice
the risk/benefit of oral anticoagulation in elderly patients, because of a greater risk of hemorrhagic complications in this group of patients. However, the WASPO (Warfarin versus Aspirin for Stroke Prevention in Octogenarians) [53] and BAFTA (Birmingham Atrial Fibrillation Treatment of the Aged) trials [54] have shown that OAC is safe and effective in older individuals. Therefore, there is no justification to avoid anticoagulation in very old individuals with AF, unless there is a clear contraindication.
Immediate Anticoagulation After Acute Cardioembolic Stroke Acute Stroke In a review of the Cochrane database system [55] 24 trials involving 23,748 participants with acute stroke were included. The anticoagulants tested were standard unfractionated heparin, low-molecular-weight heparins, heparinoids, oral anticoagulants, and thrombin inhibitors. For the analysis of the primary outcome, all of the data related to the initiation of anticoagulants within 48 h of onset, and 89 % of the evidence related to unfractionated heparin. Based on 11 trials (22,776 participants), there was no evidence that anticoagulant therapy reduced the odds of death from all causes (OR, 1.05; 95 % CI, 0.98–1.12) at the end of follow-up. Similarly, based on 8 trials (22,125 participants), there was no evidence that anticoagulants reduced the odds of being dead or dependent at the end of follow-up (OR, 0.99; 95 % CI, 0.93–1.04). Although anticoagulant therapy was associated with fewer recurrent ischemic strokes (OR, 0.76; 95 % CI, 0.65–0.88), it was also associated with an increase in symptomatic intracranial hemorrhages (OR, 2.55; 95 % CI, 1.95–3.33). Similarly, anticoagulants reduced the frequency of pulmonary emboli (OR, 0.60; 95 % CI, 0.44–0.81), but this benefit was offset by an increase in extracranial hemorrhages (OR, 2.99; 95 % CI, 2.24–3.99).
Acute Stroke with AF Hart et al. [56] presented a critical review of three randomized clinical trials testing aspirin, heparin/heparinoid, or both involving 5,029 patients with AF and acute stroke. In the International Stroke Trial (IST), 19,435 patients with suspected acute ischemic stroke within 48 h (93 % confirmed as ischemic by early CT) were randomly assigned to aspirin 300 mg/day versus no aspirin and, separately, to one of two dosages of subcutaneous heparin versus no heparin in a 2 × 3 factorial design [57]. Treatment was not masked, and there were no prespecified criteria for early recurrent stroke. Results for the subgroup of 3,169 participants (17 %) with
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AF have been reported. The Chinese Acute Stroke Trial (CAST) compared aspirin 160 mg/day with placebo (double blind) in 21,106 patients with suspected acute ischemic stroke within 48 h. AF was present in only 7 % (n = 1,411) of participants. Limited data about the subgroup of AF patients from the CAST have been published [58], with additional outcome data available combining AF patients assigned to aspirin in the CAST with those from the IST. The Heparin in Acute Embolic Stroke Trial (HAEST) randomly assigned 449 AF patients with acute ischemic stroke (all confirmed by CT) within 30 h of stroke onset from 45 Norwegian centers to a low-molecular-weight heparin (dalteparin 100 IU/kg SC twice daily) or aspirin 160 mg/day in a double-blind design, with the main outcomes of recurrent stroke during the first 14 days and functional status or death after 3 months [59]. Early recurrent ischemic stroke occurred in about 5 % of patients during the 2–4 weeks after initial stroke. Data from the two relevant randomized clinical trials conflict. The double-blind HAEST found no reduction in early recurrent ischemic stroke among AF patients randomized to receive a low-molecular-weight heparin versus aspirin [59]. In contrast, the IST found “a clear and dose-dependent reduction in recurrent ischemic stroke among patients allocated to heparin” (P = .001) given subcutaneously [60]. The overall rates of recurrent ischemic stroke in the control arms (5 % in IST, 8 % in HAEST) and of secondary brain hemorrhage (2 % in IST, 3 % in HAEST) among those given heparin/heparinoid were similar in the two trials. However, the reduction in early recurrent ischemic stroke by heparin in the IST was almost entirely offset by increased symptomatic brain hemorrhage. Data conflict about whether early use of heparin/heparinoid reduced early recurrent ischemic stroke but are consistent regarding its lack of overall benefit on long-term functional outcome. Modest benefits for reduction of early recurrent stroke and functional outcome were associated with aspirin use, based largely on subgroup analysis from a single, large, unblinded trial.
When to Start Anticoagulation After a Cardioembolic Stroke for Secondary Prevention? Subcutaneous unfractionated heparin (UFH) at low or moderate doses [57], nadroparin [61, 62], certoparin [63], tinzaparin [64], dalteparin [59], and intravenous danaparoid [65] have failed to show an overall benefit of anticoagulation when initiated within 24–48 h from stroke onset. Improvements in outcome or reductions in stroke recurrence rates were mostly counterbalanced by an increased number of hemorrhagic complications. In a meta-analysis of 22 trials, anticoagulant therapy was associated with about nine fewer recurrent ischemic strokes per 1,000 patients treated (OR, 0.76; 95 %
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CI, 0.65–0.88) and with about nine more symptomatic intracranial hemorrhages per 1,000 (OR, 2.52; 95 % CI, 1.92– 3.30) [66]. However, the quality of the trials varied considerably. On the basis of the usual timing of secondary hemorrhagic transformation between 12 h and 4 days after stroke onset, it seems reasonable to begin warfarin as soon as the patient is medically and neurologically stable, often 2–3 days after stroke, to achieve therapeutic anticoagulation 7–10 days after stroke onset. Some experts routinely repeat a CT scan before initiating warfarin and delay warfarin therapy if hemorrhagic transformation is evident. Minor degrees of hemorrhagic transformation are frequent (particularly on MRI), and the clinical significance regarding initiation of warfarin is unclear and controversial. No benefit of heparin has been demonstrated for acute stroke patients with AF; whether selected subgroups would respond differently remains to be proven. Aspirin followed by early initiation of warfarin for long-term secondary prevention is a reasonable antithrombotic management. Few clinical trials have assessed the risk/benefit ratio of very early administration of UFH in acute ischemic stroke. In one study, patients with nonlacunar stroke anticoagulated within 3 h had more self-independence (38.9 % vs. 28.6 %; P = .025), fewer deaths (16.8 % vs. 21.9 %; P = .189), and more symptomatic brain hemorrhages (6.2 % vs. 1.4 %; P = .008) [67]. In the RAPID (Rapid Anticoagulation Prevents Ischemic Damage) trial, patients allocated UFH had fewer early recurrent strokes and similar incidence of serious hemorrhagic events, compared with those receiving aspirin [68]. In the UFH group, ischemic or hemorrhagic worsening was associated with inadequate plasma levels of UFH. In view of these findings, the value of UFH administered shortly after symptom onset is still debated [69, 70].
Embolic Events During Adequate Antithrombotic Therapy In the patient who has a definite embolic episode while undergoing adequate antithrombotic therapy or INR is in range, the dosage of antithrombotic therapy should be increased, when clinically safe, as follows: (1) warfarin, INR 2.0–3.0: warfarin dose increased to achieve INR of 2.5–3.5; (2) warfarin, INR 2.5–3.5: warfarin dose may need to be increased to achieve INR of 3.5–4.5; (3) not taking aspirin: aspirin 75–100 mg/day should be initiated; (4) warfarin plus aspirin 75–100 mg/day: aspirin dose may also need to be increased to 325 mg/day if the higher dose of warfarin is not achieving the desired clinical result; and (5) aspirin alone: aspirin dose may need to be increased to 325 mg/day, clopidogrel 75 mg per day added, and/or warfarin added [71]. However, there is class IA recommendation for European Stroke Organization not to use double antiplatelets except on
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special occasions, for example, unstable angina, non-Q myocardial infarction, and after stent. When INR is in range, new anticoagulants can be used. Dabigtran, rivaroxaban and apixaban are currently approved in most of the countries. Its use can be extended to situations of hypersensibility, resistance or intolerance to classic anticoagulants, and difficulty in daily control.
Long-Term Secondary Stroke Prevention After OAC-Related ICH Another difficult decision in clinical practice is whether anticoagulants should be restarted and maintained indefinitely in patients with a history of OAC-related ICH and at risk of cardioembolic events. Stroke prevention in this situation needs to balance the risk/benefit of different antithrombotic options and the estimated risk of intracranial bleeding recurrence. To this aim, an important step is to establish the most likely cause of the bleeding. Whereas hypertensive vasculopathy appears to be the most important mechanism for ICH in deep hemispheric regions of the brain, cerebral amyloid angiopathy may be the most common underlying pathophysiology for lobar ICH. The risk of recurrent hypertensive ICH can be decreased by an adequate control of hypertension [72], whereas cerebral amyloid angiopathy lacks any known treatment. In a prospective study of elderly patients who survived lobar ICH, recurrent ICH occurred in 22 % at 2 years [73]. The rate of recurrent ICH in survivors of deep hemispheric ICH was estimated to be 2.1 % per patient-year [74]. Therefore, in patients with lobar hemorrhage and major sources of embolism, decision analysis models based on retrospective data suggest that the strategy of “do not anticoagulate” appears robust [74]. Contrarily, the risks and benefits of anticoagulation are more closely balanced when applied to patients with deep hemispheric ICH. In the latter case, OAC might be justified if the estimated risk of ischemic stroke is high.
Bleeding Risk in Orally Anticoagulated Patients The risk of major bleeding in patients receiving OAC is 3 % per year; and approximately 20 % of major bleeding events are fatal [75]. Even at safe anticoagulant levels (INR 2.0– 3.0) annual rates of major, life threatening, and fatal bleeding are 2, 1, and 0.25 %, respectively [76]. Every one-point rise in INR increases the risk of major bleeding by 42 % [77], and the interval 2.0–2.5 gives the lowest risk of stroke and death in patients with nonvalvular AF [78]. Concomitant hypertension, prior cerebrovascular accident, gastrointestinal bleeding or anticoagulation-related bleeding, use of aspirin or
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Detection and Management of Atrial Fibrillation in Patients with Stroke or TIA in Clinical Practice
nonsteroidal anti-inflammatory drugs, older age, patient reliability, and the interactions of OAC with other medications contribute to the risk of bleeding [79]. The most frequent complication of OAC is gastrointestinal bleeding, but intracranial hemorrhage (ICH) is the main cause of fatal bleeding. In a pooled analysis of the first five trials with warfarin in patients with AF, the annual rate of OAC-related ICH was 0.3 % [80]. OAC-related ICH occurs at a rate of 2–9 per 100,000 population/year, an incidence which is seven- to tenfold higher than in patients not receiving OAC [81]. The incidence of intracranial hemorrhage due to OAC is increasing, probably because of the larger number of elderly patients that receive this treatment, the association with aspirin, or the expanded use of OAC for stroke prevention [82].
New Anticoagulants Dose-adjusted oral anticoagulation (international normalized ratio [INR], 2.0–3.0) with vitamin K antagonists is highly efficient in reducing the risk of ischemic stroke in AF patients with moderate to high risk of stroke [2, 3] and superior to antiplatelet agents [4]. However, in clinical practice only about 50–70 % of AF patients with the indication
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receive stroke prevention with vitamin K antagonists [5, 6]. Reasons for this important underuse include the narrow therapeutic window with a need for frequent coagulation checks, interactions with multiple drugs and foods, as well as an important bleeding risk. Moreover, even in clinical trials, warfarin-anticoagulated patients are in the therapeutic range only about 65 % of the time [7]. Anticoagulation therapy’s associated risk of hemorrhage and cumbersome monitoring requirements have encouraged the investigation of alternative therapies for individuals with atrial fibrillation. Recently published data suggest that new anticoagulants including the direct thrombin inhibitor dabigatran and the direct factor Xa inhibitors rivaroxaban and apixaban are equivalent or even superior to warfarin in preventing stroke or systemic embolism in the setting of atrial fibrillation (AF) (see Table 17.2). Of note, there are data showing a trend toward reduction in all-cause mortality, while the most recent randomized trial demonstrated a clear reduction in the risk of death. In the three studies with 50,578 patients combined, 28,342 patients were randomized to new anticoagulants and 22,236 patients to warfarin therapy. The first pooled analysis including the RE-LY trial arm with 110 mg of dabigatran showed that new anticoagulants significantly reduced allcause mortality by 10 % compared with dose-adjusted warfarin (HR, 0.90; 95 % CI, 0.84–0.96; P = 0.002), without
Table 17.2 Three major clinical trials with new anticoagulants against warfarin – summarized results Study Objective
Inclusion criteria
Study sample Groups
Follow-up
RE-LY Compare, in a blinded fashion, fixed doses of dabigatran and, in an unblinded fashion, adjusteddose warfarin in patients with atrial fibrillation and risk for stroke
Rocket-AF Noninferiority, double-blind, double-dummy trial comparing rivaroxaban with dose-adjusted warfarin in patients with AF with stroke or at least two risk factors for stroke Patients with AF and at least one risk factor of Patients with AF and moderate stroke: to high risk for stroke: Stroke, TIA or systemic embolism Stroke, TIA or systemic LVEF < 40 % embolism Heart failure ≥ NYHA II Or 2 or more RF Age ≥75 years Heart failure and LVEF Age 65–74 associated with one risk factor ≤35 % Diabetes mellitus Hypertension Hypertension Age ≥75 years Coronary disease Diabetes mellitus Inclusion of 50 % naive patients (≤60 days to AVK) Patients with CHADS2 = 2 10 % preference for naive patients 18.113 14.264 3 ARMS: 2 ARMS: Dabigatran etexilate 110 mg bid Rivaroxaban 20 mg qd (15 mg Dabigatran etexilate 150 mg bid qd in patients with CrCl 30 at Warfarin (INR 2–3) qd 49 mL/min) Warfarin (INR 2–3) qd Minimum of 12 months Minimum 405 events Median: 2 years Median: 1.94 years
Aristotle Noninferiority, double-blind trial to compare apixaban with dose-adjusted warfarin in patients with AF and at least 1 RF for stroke Patients with flutter or AF and 1 RF for stroke: Age ≥75 years Stroke, TIA or systemic embolism Heart failure, LVEF < 40 % Hypertension 40 % naive patients
18.201 2 ARMS: Apixaban 5 mg bid (2.5 mg bid in patients ≥ 80a and ≤60 kg or with CrCl ≥1.5 mg/dL Warfarin (INR 2–3) qd Minimum 448 events Median: 1.8 years (continued)
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Table 17.2 (continued) Study Primary outcome Primary safety outcome Statistical analysis
RE-LY Stroke or systemic embolism Major hemorrhage
Rocket-AF Stroke or systemic embolism Major hemorrhage
Aristotle Stroke or systemic embolism Major hemorrhage
Noninferiority study. All analysis based on ITT
Noninferiority study hemorrhagic events: safety on treatment
Mean age Men Hypertension Diabetes mellitus Heart failure Prior stroke, TIA or systemic embolism Naïve CHADS2 mean CHADS2: 3–6 CHADS2: 0–1 CHADS2: 2 CHADS2: 3–6 Discontinuation
71 64 % 79 % 23 % 32 % 19.9 %
Noninferiority study. Superiority studied as safety on treatment and later on ITT Other variables: safety on treatment 73 61 % 90.5 % 40 % 62.5 % 54.8 %
50 % 2.1 33 % 32 % 35 % 33 Warfarin 10 %, DE 15 %, 1 year Warfarin 16 %, DE: 21 %, 2 years 64.4 % (average) 67.3 % (median) DE 150 mg vs. DE 110 mg vs. warfarin warfarin
38 % 3.5 86 % 0% 14 % 86 % Warfarin: 22 % Rivaroxaban: 24 % 55 % (average) 58 % (median) Rivaroxaban 20 mg vs. warfarin
43 % 2.1 30 % 34 % 36 % 30 % Warfarin: 27 % Apixaban: 25 % 62 % (average) 66 % (median)
ND (ITT)
Superior (ITT) RRR 35 %
Noninferior (PP and ITT)
Superior (ITT) RRR 21 %
ND ND RRR 69 % ND ND ND (0.82 % vs. 0.64 %)
RRR 36 % RRR 24 % RRR 74 % RRR 15 % ND ND (0.81 % vs. 0.64)
ND ND RRR 41 % ND ND ND (0.91 % vs. 1.12 %)
RRR 21 % Without differences RRR 49 % ND RRR 11 % ND (0.53 % vs. 0.61 %)
ND(Var. Pral)
RRR 32 %
Time in therapeutic range of warfarin
Efficacy Principal variable: stroke or systemic embolism All strokes Ischemic stroke Hemorrhagic stroke Vascular death Any death Myocardial infarction Safety results Major hemorrhage or clinically relevant Major hemorrhage Life-threatening bleeding Major bleeding
Apixaban 5 mg vs. warfarin
RRR 20 % (Var. Pral) RRR 32 %
ND (Var. Pral) RRR 19 %
ND
RRR 31 % (Var. Pral)
ND (1.12 % vs. 1.02 %)
Worst DE 150 mg (1.51 % vs. 1.02 %; RRR 1.50)
Worst rivaroxaban 20 mg (3.15 % vs. 2.16 %; RRR 1.46)
ND (0.76 % vs. 0.86 %)
Reduction in HB > 2G/dL Transfusion Critical bleeding Fatal bleeding Intracranial hemorrhage
70 65 % 87.5 % 25 % 35.5 % 19.5 %
RRR 42 % RRR 69 %
RRR 30 % RRR 60 %
Worst rivaroxaban 20 mg (4.3 % vs. 3.6 %; RR 1.22) Worst rivaroxaban 20 mg (2.6 % vs. 2.1 %; RR 1.25) RRR 31 % RRR 50 % 34 patients vs. 55 patients RRR 33 % RRR 58 %
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Detection and Management of Atrial Fibrillation in Patients with Stroke or TIA in Clinical Practice
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Table 17.2 (continued) Study Minor hemorrhage clinically relevant Minor hemorrhage All bleedings Other adverse events All patients with AE Dyspepsia and GI AE Epistaxis Hematuria Conclusion
RE-LY
Rocket-AF ND
RRR 21 % RRR 22 % (14.62 % vs. 18.15 %)
RRR 9 % RRR 9 % (16.42 % vs. 18.15 %)
ND
ND
Worst DE 110 mg (11.8 % vs. 5.8 %) ND (1.1 % vs. 1.8 %)
RRR 29 % (18.1 % vs. 25.8 %)
ND
Worst DE 150 mg (11.3 % vs. 5.8 %) ND (1.1 % vs. 1.8 %) Worst rivaroxaban 20 mg (10.14 % vs. 8.55 %) ND (0.8 % vs. 1.1 %) ND (1.0 % vs. 1.1 %) Worst rivaroxaban 20 mg (4.16 % vs. 3.40 %) In patients with atrial fibrillation, dabigatran given In patients with AF, rivaroxaban at a dose of 110 mg was associated with rates of was noninferior to warfarin in stroke and systemic embolism that were similar to prevention of stroke or systemic those associated with warfarin, as well as lower embolism. There was no rates of major hemorrhage. Dabigatran administered difference in risk of major at a dose of 150 mg, as compared with warfarin, hemorrhage, but intracranial and was associated with lower rates of stroke and fatal hemorrhages were less systemic embolism but similar rates of major frequent (NCT 00403767) hemorrhage (ClinicalTrials.gov number NCT00262600)
significant heterogeneity (P = 0.86) [83]. In the same line, the second pooled analysis including the RE-LY trial arm with 150 mg of dabigatran demonstrated that new anticoagulants significantly reduced the all-cause mortality by 9 % compared with dose-adjusted warfarin (HR, 0.91; 95 % CI, 0.85– 0.97; P = 0.004), without significant heterogeneity (P = 0.91). This meta-analysis suggests that the use of new oral anticoagulants in AF including direct thrombin and direct factor Xa inhibitors is associated with a 9–10 % reduction of allcause mortality compared with dose-adjusted warfarin. The exact mechanisms for this benefit are not clear although the reduction in hemorrhagic stroke and fatal bleeding complications represents reasonable explanations. Apart from stroke prevention, the potential advantage of new oral anticoagulation agents with regard to all-cause mortality represents a significant step forward in the treatment of AF [84–86].
Dabigatran and the RE-LY Trial The RE-LY trial included 18,113 patients with AF and at least one vascular risk factor (prior stroke, TIA or systemic embolism, left ventricular ejection fraction <40 %, congestive heart failure New York Heart Association ≥II, age ≥75 years, or age ≥65 years, and additional vascular risk factors). Patients were randomized into one of three groups and treated with warfarin (target INR 2.0–3.0), dabigatran
Aristotle
ND ND ND ND In patients with AF, apixaban was superior to warfarin in prevention of stroke and systemic embolism. There were less hemorrhages and mortality (NCT 00412984)
110 mg twice a day (bid), or dabigatran 150 mg bid over a median follow-up of 2 years. Doses of dabigatran were blinded, whereas warfarin was given open label. The primary outcome in this noninferiority trial was a composite of stroke and systemic embolism with adjudication blinded to treatment (PROBE design). The primary outcome occurred in 1.69 % of patients per year in the warfarin group compared with 1.53 % patients per year in the 110 mg bid dabigatran group (P < 0.001 for noninferiority) and 1.11 % in the 150 mg bid dabigatran group (P < 0.001 for superiority). The rate of major bleeding was 3.36 % per year in the warfarin group compared with 2.71 % in the 110 mg bid dabigatran group (P = 0.003) and 3.11 % per year in 150 mg bid dabigatran group (not significant). The rate of hemorrhagic stroke was 0.38 % per year in the warfarin group, compared with 0.12 % and 0.10 % in the 110 and 150 mg bid dabigatran groups, which corresponds to a relative risk reduction of 59–70 % for dabigatran versus warfarin. The rate of discontinuation was higher in both dabigatran groups (21 %) compared with warfarin (17 %) mainly due to dyspepsia, nausea, or diarrhea. There was a nonstatistically significant increase of myocardial infarctions in both dabigatran groups compared with warfarin [83]. Based on the results of the RE-LY trial, both doses of dabigatran were licensed in Europe. In the USA, only the higher dose of dabigatran (150 mg bid) was approved because the US Food and Drug Administration (FDA) considered the superiority in stroke prevention more important
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than the reduction of major bleeding complications seen with the lower dose (110 mg bid) of dabigatran. Despite the lack of clinical outcome data, dabigatran, 75 mg bid, was approved for AF patients with a reduced creatinine clearance (CrCl) of 15–30 mL/min in the USA but not in Europe. In conclusion the RE-LY study showed that dabigatran is more effective or safer compared with warfarin. Treatment with dabigatran can be recommended immediately in patients with a TIA, 3–5 days after stroke onset in patients with minor stroke, and 10–14 days after stroke onset in patients with severe stroke. The anticoagulant effect of dabigatran is established within hours and can be quantified by the Hemoclot thrombin inhibitor test. Current treatment with dabigatran within the last 48 h is a contraindication for systemic thrombolysis, although this could become a treatment option in patients with dabigatran serum levels below 50 ng/mL. Major or intracranial bleeding in patients taking dabigatran can be treated with prothrombin complex concentrates, fresh frozen plasma, or recombinant factor VIIa. The combination of dabigatran and platelet inhibitors increases bleeding risk and is of unproven benefit [85].
Dose Selection and Monitoring Anticoagulant Effect Dabigatran is administered as a prodrug (dabigatran etexilate), which is metabolized to the active form, dabigatran. Renal excretion of unchanged dabigatran is the predominant elimination pathway, with about 80 % excreted unchanged in the urine [87–91]. Anticoagulant monitoring is not necessary during routine dabigatran treatment. However, it may be indicated in certain situations, such as suspected overdose, and emergency situations, in the perioperative setting, in the event of bleeding or to identify patients at increased bleeding risk due to excessive dabigatran exposure or in patients with progressive or severe renal dysfunction. The anticoagulant tests can be broadly categorized as qualitative (i.e., suitable for detection of excess anticoagulant activity) or quantitative. Guidance for cutoff values for coagulation assays are indicative of increased bleeding risk. Clinicians should be aware that a blood sample taken 2 h after dabigatran dosage (~peak level) will have a higher result in all clotting tests compared with samples taken at 10–12 h (trough level). The INR test is not recommended for monitoring as it is insensitive to dabigatran [92–94]. Both the aPTT and thrombin time (TT) test may be useful as qualitative measures to detect an excess of anticoagulant activity [88, 92]. At a dose of 150 mg bid, the aPTT is approximately twice the baseline value although there is some variability due to different test reagents [95]. A trough aPTT >80 s (s) (or two- to threefold of baseline value) is
J. Krupinski et al.
associated with a higher risk of bleeding [88, 92]. The TT is a more sensitive test and is significantly raised at therapeutic doses, and thus, a normal TT or aPTT measurement indicates no clinically relevant anticoagulant effect of dabigatran. Once again, there is some variability depending on the coagulometer and the thrombin reagent used for the measurement.
Special Situations Thrombolysis in Patients with Acute Ischemic Stroke In the setting of acute ischemic stroke, intravenous administration of recombinant tissue plasminogen activator (rtPA) is proven if given to eligible patients within 4.5 h of symptom onset [96]. Warfarin-treated patients with stroke are not considered eligible for thrombolysis unless the INR less than 1.7 although an increased risk of symptomatic intracerebral hemorrhage after thrombolytic treatment has been reported even in those with subtherapeutic INR levels [97]. The use of thrombolysis in patients receiving concurrent dabigatran has not been studied and may increase the risk of bleeding [88]. There are few anecdotal reports. De Smedt et al. reported successful use of rtPA in a patient 4.5 h after onset of an ischemic stroke and 7 h after receiving dabigatran [98]. Matute et al. [99] reported the use of tPA 15 h after dabigatran when plasma concentration of dabigatran was low and aPTT was normal, suggesting absence of anticoagulant effect, which could have favored the absence of complications. In both of the above cases, anticoagulation tests suggested a low risk of bleeding. In patients who are considered possible candidates for thrombolysis, measurement of the aPTT, TT, or ECT are appropriate initial tests. A normal result from one of these assays generally indicates that the risk of bleeding is low, although there is also the possibility that one or more doses of dabigatran may have been missed. Since the INR is insensitive to dabigatran, a recommendation based on INR is not useful. Whether thrombectomy with the Penumbra®, Solitaire®, or Trevo® revascularization devices is possible in patients treated with dabigatran has not been evaluated. Initiation of Dabigatran After Transient Ischemic Attack or Ischemic Stroke In RE-LY, patients with transient ischemic attack (TIA) or ischemic stroke were excluded if the event had occurred within the previous 2 weeks. However, there is no reason to assume that dabigatran carries a higher bleeding risk than warfarin when initiated early after the event. Since dabigatran achieves full anticoagulant activity 2 h post-dose, it should only be commenced when the patient is suitable for full anticoagulation. In patients with a TIA, it seems
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Detection and Management of Atrial Fibrillation in Patients with Stroke or TIA in Clinical Practice
reasonable that dabigatran can be started as soon as imaging tests have excluded a cerebral hemorrhage. We recommend that treatment can be initiated 3–5 days after a mild stroke, 5–7 days after a moderate stroke, and 2 weeks after a severe stroke [85, 100].
Rivaroxaban The coagulation cascade has three main pathways, intrinsic (contact activation pathway), extrinsic (tissue factor pathway), and a final common pathway (thrombin pathway). The common end point of the intrinsic and extrinsic pathways is the activation of factor X, also known prothrombinase or Stuart-Power factor. Factor Xa binds to factor Va and calcium (prothrombinase complex) on the surface of platelets and activates prothrombin into thrombin. The main role of thrombin is the conversion of fibrinogen into fibrin and the activation of factor XIII. Factor XIIIa cross-links fibrin polymers stabilizing the clot. By inhibiting factor Xa, generation of thrombin is attenuated [101–104]. Rivaroxaban is a small-molecule (molecular weight, 436 g/mol), oxazolidone-derivative, direct factor Xa inhibitor that antagonizes the active site of the free form, prothrombinase-bound form, and clot-associated factor Xa. This inhibition is potent, selective, and reversible. Rivaroxaban is absorbed with 80 % bioavailability. Absorption is rapid with maximal anticoagulant effect achieved 2–4 h after oral dosing. Its terminal half-life is 5–9 h in healthy volunteers and 9–13 h in the elderly [103–106]. This molecule binds proteins in a 92–95 %, with serum albumin being the main binding component [104]. The distribution volume (Vd) is moderate, approximately 50 l at steady state. The Vd is moderately affected by age, body weight, and indirectly by sex. As expected, body weight directly correlated with the Vd. The influence of sex is probably due to the difference in body weight between male and female. The influence of age is also probably related to sexbody weight factors because of the major expectative of life in women. Vd influences in rivaroxaban exposure, so decreases in Vd induce an increase in rivaroxaban exposure [107]. The pharmacokinetic profile of rivaroxaban is not affected by food or drugs, except by potent inhibitors of CYP3A4 (see below). Body weight and gender do not affect the pharmacokinetic or pharmacodynamic profile of rivaroxaban. Rivaroxaban clearance is one-third renal as unchanged drug and two-thirds via hepatic metabolism. Of the rivaroxaban metabolized in the liver, half is metabolized via CYP3A4 and CYP2J2 with metabolites excreted in the feces and the other half via independent cytochrome P450 pathways which inactive metabolites are renal eliminated. Intestinal excretion
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of rivaroxaban is mediated by P-glycoprotein (P-gp). Its clearance is impaired with advancing age, diminished creatinine clearance, and co-administration of strong CYP3A4 and P-gp inhibitors such as HIV protease inhibitors and azole antimycotics [105, 106]. Because of this partial renal elimination, renal impairment decreases renal clearance of rivaroxaban, increasing the overall exposure to the drug. However, the influence of renal function on rivaroxaban clearance is moderate as expected for a drug partially renal excreted. No dose adjustment is required in mild (creatinine clearance (CrCl) 50–80 mL/min) or moderate (CrCl 30–49 mL/min) renal impairment. The pharmacokinetic of rivaroxaban is similar when given once or twice daily. As expected, rivaroxaban given once daily correlated with higher Cmax and lower Cthrough than when given twice daily. These differences are within the 5th– 95th percentile ranges. This suggests that once-daily dosage should not expose patients to a greater risk of bleeding or thrombus than twice-daily dosage [104, 107]. Rivaroxaban inhibits factor Xa in a dose-dependent manner. Because of this factor Xa inhibition, factor Xa prolongs both prothrombin time (PT) and activated partial thromboplastin time (aPTT). However, these parameters cannot be used to monitor rivaroxaban treatment because the alteration of these parameters varies significantly depending on the clotting assays and condition used. Rivaroxaban plasma concentrations correlated closely with PT prolongation with rivaroxaban concentrations <500 μg/L. This correlation becomes non-linear at higher concentrations; however, higher concentrations are unlikely to be achieved in clinical practice [106, 107]. Rivaroxaban and the other oral factor Xa inhibitors exhibit no direct effect on platelet aggregation by contrast to direct thrombin inhibitors. Because of its selectiveness, this drug does not affect other serine proteases involved in the coagulation cascade [104–106]. As far as potential drug interactions, bleeding time is prolonged with association with ASA, but this effect is small and is considered clinically irrelevant. In the same way, the co-administration of naproxen reveals similar results. The interactions with CYP3A4 inhibitors have been mentioned above; CYP3A4 inducers such as carbamazepine, phenobarbital, or rifampicin should be co-administered with rivaroxaban with caution. Other studies have been conducted with atorvastatin, enoxaparin, ranitidine, and digoxin, revealing low propensity for clinically relevant drug-drug interactions [104, 106, 107]. Several trials have demonstrated the efficacy of rivaroxaban in deep vein thrombosis [108–113], and in acute coronary syndrome [114]. Recently, the ROCKET AF study has been publicated. This was a multicenter, randomized, double-blind,
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double-dummy, event-driven trial. The patients recruited had nonvalvular AF who were at moderate to high risk for stroke. The elevated risk was indicated by a history of stroke, transient ischemic attack or systemic embolism, or at least two of the following risk factors: heart failure or left ventricular ejection fraction of 35 % or less, hypertension, age 75 years or more, or diabetes mellitus. Because of these inclusion criteria, 13 % of patients had a CHADS2 2 and 87 % 3 or higher. Patients were randomly assigned to receive 20 mg of rivaroxaban or dose-adjusted warfarin (target INR 2.0–3.0). In the per-protocol population, stroke or systemic embolism occurred in 1.7 % patients per year in the rivaroxaban group and in 2.2 % patients per year in the warfarin group (HR, 0.79; CI, 0.66–0.96; P < 0.001 for noninferiority). In the astreated safety population, primary events occurred in 1.7 % patients per year and in 2.2 patients per year in the warfarin group (HR, 0.79; CI, 0.65–0.95; P = 0.01 for superiority). In the intention-to-treat analysis, primary events occurred in 2.1 % patients per year and in 2.4 % patients per year in the warfarin group (HR, 0.88; CI, 0.74–1.03; P < 0.001 for noninferiority; P = 0.12 for superiority). Major and clinically relevant nonmajor bleeding occurred in 14.9 % and in 14.5 % patients per year in the rivaroxaban and warfarin groups, respectively (HR, 1.03; CI 0.96–1.11; P = 0.44). Intracranial hemorrhages were significantly lower in the rivaroxaban group than in warfarin group: 0.5 % versus 0.7 % patients per year (HR, 0.67; CI 0.47–0.93; P = 0.02). Major gastrointestinal bleeding was more common in the rivaroxaban group than in warfarin one: 3.2 % versus 2.2 % patient per year. Taken all these data together, rivaroxaban was noninferior to warfarin in the prevention of stroke and systemic embolism, with no difference in the rate of major or nonmajor clinically relevant bleeding. Intracranial bleeding occurred less frequently in the rivaroxaban group, but gastrointestinal hemorrhage was more frequent [115]. A prespecified subgroup was patients with creatinine clearance of 30–49 mL/min. These patients were randomly assigned to 15 mg of rivaroxaban or dose-adjusted warfarin (target INR 2.0–3.0). Of the 14,264 patients randomized in the ROCKET AF trial, 2,950 (20.7 %) had moderate renal impairment. Patients with renal impairment were older and had higher CHADS2 scores, higher prevalence of heart failure, peripheral vascular disease, and prior myocardial infarction. On the other hand, these patients had lower body mass indices and less frequent history of stroke or transient ischemic attack and were less likely to be diabetic. Stroke or systemic embolism occurred in 1.71 % patients per year in the rivaroxaban group and 2.16 % in warfarin group (HR, 0.79; CI, 0.66–0.96; P < 0.001 for noninferiority). Rates of stroke and systemic embolism were higher regardless of treatment received. These findings were consistent with those seen in patients without renal impairment. The principal safety end point occurred more frequently in patients with moderate
J. Krupinski et al.
renal impairment regardless of treatment assigned. There was no excess of major or clinically relevant nonmajor bleeding in patients treated with rivaroxaban versus warfarin (HR, 0.98; CI, 0.84–1.14). Furthermore, critical organ bleeding (including hemorrhagic stroke) and fatal bleeding were less frequent with rivaroxaban, but gastrointestinal bleeding was more common. These findings also were consistent with data of patients without renal insufficiency [116, 117].
Apixaban Apixaban is a direct and competitive inhibitor of factor Xa [118]. It has about 50 % bioavailability, and approximately 25 % is excreted by the kidney. Apixaban, at a dose of 2.5 mg twice daily, has been shown to be effective and safe for the prevention of venous thromboembolism after elective orthopedic surgery [119, 120]. The AVERROES (Apixaban Versus Acetylsalicylic Acid [ASA] to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment) study was therefore designed to determine the efficacy and safety of apixaban, at a dose of 5 mg twice daily, as compared with aspirin, at a dose of 81–324 mg daily, for the treatment of patients with atrial fibrillation for whom vitamin K antagonist therapy was considered unsuitable. In patients with atrial fibrillation for whom vitamin K antagonist therapy was unsuitable, apixaban reduced the risk of stroke or systemic embolism without significantly increasing the risk of major bleeding or intracranial hemorrhage. In ARISTOTLE randomized, double-blind trial, apixaban (at a dose of 5 mg twice daily) was compared with warfarin (target international normalized ratio, 2.0–3.0) in 18,201 patients with atrial fibrillation and at least one additional risk factor for stroke. The primary outcome was ischemic or hemorrhagic stroke or systemic embolism. The trial was designed to test for noninferiority, with key secondary objectives of testing for superiority with respect to the primary outcome and to the rates of major bleeding and death from any cause [121]. The median duration of follow-up was 1.8 years. The rate of the primary outcome was 1.27 % per year in the apixaban group, as compared with 1.60 % per year in the warfarin group (hazard ratio with apixaban, 0.79; 95 % confidence interval [CI], 0.66–0.95; P < 0.001 for noninferiority; P = 0.01 for superiority). The rate of major bleeding was 2.13 % per year in the apixaban group, as compared with 3.09 % per year in the warfarin group (hazard ratio, 0.69; 95 % CI, 0.60–0.80; P < 0.001), and the rates of death from any cause were 3.52 % and 3.94 %, respectively (hazard ratio, 0.89; 95 % CI, 0.80–0.99; P = 0.047). The rate of hemorrhagic stroke was 0.24 % per year in the apixaban group, as compared with 0.47 % per year in the warfarin group (hazard ratio, 0.51; 95 % CI, 0.35–0.75; P < 0.001), and the rate
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Detection and Management of Atrial Fibrillation in Patients with Stroke or TIA in Clinical Practice
of ischemic or uncertain type of stroke was 0.97 % per year in the apixaban group and 1.05 % per year in the warfarin group (hazard ratio, 0.92; 95 % CI, 0.74–1.13; P = 0.42). In conclusion, in patients with atrial fibrillation, apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality.
11.
Conclusions
Patients with ischemic stroke or TIA of unknown etiology should be studied for paroxysmal AF. This condition is clearly associated with subsequent stroke risk and should be treated with anticoagulants if CHADS2 is ≥1. Based on recently published three large clinical trials with new anticoagulants, including the direct thrombin inhibitor dabigatran, and the direct factor Xa inhibitors rivaroxaban and apixaban, we can conclude that new ACOs are superior to warfarin in preventing stroke or systemic embolism in patients with atrial fibrillation. Apart from stroke prevention, the potential advantage of new oral anticoagulation agents with regard to all-cause mortality represents a significant step forward in the treatment of AF and patients safety.
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References 18. 1. You JJ, Singer DE, Howard PA, Lane DA, Eckman MH, Fang MC, Hylek EM, Schulman S, Go AS, Hughes M, Spencer FA, Manning WJ, Halperin JL, Lip GY. Antithrombotic therapy for atrial fibrillation: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians EvidenceBased Clinical Practice Guidelines. Chest. 2012;141(2 Suppl): e531S–75. 2. Font MA, Krupinski J, Arboix A. Antithrombotic medication for cardioembolic stroke prevention. Stroke Res Treat. (2011);2011: 607852, p. 23. doi:10.4061/2011/607852. 3. Arboix A, Martí-Vilalta JL. Presumed cardioembolic lacunar infarcts. Stroke. 1992;23(12):1841–2. 4. Lodder J, Bamford JM, Sandercock PAG, Jones LN, Warlow CP. Are hypertension or cardiac embolism likely causes of lacunar infarction? Stroke. 1990;21(3):375–81. 5. Fisher CM. Capsular infarcts: the underlying vascular lesions. Arch Neurol. 1979;36(2):65–73. 6. Guidelines for management of ischaemic stroke and transient ischaemic attack 2008. Cerebrovasc Dis. 2008;25(5):457–507. 7. Cervera A, Amaro S, Obach V, Chamorro A. Prevention of ischemic stroke: antithrombotic therapy in cardiac embolism. Curr Drug Targets. 2007;8(7):824–31. 8. Whitlon DS, Sadowski JA, Suttie JW. Mechanism of coumarin action: significance of vitamin K epoxide reductase inhibition. Biochemistry. 1978;17(8):1371–7. 9. Schulman S, Beyth RJ, Kearon C, Levine MN. Hemorrhagic complications of anticoagulant and thrombolytic treatment: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest. 2008;133 Suppl 6: 257S–98. 10. Fuster V, Rydén LE, Cannom DS, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation – executive summary: a report of the American College of Cardiology/
19.
20.
21.
22. 23.
24.
25.
26.
233
American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation). J Am Coll Cardiol. 2006;48(4):854–906. Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study. J Am Med Assoc. 2001; 285(18):2370–5. Anderson DC, Kappelle LJ, Eliasziw M, Babikian VL, Pearce LA, Barnett HJM. Occurrence of hemispheric and retinal ischemia in atrial fibrillation compared with carotid stenosis. Stroke. 2002;33(8):1963–7. Hart RG, Benavente O, McBride R, Pearce LA. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a metaanalysis. Ann Intern Med. 1999;131(7):492–501. Lip GYH, Edwards SJ. Stroke prevention with aspirin, warfarin and ximelagatran in patients with non-valvular atrial fibrillation: a systematic review and meta-analysis. Thromb Res. 2006; 118(3):321–33. Singer DE, Albers GW, Dalen JE, Go AS, Halperin JL, Manning WJ. Antithrombotic therapy in atrial fibrillation: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126 Suppl 3:429S–56. Wolf PA, Dawber TR, Thomas Jr HE, Kannel WB. Epidemiologic assessment of chronic atrial fibrillation and risk of stroke: the Framingham study. Neurology. 1978;28(10):973–7. Atrial Fibrillation Investigators. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation: analysis of pooled data from five randomized controlled trials. Arch Intern Med. 1994;154(13):1449–57. Guidelines for the management of patients with atrial fibrillation. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to develop guidelines for the management of patients with atrial fibrillation) developed in collaboration with the North American Society of Pacing and Electrophysiology. Eur Heart J. 2001;22:1852–923. The Task Force for the Management of the Atrial Fibrillation of the European Society of Cardiology. Guidelines for the management of atrial fibrillation. Eur Heart J. 2010;31:2369–429. Sá S, Rodrigues RP, Santos-Antunes J, Rocha-Gonçalves F, Nunes JP. Antithrombotic therapy in nonvalvular atrial fibrillation: a narrative review. Rev Port Cardiol. 2011;30:905–24. Liao J, Khalid Z, Scallan C, Morillo C, O’Donnell M. Noninvasive cardiac monitoring for detecting paroxysmal atrial fibrillation or flutter after acute ischemic stroke: a systematic review. Stroke. 2007;3:2935–40. Russell JK, Gehman S. Early experience with a novel ambulatory monitor. J Electrocardiol. 2007;40:S160–4. Mittal S, Movsowitz C, Steinberg JS. Ambulatory external electrocardiographic monitoring. J Am Coll Cardiol. 2011; 58:1741–9. Bell C, Kapral M. Use of ambulatory electrocardiography for the detection of paroxysmal atrial fibrillation in patients with stroke. Canadian Task Force on Preventive Health Care. Can J Neurol Sci. 2000;27:25–31. Yu EH, Lungu C, Kanner RM, Libman RB. The use of diagnostic tests in patients with acute ischemic stroke. J Stroke Cerebrovasc Dis. 2009;133:754–62. Barthelemy JC, Gerard SF, Garnier P, et al. Automatic cardiac event recorders reveal paroxysmal atrial fibrillation after unexplained strokes or transient ischemic attacks. Ann Noninvasive Electrocardiol. 2003;8:194–9.
234 27. Jabaudon D, Sztajzel J, Sievert K, Landis T, Sztajzel R. Usefulness of ambulatory 7-day ECG monitoring for the detection of atrial fibrillation and flutter after acute ischemic stroke and transient ischemic attacks. Stroke. 2004;35:1647–51. 28. Tayal AH, Tian M, Kelly MK, Jones SC, Wrigth DG, Singh D, et al. Atrial fibrillation detected by mobile cardiac outpatient telemetry in cryptogenic TIA or stroke. Neurology. 2008;71:1696–701. 29. European Atrial Fibrillation Trial Study Group. Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke. Lancet. 1993;342(8882):1255–62. 30. Cervera A, Chamorro A. Antithrombotic therapy in cardiac embolism. Curr Cardiol Rev. 2010;6:227–37 [PMC free article] [PubMed]. 31. The Atrial Fibrillation Investigators. The efficacy of aspirin in patients with atrial fibrillation: analysis of pooled data from 3 randomized trials. Arch Intern Med. 1997;157(11):1237–40. 32. Albers GW. Atrial fibrillation and stroke: three new studies, three remaining questions. Arch Intern Med. 1994;154(13):1443–8. 33. Van Walraven C, Hart RG, Singer DE, et al. Oral anticoagulants vs aspirin in nonvalvular atrial fibrillation: an individual patient metaanalysis. J Am Med Assoc. 2002;288(19):2441–8. 34. Stroke Prevention in Atrial Fibrillation Investigators. Risk factors for thromboembolism during aspirin therapy in patients with atrial fibrillation: the stroke prevention in atrial fibrillation study. J Stroke Cerebrovasc Dis. 1995;5(3):147–57. 35. Stroke Prevention in Atrial Fibrillation Investigators. Dose-adjusted warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: stroke prevention in atrial fibrillation III randomized clinical trial. Lancet. 1996;348(9028): 633–8. 36. Dentali F, Douketis JD, Lim W, Crowther M. Combined aspirinoral anticoagulant therapy compared with oral anticoagulant therapy alone among patients at risk for cardiovascular disease: a meta-analysis of randomized trials. Arch Intern Med. 2007;167(2):117–24. 37. The III SPAF, Writing Committee for the Stroke Prevention in Atrial Fibrillation Investigators. Patients with nonvalvular atrial fibrillation at low risk of stroke during treatment with aspirin: Stroke Prevention in Atrial Fibrillation III Study. J Am Med Assoc. 1998;279(16):1237–77. 38. ACTIVE Investigators. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet. 2006;367(9526): 1903–12. 39. Connolly SJ, Pogue J, Hart RG, et al. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med. 2009;360(20):2066–78. 40. Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. J Am Med Assoc. 2001;285(22):2864–70. 41. Wang TJ, Massaro JM, Levy D, et al. A risk score for predicting stroke or death in individuals with new-onset atrial fibrillation in the community: the Framingham Heart Study. J Am Med Assoc. 2003;290(8):1049–56. 42. Stroke Risk in Atrial Fibrillation Working Group. Independent predictors of stroke in patients with atrial fibrillation: a systematic review. Neurology. 2007;69(6):546–54. 43. Gage BF, Yan Y, Milligan PE, et al. Clinical classification schemes for predicting hemorrhage: results from the National Registry of Atrial Fibrillation (NRAF). Am Heart J. 2006; 151(3):713–9. 44. Hylek EM, Singer DE. Risk factors for intracranial hemorrhage in outpatients taking warfarin. Ann Intern Med. 1994;120(11): 897–902.
J. Krupinski et al. 45. Goldstein LB, Adams R, Alberts MJ, et al. Primary prevention of ischemic stroke: a guideline from the American Heart Association/ American Stroke Association Stroke Council: cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group: the American Academy of Neurology affirms the value of this guideline. Stroke. 2006;37(6):1583–633. 46. Hylek EM, Skates SJ, Sheehan MA, Singer DE. An analysis of the lowest effective intensity of prophylactic anticoagulation for patients with nonrheumatic atrial fibrillation. N Engl J Med. 1996;335(8):540–6. 47. Samsa GP, Matchar DB, Goldstein LB, et al. Quality of anticoagulation management among patients with atrial fibrillation: results of a review of medical records from 2 communities. Arch Intern Med. 2000;160(7):967–73. 48. Bungard TJ, Ackman ML, Ho G, Tsuyuki RT. Adequacy of anticoagulation in patients with atrial fibrillation coming to a hospital. Pharmacotherapy. 2000;20(9):1060–5. 49. Gage BF, Van Walraven C, Pearce L, et al. Selecting patients with atrial fibrillation for anticoagulation: stroke risk stratification in patients taking aspirin. Circulation. 2004;110(16):2287–92. 50. Kalra L, Lip GY. Guideline Development Group for the NICE clinical guideline for the management of atrial fibrillation. Antithrombotic treatment in atrial fibrillation. Heart. 2007;93(1):39– 44 [PMC free article] [PubMed]. 51. The Atrial Fibrillation Followup Investigation of Rhythm Management Investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med. 2002;347(23):1825–33. 52. Hylek EM, Go AS, Chang Y, et al. Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N Engl J Med. 2003;349(11):1019–26. 53. Rash A, Downes T, Portner R, Yeo WW, Morgan N, Channer KS. A randomised controlled trial of warfarin versus aspirin for stroke prevention in octogenarians with atrial fibrillation (WASPO). Age Ageing. 2007;36(2):151–6. 54. Mant J, Hobbs FD, Fletcher K, et al. Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial. Lancet. 2007;370(9586):493–503. 55. Sandercock PA, Counsell C, Kamal AK. Anticoagulants for acute ischaemic stroke. Cochrane Database Syst Rev. 2008;8(4); CD000024. 56. Hart RG, Palacio S, Pearce LA. Atrial fibrillation, stroke, and acute antithrombotic therapy: analysis of randomized clinical trials. Stroke. 2002;33(11):2722–7. 57. International Stroke Trial Collaborative Group. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19,435 patients with acute ischaemic stroke. Lancet. 1997;349(9065):1569–81. 58. CAST (Chinese Acute Stroke Trial) Collaborative Group. CAST: randomised placebo-controlled trial of early aspirin use in 20,000 patients with acute ischaemic stroke. Lancet. 1997;349(9066):1641–9. 59. Berge E, Abdelnoor M, Nakstad PH, Sandset PM. Low molecularweight heparin versus aspirin in patients with acute ischaemic stroke and atrial fibrillation: a double-blind randomised study. Lancet. 2000;355(9211):1205–10. 60. Saxena R, Lewis S, Berge E, Sandercock PAG, Koudstaal PJ. Risk of early death and recurrent stroke and effect of heparin in 3,169 patients with acute ischemic stroke and atrial fibrillation in the International Stroke Trial. Stroke. 2001;32(10):2333–7.
17
Detection and Management of Atrial Fibrillation in Patients with Stroke or TIA in Clinical Practice
61. Kay R, Wong KS, Yu YL, et al. Low-molecular-weight heparin for the treatment of acute ischemic stroke. N Engl J Med. 1995;333(24):1588–93. 62. Wong KS, Chen C, Ng PW, et al. Low-molecular-weight heparin compared with aspirin for the treatment of acute ischaemic stroke in Asian patients with large artery occlusive disease: a randomised study. Lancet Neurol. 2007;6(5):407–13. 63. Diener HC, Ringelstein EB, Von Kummer R, et al. Treatment of acute ischemic stroke with the low-molecular-weight heparin certoparin: results of the TOPAS trial. Therapy of Patients With Acute Stroke (TOPAS) Investigators. Stroke. 2001;32(1):22–9. 64. Bath PM, Lindenstrom E, Boysen G, et al. Tinzaparin in acute ischaemic stroke (TAIST): a randomised aspirin-controlled trial. Lancet. 2001;358(9283):702–10. 65. Hassaballa H, Gorelick PB, West CP, Hansen MD, Adams Jr HP. Ischemic stroke outcome: racial differences in the trial of danaparoid in acute stroke (TOAST). Neurology. 2001; 57(4):691–7. 66. Gubitz G, Sandercock P, Counsell C. Anticoagulants for acute ischaemic stroke. Cochrane Database Syst Rev. 2004;(3): CD000024. 67. Krupinski J, Ustrell X, Font MA, Arboix A. Guidelines for management of acute stroke and transient ischaemic attack. 2nd ed. Barcelona: Catalan Neurological Society; 2011. 68. Chamorro A, Busse O, Obach V, et al. The rapid anticoagulation prevents ischemic damage study in acute stroke – final results from the writing committee. Cerebrovasc Dis. 2005;19(6):402–4. 69. Chamorro A. Immediate anticoagulation for acute stroke in atrial fibrillation: yes. Stroke. 2006;37(12):3052–3. 70. Sandercock P. Immediate anticoagulation for acute stroke in atrial fibrillation: no. Stroke. 2006;37(12):3054–5. 71. Bonow RO, Carabello BA, Kanu C, et al. ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease): developed in collaboration with the Society of Cardiovascular Anesthesiologists: endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. Circulation. 2006; 114(5):e84–231. 72. PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet. 2001;358(9287):1033–41. 73. O’Donnell HC, Rosand J, Knudsen KA, et al. Apolipoprotein E genotype and the risk of recurrent lobar intracerebral hemorrhage. N Engl J Med. 2000;342(4):240–5. 74. Eckman MH, Rosand J, Knudsen KA, Singer DE, Greenberg SM. Can patients be anticoagulated after intracerebral hemorrhage? A decision analysis. Stroke. 2003;34(7):1710–6. 75. Landefeld CS, Beyth RJ. Anticoagulant-related bleeding: clinical epidemiology, prediction, and prevention. Am J Med. 1993;95(3): 315–28. 76. Hirsh J, Kearon C, Ginsberg J. Duration of anticoagulant therapy after first episode of venous thrombosis in patients with inherited thrombophilia. Arch Intern Med. 1997;157(19):2174–7. 77. van der Meer FJ, Rosendaal FR, Vandenbroucke JP, Briet E. Bleeding complications in oral anticoagulant therapy. An analysis of risk factors. Arch Intern Med. 1993;153(13):1557–62. 78. Odén A, Fahlén M, Hart RG. Optimal INR for prevention of stroke and death in atrial fibrillation: a critical appraisal. Thromb Res. 2006;117(5):493–9. 79. Fihn SD, McDonell M, Martin D, et al. Risk factors for complications of chronic anticoagulation. A multicenter study. Warfarin optimized outpatient follow-up study group. Ann Intern Med. 1993;118(7):511–20.
235
80. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials. Arch Intern Med. 1994;154(13):1449–57. 81. Steiner T, Rosand J, Diringer M. Intracerebral hemorrhage associated with oral anticoagulant therapy: current practices and unresolved questions. Stroke. 2006;37(1):256–62. 82. Smith NL, Psaty BM, Furberg CD, et al. Temporal trends in the use of anticoagulants among older adults with atrial fibrillation. Arch Intern Med. 1999;159(14):1574–8. 83. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener H-C, Joyner CD, Wallentin L, and the RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139–51. 84. Liu T, Korantzopoulos P, Li L, Li G. Survival benefit of new anticoagulants compared with warfarin in patients with atrial fibrillation: a meta-analysis. Int J Cardiol. 2012. doi:10.1016/j. ijcard.2011.12.093. 85. Weimar C, Hohnloser SH, Eikelboom JW, Diener H-C. Preventing cardioembolic stroke in atrial fibrillation with dabigatran. Curr Neurol Neurosci Rep. 2012;12:17–23. 86. Healey JS, Connolly SJ, Gold MR, Israel CW, Van Gelder IC, Capucci A, Lau CP, Fain E, Yang S, Bailleul C, Morillo CA, Carlson M, Themeles E, Kaufman ES, Hohnloser SH, for the ASSERT Investigators. Subclinical atrial fibrillation and the risk of stroke. N Engl J Med. 2012;366:120–9. 87. Blech S, Ebner T, Ludwig-Schwellinger E, et al. The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans. Drug Metab Dispos. 2008;36:386–99. 88. European Medicines Agency. Pradaxa. Summary of product characteristics. Available at: http://www.ema.europa.eu/docs/en_GB/ document_library/EPAR__Product_Information/human/000829/ WC500041059.pdf. Accessed 25 Nov 2011. 89. U.S. Food and Drug Administration – Pradaxa® prescribing information. Nov, 2011. Available at: http://www.pradaxa.com/. Accessed 25 Nov 2011. 90. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creati-nine. Nephron. 1976;16:31–41. 91. Mateo J, Legrand M, Aribaud A, et al. The use of dabigatran in elderly patients. Arch Intern Med. 2011;171:1285–6. 92. van Ryn J, Stangier J, Haertter S, et al. Dabigatran etexilate – a novel, reversible, oral direct thrombin inhibitor: Interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost. 2010;103:1116–11127. 93. Baruch L, Sherman O. Potential inaccuracy of point-of-care INR in dabigatran- treated patients. Ann Pharmacother. 2011;45:e40. 94. Van Ryn J, Baruch L, Clemens A. Interpretation of point-of-care INR results in patients treated with dabigatran. Am J Med. 2012;125(4):417–20. 95. Lindahl TL, Baghaei F, Blixter IF, et al. Effects of the oral, direct thrombin inhibitor dabigatran on five common coagulation assays. Thromb Haemost. 2011;105:371–8. 96. Adams Jr HP, del Zoppo G, Alberts MJ, et al. Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: The American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Circulation. 2007;115:e478–534. 97. Seet RC, Zhang Y, Moore SA, et al. Subtherapeutic international normalized ratio in warfarin-treated patients increases the risk for symptomatic intracerebral hemorrhage after intravenous thrombolysis. Stroke. 2011;42:2333–5.
236 98. De Smedt A, De Raedt S, Nieboer K, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator in a stroke patient treated with dabigatran. Cerebrovasc Dis. 2010; 30:533–4. 99. Matute MC, Guillan M, Garcia-Caldentey J, et al. Thrombolysis treatment for acute ischaemic stroke in a patient on treatment with dabigatran. Thromb Haemost. 2011;106:178–9. 100. Huisman MV, Lip GYH, Diener H-C, Brueckmann M, van Ryn J, Clemens A. Dabigatran etexilate for stroke prevention in patients with atrial fibrillation: resolving uncertainties in routine practice. Thromb Haemost. 2012;107(5):838–47. doi:10.1160/ TH11-10-0718. 101. Morales-Vidal S, Schneck MJ, Flaster M, Biller J. Direct thrombin inhibitor and factor Xa inhibitors in patients with cerebrovascular disease. Expert Rev Neurother. 2012;12:179–90. 102. Schirmer SH, Baumhäkel M, Neuberger HR, Hohnloser SH, van Gelder IC, Lip GY, Böhm N. Novel anticoagulants for stroke prevention in atrial fibrillation. Current clinical evidence and future developments. J Am Coll Cardiol. 2010;56:2067–76. 103. Eriksson BI, Quinlan DJ, Eikelboom JW. Novel oral factor Xa and thrombin inhibitors in the management of thromboembolism. Annu Rev Med. 2011;62:41–57. 104. Eriksson BI, Quinlan DJ, Weitz JI. Comparative pharmacodynamics and pharmacokinetics of oral direct thrombin and factor Xa inhibitors in development. Clin Pharmacokinet. 2009;48:1–22. 105. Piccini JP, Lopes RD, Mahaffey KW. Oral factor Xa inhibitors for the prevention of stroke in atrial fibrillation. Curr Opin Cardiol. 2010;25:312–20. 106. Kreutz R. Pharmacodynamic and pharmacokinetic basics of rivaroxaban. Fundam Clin Pharmacol. 2012;26:27–32. 107. Mueck W, Lensing AW, Agnelli G, et al. Rivaroxaban. Population pharmacokinetic analyses in patients treated for acute deep-vein thrombosis and exposure simulations in patients with atrial fibrillation treated for stroke prevention. Clin Pharmacokinet. 2011;50:675–86. 108. Agnelli G, Gallus A, Goldhaber SZ, et al. Treatment of proximal deep-vein thrombosis with the oral direct factor Xa inhibitor rivaroxaban (BAY 59–7939): the ODIXa-DVT (Oral Direct Factor Xa Inhibitor BAY 59–7939 in Patients with Acute Symptomatic Deep-Vein Thrombosis) study. Circulation. 2007;116:180–7. 109. Kakkar K, Brenner B, Dahl OE, et al. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet. 2008;372:31–9. 110. Eriksson BI, Borris LC, Friedman RJ, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008;358:2765–75.
J. Krupinski et al. 111. Lassen MR, Ageno W, Borris LC, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008;358:2776–86. 112. Turpie AG, Lassen MR, Davidson BL, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet. 2009;373:1673–80. 113. Bauersachs R, Berkowitz SD, Brenner B, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;23:2499–510. 114. Mega JL, Braunwald E, Mohanavelu S, et al. Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACSTIMI 46): a randomised, double blind, phase II trial. Lancet. 2009;374:29–38. 115. Pattel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF, Berkowitz SD, Fox KA, Califf RM, and the ROCKET AF Steering Committee for the ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883–91. 116. Fox KA, Piccini JP, Wojdyla D, Becker RC, Halperin JL, Nessel CC, Paolini JF, Hankey GJ, Mahaffey KW, Patel MR, Singer DE, Califf RM. Prevention of stroke and systemic embolism with rivaroxaban compared with warfarin in patients with non-valvular atrial fibrillation and moderate renal impairment. Eur Heart J. 2011;32:2387–94. 117. Altman R, Vidal HO. Battle of oral anticoagulants in the field of atrial fibrillation scrutinized from a clinical practice (the real world) perspective. Thromb J. 2011;9:12–9. 118. Eikelboom JW, Weitz JI. New anticoagulants. Circulation. 2010;121:1523–32. 119. Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med. 2009;361:594–604. [Erratum, N Engl J Med 2009; 361:1814.]. 120. Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Hornick P. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet. 2010;375:807–15. 121. Connolly SJ, Eikelboom J, Joyner C, Diener HC, Hart R, Golitsyn S, Flaker G, Avezum A, Hohnloser SH, Diaz R, Talajic M, Zhu J, Pais P, Budaj A, Parkhomenko A, Jansky P, Commerford P, Tan RS, Sim KH, Lewis BS, Van Mieghem W, Lip GY, Kim JH, Lanas-Zanetti F, Gonzalez-Hermosillo A, Dans AL, Munawar M, O’Donnell M, Lawrence J, Lewis G, Afzal R, Yusuf S, AVERROES Steering Committee and Investigators. Apixaban in patients with atrial fibrillation. N Engl J Med. 2011;364:806–17.
Ventricular Arrhythmias During Acute Myocardial Ischemia/Infarction: Mechanisms and Management
18
Theofilos M. Kolettis
Abstract
Ventricular arrhythmias during the acute phase of myocardial infarction are common and account for approximately 80 % of sudden cardiac death cases. A biphasic curve has been observed in various species and possibly applies also in man. The incidence of ventricular arrhythmias in the prehospital phase has remained stable during the past decade, but inhospital rates have declined markedly, mainly due to the widespread use of reperfusion therapies. Ventricular tachycardia and fibrillation are generated by all known arrhythmogenic mechanisms, acting successively or in combination. However, the factors governing the susceptibility to ischemia-related arrhythmias remain incompletely understood. Beta-blockade is the mainstay of treatment; class I agents have been largely superseded by amiodarone, but combined administration may be warranted in difficult cases. The effect of ventricular arrhythmias on long-term prognosis needs to be examined in large-scale studies. Keywords
Myocardial ischemia • Myocardial infarction • Monomorphic ventricular tachycardia • Polymorphic ventricular tachycardia • Ventricular fibrillation
Abbreviations
Introduction
APD Action potential duration ATP Adenosine triphosphate ERP Effective refractory period ET Endothelin MI Myocardial infarction VF Ventricular fibrillation VT Ventricular tachycardia
Myocardial infarction (MI) remains a leading cause of death worldwide [1]. In the majority of cases, short- and long-term prognosis is affected by the two main sequelae of acute coronary occlusion, namely, pump failure and arrhythmogenesis. This chapter will discuss the mechanisms and management of ventricular tachycardia (VT) and ventricular fibrillation (VF) occurring during the acute phase of MI. These arrhythmias are generated by all known arrhythmogenic mechanisms, acting successively or in combination, and account for much of the morbidity and mortality associated with acute coronary syndromes.
Historical Aspects T.M. Kolettis, MD, PhD, FESC Department of Cardiology, University of Ioannina, 1 Stavrou Niarxou Avenue, Ioannina 45110, Greece e-mail:
[email protected] A.S. Kibos et al. (eds.), Cardiac Arrhythmias, DOI 10.1007/978-1-4471-5316-0_18, © Springer-Verlag London 2014
Although the first description of sudden cardiac death can be found in the Hippocratic aphorisms, it was only after 22 centuries that it was realized that, in most instances, sudden 237
238
cardiac death is caused by VF [2]. The causal relationship of acute coronary occlusion and VF was first documented in the mid-nineteenth century after studies of coronary artery ligation in the pig and was described as “tremulous and irregular” behavior of the ventricles [3].
T.M. Kolettis 100 90 80
VT/VF
70
no VT/VF
20 10 0
Epidemiology Due to the high incidence of ischemic heart disease, ventricular arrhythmias secondary to acute coronary occlusion account for approximately 80 % of sudden cardiac death cases and comprise 13 % of all natural causes [4]. Among the presenting clinical manifestations of coronary artery disease, ischemia-induced VT/VF is encountered in a substantial proportion (20–25 %) of patients, while the annual number of sudden cardiac deaths related to acute MI in the general population is estimated at 250/million, with rates remaining stable during the past decade [5, 6]. These epidemiological data signify ischemia-induced VT/VF as a major health-related problem in many countries. The incidence of sustained VT and VF during the prehospital phase of acute MI ranges from 3 to 20 % in various published studies and registries [5, 6]. In an early series of patients with acute MI, who were monitored either in an ambulance or in the hospital within 1 h after the onset of symptoms, the incidence of primary VF was 11 %, being more frequent in patients with ST-elevation MI [7]. Importantly, these rates appear unchanged during the past decade, as indicated in more recent observational studies [8]. Thus, based on the available evidence, it can be estimated that acute MI presents clinically with VT/VF in approximately 10 % of patients (Fig. 18.1).
Risk Factors A number of studies have examined the clinical characteristics of MI patients with and without primary ventricular arrhythmias. However, hitherto efforts to describe the clinical profile of patients presenting with VT/VF have been largely disappointing. A large meta-analysis of 21 cohort studies describing over 57,000 patients with acute MI evaluated potential risk factors of primary VF [9]; in this report, patients with primary VF were more commonly male smokers, with absence of history of angina, admitted earlier to the hospital. On admission, ST-segment elevation MI, atrioventricular conduction abnormalities, lower heart rate, and lower serum potassium were more likely findings. However, despite their usefulness, these findings confer limited added value to current understanding and underscore the need for future concerted research at basic and clinical level. This is further necessitated by the complexity of factors governing
ital
hosp
Pre-
<24
h
>24
h
Fig. 18.1 Incidence of VT/VF during acute MI. The incidence of VT/ VF is ~10 % in the prehospital phase of MI and drops to ~5 % during hospitalization
the susceptibility of MI-related ventricular arrhythmias, determined by interactions between ischemia-induced functional and structural changes, as well as by environmental and genetic factors. In contrast to the prehospital phase, the incidence of inhospital arrhythmias has declined markedly during the past decades, due to the refinements in medical treatment and advances and widespread use of reperfusion strategies. During the first 24-h period of hospitalization, VF occurs at the range of 5 %, decreasing to <1 % during the subsequent 24 h [10]; for example, in a recent study [11] examining patients who underwent percutaneous coronary intervention for ST-elevation MI, the incidence of sustained arrhythmias was 4.7 %, 92 % of which occurred during the first 48 h. Recurrent VF may be observed during acute MI, this possibility being higher in cases where the initial VF episode occurs late postcoronary occlusion [10, 11]. Rarely, clusters of VF occur in the early post-MI period, a condition referred to as “electrical storm,” which invariably requires multiple therapeutic measures due to its poor prognosis [12]. Patients with VF and/or sustained VT or have a 4-fold increase in inhospital mortality, a 3-fold increase in major adverse cardiac events, and a 50 % increase in hospital length of stay. The predictors of in-hospital ventricular arrhythmias are not well defined, but recurrent ischemia and lack of β-blocker treatment appear to play a key role [11]; in a report on 9,000 patients, heart failure, cardiogenic shock, chronic kidney disease, and presentation within 6 h of symptom onset were major predictors of VF and sustained VT [8].
General Considerations Myocardial ischemia profoundly changes electrical activity in the region of injury, resulting in a wide spectrum of ventricular arrhythmias. Thus, during the course of acute MI, single premature ventricular contractions, couplets, VT, and VF can be encountered. VT can be either non-sustained or sustained, as well as either monomorphic (QRS complexes
18 Ventricular Arrhythmias During Acute Myocardial Ischemia/Infarction: Mechanisms and Management
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Fig. 18.2 Polymorphic VT during acute MI. Example of polymorphic VT induced by ST-segment elevation MI
Fig. 18.3 Arrhythmia mechanisms. Myocardial ischemia alters electrophysiologic milieu, shortens action potential duration, and induces ventricular arrhythmias via triggered activity and reentry (see text for details)
with a single morphology in the same lead) or (mainly) polymorphic (varying QRS morphology during an episode in one lead) (Fig. 18.2). Furthermore, reperfusion of the ischemic area causes a second wave of abrupt changes in myocardial electrophysiologic properties, frequently resulting in rhythm disturbances [5]. As a general rule, the mechanisms of arrhythmias during acute ischemia differ from those seen in chronic stable coronary artery disease, where an infarction scar invariably provides the substrate for monomorphic VT. Acute interruption of blood supply inhibits oxidative metabolism, decreases cellular energy storages, and produces biochemical, electrical, and mechanical alterations in the myocardium. The changes in the electrophysiologic milieu are mediated by altered intra- and extracellular ion concentrations, disturbed lipid metabolism, and secretion of neurotransmitters, hormones, and metabolites. Despite the extensive research during the past decades, the complex mechanisms underlying ischemia-induced VT/VF are incompletely understood and perhaps speculative, as their description originates mostly from animal models [13].
Although interrelated and inseparable, the significance of the each contributory factor will be discussed independently in this chapter, for better illustrative and didactic purposes. An overview of the arrhythmia mechanisms during myocardial ischemia is depicted in Fig. 18.3.
Action Potential Changes Within minutes of myocardial ischemia, extracellular K+ concentration rises and resting membrane potential increases in the ischemic area, and these changes generate an “injury current” towards normal myocardial areas [14]. Na+ conductance diminishes secondary to inactivation of Na+ channels, causing a decrease in the amplitude and slope of phase 0, eventually slowing conduction and altering refractoriness [14]. There is an initial prolongation of the action potential duration (APD) caused by elevated intracellular Na+, secondary to increased late Na+ current. After the initial stages of ischemia, APD shortens, while the effective refractory period (ERP) gradually increases, as a result of
240 Fig. 18.4 Arrhythmogenic phases. During phases I (with subphases A and B) and II, polymorphic VT prevails, as opposed to the chronic stage (phase III), where monomorphic VT is more common (Adapted from Oikonomidis et al. [17], with permission of Springer
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reduced fast Na+ current and prolonged recovery of Na+ channels from inactivation, in the setting of increased resting membrane potential [15]. APD shortening during ischemia is caused by decreased inward currents, activation of Cl− channels and, mainly, by enhanced outward K+ currents; changes in inward currents contribute far less to APD shortening, while the K+ currents activated under normal conditions are decreased [14]. The differences in the duration and amplitude of the action potential between ischemic and nonischemic myocardial areas constitute the main mechanism of ST elevation in the electrocardiogram.
Time Course In response to ischemic injury, two temporally distinct peaks (phases I and II) of ventricular arrhythmias can be observed [16, 17] (Fig. 18.4). This pattern has been described in various species, such as dogs, pigs, sheep, and rats, while it is less discernible in cats and rabbits. There is a paucity of information, but a substantial body of epidemiological data indicate that a similar curve may apply in man [7, 8, 18–21]. Despite the lack of firm evidence on the existence of a biphasic pattern, such classification is practical and may be followed in the clinical setting [5, 16]. Phase I is observed during the reversible stage of acute MI, lasting for 30–45 min postcoronary occlusion. It can be divided in two subphases (IA and IB), but, as with the phase I and II distinction, such division is not universal among species. Data from out-of-hospital emergency registries [7, 8, 18–21] indicate that phase IA may correspond to cases of sudden collapse in the absence of or with minimal prior symptoms, whereas phase IB events are related to VF
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occurring usually in the ambulance, en route to the hospital. It is estimated that approximately 30–50 % of sudden cardiac death cases during acute MI occur during phase I; since myocardial necrosis is minimal at this stage, autopsy in these patients typically does not verify an MI. Observational studies using continuous electrocardiographic recordings in patients with evidence of coronary artery disease that died suddenly due to VT/VF lend support to this statement [22]. The relative significance of the two subphases is unknown, but the IB appears to be more arrhythmogenic than the IA subphase [23]. However, arrhythmias during subphase IA are clinically important, because they occur usually before the arrival of medical attendance. Ventricular arrhythmias during subphase IB evolve into VF more frequently, possibly due to the added arrhythmogenic effect of accentuation of Ca2+ loading [14], gap junctional uncoupling, and the resultant decrease in longitudinal conductance [24]. For reasons not fully understood, there is a period of low arrhythmogenesis between phases I and II, lasting for 30–60 min. Phase II, representing the infarct evolution phase, begins approximately 1–2 h after coronary occlusion and lasts for 24–48 h [5, 16].
Biochemical and Electrophysiological Alterations During Ischemia Under aerobic conditions, intracellular K+ concentration is high, while extracellular concentration is low, and passive K+ efflux is compensated by active influx via the Na+/K+ pump. During ischemia, this dynamic equilibrium becomes unbalanced, resulting in accumulation of extracellular K+ [25]. Furthermore, ischemia depletes intracellular ATP stores and shifts cellular metabolism to anaerobic glycolysis; as a result,
18 Ventricular Arrhythmias During Acute Myocardial Ischemia/Infarction: Mechanisms and Management
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Fig. 18.5 Lipid metabolism during ischemia. Peripheral and myocardial lipid metabolism during myocardial ischemia. CoA coenzyme A, FFA free fatty acid, TG triglyceride (From Oliver [29], with permission of Elsevier) FFAs ++ Adipose tissue glycolysis + Catecholamine release Acute pain or stress Cortisol +
TG FFAs
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lactic acid and ATP-derived hydrogen ions accumulate, decreasing intracellular pH. Acidosis activates the Na+/H+ exchanger, as well as the Na+/HCO3− co-transporter, but these mechanisms can only partly compensate for the increased intracellular H+ concentrations. ATP-sensitive K+ current, activated by the reduction in intracellular ATP, increases K+ current in the ischemic zone, thereby causing marked differences between ischemic and nonischemic myocardial areas [26]. The cellular compensatory mechanisms for acidosis result in H+ extrusion in exchange for Na+ entry, leading to elevated intracellular Na+; in turn, Na+ is extruded in exchange for Ca2+ via the Na+/Ca2+ exchanger operating in the reverse mode, resulting in Ca2+ overload. An increase of cytosolic Ca2+ produces oscillations in the membrane potential, resulting in early and delayed afterdepolarizations. Furthermore, fluctuations in intracellular Ca2+ produce spatial and temporal variations in the APD [27], a mechanism underlying T wave alternans, which often precedes VF [27, 28].
Free Fatty Acids Under aerobic conditions, fatty acids derived from hydrolysis of triacylglycerols and phospholipids are rapidly removed from the extracellular space. During ischemia, the concentration of fatty acids rises because of enhanced breakdown of membrane phospholipids, while the accompanying catecholamine surge stimulates tissue lipolysis [29] (Fig. 18.5). Free fatty acids have been linked to ischemiainduced VF [30], but the underlying arrhythmogenic mechanisms are complex and incompletely understood; they can be divided into circulatory, metabolic, and direct electrophysiologic actions [31].
First, high free fatty acid levels impair capillary recruitment and acetylcholine-mediated vasodilatation [32], thereby further decreasing myocardial blood supply. Second, free fatty acids aggravate ischemia at the cellular level by suppressing glucose oxidation, through inhibition of pyruvate dehydrogenase; in addition, they reduce insulin-stimulated glucose transport, mediated by decreased insulin-responsive glucose transporter translocation [33]. Free fatty acids can enter cardiomyocytes, where they produce uncoupling of mitochondrial respiration [33]; furthermore, lipid oxidation in mitochondria may also be inhibited, with accumulation of acylcarnitine and acyl-CoA, leading to cytosolic Ca2+ overload. Third, free fatty acids increase extracellular K+ and accumulate on the plasma membrane, where they interact directly with channel proteins and gap junctions or with the surrounding phospholipids [34]; for example, they can inhibit the Na+/K+ pump, leading to high intracellular Na+ and eventually Ca2+ concentrations. While the “lipid hypothesis” has been active for over 40 years [35], the precise role of free fatty acids on arrhythmogenesis has not been defined either experimentally or clinically. With reference to the latter, there is a need for trials examining the potential of reducing sudden cardiac death rates with interventions that control free fatty acids in the setting of acute MI [36].
Gap Junctions Gap junctions at the intercalated disks allow intercellular exchange of ions and small molecules and equilibrate ionic concentrations, thereby facilitating the propagation of the action potential. Increased intracellular Ca2+ and H+, as well as accumulation of lysophosphoglycerides and arachidonic acid
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a Incidence of VF (% of hearts)
Fig. 18.6 Effects of catecholamines on ischemia-induced VF. The effects of catecholamines on the overall (a) and temporal (b) incidence of VF in a Langendorff-perfused mouse model of regional ischemia, induced by left coronary artery occlusion (Adapted from Stables and Curtis [41], with permission of Oxford University Press)
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metabolites contribute to dephosphorylation of gap junction connexin 43 [37], which is transferred from the intercalated disks towards the cytoplasm [37]. Reduced electrical coupling slows conduction and increases tissue impedance and tissue anisotropy. Modifications in gap junctions are not uniform over the infarct zone, with the border zone showing the highest variability in tissue impedance [38], because this area consists of islets of ischemic and normal myocardium. Furthermore, the electrophysiological properties may differ in surviving subepicardial and subendocardial rims surrounding large ischemic areas, leading into anisotropic slow conduction that promotes the formation of reentrant circuits [38]. Despite these considerations, the role of gap junctional uncoupling in arrhythmogenesis has not been completely elucidated. This uncertainty stems from the fact that the number of available gap junctions is much larger than needed for propagation of the action potential. Thus, extreme electrophysiological alterations are required for a clinically meaningful effect; for example, a 50 % reduction of connexin-43 decreases conduction velocity by only 25 %, while an approximately 90 % reduction is required to decrease conduction velocity by 50 % [39]. A more in-depth discussion on the role of gap junctions on arrhythmogenesis can be found in Chap. 3.
β-adrenergic receptors increases Ca2+ release from the sarcoplasmic reticulum and enhances the Ca2+ current, the pacemaker current, the transient inward and outward currents, and the slow component of the delayed rectifier K+ current [40]. As a result, sympathetic stimulation further shortens APD and increases intracellular Ca2+ concentration in partially depolarized myocytes, thereby producing delayed afterdepolarizations, leading to triggered activity [40, 41]. Figure 18.6 depicts the effects of catecholamines on ischemiainduced VF in a Langendorff-perfused mouse model.
Thrombin Thrombin production at the site of coronary occlusion exerts arrhythmogenic properties via the activation of phospholipase A2 [42]; this leads to accumulation of lysophosphatidylcholines that activate the voltage-gated Na+ channel, as well as the Na+/H+ exchanger, thereby enhancing Na+ influx [43]. In turn, increased Na+ concentration causes Ca2+ influx and potentates triggered activity.
Endothelin Autonomic Nervous System The pathophysiologic link between sympathetic activation and arrhythmogenesis during myocardial ischemia is well established [40]. Acute coronary occlusion causes an immediate release of catecholamines in the systemic circulation via a centrally acting mechanism; this is followed by increased norepinephrine concentration locally in the myocardium, caused initially by inhibition and subsequently by reversal of norepinephrine reuptake in nerve endings. Activation of α-adrenergic receptors decreases gap junction conductance and enhances the function of the Na+/K+ pump, as well as of the Na+/Ca2+ and Na+/H+ exchangers. Activation of
Endothelin-1 is a 21-amino-acid peptide, first described by Yanagisawa and coworkers in 1988 [44] and produced in response to various stimuli. In addition to its vasoconstrictive and proliferative actions, endothelin-1 exerts prominent electrophysiologic effects on the myocardium, partly mediated by the inositol 1,4,5-trisphosphate pathway [45]. Endothelin-1 prolongs APD in ventricular myocytes [46] resulting in early afterdepolarizations and VT/VF via triggered activity. Experimental [47] and clinical [48] studies have shown that the production of endothelin-1 increases markedly during acute MI. Endothelin-1 exerts significant direct (as outlined above) and indirect (by aggravating myocardial ischemia) electrophysiologic effects and
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Fig. 18.7 Arrhythmogenic effects of endothelin-1 during MI. The main arrhythmogenic mechanisms of endothelin-1 consist of early afterdepolarizations and microreentry (From Oikonomidis et al. [17], with permission of Springer)
contributes to the genesis of ischemic ventricular tachyarrhythmias [17]. An overview of the arrhythmogenic effects of endothelin-1 during MI is depicted in Fig. 18.7. A major aspect of neurohumoral activation during acute MI is the complex interaction between the endothelin system and the sympathetic nervous system, which occurs at the adrenal gland and at the ventricular myocardial levels [17]. The effects of endothelin-1 on ventricular arrhythmogenesis during myocardial ischemia are mediated mainly via activation of the ETA receptor [49], while the role of the ETB receptor remains controversial. In the in vivo model of MI, a protective effect of the ETB receptor on ventricular arrhythmogenesis was found during the early phase, albeit this effect was lost during subsequent stages [50]. More data on the role of endothelin-1 and the relative importance of its two receptors are awaited.
Genetic Factors Observational studies have reported positive family history of sudden cardiac death in a substantial proportion of patients manifesting malignant ventricular arrhythmias during acute coronary syndrome, indicating genetic predisposition [5, 51]. Indeed, there is a growing body of evidence demonstrating genetic variations (mutations and polymorphisms) of genes encoding ion channel proteins that are linked to increased vulnerability of the ischemic myocardium to VT/VF [13, 51]. For instance, a loss of function-mutation was described in the SCN5A gene encoding Na+ channel, associated with the development of VT/VF during the first 12 h of acute MI [52, 53]. Furthermore, a polymorphism of KCNH2 gene encoding HERG-K+ channel was also identified as being
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Fig. 18.8 Reentry. Critical conditions for reentry (Adapted from Coronel et al. [62], with permission of Elsevier)
associated with increased risk for the development of QT prolongation and torsade de pointes following acute MI [53]. However, identification of patients at risk of acute MI-induced lethal ventricular arrhythmias remains a clinical challenge and further studies at preclinical and clinical level are eagerly awaited.
Main Mechanisms: Triggers and Reentry A fundamental electrophysiologic concept of the arrhythmogenic mechanisms is the combination of an initiator, acting on a suitable substrate that will permit the perpetuation of the abnormal rhythm (Fig. 18.8). During acute MI, various factors, such as increased extracellular K+ concentration, catecholamine surge and acidosis, cause premature beats and induce heterogeneities in excitability, refractoriness and conduction, thereby modulating both triggers and substrate.
Triggers Most triggers occur at the border zone between the ischemic and normal myocardium and consist of premature ventricular contractions, couplets, or triplets. These rhythms are produced by abnormal automaticity or by triggered activity following Ca2+ overload; in addition, spatial differences in repolarization generate electrotonic currents from areas with prolonged towards areas with early repolarization and depolarization ensues from suprathreshold stimuli [54]. Nonsustained VT triggering sustained VT or VF can be reentrant
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Fig. 18.9 Importance of border zone. The border zone between the ischemic and normal myocardium is often the site of origin of VT/VF via reentrant and non-reentrant mechanisms
or non-reentrant in origin [55] (Fig. 18.9). Because the specialized conductive tissue is more resistant to acute ischemia than the working myocardium [56], abnormal automaticity in surviving Purkinje fibers may be one arrhythmogenic mechanism during phase II. Lastly, the mechanical stretch induced by the viable myocardium that surrounds the ischemic zone may also result in premature ventricular contractions [57]. The role of stretch in arrhythmogenesis has received attention during the recent years, after the demonstration that it can produce inward as well as outward ionic currents through activation of specific channels [58]. At negative resting membrane potential values, inward currents prevail and can cause depolarization, while at more positive levels, outward currents may shorten the plateau phase of the action potential. Reduction of ventricular wall stress may decrease the occurrence of extrasystoles, but the precise role of stretch-sensitive channels in arrhythmogenesis remains under investigation.
Reentry Reentry is the underlying electrophysiological mechanism in the vast majority of ischemia-induced VT/VF. During this process, an electrical impulse persists to re-excite the myocardium that is no longer refractory, instead of terminating after complete activation. The length of the reentrant circuit is determined by its wavelength, defined as the product of the conduction velocity times the refractory period, with the addition of an excitable gap. Various models of reentry have been described during ischemia-induced VF, such as three-dimensional rotors and figure-of-eight reentry [59, 60]. Prerequisites for reentry include unidirectional block at a region with a relatively short ERP and slow conduction that permits the impulse to propagate around the area of block. In the ischemic myocardium, areas with delayed repolarization
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remain refractory when a trigger arrives and serve as functional obstacles; this occurs because the impulse fails to propagate into the tissue with late repolarization but instead conducts around it and reenters the tissue of origin. Thus, differences in the electrophysiological properties in various myocardial areas, as well as across the myocardial layers, are the hallmark underlying arrhythmogenesis during myocardial ischemia. To this end, the aforementioned inhomogeneous changes in extracellular K+ and acidosis produce disparate conditions across the ventricular wall; moreover, a marked dispersion in excitability, refractoriness, and conduction exists over the border zone, a condition enhanced by sympathetic stimulation, and sets the stage for reentrant mechanisms. Once reentry is initiated, spatial inhomogeneities cause dispersion of refractoriness that can break a reentrant wave into two or more daughter waves [61, 62]. In addition, variable diastolic intervals introduce temporal heterogeneity in the action potential duration, ERP, and conduction velocity [61]; thus, due to the restitution properties of the myocardium, reentrant waves can break down into smaller ones that tend to perpetuate the arrhythmia. The state of myocardium at the time of ischemia/infarction is another critical factor for VT/VF maintenance, as previous healed infarcted tissue presents an abnormal anatomical obstacle, favoring not only the formation of reentry but also wave break. Moreover, preexisting interstitial fibrosis decreases the number of gap junctions and causes cellular uncoupling and activation delay across myocardial fibers, rendering the ischemic myocardium more susceptible to arrhythmias [63].
Reperfusion Arrhythmias Restoration of blood flow after acute coronary occlusion is the mainstay of management in patients with acute MI. This can be accomplished with thrombolysis or (preferably) with primary percutaneous coronary intervention and has been unequivocally shown to decrease acute and long-term mortality. However, the “Achilles heel” of these treatments is reperfusion injury, defined as myocardial damage initiated after restoration of coronary blood flow. Reperfusion injury produces a second peak of myocardial necrosis associated with ventricular arrhythmias; reperfusion injury depends on the duration of preceding ischemia and significantly alters the arrhythmia time course of acute MI (Fig. 18.10). Thus, delayed reperfusion arrhythmias appear as a second arrhythmia clustering, especially after prolonged preceding periods of ischemia. Restoration of coronary blood flow decreases extracellular K+ and lowers the membrane resting potential, but the APD remains shortened, possibly due to activation of Na+/
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Fig. 18.10 Reperfusion arrhythmias. Mechanisms and time course of reperfusion arrhythmias. See text for details
K+ pump, producing an outward current. These changes are not homogenous, resulting in spatial differences in extracellular K+, APD, and ERP. The Na+/H+ exchanger becomes immediately reactivated upon reperfusion, causing Na+ influx [64], in exchange for H+; this, in turn, results in Ca2+ overload through the Na+/Ca2+ exchanger functioning in reverse mode that produces Ca2+ oscillations and delayed afterdepolarizations. Thus, abrupt Ca2+ overload is considered a central mechanism of reperfusion arrhythmias [65], a process which is enhanced by sympathetic stimulation. These arrhythmias can occur within seconds after reperfusion, initiated by a trigger, frequently located at the border subendocardium of the reperfused myocardium. Slow conduction is present, secondary to elevated intracellular Ca2+, acting negatively on gap junction conductance. Other common triggering foci originate in surviving Purkinje fibers adjacent to the ischemic zone, and impulse conduction expands in a centrifugal manner through the Purkinje arborization. The underlying mechanism has been debated, with possible candidates being reentry within the Purkinje network or (more likely) abnormal automaticity in partially depolarized cells [66]. Due to the central role of Ca2+ overload in reperfusion injury [65], agents inhibiting the Na+/Ca2+ exchanger or the Na+/H+ exchanger have been considered potential candidates for ameliorating reperfusion injury and arrhythmias [67].
Management Ventricular arrhythmias during acute MI encompass a continuum ranging from benign disturbances to single or repeated episodes of life-threatening rhythm disorders. Accordingly, the management of ischemia-induced ventricular tachyarrhythmias includes measures to prevent the onset of VF, prompt termination of polymorphic VT/VF and prevention of subsequent VF episodes. Admission to an appropriately equipped coronary care unit with experienced personnel decreases arrhythmia-related mortality and is mandatory during the initial 24–48 h of acute MI.
Extrasystoles and Couplets Although frequent premature ventricular contractions and couplets may be a harbinger of serious rhythm disturbances, treatment is not recommended, because their specificity in predicting forthcoming VT/VF is extremely low. If premature ventricular contractions are present in the setting of sinus tachycardia, they usually respond satisfactorily to β-blockade. Importantly, frequent premature ventricular contractions may be an early sign of hemodynamic deterioration and their management depends on the optimization of acute heart failure treatment. Prophylactic administration of class I antiarrhythmic agents and particularly lidocaine is
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associated with increased risk of bradycardic and asystolic events, such as sinoatrial block, atrioventricular block, and other conduction disorders [68]. Since these side effects outweigh the expected benefit, current guidelines have recommended against the use of prophylactic lidocaine in acute MI patients [4, 6].
rely on monitor recordings [75]. Nonetheless, as a general rule, a wide complex tachycardia should always be considered ventricular in origin, unless proven otherwise [75]. Sustained VT should be treated promptly with pharmacologic agents or with direct-current cardioversion, depending on the hemodynamic tolerance.
Accelerated Idioventricular Rhythm
Polymorphic VT
Accelerated idioventricular rhythm, at a rate ranging between 50 and 120 beats/min, is frequently observed during acute MI. It can be observed as an escape rhythm in cases of highdegree atrioventricular block or it may be the result of abnormal automaticity; the latter is encountered in the context of sympathetic stimulation or treatment with positive inotropic agents. More commonly, accelerated idioventricular rhythm is associated with reperfusion following thrombolytic therapy, administered usually within 4 h of the onset of symptoms [69]. This rhythm is considered benign and no specific treatment is recommended.
Non-sustained polymorphic VT has an overall incidence of 2–3 % in acute MI and may be caused by sinus bradycardia or preceding sinus pauses, as well as by electrolyte abnormalities. However, the most common cause is recurrent myocardial ischemia [76] and treatment should be focused mainly towards this direction. Torsade de pointes, i.e., polymorphic VT related to a prolonged QTc interval is occasionally observed in the setting of myocardial ischemia, especially when hypokalemia coexists. Sustained polymorphic VT degenerates into VF and requires prompt defibrillation.
Sustained Ventricular Arrhythmias Monomorphic VT Non-sustained monomorphic VT (lasting <30 s) is not uncommonly observed during acute MI, although the exact incidence is not well defined. Episodes of monomorphic non-sustained VT often accompany reperfusion, along with accelerated idioventricular rhythm, and do not need specific management. In contrast, frequent runs of monomorphic VT bursts may require treatment, particularly when they cause hemodynamic compromise. The hemodynamic tolerance during a VT episode depends on several factors [70, 71], the most important being VT rate, the site of arrhythmia origin within the myocardium [72], and left ventricular function [73]. For example, significant hemodynamic compromise can occur if frequent runs of rapid VT occur in the setting of an extensive MI. Another important factor that determines the management of non-sustained VT is the presence of ischemia; high rate and high degree of asynchrony in ventricular excitation (and contraction) caused by the arrhythmia [72] increase myocardial oxygen demand, exacerbate ischemia, and may extend the infarcted area [74]. Consequently, treatment should be initiated if frequent runs of rapid VT are associated with signs of recurrent ischemia. In cases of hemodynamically stable monomorphic VT, either non-sustained or sustained, specific care should be taken for obtaining 12-lead electrocardiograms. Ideally, differential diagnosis of wide QRS tachycardias should be made between ventricular and supraventricular rhythms with aberrant conduction, and therapeutic decisions should not
During the in-hospital phase, sustained ventricular arrhythmias are associated with worse outcome despite successful percutaneous coronary intervention.
Ventricular Fibrillation Prompt recognition and defibrillation of VF as well as deep knowledge of resuscitation algorithms is a prerequisite for coronary care unit personnel. The detailed management of VF is beyond the scope of the present chapter and the reader should refer to current advanced cardiac life support guidelines. Electrical storm is a rare complication of acute MI and is defined as three or more VT/VF episodes within 24 h. It presents a medical emergency with an invariably difficult management, necessitating the consideration of several parameters. In this respect, treatment often requires β-blockade and antiarrhythmic agents (preferably given in combination), correction of electrolyte abnormalities, residual ischemia and hemodynamic status (intra-aortic balloon may be considered), overdrive pacing, and deep anesthesia [12]. In cases refractory to drug therapy, radiofrequency catheter ablation of the arrhythmogenic myocardial substrate is recommended in cases of monomorphic VT; this approach was first described in case reports [77, 78] and the accumulated experience resulted in the publication of larger patient cohorts [79]. Although polymorphic VT has been considered as not amenable to ablation, more recent evidence indicated that this is feasible in selected cases [80], as described in Chap. 23.
18 Ventricular Arrhythmias During Acute Myocardial Ischemia/Infarction: Mechanisms and Management
Pharmacologic Management β-Blockade β-Blockade during acute ischemia and MI reduces mortality, partly because of reduction of ventricular rupture but has also prominent antiarrhythmic effects; moreover, β-blockade decreases sympathetic drive, exerts anti-ischemic properties, and increases fibrillation threshold. Thus, β-adrenergic blockade should be initiated in patients with stable hemodynamic condition during the acute phase of MI, under close monitoring. The choice of β-blocking agent remains debatable, although mixed β1- and β2-adrenergic blockers have been better studied and their use may be preferred in cases of recurrent arrhythmias [81]. Furthermore, lipophilic agents should be probably preferred, because they cross the bloodbrain barrier and exert additional blockade of central and pre-junctional receptors in the central nervous system [81].
Amiodarone Amiodarone has largely replaced class I agents as first-line therapy for VT and VF [6]. Intravenous administration blocks fast Na+ channels in a use-dependent fashion (producing more channel blockade at faster heart rates), decreases outward K+ currents, and blocks L-type Ca2+ channels. Prolongation of ventricular ERP, a central electrophysiologic mechanism of amiodarone may be delayed, being overt after sustained administration [82]. An additional action of amiodarone includes the enhancement of intraneuronal norepinephrine metabolism in intramyocardial nerve endings; this action on vesicular norepinephrine storage decreases local norepinephrine release in the myocardium [83] and consequent plasma spillover [84]. Although intravenous amiodarone produces negative inotropic effects, its use is generally safe in patients with depressed left ventricular systolic function. Moreover, the incidence of torsade de pointes is low, despite the potential for significant prolongation of the QTc interval. Whenever possible, amiodarone should be combined with β-blockade, because of increased efficacy of this regimen, albeit hemodynamic monitoring is essential. In some cases, sotalol can be given instead of amiodarone, although there is limited experience with the use of this agent in the setting of acute ischemia and MI.
Sodium-Channel Blocking Agents (Class I) Lidocaine binds to fast Na+ channels in a use-dependent fashion and such binding increases in the ischemic myocardium [85]. The use of intravenous lidocaine has declined and is currently used as a second-line agent in cases
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of monomorphic or, mainly, polymorphic VT that is associated with recurrent ischemia [6]. It should be noted that there is a lack of large observational studies and randomized clinical trials examining the use of either amiodarone or lidocaine in patients with acute coronary syndromes; thus, recommendations are based on relatively small patient cohorts, expert consensus, and retrospective analyses, the latter carrying potential selection biases [86]. Thus, the effects of amiodarone and lidocaine on short-term mortality in patients with acute ischemic syndromes is largely unknown [86] and large-scale prospective data are needed for firm conclusions. Procainamide has a similar to lidocaine mode of action, but its active metabolite, N-acetyl-procainamide, blocks potassium channels and accounts for much of the antiarrhythmic effect; as a result of this action, procainamide prolongs the QTc interval and can cause torsade de pointes. Its use is contraindicated in patients with impaired renal function, because N-acetyl-procainamide is excreted by the kidneys. In general, the use of procainamide is restricted as a second- or third-tier therapy, when other antiarrhythmic agents have failed, or in combination regimens [4, 6]. In cases of shock-resistant VF, intravenous procainamide may be administered as a bolus dosage prior to repeated defibrillations [4, 6].
Prehospital VF Due to the poor outcome of out-of-hospital VF, policies for its management have been at the center of health-care systems for many years. The efficacy of defibrillation, as well as the immediate and long-term prognosis, decreases markedly with delays in successful defibrillation. As a rule of thumb, after each minute between arrhythmia onset and defibrillation, mortality is increased by 10 % [4, 6]. It has been proposed that VF can be divided into three phases, namely, into electrical (0–4 min), circulatory (4–10 min), and metabolic (>10 min), each phase presenting different main pathophysiologic features [87]. Over these phases, the electrical activity decreases in amplitude and ultimately asystole and death occurs. Short “time-to-shock” has been a constant goal of organized emergency health systems, involving trained personnel, well-equipped ambulances, and even air transport. The advent of these systems has improved the prognosis of out-of-hospital cardiac arrest, but the combined incidence of mortality and hypoxemic encephalopathy has remained fairly stable during the past decade. Due to the success rates of emergency medical systems reaching a plateau during the recent years, the concept of identification of patients at high risk of ischemia-induced ventricular arrhythmias has been recently emerging, with a view of aggressively treating known risk factors and perhaps
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prophylactic employment of antiarrhythmic strategies in selected individuals. The task of successfully preventing prehospital ventricular arrhythmias is extremely difficult, since clinical studies are scarce and often inconclusive and animal data or computer simulations should be extrapolated in man with caution. Progressive in-depth understanding of the complex pathophysiology of ischemia-induced ventricular arrhythmias may make this goal attainable in the future.
Long-Term Prognosis The occurrence of VT during the acute phase of MI (i.e., within the first 48 h) is associated with higher in-hospital mortality. A substantial body of evidence indicates that after discharge, long-term prognosis may be comparable in patients with and without ventricular arrhythmias [4, 5]. However, data from the antiarrhythmics versus implantable defibrillators (AVID) trial indicate that long-term mortality of patients with ischemia-induced VT/VF (and other “correctable” causes) is similar or even worse than that of the primary VT/VF population [88]. Therefore, patients with ischemia-induced VT/VF may require meticulous evaluation, close follow-up, and perhaps more aggressive treatment [71, 89]. Clearly, more clinical information encompassing long follow-up periods is needed before firm inferences can be drawn.
Investigational Treatments The advent of experimental techniques at the cellular and organ level, as well as the introduction of various in vivo animal models, resulted in an enormous flourishing of basic cardiac electrophysiology during the past decades. This development, coupled with the major advances in the clinical field, lead to a parallel growth of pharmacological research for antiarrhythmic agents. However, the clinical use of these agents has undergone through a phase of skepticism, after the demonstration of the proarrhythmic potential of various agents. Progressive understanding of arrhythmogenic mechanisms together with the necessity for novel antiarrhythmic targets continues to fuel pharmacological research. A few investigational treatments are worth mentioning with emphasis on their use during acute MI. Increased gap junctional coupling represent a new field in antiarrhythmic therapy. Several agents that increase gap junctional conductance and maintain conduction velocity are under investigation. These agents may decrease the dispersion in APD and refractoriness, but they show variable success in the prevention of VT/VF [90, 91]. Ito blockers may also exert antiarrhythmic properties by maintaining APD during the early stages of acute MI [92].
T.M. Kolettis
More attention has been devoted to the inhibition of the late Na+ current, which increases at the early stages of ischemia and upon reperfusion, probably secondary to the formation of oxygen-derived free radicals. Late Na+ current contributes to the increase in intracellular Na+, which in turn leads to Ca2+ overload. Ranolazine, an antianginal agent, inhibits late Na+ current and has been demonstrated to be antiarrhythmic in the in vivo rat [93] and porcine [94] models of regional ischemia. Clinical data provide support to these observations and experimental and clinical research on this agent is expanding. Given the important role of endothelin-1 in arrhythmogenesis, endothelin receptor blockade may exert antiarrhythmic actions [17]. Experimental animal studies using selective ETA [95] and dual (ETA and ETB) [96] receptor blockade have reinforced this notion, but there are no published data examining the effects of endothelin receptor antagonists on ventricular arrhythmogenesis in patients with acute MI. In addition to direct antiarrhythmic approach, therapies initiated during the early stages of acute MI, directed towards ameliorating left ventricular remodeling, may confer additional antiarrhythmic benefit [97].
Concluding Remarks Acute myocardial ischemia is arrhythmogenic and often fatal during the early, prehospital phase after coronary occlusion. A second peak occurs usually after admission in the coronary care unit and affects in-hospital mortality. The disparate electrophysiological properties of ischemic, nonischemic, and border zones favor the genesis of VT and VF that are perpetuated via reentrant mechanisms. The electrical consequences of myocardial ischemia are governed by complex mechanisms, which include changes in the function of ion channels and gap junctions, sympathetic stimulation, myocardial stretch, electrolyte abnormalities, and endothelin system activation. Progress in our knowledge on the pathophysiology of reperfusion injury and ischemic ventricular arrhythmias is expected to generate novel antiarrhythmic agents that will improve short- and long-term prognosis. Lastly, continuing efforts to understand the underlying mechanisms of ischemic ventricular arrhythmias, with ensuing preclinical and clinical studies, will bring closer the goal of early identification of patients prone to sudden cardiac death.
References 1. Roger VL. Epidemiology of myocardial infarction. Med Clin North Am. 2007;91:537–52. 2. Luderitz B. Past and future aspects of clinical electrophysiology. Cardiol J. 2008;15:293–7. 3. Erichsen JE. On the influence of the coronary circulation on the action of the heart. Lond Med Gaz. 1842;2:561.
18 Ventricular Arrhythmias During Acute Myocardial Ischemia/Infarction: Mechanisms and Management 4. Zipes DP, Camm AJ, Borggrefe M, et al. ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (writing committee to develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation. 2006;114:e385–484. 5. Luqman N, Sung RJ, Wang CL, Kuo CT. Myocardial ischemia and ventricular fibrillation: pathophysiology and clinical implications. Int J Cardiol. 2007;119:283–90. 6. Van de Werf F, Bax J, Betriu A, et al. Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation: the Task Force on the Management of ST-Segment Elevation Acute Myocardial Infarction of the European Society of Cardiology. Eur Heart J. 2008;29:2909–45. 7. O’Doherty M, Tayler DI, Quinn E, Vincent R, Chamberlain DA. Five hundred patients with myocardial infarction monitored within one hour of symptoms. Br Med J (Clin Res Ed). 1983;286:1405–8. 8. Piccini JP, Berger JS, Brown DL. Early sustained ventricular arrhythmias complicating acute myocardial infarction. Am J Med. 2008;121:797–804. 9. Gheeraert PJ, De Buyzere ML, Taeymans YM, Gillebert TC, Henriques JPS, Backer G, De Bacquer D. Risk factors for primary ventricular fibrillation during acute myocardial infarction: a systematic review and meta-analysis. Eur Heart J. 2006;27:2499–510. 10. Mehta RH, Starr AZ, Lopes RD, Hochman JS, Widimsky P, Pieper KS, Armstrong PW, Granger CB. Incidence of and outcomes associated with ventricular tachycardia or fibrillation in patients undergoing primary percutaneous coronary intervention. JAMA. 2009;301:1779–89. 11. Ohlow MA, Geller JC, Richter S, Farah A, Muller S, Fuhrmann JT, Lauer B. Incidence and predictors of ventricular arrhythmias after ST-segment elevation myocardial infarction. Am J Emerg Med. 2012;30:580–6. 12. Eifling M, Razavi M, Massumi A. The evaluation and management of electrical storm. Tex Heart Inst J. 2011;38:111–21. 13. Di Diego JM, Antzelevitch C. Ischemic ventricular arrhythmias: experimental models and their clinical relevance. Heart Rhythm. 2011;8:1963–8. 14. Carmeliet E. Cardiac ionic currents and acute ischemia: from channels to arrhythmias. Physiol Rev. 1999;79:917–1017. 15. Verkerk AO, Veldkamp MW, van Ginneken AC, Bouman LN. Biphasic response of action potential duration to metabolic inhibition in rabbit and human ventricular myocytes: role of transient outward current and ATP-regulated potassium current. J Mol Cell Cardiol. 1996;28:2443–56. 16. Clements-Jewery H, Hearse DJ, Curtis MJ. Phase 2 ventricular arrhythmias in acute myocardial infarction: a neglected target for therapeutic antiarrhythmic drug development and for safety pharmacology evaluation. Br J Pharmacol. 2005;145:551–64. 17. Oikonomidis DL, Baltogiannis GG, Kolettis TM. Do endothelin receptor antagonists have an antiarrhythmic potential during acute myocardial infarction? Evidence from experimental studies. J Interv Card Electrophysiol. 2011;28:157–65. 18. de Vreede-Swagemakers JJ, Gorgels AP, Dubois-Arbouw WI, Dalstra J, Daemen MJ, van Ree JW, Stijns RE, Wellens HJ. Circumstances and causes of out-of-hospital cardiac arrest in sudden death survivors. Heart. 1998;79:356–61. 19. Campbell RW, Murray A, Julian DG. Ventricular arrhythmias in first 12 hours of acute myocardial infarction. Natural history study. Br Heart J. 1981;46:351–7. 20. Adgey AA, Devlin JE, Webb SW, Mulholland HC. Initiation of ventricular fibrillation outside hospital in patients with acute ischaemic heart disease. Br Heart J. 1982;47:55–61.
249
21. Waalewijn RA, de Vos R, Koster RW. Out-of-hospital cardiac arrests in Amsterdam and its surrounding areas: results from the Amsterdam resuscitation study (ARREST) in ‘Utstein’ style. Resuscitation. 1998;38:157–67. 22. Wang FS, Lien WP, Fong TE, Lin JL, Cherng JJ, Chen JH, Chen JJ. Terminal cardiac electrical activity in adults who die without apparent cardiac disease. Am J Cardiol. 1986;58:491–5. 23. Smith 4th WT, Fleet WF, Johnson TA, Engle CL, Cascio WE. The Ib phase of ventricular arrhythmias in ischemic in situ porcine heart is related to changes in cell-to-cell electrical coupling. Experimental Cardiology Group, University of North Carolina. Circulation. 1995;92:3051–60. 24. Cascio WE, Yang H, Muller-Borer BJ, Johnson TA. Ischemiainduced arrhythmia: the role of connexins, gap junctions, and attendant changes in impulse propagation. J Electrocardiol. 2005;38:55–9. 25. Wilde AA, Aksnes G. Myocardial potassium loss and cell depolarisation in ischaemia and hypoxia. Cardiovasc Res. 1995;29:1–15. 26. Marban E, Kitakaze M, Koretsune Y, Yue DT, Chacko VP, Pike MM. Quantification of [Ca21]i in perfused hearts. Critical evaluation of the 5F-BAPTA and nuclear magnetic resonance method as applied to the study of ischemia and reperfusion. Circ Res. 1990;66:1255–67. 27. Qian YW, Clusin WT, Lin SF, Han J, Sung RJ. Spatial heterogeneity of calcium transient alternans during the early phase of myocardial ischemia in the blood-perfused rabbit heart. Circulation. 2001;104:2082–7. 28. Sutton PM, Taggart P, Opthof T, Coronel R, Trimlett R, Pugsley W, Kallis P. Repolarisation and refractoriness during early ischaemia in humans. Heart. 2000;84:365–9. 29. Oliver MF. Metabolic causes and prevention of ventricular fibrillation during acute coronary syndromes. Am J Med. 2002;112:305–11. 30. Tansey MJ, Opie LH. Relation between plasma free fatty acids and arrhythmias within the first twelve hours of acute myocardial infarction. Lancet. 1983;2:419–22. 31. Hendrickson SC, St Louis JD, Lowe JE, Abdel-aleem S. Free fatty acid metabolism during myocardial ischemia and reperfusion. Mol Cell Biochem. 1997;166:85–94. 32. de Jongh RT, Serne EH, Ijzerman RG, de Vries G, Stehouwer CD. Free fatty acid levels modulate microvascular function: relevance for obesity-associated insulin resistance, hypertension, and microangiopathy. Diabetes. 2004;53:2873–82. 33. Murray AJ, Anderson RE, Watson GC, Radda GK, Clarke K. Uncoupling proteins in human heart. Lancet. 2004;364:1786–8. 34. Kim D, Duff RA. Regulation of K+ channels in cardiac myocytes by free fatty acids. Circ Res. 1990;67:1040–6. 35. Oliver MF, Kurien VA, Greenwood TW. Relation between serumfree-fatty acids and arrhythmias and death after acute myocardial infarction. Lancet. 1968;1:710–4. 36. Oliver MF. Control of free fatty acids during acute myocardial ischaemia. Heart. 2010;96:1883–4. 37. Beardslee MA, Lerner DL, Tadros PN, Laing JG, Beyer EC, Yamada KA, Kleber AG, Schuessler RB, Saffitz JE. Dephosphorylation and intracellular redistribution of ventricular connexin43 during electrical uncoupling induced by ischemia. Circ Res. 2000;87:656–62. 38. de Groot JR, Wilms-Schopman FJ, Opthof T, Remme CA, Coronel R. Late ventricular arrhythmias during acute regional ischemia in the isolated blood perfused pig heart. Role of electrical cellular coupling. Cardiovasc Res. 2001;50:362–72. 39. Jongsma HJ, Wilders R. Gap junctions in cardiovascular disease. Circ Res. 2000;86:1193–7. 40. Lameris TW, de Zeeuw S, Alberts G, Boomsma F, Duncker DJ, Verdouw PD, Veld AJ, van Den Meiracker AH. Time course and mechanism of myocardial catecholamine release during transient ischemia in vivo. Circulation. 2000;101:2645–50.
250 41. Stables CL, Curtis MJ. Development and characterization of a mouse in vitro model of ischaemia-induced ventricular fibrillation. Cardiovasc Res. 2009;83:397–404. 42. McHowat J, Creer MH. Thrombin activates a membrane-associated calcium-independent PLA2 in ventricular myocytes. Am J Physiol. 1998;274:C447–54. 43. Pinet C, Le Grand B, John GW, Coulombe A. Thrombin facilitation of voltage-gated sodium channel activation in human cardiomyocytes: implications for ischemic sodium loading. Circulation. 2002;106:2098–103. 44. Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, Yazaki Y, Goto K, Masaki T. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature. 1988;332:411–5. 45. Proven A, Roderick HL, Conway SJ, Berridge MJ, Horton JK, Capper SJ, Bootman MD. Inositol 1,4,5-trisphosphate supports the arrhythmogenic action of endothelin-1 on ventricular cardiac myocytes. J Cell Sci. 2006;119:3363–75. 46. Yorikane R, Koike H, Miyake S. Electrophysiological effects of endothelin-1 on canine myocardial cells. J Cardiovasc Pharmacol. 1991;17 Suppl 7:S159–62. 47. Kurz RW, Ren XL, Franz MR. Dispersion and delay of electrical restitution in the globally ischaemic heart. Eur Heart J. 1994;15:547–54. 48. Stewart DJ, Kubac G, Costello KB, Cernacek P. Increased plasma endothelin-1 in the early hours of acute myocardial infarction. J Am Coll Cardiol. 1991;18:38–43. 49. Doggrell SA. The endothelin system and its role in acute myocardial infarction. Expert Opin Ther Targets. 2004;8:191–201. 50. Oikonomidis DL, Tsalikakis DG, Baltogiannis GG, et al. Endothelin-B receptors and ventricular arrhythmogenesis in the rat model of acute myocardial infarction. Basic Res Cardiol. 2011;105:235–45. 51. Rubart M, Zipes DP. Mechanisms of sudden cardiac death. J Clin Invest. 2005;115:2305–15. 52. Hu D, Viskin S, Oliva A, et al. Novel mutation in the SCN5A gene associated with arrhythmic storm development during acute myocardial infarction. Heart Rhythm. 2007;4:1072–80. 53. Crotti L. Pleiotropic mutations in ion channels: what lies behind them? Heart Rhythm. 2011;8:56–7. 54. Janse MJ, van Capelle FJ, Morsink H, Kleber AG, WilmsSchopman F, Cardinal R, d’Alnoncourt CN, Durrer D. Flow of “injury” current and patterns of excitation during early ventricular arrhythmias in acute regional myocardial ischemia in isolated porcine and canine hearts. Evidence for two different arrhythmogenic mechanisms. Circ Res. 1980;47:151–65. 55. Pogwizd SM, Corr PB. Reentrant and nonreentrant mechanisms contribute to arrhythmogenesis during early myocardial ischemia: results using three-dimensional mapping. Circ Res. 1987;61:352–71. 56. Friedman PL, Stewart JR, Fenoglio Jr JJ, Wit AL. Survival of subendocardial Purkinje fibers after extensive myocardial infarction in dogs. Circ Res. 1973;33:597–611. 57. Hansen DE, Craig CS, Hondeghem LM. Stretch-induced arrhythmias in the isolated canine ventricle. Evidence for the importance of mechanoelectrical feedback. Circulation. 1990;81:1094–105. 58. Parker KK, Lavelle JA, Taylor LK, Wang Z, Hansen DE. Stretchinduced ventricular arrhythmias during acute ischemia and reperfusion. J Appl Physiol. 2004;97:377–83. 59. Banville I, Gray RA, Ideker RE, Smith WM. Shock-induced figureof-eight reentry in the isolated rabbit heart. Circ Res. 1999;85: 742–52. 60. Jalife J. Ventricular fibrillation: mechanisms of initiation and maintenance. Annu Rev Physiol. 2000;62:25–50. 61. Weiss JN, Chen PS, Qu Z, Karagueuzian HS, Lin SF, Garfinkel A. Electrical restitution and cardiac fibrillation. J Cardiovasc Electrophysiol. 2002;13:292–5.
T.M. Kolettis 62. Coronel R, Wilms-Schopman FJ, Opthof T, Janse MJ. Dispersion of repolarization and arrhythmogenesis. Heart Rhythm. 2009;6:537–43. 63. Kawara T, Derksen R, de Groot JR, et al. Activation delay after premature stimulation in chronically diseased human myocardium relates to the architecture of interstitial fibrosis. Circulation. 2001;104:3069–75. 64. Aye NN, Xue YX, Hashimoto K. Antiarrhythmic effects of cariporide, a novel Na+−H+ exchange inhibitor, on reperfusion ventricular arrhythmias in rat hearts. Eur J Pharmacol. 1997;339:121–7. 65. Imahashi K, Pott C, Goldhaber JI, Steenbergen C, Philipson KD, Murphy E. Cardiac-specific ablation of the Na+−Ca2+ exchanger confers protection against ischemia/reperfusion injury. Circ Res. 2005;97:916–21. 66. Pogwizd SM, Corr PB. Electrophysiologic mechanisms underlying arrhythmias due to reperfusion of ischemic myocardium. Circulation. 1987;76:404–26. 67. Hobai IA, O’Rourke B. The potential of Na+/Ca2+ exchange blockers in the treatment of cardiac disease. Expert Opin Investig Drugs. 2004;13:653–64. 68. Hine LK, Laird N, Hewitt P, Chalmers TC. Meta-analytic evidence against prophylactic use of lidocaine in acute myocardial infarction. Arch Intern Med. 1989;149:2694–8. 69. Gorgels AP, Vos MA, Letsch IS, Verschuuren EA, Bar FW, Janssen JH, Wellens HJ. Usefulness of the accelerated idioventricular rhythm as a marker for myocardial necrosis and reperfusion during thrombolytic therapy in acute myocardial infarction. Am J Cardiol. 1988;61:231–5. 70. Steinbach KK, Merl O, Frohner K, Hief C, Nurnberg M, Kaltenbrunner W, Podczeck A, Wessely E. Hemodynamics during ventricular tachyarrhythmias. Am Heart J. 1994;127:1102–6. 71. Kolettis TM, Saksena S. Prophylactic implantable cardioverter defibrillator therapy in high-risk patients with coronary artery disease. Am Heart J. 1994;127:1164–70. 72. Kolettis TM, Kyriakides ZS, Popov T, Mesiskli T, Papalambrou A, Kremastinos DT. Importance of the site of ventricular tachycardia origin on left ventricular hemodynamics in humans. Pacing Clin Electrophysiol. 1999;22:871–9. 73. Kolettis TM, Psarros E, Kyriakides ZS, Katsouras CS, Michalis LK, Sideris DA. Haemodynamic and catecholamine response to simulated ventricular tachycardia in man: effect of baseline left ventricular function. Heart. 2003;89:306–10. 74. Berger PB, Ruocco NA, Ryan TJ, Frederick MM, Podrid PJ. Incidence and significance of ventricular tachycardia and fibrillation in the absence of hypotension or heart failure in acute myocardial infarction treated with recombinant tissue-type plasminogen activator: results from the Thrombolysis in Myocardial Infarction (TIMI) Phase II trial. J Am Coll Cardiol. 1993;22:1773–9. 75. Stewart RB, Bardy GH, Greene HL. Wide complex tachycardia: misdiagnosis and outcome after emergent therapy. Ann Intern Med. 1986;104:766–71. 76. Wolfe CL, Nibley C, Bhandari A, Chatterjee K, Scheinman M. Polymorphous ventricular tachycardia associated with acute myocardial infarction. Circulation. 1991;84:1543–51. 77. Kolettis TM, Naka KK, Katsouras CS. Radiofrequency catheter ablation for electrical storm in a patient with dilated cardiomyopathy. Hellenic J Cardiol. 2005;46:366–9. 78. Enjoji Y, Mizobuchi M, Shibata K, Yokouchi I, Funatsu A, Kanbayashi D, Kobayashi T, Nakamura S. Catheter ablation for an incessant form of antiarrhythmic drug-resistant ventricular fibrillation after acute coronary syndrome. Pacing Clin Electrophysiol. 2006;29:102–5. 79. Carbucicchio C, Santamaria M, Trevisi N, et al. Catheter ablation for the treatment of electrical storm in patients with implantable cardioverter-defibrillators: short- and long-term outcomes in a prospective single-center study. Circulation. 2008;117:462–9.
18 Ventricular Arrhythmias During Acute Myocardial Ischemia/Infarction: Mechanisms and Management 80. Schreieck J, Zrenner B, Deisenhofer I, Schmitt C. Rescue ablation of electrical storm in patients with ischemic cardiomyopathy: a potential-guided ablation approach by modifying substrate of intractable, unmappable ventricular tachycardias. Heart Rhythm. 2005;2:10–4. 81. Tsagalou EP, Kanakakis J, Rokas S, Anastasiou-Nana MI. Suppression by propranolol and amiodarone of an electrical storm refractory to metoprolol and amiodarone. Int J Cardiol. 2005;99:341–2. 82. Kodama I, Kamiya K, Honjo H, Toyama J. Acute and chronic effects of amiodarone on mammalian ventricular cells. Jpn Heart J. 1996;37:719–30. 83. Du XJ, Esler MD, Dart AM. Sympatholytic action of intravenous amiodarone in the rat heart. Circulation. 1995;91:462–70. 84. Agelaki MG, Pantos C, Korantzopoulos P, Tsalikakis DG, Baltogiannis GG, Fotopoulos A, Kolettis TM. Comparative antiarrhythmic efficacy of amiodarone and dronedarone during acute myocardial infarction in rats. Eur J Pharmacol. 2007;564:150–7. 85. Nasir Jr N, Taylor A, Doyle TK, Pacifico A. Evaluation of intravenous lidocaine for the termination of sustained monomorphic ventricular tachycardia in patients with coronary artery disease with or without healed myocardial infarction. Am J Cardiol. 1994;74:1183–6. 86. Piccini JP, Schulte PJ, Pieper KS, et al. Antiarrhythmic drug therapy for sustained ventricular arrhythmias complicating acute myocardial infarction. Crit Care Med. 2011;39:78–83. 87. Weisfeldt ML, Becker LB. Resuscitation after cardiac arrest: a 3-phase time-sensitive model. JAMA. 2002;288:3035–8. 88. Wyse DG, Friedman PL, Brodsky MA, et al. Life-threatening ventricular arrhythmias due to transient or correctable causes: high risk for death in follow-up. J Am Coll Cardiol. 2001;38:1718–24. 89. Viskin S, Halkin A, Olgin JE. Treatable causes of sudden death: not really “treatable” or not really the cause? J Am Coll Cardiol. 2001;38:1725–7.
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90. Weng S, Lauven M, Schaefer T, Polontchouk L, Grover R, Dhein S. Pharmacological modification of gap junction coupling by an antiarrhythmic peptide via protein kinase C activation. FASEB J. 2002;16:1114–6. 91. Kjolbye AL, Holstein-Rathlou NH, Petersen JS. Anti-arrhythmic peptide N-3-(4-hydroxyphenyl)propionyl Pro-Hyp-Gly-AlaGly-OH reduces dispersion of action potential duration during ischemia/reperfusion in rabbit hearts. J Cardiovasc Pharmacol. 2002;40:770–9. 92. Di Diego JM, Sun ZQ, Antzelevitch C. I(to) and action potential notch are smaller in left vs. right canine ventricular epicardium. Am J Physiol. 1996;271:H548–61. 93. Dhalla AK, Wang WQ, Dow J, Shryock JC, Belardinelli L, Bhandari A, Kloner RA. Ranolazine, an antianginal agent, markedly reduces ventricular arrhythmias induced by ischemia and ischemia-reperfusion. Am J Physiol Heart Circ Physiol. 2009;297:H1923–9. 94. Nieminen T, Nanbu DY, Datti IP, Vaz GR, Tavares CA, Pegler JR, Nearing BD, Belardinelli L, Verrier RL. Antifibrillatory effect of ranolazine during severe coronary stenosis in the intact porcine model. Heart Rhythm. 2011;8:608–14. 95. Baltogiannis GG, Tsalikakis DG, Mitsi AC, Hatzistergos KE, Elaiopoulos D, Fotiadis DI, Kyriakides ZS, Kolettis TM. Endothelin receptor-A blockade decreases ventricular arrhythmias after myocardial infarction in rats. Cardiovasc Res. 2005;67:647–54. 96. Kolettis TM, Baltogiannis GG, Tsalikakis DG, Tzallas AT, Agelaki MG, Fotopoulos A, Fotiadis DI, Kyriakides ZS. Effects of dual endothelin receptor blockade on sympathetic activation and arrhythmogenesis during acute myocardial infarction in rats. Eur J Pharmacol. 2008;580:241–9. 97. Elaiopoulos DA, Tsalikakis DG, Agelaki MG, Baltogiannis GG, Mitsi AC, Fotiadis DI, Kolettis TM. Growth hormone decreases phase II ventricular tachyarrhythmias during acute myocardial infarction in rats. Clin Sci (Lond). 2007;112:385–91.
Arrhythmias and Hypertrophic Cardiomyopathy
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Krishnakumar Nair, Douglas Cameron, Gil Moravsky, and Jagdish Butany
Abstract
Hypertrophic cardiomyopathy (HCM) accounts for an estimated third of all sudden cardiac deaths (SCD) in young athletes secondary to lethal ventricular arrhythmias. Current guidelines restrict patients with HCM from participating in competitive sports because the risk for SCD is increased during intense physical exertion. Both atrial and ventricular arrhythmias occur in HCM. The most common documented arrhythmia in patients with HCM is atrial fibrillation. Ventricular arrhythmias in patients with HCM may present as sudden cardiac death. Primary prevention indications for ICDs in patients with HCM should be individualized with careful family screening of family members as arrhythmias may be the first clinical manifestation of the disease. This review article discusses the features of atrial and ventricular arrhythmias in HCM and their management. In addition, the review discusses the risk factors for sudden cardiac death, the role of alternative strategies in HCM like dual chamber pacing and the arrhythmias that occur after septal myectomy. Keywords
Hypertrophic cardiomyopathy • Sudden cardiac death • Septal myectomy • Dual chamber pacing
Introduction
Electrocardiogram (ECG)
Hypertrophic cardiomyopathy (HCM) accounts for an estimated third of all sudden cardiac deaths (SCD) in young athletes [1, 2] secondary to lethal ventricular arrhythmias. Current guidelines [3] restrict patients with HCM from participating in competitive sports because the risk for SCD is increased during intense physical exertion [3]. Both atrial and ventricular arrhythmias occur in HCM.
The 12-lead ECG pattern is abnormal in 75–95 % of HCM patients and typically demonstrates a wide variety of patterns [1–6]. The ECG abnormalities most commonly described are left ventricular hypertrophy (LVH) (Fig. 19.1), ST segment alterations and T wave inversion, left atrial enlargement, abnormal Q waves, and diminished or absent R waves in the lateral precordial leads. Normal ECGs are most commonly encountered in family members identified as part of pedigree screening or when associated with mild localized LVH. Only a modest relation between ECG voltages and the magnitude of LVH assessed by echocardiography is evident. Nevertheless, ECGs have diagnostic value in raising a suspicion of HCM in family members without LVH on echocardiogram and in targeting athletes for diagnostic echocardiography as part of pre-participation screening [7].
K. Nair • D. Cameron • G. Moravsky Division of Cardiology, Department of Medicine, University of Toronto, Toronto, ON, Canada J. Butany, MBBS, MS, FRCPC (*) Division of Pathology, Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada e-mail:
[email protected]
A.S. Kibos et al. (eds.), Cardiac Arrhythmias, DOI 10.1007/978-1-4471-5316-0_19, © Springer-Verlag London 2014
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Fig. 19.1 12-lead electrocardiogram shows normal sinus rhythm, mild left axis deviation and left ventricular hypertrophy with strain (repolarization) changes, as indicated by prominent R waves, and T inversion in anterolateral leads
Atrial Arrhythmias
Therapies for AF
Atrial Fibrillation
Anticoagulation
Atrial fibrillation (AF) is the most common documented arrhythmia in patients with hypertrophic cardiomyopathy occurring in 20–25 % of these patients (Fig. 19.2) [1, 8, 9]. The risk of atrial fibrillation in HCM increases with age and is uncommon below the age of 30 years [3]. Other risk factors for AF in HCM include congestive heart failure and left atrial size [8, 10]. AF is often poorly tolerated in these patients in part due to reduced diastolic compliance with a greater dependence on atrial contribution to stroke output. There is evidence that AF is an indicator of unfavorable prognosis in HCM patients, including increased risk of HCM-related heart failure, death, and stroke [8, 11]. Importantly, AF has been associated with progressive heart failure [8, 12] as well as a higher risk of cardiovascular death in several studies [8, 11, 13–19]. The association of AF with risk of SCD is less clear; one study has found a relationship [18], while three other larger studies failed to identify a significant relationship [15, 20, 21].
The risk of systemic embolization is high in patients with HCM with AF [22, 23]. The 2011 ACCF/AHA/HRS Focused Updates of the ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation [24] suggest that even a single episode of AF should be cause to consider lifetime anticoagulation because the likelihood of recurrent AF is high and because of the high risk of thromboembolism in HCM. The role of aspirin or that of LA occlusion devices in AF patients with HCM is not established [24, 25].
Rate Control Rate control is not the preferred approach in HCM patients with AF. Even though there are no trials that compared rate control to rhythm control in the HCM population, the potentially adverse consequences of loss of AV synchrony associated with diastolic dysfunction argue in favour of attempts to maintain sinus rhythm over rate control strategies [23].
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Fig. 19.2 12-lead electrocardiogram shows atrial fibrillation in a patient with hypertrophic cardiomyopathy. Also seen is mild left axis deviation and prominent S waves V2 and V3
In patients in whom maintaining sinus rhythm is not feasible, rate control is best maintained by beta blockers or calcium channel blockers (verapamil or diltiazem). Calcium channel blockers may be useful but need to be used with care as they may potentially aggravate outflow obstruction in obstructive patients. While digoxin is contraindicated in HCM patients with left ventricular outflow (LVOT) obstruction, as it may aggravate intracavitary gradients, it may be used in nonobstructive patients, especially in the presence of systolic dysfunction (i.e., burnt out HCM).
Rhythm Control Drugs There are no major drug trials for AF in HCM. The 2011ACCF/AHA/HRS Focused Updates incorporated into the ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation state that disopyramide and amiodarone are potential agents for rhythm control [24]. Amiodarone is the most effective antiarrhythmic drug for prevention of atrial fibrillation in patients with HCM [9, 26–28]. The safety and efficacy of disopyramide in AF are not well established, though it has been prescribed in left ventricular outflow tract obstruction [29, 30]. There are no data regarding the efficacy of dronedarone, flecainide or propafenone in patients with HCM.
Radiofrequency Ablation Though some studies have shown that early success and complication rates are similar, for AF in HCM [31–35], overall, the evidence regarding the efficacy of radiofrequency ablation for AF in HCM patients is limited [31]. Surgical Maze Procedure The surgical maze procedure for AF has shown some success in HCM patients [36] and is reasonable (with combination of closure of left atrium appendage) in those patients with history of AF undergoing septal myectomy [3, 36].
Atrial Flutter The management of atrial flutter in HCM is similar to that in other disease states, including the role of radiofrequency ablation.
Ventricular Arrhythmias The Substrate Two features of hypertrophic cardiomyopathy [12] that likely predispose to macro-reentry are myocardial disarray and small vessel disease.
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Fig. 19.3 Rhythm strip (leads I and II) on a Holter recording in a patient with hypertrophic cardiomyopathy shows a run of monomorphic ventricular tachycardia at 190 bpm
Myocardial Disarray Myocardial disarray, one of the more salient histological features of HCM, consists of bizarre myocytes aligned at oblique and perpendicular angles and resulting in a chaotic or disordered myocardial architecture [37, 38]. Myocardial disarray has been found in about 95 % of patients dying of HCM and may occupy about 33 % of septum and 25 % of free wall of the left ventricle [37, 38]. Another important characteristic of HCM is myocardial fibrosis [39, 40]. All these factors together may promote dispersion of electrical depolarization and repolarization and may produce unidirectional conduction block and delay which promote reentry [41, 42]. This may trigger lethal ventricular tachyarrhythmias and SCD [37, 38]. Small Vessel Disease Arterioles in HCM may have thickened walls, due to increased intimal and/or medial components, associated with apparent luminal narrowing leading to a form of “small vessel disease.” This finding may be observed in about 80 % of patients studied at necropsy, most commonly in the ventricular septum and in proximity to areas of fibrosis [12, 43]. These abnormalities may be responsible for regions of silent regional myocardial ischemia and may ultimately lead to myocardial scar formation [43].
Triggers and Mechanism for Ventricular Arrhythmias in HCM A single-center observational cohort study of 230 consecutively evaluated implantable cardioverter defibrillator (ICD) recipients with HCM [median age 42 years, 97 % primary prevention, 51 % with anti-tachycardia pacing (ATP)]
revealed that late-coupled PVC initiated the majority (72 %) of ventricular arrhythmias (VA), which were primarily monomorphic (86 % of cases). Premature ventricular complexes were seen in 80–90 % of HCM patients [39, 44]. Though the majority of VA in HCM were triggered by PVCs as in other cardiac diseases [45–47], not all PVCs lead to sustained VA (Fig. 19.3) in HCM which is intuitive and again parallels other diseases [48]. The overall incidence of VA in most reported HCM populations is paradoxically low [49–53]. Though sudden-onset VAs without preceding PVCs are likely to involve abnormal automaticity, triggered activity, or a combination of arrhythmogenic mechanisms [47]; the majority of VA in one study were monomorphic and effectively terminated by ATP, in keeping with another previous study [54] suggesting reentry as the mechanism [55].
Circadian Variability in VA in HCM There appears to be no circadian pattern to arrhythmia vulnerability in patients with HCM. The circadian arrhythmia pattern observed in ischemic heart disease patients of reduced VA’s during sleep presumably during periods of heightened parasympathetic tone [56–58] with peaking during early morning arousal associated with heightened sympathetic tone is not seen in studies of HCM patients with ICDs [56, 58–60].
Sudden Cardiac Death Risk Factors: Major and Minor For secondary prevention, ICD placement is recommended (Class I ACC/AHA) for patients with HCM with prior
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Table 19.1 Indications for AICD implantation in HCM Indication Aborted sudden death Ventricular fibrillation Hemodynamically significant VT Family history – SCD in first-degree relative Septum ≥30 mm Recent unexplained syncope Nonsustained VT on Holter Abnormal BP response on exercise test
Strength of recommendation Class I
Remarks Secondary prevention
Class IIa
LVOT obstruction LGE on CMR imaging LV apical aneurysm Genetic mutations
Class III
Primary prevention Major risk factors One of the following is sufficient Primary prevention IIa – with one other SCD risk factor/modifier IIb – in the absence of other SCD risk factors Primary prevention Potential SCD risk modifiers
Class IIa/IIb
AICD automatic implantable cardioverter defibrillator, SCD sudden cardiac death, VT ventricular tachycardia, LVOT left ventricular outflow, LGE late gadolinium enhancement, CMR cardiovascular magnetic resonance, LV left ventricle
documented cardiac arrest, ventricular fibrillation, or hemodynamically significant VT [3, 51, 61–64]. The ACC/ AHA includes as a Class IIa recommendation an ICD for patients with HCM with major risk factors of sudden death presumably caused by HCM in 1 or more first-degree relatives [65], a maximum LV wall thickness equal or greater than 30 mm [66–69], and one or more recent, unexplained syncopal episodes [70]. The other Class IIa AHA/ACC recommendations are that an ICD can be useful in select patients with NSVT (particularly those <30 years of age) in the presence of other SCD risk factors or modifiers [71, 72] and that an ICD can be considered in select patients with HCM with an abnormal blood pressure response with exercise in the presence of other SCD risk factors or modifiers [21, 73, 74]. The other potential SCD risk modifiers are significant LVOT obstruction, late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) imaging, LV apical aneurysm, and double/compound mutations [3]. However, some investigators do mandate a minimum of two risk factors as indications for a prophylactic ICD [51, 75]. Table 19.1 summarizes the indication for ICD implantation in HCM based on the recent ACC/AHA guidelines [3].
Duration of NSVT Although some authors have suggested that NSVT is only of prognostic value if prolonged, repetitive, or symptomatic [76, 77], the study by Monserrat et al. demonstrated a substantial increase in risk of SCD in patients with evidence of NSVT [72]. The authors demonstrated no relationship between the duration or frequency of NSVT and the risk of sudden death, but the risk was highest in those patients under the age of 30 years. In those under the age of 30 years, the odds ratio for SCD was 4.35 compared with 2.16 in those aged 30 years and above [72].
In the absence of any other SCD risk factors or modifiers, the usefulness of an ICD is uncertain in patients with HCM with isolated bursts of NSVT (Fig. 19.2) or an abnormal blood pressure response with exercise (particularly in the presence of significant outflow obstruction), and these have been classified as Class IIb recommendations [3].
Late Gadolinium Enhancement A risk factor for SCD prediction that is becoming important in HCM is evidence of late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) imaging [78, 79]. However, more robust data is needed before classifying this as a major risk factor for SCD. Presently, there is a possible role for LGE especially in “gray” areas in primary prevention. Areas of LGE could represent myocardial fibrosis or scarring, and this could represent a substrate predisposing to ventricular tachyarrhythmias. Patients with greater extent of LGE tend to have more NSVT on Holter monitoring than patients without LGE [80, 81], while LGE has not yet been associated with clinical SCD or ICD discharge, a few recent studies have shown a relationship between LGE and SCD and heart failure, but with low positive predictive accuracy (74). Since LGE is a common feature observed in HCM patients, and also there is no consensus on the threshold for detection of LGE, its role in the risk stratification for SCD in HCM is currently limited. Considering all these factors, the decision to implant an ICD for primary prophylaxis in a patient with HCM should be individualized.
Results of ICD Therapy in HCM The annualized rate of subsequent appropriate ICD discharge in an international, multicenter registry for secondary
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prevention indications was 10 % per year [82, 83]. Patients with primary prevention ICDs implanted on the basis of 1 or more of the conventional risk markers experienced appropriate ICD therapy at a rate of approximately 4 % per year [51, 82]. The number of risk markers present did not predict subsequent device discharge. The relative weight of the individual risk markers in predicting device discharge rate has not been reported [50, 51]. The largest multicenter registry to date provided data on 506 patients implanted with an ICD [1, 51]. The annual discharge rate in the secondary prevention group was 10.6 %, which was higher as compared to an annual discharge rate of 3.6 % in the primary prevention group. One-third of patients experienced an inappropriate shock due to sinus tachycardia, atrial fibrillation, or lead malfunction. Significant predictors of an increased risk of inappropriate device therapy include an age less than 35 years and the presence of atrial fibrillation. Conversely, the use of beta blockers or the addition of an atrial lead in a dual-chamber device had no effect on the frequency of inappropriate shocks [50]. Woo et al. studied 61 patients with HCM who received ICDs for the primary or secondary prevention of sudden cardiac death (SCD). Multivariate Cox regression analysis identified the same two significant predictors of inappropriate ICD discharges: (a) age <30 years at the time of ICD insertion (hazard ratio (HR) = 3.0 (95 % CI 1.1–8.0; p = 0.03) and (b) history of atrial fibrillation (HR) = 3.1 (95 % CI 1.2–8.1; p = 0.02) [53].
Complications of ICD Therapy in HCM Late complications include high defibrillation threshold necessitating lead revision and inappropriate shocks, that is, shocks triggered by supraventricular arrhythmias, sinus tachycardia, oversensing, and double counting. Reported rates of complications include approximately 25 % of patients with HCM who experienced inappropriate ICD discharge [50, 51]. The rate of inappropriate shocks and lead fractures appears to be higher in children than in adults [84]. Selected patients with extreme hypertrophy or who have received amiodarone may require high-energy output generators or epicardial lead systems [85]. The importance of appropriate programming to minimize inappropriate shocks, and the importance of reinforcing the need for drug compliance cannot be overemphasized.
Arrhythmias After Alcohol Septal Ablation and Surgical Myectomy According to the ACC guidelines, surgical septal myectomy, when performed in experienced centers, can be beneficial and is the first consideration for the majority of eligible patients with HCM with severe drug-refractory symptoms and LVOT obstruction (Class IIa recommendation) [3]. The
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ACC/AHA recommendations also state that when surgery is contraindicated or the risk is considered unacceptable because of serious comorbidities or advanced age, alcohol septal ablation (ASA), when performed in experienced centers, can be beneficial in eligible adult patients with HCM with LVOT obstruction and severe drug-refractory symptoms (usually NYHA functional Classes III or IV) [86–92]. It must also be demonstrated that the obstruction is caused by apposition of the mitral valve with the hypertrophied septum (and not attributable to systolic cavity obliteration) [93, 94]. In a nonrandomized retrospective evaluation of patients with HCM <65 years of age, survival free from recurrent symptoms favored myectomy over alcohol septal ablation (89 % versus 71 %, p < 0.01) [86].
Conduction Abnormalities and Bradyarrhythmias Reduction of LVOT obstruction in HCM could be achieved by the excision of a segment of the hypertrophied septum in surgical myectomy [95, 96] or by the infarction of the proximal septum with alcohol infused into a septal perforator branch in ASA [96, 97]. Because the atrioventricular bundles course through the superior margin of the muscular ventricular septum beneath the membranous septum, any excision or infarction to this region may damage the conduction system, resulting in right bundle branch block (RBBB), left bundle branch block (LBBB), or complete atrioventricular block [97]. Alcohol injected through the first or second perforator branch of the left anterior descending artery during ASA results in a localized myocardial infarction in the proximal ventricular septum and may damage the right bundle branch because of edema, ischemia, or necrosis [97]. The incidence of RBBB after ASA has been reported to occur in 45–85 % of patients [97–99]. The left bundle branch lies under the left side of the muscular ventricular septum, beneath the membranous septum. With intentional and extensive resection of the myocardium in this region during septal myectomy, a LBBB is created. Many patients in most surgical series developed LBBB after septal myectomy, and in one series, 93 % had new LBBB with preexisting normal conduction [97, 100]. Bradyarrhythmias are the most common rhythm complication following ASA. In approximately half of patients undergoing ASA, temporary complete atrioventricular block occurs during the procedure [101–104]. Persistent complete AV block occurs in 10–20 % of patients based on the available data [105, 106]. The risk of complete heart block is approximately 2 % with myectomy (higher in patients with preexisting right bundle branch block) [107]. Predictors of the need for permanent pacing in alcohol septal ablation have been identified in two studies. Sherrid et al. have devised a scoring system, based on the assessment of the ECG (i.e., QRS duration, PQ duration, atrioventricular block occurrence and persistence or recovery, heart rate) as well as
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hemodynamic variables (baseline gradient) and myocardial enzyme kinetics (time-point of peak alanine amino-transferase) [108]. They have suggested female sex, bolus alcohol injection, occlusion of more than one septal branch, preexisting left bundle branch block, and first-degree atrioventricular block as predictors for need of permanent pacing [109].
rate-adaptive AV pacing is necessary to obtain full preexcitation of the ventricle at rest and during exercise. Too short AV delay may lead to hemodynamic deterioration, and too long an AV delay may not cause complete preexcitation [130]. The pacemaker lead itself should be at the apex for optimal hemodynamic results [131].
Tachyarrhythmias After ASA
Mechanisms of Benefit of Dual-Chamber Pacing
There is concern that the potential ventricular arrhythmogenicity of the scar created by ASA might augment risk in the HCM population. The incidence of sustained ventricular arrhythmias after myectomy is extremely low (0.2–0.9 % per year) [110, 111] as opposed to the documentation of sustained ventricular arrhythmias [98, 112–119] and SCD following septal ablation [120] (about 3–10 % of patients both with or without risk factors for SCD). In a single-center experience (n = 91) post-ablation, 21 % of patients experienced sudden or other cardiac death, aborted SCD, and/or appropriate ICD discharge resulting in an annualized event rate of 4.4 % per year [120]. In a second single-center experience (n = 89), no mortality was attributable to SCD in 5.0 ±2.3 years of follow-up. However, in a selected subset of 42 patients with an ICD or permanent pacemaker that allowed detection of device stored electrograms, the annualized event rate (VT, ventricular fibrillation, and/or appropriate ICD discharge, including periprocedural arrhythmias) was 4.9 % per year [118]. Data from another center suggests appropriate ICD therapy rates after ablation of 2.8 % per year [121]; similarly, the multicenter HCM ICD registry (n = 506) demonstrated that the rate of appropriate ICD therapy among ablation patients with primary prevention ICDs was three to four times more frequent than in other patients in that registry (10.3 % per year compared with 2.6 % per year) [51]. Patients with HCM considered to carry sufficient risk to warrant ICD placement have an annual incidence of appropriate interventions for VT/ventricular fibrillation of 3–10 % [51, 116, 121]. Ventricular arrhythmias in the early postprocedure phase have been reported, possibly as an effect of ischemia. Approximately 5 % of patients have sustained ventricular tachyarrhythmia during hospitalization [122–125]. However, in the long term, only one study has described significant ventricular arrhythmias [126–129]. A less successful hemodynamic outcome may be associated with a higher arrhythmic risk, with the risk of arrhythmia increasing as the post-interventional gradient increases [73].
Role of DDD Pacing DDD pacing has been tried in patients with HCM to reduce left ventricular outflow tract (LVOT) gradient. Atrioventricular (AV) delay should be optimized by programming. Programming of short AV delays with associated
There are three proposed mechanisms of benefit of dualchamber pacing in HCM: 1. RV pacing results in apical preexcitation which induces early contraction of the apex, delayed contraction of the base of the heart, and an overall reduction in septal motion [132, 133]. This leads to a larger LVOT diameter, a reduced LVOT gradient, and a reduction in systolic anterior motion of the mitral valve [134–136]. 2. An alternative explanation applicable in preexisting left bundle branch block and LVOT obstruction is that the dyssynchrony produced by RV apical pacing results in a reduction in LV contractility and a fall in LV stroke work [137]. Leclerq and colleagues have demonstrated a reduction in LV ejection fraction and positive dp/dt during DDD pacing compared with AAI [138], and similar findings have been demonstrated in HCM patients by Nishimura et al. [130]. 3. Benefit may also be through the mechanism of long-term remodelling [139].
Evidence of Clinical Benefit Observational Studies Several nonrandomized observational studies have reported a reduction of the outflow tract gradient along with symptomatic relief and improvement in exercise capacity [132, 135, 139, 140].
Prospective and Randomized Trials Three randomized controlled trials have been conducted in patients with obstructive HCM and drug-refractory symptoms. The European Pacing in Cardiomyopathy (PIC) study was the largest of these studies. This study demonstrated a significant improvement in exercise tolerance, a reduction in symptomatic status, and a documented hemodynamic improvement with active DDD pacing [134]. However, a significant placebo effect was demonstrated even during the inactive AAI backup phase of pacing. In addition, this beneficial effect could not be reproduced in the other two studies: the Multicenter Study of Pacing Therapy for Hypertrophic Cardiomyopathy
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(M-PATHY) and the Mayo Clinic study [141, 142]. Similarly, Oomen et al. showed that symptomatic benefit was seen only in 47 % in the pacing group in their study as opposed to benefit in 90 % in the surgical myectomy arm [94].
Long-Term Follow-Up Long-term follow-up studies by Galve et al. and Megevand et al. have demonstrated a statistically significant decline in LVOT gradient over time [2, 143]. Presently, no data indicates that dual-chamber pacing reduces the risk of SCD in HCM, alters the underlying progression of disease [139, 141, 144], or is of benefit in nonobstructive HCM [144]. Therefore, the ACC recommendations caution against permanent pacemaker implantation for the purpose of reducing gradient in patients with HCM who are asymptomatic or whose symptoms are medically controlled [134, 141, 142] and as a first-line therapy to relieve symptoms in medically refractory symptomatic patients with HCM and LVOT obstruction who are candidates for septal reduction [134, 141, 142]. The ACC recommendations state that in patients with HCM who have had a dual-chamber device implanted for non-HCM indications, it is reasonable to consider a trial of dual-chamber atrial-ventricular pacing (from the right ventricular apex) for the relief of symptoms attributable to LVOT obstruction [94, 145–147] and include this as a Class IIa recommendation. Permanent pacing in medically refractory symptomatic patients with obstructive HCM who are suboptimal candidates for septal reduction therapy [94, 141, 146, 147] has been included as a Class II b recommendation.
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4.
5.
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7. 8.
9.
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12. 13.
14.
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Conclusion
The most common documented arrhythmia in patients with HCM is atrial fibrillation. Ventricular arrhythmias in patients with HCM may present as sudden cardiac death. Primary prevention indications for ICDs in patients with HCM should be individualized with careful family screening of family members as arrhythmias may be the first clinical manifestation of the disease.
References 1. Beadle R, Williams L. Device therapy in hypertrophic cardiomyopathy. Expert Rev Cardiovasc Ther. 2010;8:1767–75. 2. Megevand A, Ingles J, Richmond DR, Semsarian C. Long-term follow-up of patients with obstructive hypertrophic cardiomyopathy treated with dual-chamber pacing. Am J Cardiol. 2005;95:991–3. 3. Gersh BJ, Maron BJ, Bonow RO, Dearani JA, Fifer MA, Link MS, Naidu SS, Nishimura RA, Ommen SR, Rakowski H, Seidman CE, Towbin JA, Udelson JE, Yancy CW. 2011 accf/aha guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: a
16.
17.
18.
19.
20.
21.
report of the american college of cardiology foundation/american heart association task force on practice guidelines. Circulation. 2011;124:e783–831. Maron BJ, Niimura H, Casey SA, Soper MK, Wright GB, Seidman JG, Seidman CE. Development of left ventricular hypertrophy in adults in hypertrophic cardiomyopathy caused by cardiac myosin-binding protein c gene mutations. J Am Coll Cardiol. 2001;38:315–21. Maron BJ. The electrocardiogram as a diagnostic tool for hypertrophic cardiomyopathy: revisited. Ann Noninvasive Electrocardiol. 2001;6:277–9. Charron P, Dubourg O, Desnos M, Isnard R, Hagege A, Millaire A, Carrier L, Bonne G, Tesson F, Richard P, Bouhour JB, Schwartz K, Komajda M. Diagnostic value of electrocardiography and echocardiography for familial hypertrophic cardiomyopathy in a genotyped adult population. Circulation. 1997;96:214–9. Maron BJ. Hypertrophic cardiomyopathy: a systematic review. JAMA. 2002;287:1308–20. Olivotto I, Maron BJ, Cecchi F. Clinical significance of atrial fibrillation in hypertrophic cardiomyopathy. Curr Cardiol Rep. 2001;3:141–6. Robinson K, Frenneaux MP, Stockins B, Karatasakis G, Poloniecki JD, McKenna WJ. Atrial fibrillation in hypertrophic cardiomyopathy: a longitudinal study. J Am Coll Cardiol. 1990;15:1279–85. Losi MA, Betocchi S, Aversa M, Lombardi R, Miranda M, D’Alessandro G, Cacace A, Tocchetti CG, Barbati G, Chiariello M. Determinants of atrial fibrillation development in patients with hypertrophic cardiomyopathy. Am J Cardiol. 2004;94:895–900. Doi Y, Kitaoka H. Hypertrophic cardiomyopathy in the elderly: significance of atrial fibrillation. J Cardiol. 2001;37 Suppl 1: 133–8. Maron BJ. Sudden death in hypertrophic cardiomyopathy. J Cardiovasc Transl Res. 2009;2:368–80. Christiaans I, van Engelen K, van Langen IM, Birnie E, Bonsel GJ, Elliott PM, Wilde AA. Risk stratification for sudden cardiac death in hypertrophic cardiomyopathy: systematic review of clinical risk markers. Europace. 2010;12:313–21. Autore C, Bernabo P, Barilla CS, Bruzzi P, Spirito P. The prognostic importance of left ventricular outflow obstruction in hypertrophic cardiomyopathy varies in relation to the severity of symptoms. J Am Coll Cardiol. 2005;45:1076–80. Maron MS, Olivotto I, Betocchi S, Casey SA, Lesser JR, Losi MA, Cecchi F, Maron BJ. Effect of left ventricular outflow tract obstruction on clinical outcome in hypertrophic cardiomyopathy. N Engl J Med. 2003;348:295–303. Cannan CR, Reeder GS, Bailey KR, Melton 3rd LJ, Gersh BJ. Natural history of hypertrophic cardiomyopathy. A populationbased study, 1976 through 1990. Circulation. 1995;92:2488–95. Higashikawa M, Nakamura Y, Yoshida M, Kinoshita M. Incidence of ischemic strokes in hypertrophic cardiomyopathy is markedly increased if complicated by atrial fibrillation. Jpn Circ J. 1997;61:673–81. Sorajja P, Ommen SR, Nishimura RA, Gersh BJ, Berger PB, Tajik AJ. Adverse prognosis of patients with hypertrophic cardiomyopathy who have epicardial coronary artery disease. Circulation. 2003;108:2342–8. Cecchi F, Olivotto I, Montereggi A, Santoro G, Dolara A, Maron BJ. Hypertrophic cardiomyopathy in Tuscany: clinical course and outcome in an unselected regional population. J Am Coll Cardiol. 1995;26:1529–36. Kofflard MJ, Ten Cate FJ, van der Lee C, van Domburg RT. Hypertrophic cardiomyopathy in a large community-based population: clinical outcome and identification of risk factors for sudden cardiac death and clinical deterioration. J Am Coll Cardiol. 2003;41:987–93. Maki S, Ikeda H, Muro A, Yoshida N, Shibata A, Koga Y, Imaizumi T. Predictors of sudden cardiac death in hypertrophic cardiomyopathy. Am J Cardiol. 1998;82:774–8.
19
Arrhythmias and Hypertrophic Cardiomyopathy
22. Maron BJ, Olivotto I, Spirito P, Casey SA, Bellone P, Gohman TE, Graham KJ, Burton DA, Cecchi F. Epidemiology of hypertrophic cardiomyopathy-related death: revisited in a large non-referralbased patient population. Circulation. 2000;102:858–64. 23. Olivotto I, Cecchi F, Casey SA, Dolara A, Traverse JH, Maron BJ. Impact of atrial fibrillation on the clinical course of hypertrophic cardiomyopathy. Circulation. 2001;104:2517–24. 24. Fuster V, Ryden LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, Halperin JL, Kay GN, Le Huezey JY, Lowe JE, Olsson SB, Prystowsky EN, Tamargo JL, Wann LS, Smith Jr SC, Priori SG, Estes 3rd NA, Ezekowitz MD, Jackman WM, January CT, Page RL, Slotwiner DJ, Stevenson WG, Tracy CM, Jacobs AK, Anderson JL, Albert N, Buller CE, Creager MA, Ettinger SM, Guyton RA, Hochman JS, Kushner FG, Ohman EM, Tarkington LG, Yancy CW. 2011 accf/aha/hrs focused updates incorporated into the acc/aha/esc 2006 guidelines for the management of patients with atrial fibrillation: a report of the American college of cardiology foundation/American heart association task force on practice guidelines. Circulation. 2011;123:e269–367. 25. Maisel WH. Left atrial appendage occlusion–closure or just the beginning? N Engl J Med. 2009;360:2601–3. 26. Harris L, McKenna WJ, Rowland E, Holt DW, Storey GC, Krikler DM. Side effects of long-term amiodarone therapy. Circulation. 1983;67:45–51. 27. McKenna WJ, Harris L, Rowland E, Kleinebenne A, Krikler DM, Oakley CM, Goodwin JF. Amiodarone for long-term management of patients with hypertrophic cardiomyopathy. Am J Cardiol. 1984;54:802–10. 28. McKenna WJ, Harris L, Mulrow JP, Rowland E, Holt DW. Amiodarone dose titration: a method to minimise side effects during long term therapy. Br J Clin Pract Suppl. 1986;44:121–31. 29. Sherrid MV, Barac I, McKenna WJ, Elliott PM, Dickie S, Chojnowska L, Casey S, Maron BJ. Multicenter study of the efficacy and safety of disopyramide in obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol. 2005;45:1251–8. 30. Matsubara H, Nakatani S, Nagata S, Ishikura F, Katagiri Y, Ohe T, Miyatake K. Salutary effect of disopyramide on left ventricular diastolic function in hypertrophic obstructive cardiomyopathy. J Am Coll Cardiol. 1995;26:768–75. 31. Di Donna P, Olivotto I, Delcre SD, Caponi D, Scaglione M, Nault I, Montefusco A, Girolami F, Cecchi F, Haissaguerre M, Gaita F. Efficacy of catheter ablation for atrial fibrillation in hypertrophic cardiomyopathy: impact of age, atrial remodelling, and disease progression. Europace. 2010;12:347–55. 32. Bunch TJ, Munger TM, Friedman PA, Asirvatham SJ, Brady PA, Cha YM, Rea RF, Shen WK, Powell BD, Ommen SR, Monahan KH, Haroldson JM, Packer DL. Substrate and procedural predictors of outcomes after catheter ablation for atrial fibrillation in patients with hypertrophic cardiomyopathy. J Cardiovasc Electrophysiol. 2008;19:1009–14. 33. Gaita F, Di Donna P, Olivotto I, Scaglione M, Ferrero I, Montefusco A, Caponi D, Conte MR, Nistri S, Cecchi F. Usefulness and safety of transcatheter ablation of atrial fibrillation in patients with hypertrophic cardiomyopathy. Am J Cardiol. 2007;99:1575–81. 34. Kilicaslan F, Verma A, Saad E, Themistoclakis S, Bonso A, Raviele A, Bozbas H, Andrews MW, Beheiry S, Hao S, Cummings JE, Marrouche NF, Lakkireddy D, Wazni O, Yamaji H, Saenz LC, Saliba W, Schweikert RA, Natale A. Efficacy of catheter ablation of atrial fibrillation in patients with hypertrophic obstructive cardiomyopathy. Heart Rhythm. 2006;3:275–80. 35. Liu X, Ouyang F, Mavrakis H, Ma C, Dong J, Ernst S, Bansch D, Antz M, Kuck KH. Complete pulmonary vein isolation guided by three-dimensional electroanatomical mapping for the treatment of paroxysmal atrial fibrillation in patients with hypertrophic obstructive cardiomyopathy. Europace. 2005;7:421–7. 36. Chen MS, McCarthy PM, Lever HM, Smedira NG, Lytle BL. Effectiveness of atrial fibrillation surgery in patients with hypertrophic cardiomyopathy. Am J Cardiol. 2004;93:373–5.
261 37. Maron BJ, Roberts WC. Quantitative analysis of cardiac muscle cell disorganization in the ventricular septum of patients with hypertrophic cardiomyopathy. Circulation. 1979;59:689–706. 38. Maron BJ, Anan TJ, Roberts WC. Quantitative analysis of the distribution of cardiac muscle cell disorganization in the left ventricular wall of patients with hypertrophic cardiomyopathy. Circulation. 1981;63:882–94. 39. O’Mahony C, Lambiase PD, Rahman SM, Cardona M, Calcagnino M, Quarta G, Tsovolas K, Al-Shaikh S, McKenna W, Elliott P. The relation of ventricular arrhythmia electrophysiological characteristics to cardiac phenotype and circadian patterns in hypertrophic cardiomyopathy. Europace. 2012;14:724–33. 40. Maron BJ, McKenna WJ, Danielson GK, Kappenberger LJ, Kuhn HJ, Seidman CE, Shah PM, Spencer 3rd WH, Spirito P, Ten Cate FJ, Wigle ED. American college of cardiology/ European society of cardiology clinical expert consensus document on hypertrophic cardiomyopathy. A report of the American college of cardiology foundation task force on clinical expert consensus documents and the European society of cardiology committee for practice guidelines. J Am Coll Cardiol. 2003;42: 1687–713. 41. Kawara T, Derksen R, de Groot JR, Coronel R, Tasseron S, Linnenbank AC, Hauer RN, Kirkels H, Janse MJ, de Bakker JM. Activation delay after premature stimulation in chronically diseased human myocardium relates to the architecture of interstitial fibrosis. Circulation. 2001;104:3069–75. 42. Saumarez RC, Camm AJ, Panagos A, Gill JS, Stewart JT, de Belder MA, Simpson IA, McKenna WJ. Ventricular fibrillation in hypertrophic cardiomyopathy is associated with increased fractionation of paced right ventricular electrograms. Circulation. 1992;86:467–74. 43. Maron BJ, Wolfson JK, Epstein SE, Roberts WC. Intramural (“small vessel”) coronary artery disease in hypertrophic cardiomyopathy. J Am Coll Cardiol. 1986;8:545–57. 44. Adabag AS, Maron BJ. Implications of arrhythmias and prevention of sudden death in hypertrophic cardiomyopathy. Ann Noninvasive Electrocardiol. 2007;12:171–80. 45. Taylor E, Berger R, Hummel JD, Dinerman JL, Kenknight B, Arria AM, Tomaselli G, Calkins H. Analysis of the pattern of initiation of sustained ventricular arrhythmias in patients with implantable defibrillators. J Cardiovasc Electrophysiol. 2000;11:719–26. 46. Wood MA, Ellenbogen KA. Initiation of spontaneous ventricular tachycardia: from spark to fire. J Cardiovasc Electrophysiol. 2000;11:727–9. 47. Saeed M, Link MS, Mahapatra S, Mouded M, Tzeng D, Jung V, Contreras R, Swygman C, Homoud M, Estes 3rd NA, Wang PJ. Analysis of intracardiac electrograms showing monomorphic ventricular tachycardia in patients with implantable cardioverterdefibrillators. Am J Cardiol. 2000;85:580–7. 48. Elliott P, Spirito P. Prevention of hypertrophic cardiomyopathyrelated deaths: theory and practice. Heart. 2008;94:1269–75. 49. O’Mahony C, Lambiase PD, Quarta G, Cardona M, Calcagnino M, Tsovolas K, Al-Shaikh S, Rahman SM, Arnous S, Jones S, McKenna W, Elliott P. The long-term survival and the risks and benefits of implantable cardioverter defibrillators in patients with hypertrophic cardiomyopathy. Heart. 2012;98:116–25. 50. Lin G, Nishimura RA, Gersh BJ, Phil D, Ommen SR, Ackerman MJ, Brady PA. Device complications and inappropriate implantable cardioverter defibrillator shocks in patients with hypertrophic cardiomyopathy. Heart. 2009;95:709–14. 51. Maron BJ, Spirito P, Shen WK, Haas TS, Formisano F, Link MS, Epstein AE, Almquist AK, Daubert JP, Lawrenz T, Boriani G, Estes 3rd NA, Favale S, Piccininno M, Winters SL, Santini M, Betocchi S, Arribas F, Sherrid MV, Buja G, Semsarian C, Bruzzi P. Implantable cardioverter-defibrillators and prevention of sudden cardiac death in hypertrophic cardiomyopathy. JAMA. 2007;298:405–12.
262 52. Syska P, Przybylski A, Chojnowska L, Lewandowski M, Sterlinski M, Maciag A, Gepner K, Pytkowski M, Kowalik I, MaczynskaMazuruk R, Ruzyllo W, Szwed H. Implantable cardioverterdefibrillator in patients with hypertrophic cardiomyopathy: efficacy and complications of the therapy in long-term follow-up. J Cardiovasc Electrophysiol. 2010;21:883–9. 53. Woo A, Monakier D, Harris L, Hill A, Shah P, Wigle ED, Rakowski H, Rozenblyum E, Cameron DA. Determinants of implantable defibrillator discharges in high-risk patients with hypertrophic cardiomyopathy. Heart. 2007;93:1044–5. 54. Cha YM, Gersh BJ, Maron BJ, Boriani G, Spirito P, Hodge DO, Weivoda PL, Trusty JM, Friedman PA, Hammill SC, Rea RF, Shen WK. Electrophysiologic manifestations of ventricular tachyarrhythmias provoking appropriate defibrillator interventions in high-risk patients with hypertrophic cardiomyopathy. J Cardiovasc Electrophysiol. 2007;18:483–7. 55. Sweeney MO. Antitachycardia pacing for ventricular tachycardia using implantable cardioverter defibrillators. Pacing Clin Electrophysiol. 2004;27:1292–305. 56. Maron BJ, Semsarian C, Shen WK, Link MS, Epstein AE, Estes 3rd NA, Almquist A, Giudici MC, Haas TS, Hodges JS, Spirito P. Circadian patterns in the occurrence of malignant ventricular tachyarrhythmias triggering defibrillator interventions in patients with hypertrophic cardiomyopathy. Heart Rhythm. 2009;6:599–602. 57. Maron BJ, Kogan J, Proschan MA, Hecht GM, Roberts WC. Circadian variability in the occurrence of sudden cardiac death in patients with hypertrophic cardiomyopathy. J Am Coll Cardiol. 1994;23:1405–9. 58. Kiernan TJ, Weivoda PL, Somers VK, Ommen SR, Gersh BJ. Circadian rhythm of appropriate implantable cardioverter defibrillator discharges in patients with hypertrophic cardiomyopathy. Pacing Clin Electrophysiol. 2008;31:1253–8. 59. Willich SN, Goldberg RJ, Maclure M, Perriello L, Muller JE. Increased onset of sudden cardiac death in the first three hours after awakening. Am J Cardiol. 1992;70:65–8. 60. Tofler GH, Gebara OC, Mittleman MA, Taylor P, Siegel W, Venditti Jr FJ, Rasmussen CA, Muller JE. Morning peak in ventricular tachyarrhythmias detected by time of implantable cardioverter/defibrillator therapy. The cpi investigators. Circulation. 1995;92:1203–8. 61. Maron BJ. Controversies in cardiovascular medicine. Surgical myectomy remains the primary treatment option for severely symptomatic patients with obstructive hypertrophic cardiomyopathy. Circulation. 2007;116:196–206. discussion 206. 62. Cecchi F, Maron BJ, Epstein SE. Long-term outcome of patients with hypertrophic cardiomyopathy successfully resuscitated after cardiac arrest. J Am Coll Cardiol. 1989;13:1283–8. 63. Elliott PM, Sharma S, Varnava A, Poloniecki J, Rowland E, McKenna WJ. Survival after cardiac arrest or sustained ventricular tachycardia in patients with hypertrophic cardiomyopathy. J Am Coll Cardiol. 1999;33:1596–601. 64. Fananapazir L, Chang AC, Epstein SE, McAreavey D. Prognostic determinants in hypertrophic cardiomyopathy. Prospective evaluation of a therapeutic strategy based on clinical, holter, hemodynamic, and electrophysiological findings. Circulation. 1992;86:730–40. 65. Bos JM, Maron BJ, Ackerman MJ, Haas TS, Sorajja P, Nishimura RA, Gersh BJ, Ommen SR. Role of family history of sudden death in risk stratification and prevention of sudden death with implantable defibrillators in hypertrophic cardiomyopathy. Am J Cardiol. 2010;106:1481–6. 66. Elliott PM, Poloniecki J, Dickie S, Sharma S, Monserrat L, Varnava A, Mahon NG, McKenna WJ. Sudden death in hypertrophic cardiomyopathy: identification of high risk patients. J Am Coll Cardiol. 2000;36:2212–8. 67. Elliott PM, Gimeno Blanes JR, Mahon NG, Poloniecki JD, McKenna WJ. Relation between severity of left-ventricular hypertrophy and prognosis in patients with hypertrophic cardiomyopathy. Lancet. 2001;357:420–4.
K. Nair et al. 68. Spirito P, Bellone P, Harris KM, Bernabo P, Bruzzi P, Maron BJ. Magnitude of left ventricular hypertrophy and risk of sudden death in hypertrophic cardiomyopathy. N Engl J Med. 2000;342:1778–85. 69. Sorajja P, Nishimura RA, Ommen SR, Ackerman MJ, Tajik AJ, Gersh BJ. Use of echocardiography in patients with hypertrophic cardiomyopathy: clinical implications of massive hypertrophy. J Am Soc Echocardiogr. 2006;19:788–95. 70. Spirito P, Autore C, Rapezzi C, Bernabo P, Badagliacca R, Maron MS, Bongioanni S, Coccolo F, Estes NA, Barilla CS, Biagini E, Quarta G, Conte MR, Bruzzi P, Maron BJ. Syncope and risk of sudden death in hypertrophic cardiomyopathy. Circulation. 2009;119:1703–10. 71. Maron BJ. Contemporary insights and strategies for risk stratification and prevention of sudden death in hypertrophic cardiomyopathy. Circulation. 2010;121:445–56. 72. Monserrat L, Elliott PM, Gimeno JR, Sharma S, Penas-Lado M, McKenna WJ. Non-sustained ventricular tachycardia in hypertrophic cardiomyopathy: an independent marker of sudden death risk in young patients. J Am Coll Cardiol. 2003;42:873–9. 73. Sadoul N, Prasad K, Elliott PM, Bannerjee S, Frenneaux MP, McKenna WJ. Prospective prognostic assessment of blood pressure response during exercise in patients with hypertrophic cardiomyopathy. Circulation. 1997;96:2987–91. 74. Olivotto I, Maron BJ, Montereggi A, Mazzuoli F, Dolara A, Cecchi F. Prognostic value of systemic blood pressure response during exercise in a community-based patient population with hypertrophic cardiomyopathy. J Am Coll Cardiol. 1999;33:2044–51. 75. Elliott P, McKenna WJ. Hypertrophic cardiomyopathy. Lancet. 2004;363:1881–91. 76. Cecchi F, Olivotto I, Montereggi A, Squillatini G, Dolara A, Maron BJ. Prognostic value of non-sustained ventricular tachycardia and the potential role of amiodarone treatment in hypertrophic cardiomyopathy: assessment in an unselected non-referral based patient population. Heart. 1998;79:331–6. 77. Spirito P, Rapezzi C, Autore C, Bruzzi P, Bellone P, Ortolani P, Fragola PV, Chiarella F, Zoni-Berisso M, Branzi A, et al. Prognosis of asymptomatic patients with hypertrophic cardiomyopathy and nonsustained ventricular tachycardia. Circulation. 1994;90:2743–7. 78. O’Hanlon R, Grasso A, Roughton M, Moon JC, Clark S, Wage R, Webb J, Kulkarni M, Dawson D, Sulaibeekh L, Chandrasekaran B, Bucciarelli-Ducci C, Pasquale F, Cowie MR, McKenna WJ, Sheppard MN, Elliott PM, Pennell DJ, Prasad SK. Prognostic significance of myocardial fibrosis in hypertrophic cardiomyopathy. J Am Coll Cardiol. 2010;56:867–74. 79. Bruder O, Wagner A, Jensen CJ, Schneider S, Ong P, Kispert EM, Nassenstein K, Schlosser T, Sabin GV, Sechtem U, Mahrholdt H. Myocardial scar visualized by cardiovascular magnetic resonance imaging predicts major adverse events in patients with hypertrophic cardiomyopathy. J Am Coll Cardiol. 2010;56:875–87. 80. Adabag AS, Maron BJ, Appelbaum E, Harrigan CJ, Buros JL, Gibson CM, Lesser JR, Hanna CA, Udelson JE, Manning WJ, Maron MS. Occurrence and frequency of arrhythmias in hypertrophic cardiomyopathy in relation to delayed enhancement on cardiovascular magnetic resonance. J Am Coll Cardiol. 2008;51:1369–74. 81. Rubinshtein R, Glockner JF, Ommen SR, Araoz PA, Ackerman MJ, Sorajja P, Bos JM, Tajik AJ, Valeti US, Nishimura RA, Gersh BJ. Characteristics and clinical significance of late gadolinium enhancement by contrast-enhanced magnetic resonance imaging in patients with hypertrophic cardiomyopathy. Circ Heart Fail. 2010;3:51–8. 82. Maron BJ, Shen WK, Link MS, Epstein AE, Almquist AK, Daubert JP, Bardy GH, Favale S, Rea RF, Boriani G, Estes 3rd NA, Spirito P. Efficacy of implantable cardioverter-defibrillators for the prevention of sudden death in patients with hypertrophic cardiomyopathy. N Engl J Med. 2000;342:365–73. 83. Maron BJ, Spirito P. Implantable defibrillators and prevention of sudden death in hypertrophic cardiomyopathy. J Cardiovasc Electrophysiol. 2008;19:1118–26.
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Arrhythmias and Hypertrophic Cardiomyopathy
84. Maron BJ. Risk stratification and role of implantable defibrillators for prevention of sudden death in patients with hypertrophic cardiomyopathy. Circ J. 2010;74:2271–82. 85. Almquist AK, Montgomery JV, Haas TS, Maron BJ. Cardioverterdefibrillator implantation in high-risk patients with hypertrophic cardiomyopathy. Heart Rhythm. 2005;2:814–9. 86. Sorajja P, Valeti U, Nishimura RA, Ommen SR, Rihal CS, Gersh BJ, Hodge DO, Schaff HV, Holmes Jr DR. Outcome of alcohol septal ablation for obstructive hypertrophic cardiomyopathy. Circulation. 2008;118:131–9. 87. Fernandes VL, Nielsen C, Nagueh SF, Herrin AE, Slifka C, Franklin J, Spencer 3rd WH. Follow-up of alcohol septal ablation for symptomatic hypertrophic obstructive cardiomyopathy the Baylor and medical university of South Carolina experience 1996 to 2007. JACC Cardiovasc Interv. 2008;1:561–70. 88. Gietzen FH, Leuner CJ, Obergassel L, Strunk-Mueller C, Kuhn H. Transcoronary ablation of septal hypertrophy for hypertrophic obstructive cardiomyopathy: feasibility, clinical benefit, and short term results in elderly patients. Heart. 2004;90:638–44. 89. Kuhn H, Lawrenz T, Lieder F, Leuner C, Strunk-Mueller C, Obergassel L, Bartelsmeier M, Stellbrink C. Survival after transcoronary ablation of septal hypertrophy in hypertrophic obstructive cardiomyopathy (tash): a 10 year experience. Clin Res Cardiol. 2008;97:234–43. 90. Kwon DH, Kapadia SR, Tuzcu EM, Halley CM, Gorodeski EZ, Curtin RJ, Thamilarasan M, Smedira NG, Lytle BW, Lever HM, Desai MY. Long-term outcomes in high-risk symptomatic patients with hypertrophic cardiomyopathy undergoing alcohol septal ablation. JACC Cardiovasc Interv. 2008;1:432–8. 91. Nagueh SF, Ommen SR, Lakkis NM, Killip D, Zoghbi WA, Schaff HV, Danielson GK, Quinones MA, Tajik AJ, Spencer WH. Comparison of ethanol septal reduction therapy with surgical myectomy for the treatment of hypertrophic obstructive cardiomyopathy. J Am Coll Cardiol. 2001;38:1701–6. 92. Qin JX, Shiota T, Lever HM, Kapadia SR, Sitges M, Rubin DN, Bauer F, Greenberg NL, Agler DA, Drinko JK, Martin M, Tuzcu EM, Smedira NG, Lytle B, Thomas JD. Outcome of patients with hypertrophic obstructive cardiomyopathy after percutaneous transluminal septal myocardial ablation and septal myectomy surgery. J Am Coll Cardiol. 2001;38:1994–2000. 93. Maron BJ, Maron MS, Wigle ED, Braunwald E. The 50-year history, controversy, and clinical implications of left ventricular outflow tract obstruction in hypertrophic cardiomyopathy from idiopathic hypertrophic subaortic stenosis to hypertrophic cardiomyopathy: from idiopathic hypertrophic subaortic stenosis to hypertrophic cardiomyopathy. J Am Coll Cardiol. 2009;54:191–200. 94. Ommen SR, Nishimura RA, Squires RW, Schaff HV, Danielson GK, Tajik AJ. Comparison of dual-chamber pacing versus septal myectomy for the treatment of patients with hypertrophic obstructive cardiomyopathy: a comparison of objective hemodynamic and exercise end points. J Am Coll Cardiol. 1999;34: 191–6. 95. McCully RB, Nishimura RA, Tajik AJ, Schaff HV, Danielson GK. Extent of clinical improvement after surgical treatment of hypertrophic obstructive cardiomyopathy. Circulation. 1996;94: 467–71. 96. Qin JX, Shiota T, Lever HM, Asher CR, Popovic ZB, Greenberg NL, Agler DA, Drinko JK, Smedira NG, Tuzcu EM, Lytle BW, Thomas JD. Conduction system abnormalities in patients with obstructive hypertrophic cardiomyopathy following septal reduction interventions. Am J Cardiol. 2004;93:171–5. 97. Sigwart U. Non-surgical myocardial reduction for hypertrophic obstructive cardiomyopathy. Lancet. 1995;346:211–4. 98. Gietzen FH, Leuner CJ, Raute-Kreinsen U, Dellmann A, Hegselmann J, Strunk-Mueller C, Kuhn HJ. Acute and long-term results after transcoronary ablation of septal hypertrophy (tash). Catheter interventional treatment for hypertrophic obstructive cardiomyopathy. Eur Heart J. 1999;20:1342–54.
263 99. Seggewiss H, Faber L, Gleichmann U. Percutaneous transluminal septal ablation in hypertrophic obstructive cardiomyopathy. Thorac Cardiovasc Surg. 1999;47:94–100. 100. Robbins RC, Stinson EB. Long-term results of left ventricular myotomy and myectomy for obstructive hypertrophic cardiomyopathy. J Thorac Cardiovasc Surg. 1996;111:586–94. 101. Chen AA, Palacios IF, Mela T, Yoerger DM, Picard MH, Vlahakes G, Lowry PA, Fifer MA. Acute predictors of subacute complete heart block after alcohol septal ablation for obstructive hypertrophic cardiomyopathy. Am J Cardiol. 2006;97:264–9. 102. Faber L, Welge D, Fassbender D, Schmidt HK, Horstkotte D, Seggewiss H. Percutaneous septal ablation for symptomatic hypertrophic obstructive cardiomyopathy: managing the risk of procedurerelated av conduction disturbances. Int J Cardiol. 2007;119:163–7. 103. Reinhard W, Ten Cate FJ, Scholten M, De Laat LE, Vos J. Permanent pacing for complete atrioventricular block after nonsurgical (alcohol) septal reduction in patients with obstructive hypertrophic cardiomyopathy. Am J Cardiol. 2004;93:1064–6. 104. Sherrid MV, Chu CK, Delia E, Mogtader A, Dwyer Jr EM. An echocardiographic study of the fluid mechanics of obstruction in hypertrophic cardiomyopathy. J Am Coll Cardiol. 1993;22:816–25. 105. Montalvo AL, Bembi B, Donnarumma M, Filocamo M, Parenti G, Rossi M, Merlini L, Buratti E, De Filippi P, Dardis A, Stroppiano M, Ciana G, Pittis MG. Mutation profile of the gaa gene in 40 Italian patients with late onset glycogen storage disease type ii. Hum Mutat. 2006;27:999–1006. 106. Falicov RE, Resnekov L, Bharati S, Lev M. Mid-ventricular obstruction: a variant of obstructive cardiomyopathy. Am J Cardiol. 1976;37:432–7. 107. ElBardissi AW, Dearani JA, Nishimura RA, Ommen SR, Stulak JM, Schaff HV. Septal myectomy after previous septal artery ablation in hypertrophic cardiomyopathy. Mayo Clin Proc. 2007;82:1516–22. 108. Sherrid MV, Gunsburg DZ, Moldenhauer S, Pearle G. Systolic anterior motion begins at low left ventricular outflow tract velocity in obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol. 2000;36:1344–54. 109. Sherrid MV. Dynamic left ventricular outflow obstruction in hypertrophic cardiomyopathy revisited: significance, pathogenesis, and treatment. Cardiol Rev. 1998;6:135–45. 110. Ommen SR, Maron BJ, Olivotto I, Maron MS, Cecchi F, Betocchi S, Gersh BJ, Ackerman MJ, McCully RB, Dearani JA, Schaff HV, Danielson GK, Tajik AJ, Nishimura RA. Long-term effects of surgical septal myectomy on survival in patients with obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol. 2005;46:470–6. 111. Maron BJ, Gardin JM, Flack JM, Gidding SS, Kurosaki TT, Bild DE. Prevalence of hypertrophic cardiomyopathy in a general population of young adults. Echocardiographic analysis of 4111 subjects in the cardia study. Coronary artery risk development in (young) adults. Circulation. 1995;92:785–9. 112. Lakkis NM, Nagueh SF, Kleiman NS, Killip D, He ZX, Verani MS, Roberts R, Spencer 3rd WH. Echocardiography-guided ethanol septal reduction for hypertrophic obstructive cardiomyopathy. Circulation. 1998;98:1750–5. 113. Boltwood Jr CM, Chien W, Ports T. Ventricular tachycardia complicating alcohol septal ablation. N Engl J Med. 2004;351:1914–5. 114. Hori Y, Ueda M, Nakayama T, Saegusa N, Uehara M, Lee K, Sekine T, Daimon M, Kobayashi Y, Funabashi N, Komuro I. Occurrence of de novo sustained monomorphic ventricular tachycardia induced after percutaneous transluminal alcohol septal myocardial ablation for hypertrophic obstructive cardiomyopathy. Int J Cardiol. 2007;119:403–7. 115. Kazmierczak J, Kornacewicz-Jach Z, Kisly M, Gil R, Wojtarowicz A. Electrocardiographic changes after alcohol septal ablation in hypertrophic obstructive cardiomyopathy. Heart. 1998;80:257–62. 116. Lawrenz T, Obergassel L, Lieder F, Leuner C, Strunk-Mueller C, Meyer Zu Vilsendorf D, Beer G, Kuhn H. Transcoronary ablation of septal hypertrophy does not alter icd intervention rates in high
264
117.
118.
119.
120.
121.
122.
123.
124.
125.
126.
127.
128.
129.
130.
131.
K. Nair et al. risk patients with hypertrophic obstructive cardiomyopathy. Pacing Clin Electrophysiol. 2005;28:295–300. McGregor JB, Rahman A, Rosanio S, Ware D, Birnbaum Y, Saeed M. Monomorphic ventricular tachycardia: a late complication of percutaneous alcohol septal ablation for hypertrophic cardiomyopathy. Am J Med Sci. 2004;328:185–8. Noseworthy PA, Rosenberg MA, Fifer MA, Palacios IF, Lowry PA, Ruskin JN, Sanborn DM, Picard MH, Vlahakes GJ, Mela T, Das S. Ventricular arrhythmia following alcohol septal ablation for obstructive hypertrophic cardiomyopathy. Am J Cardiol. 2009;104:128–32. Simon RD, Crawford 3rd FA, Spencer 3rd WH, Gold MR. Sustained ventricular tachycardia following alcohol septal ablation for hypertrophic obstructive cardiomyopathy. Pacing Clin Electrophysiol. 2005;28:1354–6. ten Cate FJ, Soliman OI, Michels M, Theuns DA, de Jong PL, Geleijnse ML, Serruys PW. Long-term outcome of alcohol septal ablation in patients with obstructive hypertrophic cardiomyopathy: a word of caution. Circ Heart Fail. 2010;3:362–9. Cuoco FA, Spencer 3rd WH, Fernandes VL, Nielsen CD, Nagueh S, Sturdivant JL, Leman RB, Wharton JM, Gold MR. Implantable cardioverter-defibrillator therapy for primary prevention of sudden death after alcohol septal ablation of hypertrophic cardiomyopathy. J Am Coll Cardiol. 2008;52:1718–23. Wigle ED, Rakowski H, Kimball BP, Williams WG. Hypertrophic cardiomyopathy. Clinical spectrum and treatment. Circulation. 1995;92:1680–92. Paulus WJ, Lorell BH, Craig WE, Wynne J, Murgo JP, Grossman W. Comparison of the effects of nitroprusside and nifedipine on diastolic properties in patients with hypertrophic cardiomyopathy: altered left ventricular loading or improved muscle inactivation? J Am Coll Cardiol. 1983;2:879–86. Bonow RO, Dilsizian V, Rosing DR, Maron BJ, Bacharach SL, Green MV. Verapamil-induced improvement in left ventricular diastolic filling and increased exercise tolerance in patients with hypertrophic cardiomyopathy: short- and long-term effects. Circulation. 1985;72:853–64. Cannon 3rd RO, Rosing DR, Maron BJ, Leon MB, Bonow RO, Watson RM, Epstein SE. Myocardial ischemia in patients with hypertrophic cardiomyopathy: contribution of inadequate vasodilator reserve and elevated left ventricular filling pressures. Circulation. 1985;71:234–43. Maron BJ, Roberts WC, Arad M, Haas TS, Spirito P, Wright GB, Almquist AK, Baffa JM, Saul JP, Ho CY, Seidman J, Seidman CE. Clinical outcome and phenotypic expression in lamp2 cardiomyopathy. JAMA. 2009;301:1253–9. Yang Z, McMahon CJ, Smith LR, Bersola J, Adesina AM, Breinholt JP, Kearney DL, Dreyer WJ, Denfield SW, Price JF, Grenier M, Kertesz NJ, Clunie SK, Fernbach SD, Southern JF, Berger S, Towbin JA, Bowles KR, Bowles NE. Danon disease as an underrecognized cause of hypertrophic cardiomyopathy in children. Circulation. 2005;112:1612–7. Colan SD, Lipshultz SE, Lowe AM, Sleeper LA, Messere J, Cox GF, Lurie PR, Orav EJ, Towbin JA. Epidemiology and causespecific outcome of hypertrophic cardiomyopathy in children: findings from the pediatric cardiomyopathy registry. Circulation. 2007;115:773–81. Gelb BD, Tartaglia M. Noonan syndrome and related disorders: dysregulated ras-mitogen activated protein kinase signal transduction. Hum Mol Genet. 2006;15(Spec No 2):R220–6. Nishimura RA, Hayes DL, Ilstrup DM, Holmes Jr DR, Tajik AJ. Effect of dual-chamber pacing on systolic and diastolic function in patients with hypertrophic cardiomyopathy. Acute Doppler echocardiographic and catheterization hemodynamic study. J Am Coll Cardiol. 1996;27:421–30. Gadler F, Linde C, Juhlin-Dannfeldt A, Ribeiro A, Ryden L. Influence of right ventricular pacing site on left ventricular outflow
132.
133.
134.
135.
136. 137.
138.
139.
140.
141.
142.
143.
144.
145.
146.
147.
tract obstruction in patients with hypertrophic obstructive cardiomyopathy. J Am Coll Cardiol. 1996;27:1219–24. Jeanrenaud X, Goy JJ, Kappenberger L. Effects of dual-chamber pacing in hypertrophic obstructive cardiomyopathy. Lancet. 1992;339:1318–23. Jeanrenaud X, Kappenberger L. Regional wall motion during pacing for hypertrophic obstructive cardiomyopathy. Pacing Clin Electrophysiol. 1997;20:1673–81. Kappenberger L, Linde C, Daubert C, McKenna W, Meisel E, Sadoul N, Chojnowska L, Guize L, Gras D, Jeanrenaud X, Ryden L. Pacing in hypertrophic obstructive cardiomyopathy. A randomized crossover study. Pic study group. Eur Heart J. 1997;18:1249–56. McDonald K, McWilliams E, O’Keeffe B, Maurer B. Functional assessment of patients treated with permanent dual chamber pacing as a primary treatment for hypertrophic cardiomyopathy. Eur Heart J. 1988;9:893–8. McDonald KM, Maurer B. Permanent pacing as treatment for hypertrophic cardiomyopathy. Am J Cardiol. 1991;68:108–10. Pak PH, Maughan WL, Baughman KL, Kieval RS, Kass DA. Mechanism of acute mechanical benefit from vdd pacing in hypertrophied heart: similarity of responses in hypertrophic cardiomyopathy and hypertensive heart disease. Circulation. 1998;98:242–8. Leclercq C, Gras D, Le Helloco A, Nicol L, Mabo P, Daubert C. Hemodynamic importance of preserving the normal sequence of ventricular activation in permanent cardiac pacing. Am Heart J. 1995;129:1133–41. Fananapazir L, Epstein ND, Curiel RV, Panza JA, Tripodi D, McAreavey D. Long-term results of dual-chamber (ddd) pacing in obstructive hypertrophic cardiomyopathy. Evidence for progressive symptomatic and hemodynamic improvement and reduction of left ventricular hypertrophy. Circulation. 1994;90:2731–42. Fananapazir L, Cannon 3rd RO, Tripodi D, Panza JA. Impact of dual-chamber permanent pacing in patients with obstructive hypertrophic cardiomyopathy with symptoms refractory to verapamil and beta-adrenergic blocker therapy. Circulation. 1992;85:2149–61. Maron BJ, Nishimura RA, McKenna WJ, Rakowski H, Josephson ME, Kieval RS. Assessment of permanent dual-chamber pacing as a treatment for drug-refractory symptomatic patients with obstructive hypertrophic cardiomyopathy. A randomized, double-blind, crossover study (m-pathy). Circulation. 1999;99:2927–33. Nishimura RA, Trusty JM, Hayes DL, Ilstrup DM, Larson DR, Hayes SN, Allison TG, Tajik AJ. Dual-chamber pacing for hypertrophic cardiomyopathy: a randomized, double-blind, crossover trial. J Am Coll Cardiol. 1997;29:435–41. Galve E, Sambola A, Saldana G, Quispe I, Nieto E, Diaz A, Evangelista A, Candell-Riera J. Late benefits of dual-chamber pacing in obstructive hypertrophic cardiomyopathy: a 10-year follow-up study. Heart. 2010;96:352–6. Cannon 3rd RO, Tripodi D, Dilsizian V, Panza JA, Fananapazir L. Results of permanent dual-chamber pacing in symptomatic nonobstructive hypertrophic cardiomyopathy. Am J Cardiol. 1994;73:571–6. Erwin 3rd JP, Nishimura RA, Lloyd MA, Tajik AJ. Dual chamber pacing for patients with hypertrophic obstructive cardiomyopathy: a clinical perspective in 2000. Mayo Clin Proc. 2000;75:173–80. Slade AK, Sadoul N, Shapiro L, Chojnowska L, Simon JP, Saumarez RC, Dodinot B, Camm AJ, McKenna WJ, Aliot E. Ddd pacing in hypertrophic cardiomyopathy: a multicentre clinical experience. Heart. 1996;75:44–9. Gadler F, Linde C, Daubert C, McKenna W, Meisel E, Aliot E, Chojnowska L, Guize L, Gras D, Jeanrenaud X, Kappenberger L. Significant improvement of quality of life following atrioventricular synchronous pacing in patients with hypertrophic obstructive cardiomyopathy. Data from 1 year of follow-up. Pic study group. Pacing in cardiomyopathy. Eur Heart J. 1999;20:1044–50.
Lai Tai, the Mysterious Death of Young Thai Men
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Gumpanart Veerakul, Lertlak Chaothawee, Kriengkrai Jirasirirojanakorn, and Koonlawee Nademanee
Abstract
It was over a century that the young villagers from Northeastern Thailand had been dying from the mysterious sleep death so-called Lai (dreaming, screaming) Tai (death). Almost all victims were healthy men and died unexpectedly between 21.00 and 07.00. Since 1994, we prospectively studied groups of Lai Tai survivors and clarify the cause of death. Most of Lai Tai victims had no structural heart disease and displayed a type 1 Brugada ECG pattern. Subsequent genetic study revealed the mutation of SCN5A genes in one-third of Lai Tai and Pokkuri (sudden death in Japan) family members and suggested that Lai Tai, Pokkuri, and Brugada syndrome were the same disease entity. After ICD implantation, primary ventricular fibrillation, either sustained or non-sustained events, explained the unexpected death or syncopal episodes. The benefit of ICD in sudden death prevention was clearly shown in the first randomized DEBUT (defibrillator versus beta-blockers in unexplained death in Thailand) trial. In asymptomatic cases with Brugada ECG, recent randomized control trial showed no benefit of ICD since the overall mortality of each group was insignificantly low. The concealed Brugada pattern can be unmasked by positioning V1 and V2 leads in higher (the second and third) intercostals space which is corresponding to the RV outflow tract (RVOT) area. Electromagnetic mapping at both sides of RV and LV elucidated the abnormal low-voltage, fractionated late potentials locating only in the epicardial surface of RVOT region. Radiofrequency (RF) ablation of this specific area not only normalized Brugada ECG pattern but also prevented recurrent VF episodes in nine cases with frequent ICD shocks, during the mean follow-up of 12 months. In brief, our studies showed clinically and genetically link the sudden explained death syndrome in SE Asian and Brugada syndrome in European. This newly recognized VF substrate sheds a light of curative treatment of this lethal syndrome by RF ablation. Keywords
Sudden cardiac death • Ventricular arrhythmia • Electrophysiologic study • Ablation
G. Veerakul, MD, FSCAI (*) Pacific Rim Electrophysiology Research Institute at Bangkok Hospital, Bangkok, Thailand Division of Cardiology, Department of Medicine, Cardiovascular Research and Prevention Center, Bhumibol Adulyadej Hospital, Bangkok, Thailand e-mail:
[email protected] L. Chaothawee, MD, MSc Division of Cardiac Imaging, Bangkok Heart Hospital, Pacific Rim Electrophysiology Research Institute at Bangkok Hospital, Bangkok, Thailand
K. Jirasirirojanakorn, MD Division of Cardiology, Department of Medicine, Cardiovascular Research and Prevention Center, Bhumibol Adulyadej Hospital, Bangkok, Thailand K. Nademanee, MD, FACC, FAHA Division of Electrophysiology, Pacific Rim Arrhythmia Research Institute at Bangkok Heart Hospital, Bangkok, Thailand
Cardiac Imaging Unit, Bangkok Heart Hospital, Bangkok, Thailand A.S. Kibos et al. (eds.), Cardiac Arrhythmias, DOI 10.1007/978-1-4471-5316-0_20, © Springer-Verlag London 2014
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Historical Background Lai Tai, SUND, and SUDS At the end of the Vietnam war in 1975, there was a significant increase of Southeast (SE) Asian refugees to the USA, as was a rise in unexplained nocturnal deaths in these refugees (Laotians, Vietnamese, and Cambodians) [1, 2]. Of 104 victims, almost all (98 %) were healthy men at relative young age (16–63 years, median age of 32 years), and they died unexpectedly during sleep from 22.00 to 08.00. Since the etiology of death was unidentified by the postmortem examination, the Center for Disease Control (CDC) initially coined the term “sudden unexpected nocturnal death (SUND)” to describe this peculiar death but later changed to “sudden unexplained death syndrome (SUDS)” since a small but significant number of these victims died during daytime [1–3]. The crude death rate of SUDS in the USA peaked in 1981, 10.2:100,000 and subsequently declined to 1.8:100,000 in 1985 [3, 4]. It should be noted that the CDC defined the SUDS cases only for victims born in Southeast Asian countries including Laos People’s Democratic Republic, Cambodia, Vietnam, Thailand, and Philippines, and there were nine similar deaths in Guam immigrants from the Philippines during the 1972–1985 period [3]. In SE Asian countries, sudden death in young men (similar to that described by the CDC) who were otherwise healthy have been well known among the locals and indigenous people for many years. Each country has its own term for this syndrome: For Filipinos, SUDS is called “Bangungut” which means moaning and dying during sleep [5, 6], and for Japanese “Pokkuri” means sudden unexpected death at night [7]; for Thai, “Lai Tai” means dream and/or scream during sleep until death [8, 9]. From the interview of octogenarian villagers in the northeastern part of Thailand, it appears that Lai Tai has existed in the northeastern (NE) region of Thailand for several decades. The predominant male victims eventually created a local ghost myth “Pee (ghost) mae-mai (widow)” who came by and took the men’s soul away at night. To fool the ghost during attacks of Lai Tai, village men hopelessly polished their fingernails and went to bed dressed as women. A large scarecrow with prominent male symbol was placed in front of their house to intimidate Pee mae-mai; see Fig. 20.1. Without medical investigation, what happened to Lai Tai victims had been in the dark for over a century. In 1990, Lai Tai received public attention after the cluster death of Thai workers in Singapore [10]. Despite autopsies by local authorities, the cause of death remained unknown. So far, this mysterious death affected Thailand nationwide from families where wives and children missed their leaders to the country that missed a significant income from the oversea workers. In 1994, we embarked in studying SUDS/ Lai Tai syndrome and our results were discussed below.
Fig. 20.1 A scarecrow with phallic symbol was placed in front of Lai Tai victim’s house to offense the Pee mae-mai (widow ghost)
Cause of Mysterious Death From the initial CDC report, ventricular fibrillation (VF) was documented in two SUDS victims but resuscitation was unsuccessful [1]. What happened to SUDS victims became clear in 1984 when Otto and colleagues reported VF arrest in three Asian immigrants (two Laotians and one Filipino) [11]. Complete investigations including coronary angiogram revealed no structural heart disease. One case remained asymptomatic for 2 years, one died suddenly 4 months later and another had inducible ventricular tachycardia on electrophysiological testing after 6 months [11]. In Thailand (1994), we examined a healthy appearing 37 years old man (B.A), from one of the NE provinces (Bureerum), who had several episodes of unexplained syncope. Despite having unremarkable electroencephalogram (EEG) and cerebral-computerized tomogram, he was diagnosed as epileptic. In April 1994, one of syncopal attacks occurred in the hospital where VF was documented. After successful cardioversion, his ECG displayed the J point ST-segment elevation in precordial leads which was similar to the ECG pattern reported by Brugada and Brugada in 1992 [12] (Fig. 20.2). Although cardiac investigations including coronary angiogram were normal, electrophysiological study revealed a prolong HV interval and easily inducible polymorphic ventricular tachycardia (PMVT) with only single extra-stimulus
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Fig. 20.2 Type I Brugada ECG pattern was noted (V2) in the first studied Lai Tai survivor (BA) who had recurrent syncope
25 mm/s
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Fig. 20.3 Inducible sustained polymorphic ventricular tachycardia/VF in Lai Tai survivor (BA) that required termination by external cardioversion (arrow)
(Fig. 20.3). An implantable cardioverter-defibrillator (ICD) was then performed. Subsequently, the patient came back within few months with recurrent syncope associated with ICD shocks. Interrogation of the ICD EGMs demonstrated spontaneous VF with appropriate shocks. Interestingly, some of the VF episodes were self-terminated (Fig. 20.4) and explained prior syncopal attacks [13].
B.A. was the first victim of Lai Tai (SUDS) survivors that displayed Brugada ECG pattern. Sustained and non-sustained primary VF was the key rhythm behind sudden cardiac death and syncope as documented by ICD. However, the precipitating cause of VF development is remained to be established. Several conditions including hypokalemia [14], fever [15], autonomic changes, i.e., high vagal tone [16], and lack of
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Sustained VF
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Fig. 20.4 Sustained (upper panel with two continuous strips) and non-sustained VF (lower panel) recorded in stored EGMs from one Lai Tai survivor
heart rate variability during sleep [17], and heavy meal [18] had been subsequently reported in BrS cases. It should be noted that the climate temperature is quite high during summer time in NE Thailand where potassium deficiency is also known as endemic disease [19]; the potential roles in VF of these factors were discussed elsewhere [20].
Diagnosis of Lai Tai
Clinical manifestation of Lai Tai or SUDS is widely ranged from no symptom to unexplained syncope or seizure and sudden death. It is worthy to mention that the diagnosis required a good history taking of index events, family history of sudden death, physical examination, ECG, and other cardiac investigations, i.e., echocardiography, exercise test, CT scan, or MRI, to rule out other organic heart disease that potentially cause syncope or sudden death such as coronary artery disease, hypertrophic, or other forms of cardiomyopathy, RV dysplasia, long QT syndrome.
Clinical Profiles and Epidemiology All of Lai Tai victims were previously healthy and suddenly experienced symptoms of intense breathing, choking, gasping, cyanotic skin, and unresponsiveness during sleep before dying [9, 10]. Like SUDS in the USA, almost all cases were men (male-to-female ratio of 20:1) [11, 12] in the same age range, 21–54 (median age 34) years, and died between 21.00 and 4.00 [9]. In epidemiologic survey by Ministry of Public Health, the highest incidence of Lai Tai was found in the NE region of Thailand; the prevalence in men (aged 20–59 years) was 20.8:100,000 [21]. In Singapore, where young men from the NE villagers of Thailand came to work, there was a high incidence of SUDS/Lai Tai in 1982 which topped at 161 cases by 1990 [10]. Cluster deaths in family were found in 18–40 % of Lai Tai victims [22] suggesting a strong genetic link. It is obvious that the clinical profiles of SUDS victims in the USA and those of Lai Tai are identical. Therefore, both of them are likely the same disease entity that was highly prevalent in the border between NE Thailand, Laos People’s Democratic Republic, and Cambodia.
The Arrhythmogenic Marker To further identify the prevalence of Brugada ECG pattern and its consequences in these patients, we prospectively studied 27 Thai men (mean age of 39 ±11 year) who experienced Lai Tai (SUDS)-like episodes (from 1994 to1996) [23]. The majority of patients had normal biventricular function and no demonstrable heart disease by screening tests including angiogram. Of the 27, 16 cases (59.2 %) had typical Brugada ECG pattern, and the remaining 11 had normal ECGs (group 2). It was evident that patients with Brugada ECG pattern (group 1) had higher proportion of VF arrest (88 % vs 27 %, p = 0.003), inducible VT/VF (93 % vs 11 %, p = 0.0002), abnormal late potentials on SAECG (92 % vs 11 %, p = 0.002), and longer HV interval (63 ± 11 vs 49 ± 6 ms, p = 0.007) in comparison with those from patients group 2 [23] (Table 20.1). Eight patients received an ICD (six cases in group 1 and two cases in group 2), others were treated with propanolol (five in group 1 and three in group 2) and amiodarone (two in group 1
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Table 20.1 Clinical characteristics of Lai Tai (SUDS) survivors, patients with Brugada ECG (group 1) and normal ECG (group 2), see text for detail
Parameters Patients number Men (%) Mean age (years) Documented VF LVEF (%) QTc (s) AH (ms) HV (ms) Abnormal late potential on SAECGa Inducible PMVT/VF
Group 1: SUDS cases with Brugada marker 16 100 40 ± 12 88 % 64 ± 10 0.45 ± 0.003 91 ± 10 62 ± 11 92 % 93 %
Group 2: SUDS cases with normal ECG 11 100 39 ± 8 27 % 64 ± 9 0.42 ± 0.003 85 ± 9 49 ± 6 11 % 11 %
p-value NS NS NS 0.003 NS NS NS 0.007 0.002 0.0002
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p = 0.0333 Cumulative proportion of survival
Cumulative proportion of VF or cardiac arrest
Fig. 20.5 Life table, KaplanMeier survival analysis showing the worse prognosis of Lai Tai (SUDS) patients who had Brugada ECG (group 1) due to recurrent sudden death or VF after a mean follow-up of 11.8 ± 7 months (From Nademanee et al. [23])
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and two in group 2), and seven cases were not treated with any antiarrhythmic medication. After a mean follow-up of 11.8 ± 7 months (3–25 months), patients with Brugada type 1 ECG pattern (group 1) had a significantly higher incidence of documented VF (87.5 % vs 27 %, relative risk of 3.2, p = 0.003) and sudden death (85.7 % vs 14.3 %, relative risk of 3.4, p = 0.047) in comparison with those with normal ECG (group 2). All events occurred between 21.00 and 07.00. The life table analysis in Fig. 20.5 clearly demonstrated the worse prognosis of Lai Tai (SUDS) cases with Brugada ECG pattern [23]. This study confirmed the high prevalence of type 1 Brugada ECG pattern in two-thirds of Lai Tai survivors. Like Brugada syndrome cases, Lai Tai (SUDS) survivors faced a significant risk of sudden cardiac death or recurrent VF.
Special Position of V1and V2 ECG Leads Since the Brugada ECG pattern can change over time, from abnormal to normal, diagnosis of Brugada Syndrome
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therefore is not always possible [24, 25] . Occasionally, diagnosis was made after unmasking of Brugada ECG pattern by the administration of sodium channel blocking agents [25]. In 1994, we studied one Lai Tai survivor whose his ECG was normal at the time of the index event. During repeat ECG, the patient developed skin blebs over the electrode areas precluding position the ECG electrode at standard positions. The CCU nurse then placed the V1 and V2 leads one intercostal space (ICS) higher (the third ICS) than the regular position (the 4th ICS), and the Brugada ECG pattern was then unmasked (Fig. 20.6). This high ICS position correlated quite well with the right ventricular outflow tract (RVOT) region (Fig. 20.7). To verify the usefulness of this new lead position, we prospectively studied 16 Lai Tai survivors in whom the Brugada ECG pattern were absent on the standard (fourth) ICS position. All of them were men (mean age of 42 ± 12 years) and had documented VF arrest. By applying the high ICS lead positioning, we could further detect the Brugada ECG pattern in 7/16 cases (43.8 %) in comparison with 1/16 (6.3 %), p = 0.03 from the regular position [26].
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Fig. 20.6 The disrupted skin (arrow, left picture) made the placement of V1-3 ECG leads in the third and second intercostals (ICS) position which turned out to display the Brugada ECG pattern (right picture)
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Fig. 20.7 Left: recommended high ICS lead position to detect Brugada ECG pattern. Right: right ventriculogram in RAO-30 view illustrating the RVOT region at the level of the second and third ICS
Therefore, beside than biological variations such as fever [15, 27] or high vagal tone [16], the missed detection of BrS cases could be caused by using the insensitive, fourth ICS position. This high ICS position should be used in routine screening patients with unexplained syncope, seizure, or sudden death survivors. In addition, this high ICS leads position had led us to identify the VF substrate later.
Pharmacological Test and High ICS Position In symptomatic patients with normal ECG who otherwise presented with unexplained syncope or seizure, it was very important to rule out Brugada syndrome by detecting the concealed Brugada pattern. To compare the sensitivity and specificity of ajmaline and procainamide in unmasking Brugada
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ECG pattern, we studied 21 Lai Tai survivors (all men, mean age of 44 years) who had normal screening ECG. Eleven cases had documented VF and others had either unexplained syncope or SUDS like episodes during sleep. All of them had no organic heart disease and 90 % were VF inducible. The control group consisted of eight healthy male volunteers with mean age of 36 years. Procainamide and ajmaline were given, for at least 24 h apart, by intravenous infusion over 15 min at dosage of 10 mg/kg and 1 mg/kg, respectively. There was
% Br ECG detection 100 80
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no Brugada pattern detected either by regular or high ICS position in all control cases. In Lai Tai survivors, Brugada pattern could be detected by regular lead (fourth ICS) position in 33 % with procainamide and 38 % with ajmaline. With higher ICS position, the detection rate increased significantly from 38 to 76 % with procainamide and to 95 % with ajmaline, p < 0.05 [28, 29] (Figs. 20.8 and 20.9). From this study we concluded that sodium channel blockers (procainamide and ajmaline) in combination with higher ICS lead (V1-3 at 2nd and 3rd ICS) have 100 % specificity and over 75 % sensitivity for diagnosis of Brugada’s ECG, and ajmaline is better than procainamide in unmasking Brugada ECC pattern (sensitivity 95 % vs 76 %, p < 0.01). Therefore, we routinely administer sodium channel blockers with high ICS leads position as a screening test in patients presenting with unexplained syncope or aborted sudden death who had no definite Brugada marker.
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Fig. 20.8 High ICS leads position in conjunction with ajmaline (1 mg/ kg) provided a significant better detection of Brugada pattern in comparison with procainamide administration (10 mg/kg), p < 0.05 (see Veerakul et al. [28])
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Brugada syndrome (BrS) had been recognized as an autosomal-dominant, genetically transmitted disease with incomplete penetration [30]. As mentioned above, clinical manifestation of SUDS and BrS were quite similar. For example, cardiac events in BrS and SUDS cases were common in men, in the 3rd and 4th decades of life [25]. Interestingly, deaths in similar fashion had been observed in
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Fig. 20.9 Brugada ECG pattern after ajmaline and procainamide administration in regular (the fourth) and higher ICS position in the same case (see Fig. 20.8 and Veerakul et al. [28])
18 to 40 % of SUDS family [22] suggestive of underlying genetic disease. In BrS, the mutation of gene encoding sodium ion channel (SCN5A mutation) had been discovered by Chen and colleagues in 1998 [31] and confirmed by others [32, 33]. These mutations resulted in decrease or inactivation of sodium ion channel function causing repolarization abnormality which was believed underlying the unique ECG pattern in BrS cases [34]. In SUDS/SUND family, Vatta and colleagues reported the SCN5A mutation in three of ten SUND (Lai Tai and Pokkuri) families in 1992 [35]. These mutations reduced the sodium channel current (INa) at the end of phase 1 of action potential similar to what had been described in BrS [31–33]. Vatta and colleagues concluded that SUNDS (Lai Tai, Pokkuri) and BrS are phenotypically, genetically, and functionally the same disorder [35]. However, it should be noted that only 10–30 % of Brugada patients were genetically identified as having a SCN5A mutation [36]. In addition, other mutations in gene encoding calcium [37] and potassium channels [38] have been recently reported in sudden death victims and BrS cases. Currently, over 100 SCN5A mutations have been found in both BrS patients and non-Br cases, and their clinical effects have been well summarized by Mizusawa and Wilde [39].
Treatment of SUDS/Brugada Cases Symptomatic Patients Nowadays, ICD implantation has been recommended as a class I indication for symptomatic Brugada cases [40]. Quinidine is the only drug that has potential to prevent VF [41, 42], but it is not available in many countries [43] including Thailand. In addition, its adverse side effects remain the problem for long-term treatment. In early 1990s, ICD was still expensive, not reimbursable and not available yet in Thailand; however, we postulated that ICD could prevent death in Lai Tai/SUDS cases. In 1995, the first randomized study, defibrillator versus beta-blocker for sudden unexplained death in Thailand (DEBUT), was conducted after approval by the Institutional and Ministry of Public Health Review Board of Human Research Committee. It was designed to compare efficacy between the ICD and β-blocker therapy in SUDS (Lai Tai) survivors [44]. The ICDs were donated by CPI-Guidant Inc., St. Paul, Minnesota. The trial was conducted in two phases, the pilot (20 cases randomized) and the main trial (155 screened cases and 66 randomized to 37 ICD and 29 beta-blocker cases). There was no difference in baseline characteristic between groups. The Brugada ECG pattern, as detected by the regular (fourth ICS) lead position, was noted in 62 % of ICD group and 55 % of controls. The primary and secondary end points
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Fig. 20.10 Kaplan-Meier survival curves showing a significant benefit from ICD over beta-blocker treatment to reduce sudden death in Lai Tai (SUDS) survivors (From Nademanee et al. [44])
were total death from any causes and recurrent VT/VF or cardiac arrest. After 3 years of follow-up, there were four deaths, all in beta-blocker arm, (14 % vs 0 %, p = 0.02). Seven ICD cases had recurrent VF episodes and all were successfully treated with ICD shocks. After interim analysis, the DEBUT trial was prematurely terminated by the data safety monitoring board, owing to the overwhelm benefit of ICD over the drug (Fig. 20.10) [44]. In 67 % of ICD cases, multiple VF episodes were successfully controlled with beta-blockers. Therefore, propanolol did not increase mortality as predicted in other study [45], in fact it reduced VF episodes by 50 %. The DEBUT trial became the first and only randomized study that confirmed the efficacy of ICD in VF prevention of SUDS/BrS survivors. Although beta-blocker (propanolol) reduced VF episodes by 50 %, it did not provide a full protection from sudden death. Therefore, we still use propanolol in ICD patients who had recurrent but infrequent ICD shock from both VF and other atrial arrhythmias. In daily practice, it is worthy to mention that certain predisposing factors such as hypokalemia [14], fever [15], and heavy meal [18] should be controlled and educated to both patients and family members for reducing the risk of recurrent VF.
Asymptomatic Brugada Cases Although the current guidelines recommended ICD implantation as a class 1 indication in symptomatic Brugada cases [39], the role of ICD in asymptomatic BrS patients remained unclear, mostly due to different ways of risk stratification. In 111 asymptomatic BrS cases that had spontaneous Brugada ECG pattern, 16 of them (14 %) had arrhythmic events (7 sudden death, 9 documented VF)
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during a mean follow-up of 27 ± 29 months [46]. Since the risk of cardiac events in this particular group who had non-inducible ventricular arrhythmias at electrophysiological testing was quite low (0.9 %), Brugada and colleagues recommended ICD implantation only in asymptomatic BrS cases who had spontaneous ECG pattern and inducible ventricular arrhythmias [46]. In contrast, Priori and colleagues did not find any significant predictive value to programmed electrical stimulation in asymptomatic cases, particularly in individuals without spontaneous Brugada ECG pattern. The risk of cardiac arrest was considered an intermediate risk in asymptomatic cases (no history of syncope) with spontaneous Brugada pattern (14 % had cardiac arrest) and a low risk in individuals with normal baseline ECG, since only 5 % of them had cardiac arrest during four decades of follow-up [47]. To study the annual mortality rate in asymptomatic patients with Brugada ECG pattern and the role of prophylactic ICD as primary prevention, we conducted a randomized trial between ICD and no ICD arm [48]. The primary end point was death and secondary end points were recurrent VT/VF or cardiac arrest. ICDs were kindly donated by Medtronic Inc. for the study. A total of 105 asymptomatic subjects with Brugada ECG pattern from Thailand, Los Angeles, and Tahiti were either randomized to ICD or no ICD. Subjects who refused ICD treatment or randomization but were willing to follow with us were then put in our registry. Of the 105 study patients, 71 % were men (median age; 36.6 years and mean age; 38 ±16 years). The Brugada ECG pattern was spontaneously present in 28 % of the subjects (4th ICS position), while the majority of the patients (72 %) had Brugada ECG pattern only after ajmaline administration. After a mean follow-up of 5.6 years, there were two deaths in the “no ICD” group and no death in “ICD” cases. Both deaths occurred in men aged 47 and 61 years who died at night after 22 and 26 months follow-up. One case was non-inducible but had family history of sudden death, while another was VF inducible but had no sudden death in family members. Our observation suggested that the mortality of asymptomatic BrS was quite low, and no statistical difference was observed between two assigned groups in this small cohort, ICD group 0 % versus no ICD group 2.3 %, p = 0.5 [48]. Since the majority of our cases required ajmaline to unmask Brugada pattern, it was possible that they represented a low-risk population as mentioned by Priori and colleagues above [47]. Recent studies had shown the less reliable predictive value of EP study in risk-stratifying asymptomatic BrS cases [49, 50]. Other promising tests including SAECG [51], augmented ST segment during exercise test [52], fragmented QRS [53] had been reported. The potential role of these factors has been discussed elsewhere [20].
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VF Substrate and Radio-Frequency Ablation Despite medication, some SUDS/BrS survivors still had frequent ICD shocks from recurrent VF episodes. Identifying substrates for VF as a target for radio-frequency (RF) ablation, if possible, would be indeed very useful for patients facing with VF storm. Since the Brugada ECG pattern can be unmasked by positioning the V1–V2 at the second and third ICS position [25], it is possible that the arrhythmogenic substrate could be close to this area. By RV angiography, as shown in Fig. 20.11, the only anatomical site that represents the second and third ICS location is the right ventricular outflow tract (RVOT). In fact, structural abnormality of the right ventricle had been formerly reported in Brugada patients [54, 55]. Electrophysiologic study of an explanted heart, from patient who received cardiac transplantation after having intolerable ICD shock, did show a conduction delay exclusively in the RVOT in conjunction with interstitial fibrosis [54]. In addition, fibrosis of right ventricle had been reported in patients with phenotypic Brugada syndrome [55]. We then carried out a study to prove the hypothesis that the substrate of RVOT area, either over the epicardium or endocardium, would have identifiable abnormal electrograms, in patients with BrS who have frequent recurrent VF episodes. This would serve as the target site for catheter ablation. We studied nine symptomatic patients with the BrS (all men; mean age 39 years) who had multiple recurrent VF episodes (4 ± 1.5) per month, requiring ICD discharges [56]. Electroanatomical mapping of the right ventricle—both endocardially and epicardially—and epicardial mapping of the left ventricle were performed in all cases during sinus rhythm. All of them had typical type 1 Brugada ECG pattern and inducible VT/VF. All patients had abnormal low-voltage, fractionated late potentials exclusively clustering in the anterior aspect of the RVOT epicardium and not seen anywhere else, either RVOT endocardium or LV epicardium; see Fig. 20.11. Ablation at these sites rendered VT/VF non-inducible in seven of the nine patients (78 %) and normalization of the Brugada ECG pattern in eight of the nine patients (89 %) [56], see Fig. 20.12. Long-term outcomes (17 ± 6 months) were excellent; there was no recurrent VT/VF in all patients off medication (except one patient on amiodarone). Based on the above findings, we concluded that the underlying electrophysiologic mechanism in patients with BrS should be delayed depolarization over the anterior aspect of the RVOT epicardium as hypothesized by Wilde and colleagues [57]. Catheter ablation over this abnormal area results in normalization of the Brugada ECG pattern and prevents VT/VF—during electrophysiological studies as well as prevents spontaneous recurrences of VT/VF—and is very effective in treating ICD storms in patients with Brugada syndrome.
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Fig. 20.11 Epicardial and endocardial mapping of one Lai Tai (SUDS/Brugada) survivor depicting the fragmented low-voltage, late potentials that were exclusively located in the anterior RVOT epicardium (From Nademanee et al. [56])
20
Lai Tai, the Mysterious Death of Young Thai Men
Baseline
ICS-4
275 ICS-3
ICS-2
V1
V2
V3
1 month post ablation
ICS-4
ICS-3
ICS-2
V1
V2
V3
Fig. 20.12 Brugada ECG pattern before (upper picture) and 1 month (lower picture) after radio-frequency ablation performed at RVOT epicardium in one Lai Tai (SUDS/Brugada) survivor who had frequent ICD shocks. There was no recurrence of VF during follow-up (12 months)
Conclusions
The mysterious sleep death, the so-called Lai Tai or SUDS in Thailand and Brugada syndrome, is the same disease entity that was highly prevalent in the borders abutting the Northeast Thailand, Laos People’s Democratic Republic, and Cambodia. Sudden death, agonal respiration, and syncope were common manifestation and were caused by sustained and non-sustained VF, respectively. Most of Lai Tai victims have no definable heart disease and often displayed Brugada ECG pattern which is best demonstrated in higher ICS leads position. SUDS survivors with Brugada
ECG pattern carried a significant risk of recurrent sudden death or VF arrest of 20 % per year. Subsequent studies have shown the genetic and biophysical links between Lai Tai (SUDS), Pokkuri, and BrS, suggesting they are indeed the same disease. The role of ICD is clear in SUDS survivor but might not help in asymptomatic cases since their overall mortality is low. Our recent observation also demonstrates that anterior aspect of RVOT epicardium is an arrhythmogenic site causing life-threatening ventricular arrhythmias in these patients. Catheter ablation over this site not only results in normalization of the ECG
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pattern but also potentially prevents VF recurrences in symptomatic patients. Further study is mandatory especially in asymptomatic Brugada cases to risk stratifying and further address treatment modalities.
G. Veerakul et al. 10. Goh KT, Chao CT, Chew CH. Sudden nocturnal death among Thai construction workers in Singapore. (Letter). Lancet. 1990; 335:1154.
Cause of Mysterious Death Acknowledgment We would like to express our sincere thanks to all investigators in the DEBUT and SUDSPAC research projects under direction of Professor Koonlawee Nademanee, to Air Marshall Peerapun Prateeprat MD, the vice president of CAPREE (Duang Tawan) foundation, all former directors of Bhumibol Adulyadej Hospital, Dr. Prasert Prasarttong-Osoth, the president of the Vejdusit Foundation under the Royal Patronage of H.R.H. Princess Galyani Vadhana Krom Luang Naradhiwas Rajanagarindra, Dr. Kitipan Visudharom MD, PhD, Pradub Sukhum MD, the former and current director of Bangkok heart hospital, to all staffs of cardiovascular research laboratory, Bhumibol Adulyadej Hospital (W. Lapanun MD, P. Tanyasiri MD, K. Watanaswad MD, P. Chamsaad MD, S. Sitakalin MD, T. Wilaiphun MD, U. Sindhuwanna RN, T. Kawkaew RN, A. Khengrang RN, P. Watanaswad RN, K. Pornchaisith RN, A. Sangwan RN, I. Chuaychuwong BSc), to cardiothoracic surgeon (S. Chaiyaroj MD, N. Boone MD), anesthesiologist team P. Chonglerdtakul MD, I. Sukcharoen MD and K. Chirasarnta MD (Bangkok heart hospital), all staffs from the Johnson & Johnson Medical Thailand (S. Iamtaweecharern, S. Charernthai, W. Khlainoi), the Medical solution (C. Supaluk, P. Kaewkhem), Mrs. Preeya Sribunrueng, Ms. Tiraphun Kuptasingkee, Foundation of Tan Tao Mahaphrom and the CAPREE (Duang Tawan) foundation, CPI-Guidant Inc. (P. Pitikulatung), Medtronic Inc., Ms. W. Suwansri (Pacific Rim Electrophysiology Research Institute at Bangkok hospital), and Ms. R. Tansebunlur for their excellent and consistent support during the past 18 years.
References
11. Otto MC, Tauxe RV, Cobb LA, et al. Ventricular fibrillation causes sudden death in Southeast Asian immigrants. Ann Intern Med. 1984;101:45–7. 12. Brugada P, Brugada J. Right bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome: a multicenter report. J Am Coll Cardiol. 1992;20:1391–6. 13. Nademanee K, Veerakul G, Nimmanit S, et al. Right bundle branch block and ST elevation, an arrhythmogenic marker for sudden unexplained death syndrome in young Thai Men. Circulation. 1995;92(Suppl I):I–335. 14. Araki J, Konno T, Itoh H, et al. Brugada syndrome with ventricular tachycardia and fibrillation related to hypokalemia. Circ J. 2003;67:93–5. 15. Porres JM, Brugada J, Urbistondo V, et al. Fever unmasking the Brugada syndrome. Pacing Clin Electrophysiol. 2002;25:1646–8. 16. Kasanuki H, Ohnishi S, Ohtuka M, et al. Idiopathic ventricular fibrillation induced with vagal activity in patients without obvious heart disease. Circulation. 1997;95:2277–85. 17. Krittayaphong R, Veerakul G, Bhuripanyo K, et al. Heart rate variability in patients with sudden unexpected cardiac arrest in Thailand. Am J Cardiol. 2003;91:77–81. 18. Ikeda T, Abe A, Yusu S, et al. The full stomach test as a novel diagnostic technique for identifying patients at risk of Brugada syndrome. J Cardiovasc Electrophysiol. 2006;17:602–7. 19. Nimannnit S, Malasit P, Chaovakul V, et al. Pathogenesis of unexplained nocturnal death and endemic distal renal tubular acidosis. Lancet. 1991;338:930–2. 20. Veerakul G, Nademanee K. Brugada syndrome: two decades of progress. Circ J. 2012;76:2713–22.
Background: Lai Tai, SUDS, and SUND Diagnosis: Clinical Profiles and Epidemiology 1. CDC. Sudden unexplained nocturnal death among Southeast Asian refugees. MMWR. 1981;30:581–4. 2. Baron RC, Thacker SB, Gorelkin L, et al. Sudden death among Southeast Asian refugees: an unexplained nocturnal phenomenon. JAMA. 1983;250:2947–51. 3. Parish RG, Tucker M, Ing R, et al. Sudden unexplained death syndrome in Southeast Asian refugees: a review of CDC surveillance. MMWR CDC Surveill Summ. 1987;36(1SS): 43SS–53SS. 4. US Centers for Disease Control. Update: sudden unexplained death syndrome among Southeast Asian refugees: United States. MMWR Morb Mortal Wkly Rep. 1988;37:568–9. 5. Nolasco JB. An inquiry into “Bangungut”. Ann Intern Med. 1957; 99:905–12. 6. Aponte GE. The enigma of bangungut. Ann Intern Med. 1960;52: 1258–63. 7. Sugai M. A pathological study on sudden and unexpected death, especially on the cardiac death autopsied by medical examiners in Tokyo. Acta Pathol Jpn. 1959;9(Suppl):723–52. 8. Nimmanit S, Malasit P, Chaowakul V, et al. Pathogenesis of unexplained nocturnal death and endemic distal renal tubular acidosis. Lancet. 1991;338:930–2. 9. Veerakul G, Nademanee K. What is the sudden death syndrome in South-east Asia males? Cardiol Rev. 2000;8:90–5.
21. Chokevivat V, Warintrawat S, Choprawon C. Epidemiology of Lai Tai in Thailand. In: Ninmmanit S, Malasit P, editors. Sudden unexplained death syndrome. Bangkok: Desire Press; 1993. p. 38–50. 22. Tasnasvivat P, Chirawatkul A, Klungboonklong V, et al. Sudden and unexplained death in sleep (Lai Tai) of young men of rural northeastern Thailand. Int J Epidemiol. 1992;21:904–10.
The Unique ECG and Arrhythmogenic Marker 23. Nademanee K, Veerakul G, Nimmanit S, et al. Arrhythmogenic marker for the sudden unexplained death syndrome in Thai men. Circulation. 1997;96:2595–600.
Special Positioning of V1 and V2 ECG Leads 24. Veerakul G, Nademanee K. Dynamic changes in the RBBB and ST-elevation pattern in the right pre-cordial leads observed in
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patients with idiopathic ventricular fibrillation: evidence of phase 2 repolarization abnormality. Circulation. 1996;64(Suppl): 3669. 25. Antzelevitch C. Brugada syndrome. A review. Pacing Clin Electrophysiol. 2006;29:1130–59. 26. Veerakul G, Chaothawee L, Nademanee K. Usefulness of positioning ECG lead at V1-3 at higher inter-costal spaces to detect Brugada syndrome. Circulation. 2000;102(Suppl):18. 27. Antzelevitch C, Brugada R. Fever and the Brugada syndrome. Pacing Clin Electrophysiol. 2002;25:1537–9.
Pharmacological Test and High ICS Lead Position 28. Veerakul G, Chaothawee L, Koananatakul B, et al. Ajmaline versus procainamide challenge test in the diagnosis of sudden unexplained death or Brugada syndrome. J Am Coll Cardiol. 2002;39:112A–3. 29. Chaothawee L, Veerakul G, Kanjanapimai S, et al. Using Ajmaline as a tool in identifying high-risk SUDS survivors. PACE. 2003;Part II:26.
Genetic Study 30. Antzelevitch C, Brugada P, Brugada J, et al. Brugada syndrome, 1992–2002. A historical perspective. J Am Coll Cardiol. 2003; 41(10):1665–71. 31. Chen Q, Kirsch GE, Zhang D, et al. Genetic basis and molecular mechanism for idiopathic ventricular fibrillation. Nature. 1998;392:293–6. 32. Bezzina C, Veldkamp MW, van Den Berg MP, et al. A single Na (+) channel mutation causing both long-QT and Brugada syndromes. Circ Res. 1999;85:1206–13. 33. Rook MB, Alshinawi CB, Groenewegen WA, et al. Human SCN5A gene mutations alter cardiac sodium channel kinetics and are associated with the Brugada syndrome. Cardiovasc Res. 1999;44:507–17. 34. Antzelevitch C, Fish JM, DiDiego JM. Cellular mechanisms underlying the Brugada syndrome. In: Anzelevitch C, editor. The Brugada syndrome: from bench to bedside. Massachusetts: Blackwell Publishing Inc., 2005. p. 52–77. 35. Vatta M, Dumaine R, Varghese G, et al. Genetic and biophysical basis of sudden unexplained nocturnal death syndrome (SUND), a disease allergic to Brugada syndrome. Hum Mol Genet. 2002;11(3):337–45. 36. Antzelevitch C. Genetic, molecular and cellular mechanisms underlying the J wave syndromes. Circ J. 2012;76:1054–65. 37. Burashnikov E, Pfeiffer R, Barajas-Martinez H, et al. Mutations in the cardiac L-type calcium channel associated with inherited J-wave syndromes and sudden cardiac death. Heart Rhythm. 2010;7:1872–82. 38. Giudicessi JR, Ye D, Tester DJ, et al. Transient outward current (Ito) gain-of-function mutations in the KCND3-encoded Kv4.3 Potassium channel and Brugada syndrome. Heart Rhythm. 2011;8:1024–32. 39. Mizusawa Y, Wilde A. Brugada syndrome. Circ Arrhythm Electrophysiol. 2012;5:606–16.
Treatment: Symptomatic Patients 40. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. A Report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines. Europace. 2006;8:746–837.
277 41. Belhassen B, Glick A, Viskin S. Efficacy of quinidine in high-risk patients with Brugada syndrome. Circulation. 2004;110:1731–7. 42. Mizusawa Y, Sakurada H, Nishizaki M, et al. Effects of low dose quinidine on ventricular tachyarrhythmias in patients with Brugada syndrome: Low-dose quinidine therapy as an adjunctive treatment. J Cardiovasc Pharmacol. 2006;47:359–64. 43. Viskin S, Antzelevitch C, Marquez MF, et al. Quinidine: a valuable medication joins the list of “endangered species”. Europace. 2007; 9:1105–6. 44. Nademanee K, Veerakul G, Mower M, et al. The defibrillator versus beta-blocker for sudden unexplained death in Thailand (DEBUT). Circulation. 2003;107:221–6. 45. Miyazaki T, Mitamura H, Miyoshi S, et al. Autonomic and antiarrhythmic drugs modulation of ST segment elevation in patients with Brugada syndrome. J Am Coll Cardiol. 1996;27:1061–70.
Asymptomatic Cases 46. Brugada J, Brugada R, Antzelevitch C, et al. Long-term follow-Up of individuals with the electrocardiographic pattern of right bundle branch block and ST-segment elevation in precordial leads V1 to V3. Circulation. 2002;105:73–8. 47. Priori S, Napolitano C, Gasparini M, et al. Natural history of Brugada syndrome: insights for risk stratification and management. Circulation. 2002;105:1342–7. 48. Veerakul G, Kamblock J, Schwab M, et al. Low mortality rate among asymptomatic Brugada syndrome patients: a multi-center control-randomized study comparing ICD VS No-ICD treatment. Circulation. 2008;118:S982. 49. Priori SG, Gasparini M, Napolitano C, et al. Risk stratification in Brugada syndrome: results of the PRELUDE (programmed electrical stimulation predictive value) registry. J Am Coll Cardiol. 2012; 59:37–45. 50. Wilde AA, Viskin S. EP testing does not predict cardiac events in Brugada syndrome. Heart Rhythm. 2011;8:1598–600. 51. Huang Z, Patel C, Li W, et al. Role of signal-averaged electrocardiograms in arrhythmic risk stratification of patients with Brugada syndrome: a prospective study. Heart Rhythm. 2009;6:1156–62. 52. Makimoto H, Nakagawa E, Takaki H, et al. Augmented ST-segment elevation during recovery from exercise predicts cardiac events in patients with Brugada syndrome. J Am Coll Cardiol. 2010;56: 1576–84. 53. Morita H, Kusano KF, Miura D, et al. Fragmented QRS as a marker of conduction abnormality and a predictor of prognosis of Brugada syndrome. Circulation. 2008;118:1697–704.
VF Substrate and Radio-Frequency Ablation 54. Coronel R, Casini S, Koopmann TT, et al. Right ventricular fibrosis and conduction delay in a patient with clinical signs of Brugada syndrome. A combined electrophysiological, genetic, histologic, and computational study. Circulation. 2005;112:2769–77. 55. Frustaci A, Priori SG, Pieroni M, et al. Cardiac histological substrate in patients with clinical phenotype of Brugada syndrome. Circulation. 2005;112:3680–7. 56. Nademanee K, Veerakul G, Chandanamattha P, et al. Prevention of ventricular fibrillation episodes in Brugada syndrome by catheter ablation over the anterior right ventricular outflow tract epicardium. Circulation. 2011;123:1270–9. 57. Wilde AA, Postema PG, Di Diego JM, et al. The pathophysiological mechanism underlying Brugada syndrome: depolarization versus repolarization. J Mol Cell Cardiol. 2010;49:543–53.
Cardiac Arrest Arrhythmias
21
Riccardo Proietti, Jacqueline Joza, Florea Costea, Mihai Toma, Dan Mǎnǎstireanu, and Vidal Essebag
Abstract
Cardiac arrest (CA) is a clinical condition defined by the absence of an effective circulatory blood flow due to the inability of the heart to provide consistent hemodynamic support. Two main characteristics challenge the treatment of CA: its unpredictable onset and the very short time in which to intervene in order to avoid irreversible and dramatic organ damage. The cardiology community has attempted to address the difficulties related to the management of CA through the development of standardized protocols aimed at treating CA. The current guidelines place strong consideration on the initial rhythm and the restoration of spontaneous circulation with resuscitation. What is not sufficiently emphasized in the current approach to CA is the dynamic transition of different cardiac rhythms during the acute event. In this chapter, the temporal sequence of different cardiac arrhythmias during CA and their prognostic significance are described. The proarrhythmic effects of pharmacological and electrical treatment utilized during the resuscitation are also discussed. In recent years, therapeutic hypothermia has been introduced for the treatment of survivors of CA in an effort to reduce neurological damage. Electrocardiographic abnormalities associated with therapeutic hypothermia are briefly described. Keywords
Cardiac arrest • Sudden cardiac death • Cardiac rhythm transition • Ventricular arrhythmias
Cardiac arrest (CA) is a clinical condition defined by the absence of an effective circulatory blood flow due to the inability of the heart to provide consistent hemodynamic support. CA represents the most severe complication of any
R. Proietti (*) • J. Joza • V. Essebag Division of Cardiology, McGill University Health Centre, Montreal, QC, Canada e-mail:
[email protected] F. Costea • M. Toma Department of Emergency, Central University Emergency Military Hospital “Dr Carol Davila”, Bucarest, Romania D. Mǎnǎstireanu Faculty of Medicine, Titu Maiorescu University, Bucarest, Romania A.S. Kibos et al. (eds.), Cardiac Arrhythmias, DOI 10.1007/978-1-4471-5316-0_21, © Springer-Verlag London 2014
cardiac disease and can also constitute the final evolution of a wide spectrum of noncardiac illnesses. The main challenges in the management of cardiac arrest stem from its unpredictable onset in addition to the very short time in which to intervene in order to avoid irreversible organ damage. A lack of understanding of the mechanisms of cardiac arrhythmias makes this clinical entity extremely difficult to treat.
Cardiopulmonary Resuscitation The cardiology community has attempted to address the difficulties surrounding the management of CA by developing standardized treatment protocols. This standardized 279
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approach, termed cardiopulmonary resuscitation (CPR) [1], provides guidelines for the treatment of cardiac rhythm abnormalities in an effort to preserve oxygen supply to vital organs. Because of the sudden nature of the event, often occurring in a nonmedical environment and involving family members or persons with no medical training, a simplified approach has been developed, emphasizing the importance of cardiac rhythm analysis during the first 2 min of the CA, followed by treatment as dictated by standardized algorithms. This oversimplified approach has resulted in two misconceptions: one which identifies success as only the restoration of spontaneous circulation and one which identifies CA according to only the initial arrhythmia without consideration for the possibility of degeneration into a different arrhythmia. Regarding the first misconception, the success of resuscitation should not simply be defined as the return of spontaneous circulation (ROSC), but should be measured by a patient’s survival to discharge from hospital. Descriptive analysis shows that sustained ROSC occurs in approximately half of the cases of CA. In the remaining cases, ROSC is merely a temporary condition. The significance of this distinction is evident in the disparity between published rates of on-scene ROSC versus rates of survival of CA upon hospital discharge. For instance, a meta-analysis of published studies reporting outcomes after out-of-hospital CA indicates that the median rate of survival to hospital discharge is only 6.4 % [2]. However, the reported incidence of on-scene ROSC of out-of-hospital CA, while variable, is significantly higher, ranging from 35 to 61 % [3, 4]. There are several reasons accounting for this discrepancy, including the neurologic response to circulatory arrest, complications arising during hospitalization, and repetitive spontaneous arrests prior to arrival to hospital. However, the most critical of all variables is the initial presenting cardiac rhythm during which appropriate therapy can have a very relevant impact on the survival to hospital discharge. The second misconception as a result of the oversimplification of management algorithms suggests that the CA is due to, and should be solely treated as per the initial presenting rhythm. However, if the phases preceding the sudden onset of CA have been extensively studied without conclusive insight, much less attention has been paid to the rhythm transition after CA. Moreover, few data are available on the effect of medication and electrical therapy in the dynamic sequence of cardiac rhythms during CA. The phases following CA can present many more complex challenges in terms of rhythm diagnosis and treatment than the onset. External thoracic compressions as well as the precordial blow can produce artifactual rhythms that may simulate the return of cardiac activity, thereby triggering an incorrect cessation of treatment by nonmedical persons. Electrocardiographic modifications can be more difficult to diagnose after the resuscitation maneuver, and some of the
R. Proietti et al.
drug administration protocols, for example, high doses of epinephrine, can generate a return of a tachyarrhythmia. It is therefore useful to separate post-CA arrhythmias into three different categories: 1. Arrhythmias causing cardiac arrest 2. Arrhythmias generated by the administered treatment for cardiac arrest 3. Artifactual postresuscitation arrhythmias – induced by specific CPR maneuvers (precordial blow, thoracic compressions, and repeated defibrillation) In this manner, we are able to differentiate between two important categories of rhythms: arrhythmias that begin prior to CA and arrhythmias that are generated during CPR maneuvers which may or may not promote successful return of circulation.
Pathophysiology of Cardiac Arrest The pathophysiology of CA is believed to require the interaction between a transient event and an underlying substrate. These factors may culminate in electric instability and lethal ventricular arrhythmias followed by hemodynamic collapse. The challenge remains to predict when such interactions prove harmful. Physical activity, psychosocial stress, and air pollution have been proposed as risk factors in timing of onset of CA [5]. The presence of prior cardiac disease plays a critical role in the dynamic process that characterizes CA. Arrhythmias in patients with structurally abnormal hearts with depleted functional reserves have less chance of successful resuscitation as compared to patients with no prior cardiac history [5]. Risk factors for CA include advanced age, male sex, cigarette smoking, hypertension, diabetes mellitus, hypercholesterolemia, obesity, and a family history of coronary artery disease. Not surprisingly, these risk factors are also predictors of coronary heart disease–related death and all-cause mortality. Coronary heart disease is the most common substrate underlying CA in the Western world, being responsible for 75 % of CA [5]. Cardiomyopathies (dilated, hypertrophic, and right ventricular arrhythmogenic dysplasia), and primary electrical disorders due to underlying channelopathies (Brugada syndrome, Long QT syndrome, short QT syndrome, and catecholaminergic polymorphic ventricular tachycardia) account for most of the remainder. Channelopathies are inherited arrhythmia disorders characterized by ion channel defects in structurally normal hearts capable of causing electrical disturbances leading to ventricular fibrillation. Finally, CA may also occur in the context of drowning, hanging, electrocution, and severe trauma. Existing energy reserves and the underlying functional integrity of the heart muscle can ensure positive results from CPR. In contrast, CAs that present in patients with structurally or electrically abnormal hearts are often associated with
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poor CPR outcomes [5]. The pattern of arrhythmias initiating a CA is also likely to be influenced by the underlying heart disease.
Cardiac Rhythms Associated with Cardiac Arrest Four main electrocardiographic rhythms are associated with CA: ventricular fibrillation (VF), pulseless ventricular tachycardia (VT), asystole, and pulseless electrical activity (PEA). VF can be defined as a spatiotemporal electric turbulence compromising the heart’s ability to pump blood efficiently and is the mechanism underlying most sudden CA episodes. By contrast, VT might not initially present with hemodynamic impairment. However, if left untreated, VT may progress to pulseless CA with subsequent degeneration into VF. Because clinical “pulseless VT” is an organized rhythm that may be associated with some degree of effective cardiac output, it is thought that outcomes from VT are more favorable than those from VF. Asystole is characterized by the absence of electrical cardiac activity. In contrast, PEA is, by definition, characterized by the presence of electrical cardiac activity, but without effective systemic perfusion. There may, however, be some degree of systemic perfusion despite the lack of palpable pulses. Not surprisingly, PEA has been associated with better outcomes than asystole during in-hospital and out-of-hospital cardiac arrest [5]. VF or VT has been reported to be the first presenting rhythm in 75–84 % of cases of CA, while asystole and PEA account for the remainder [5]. All of these arrhythmias necessitate rapid initiation of CPR maneuvers to ensure patient recovery. The return and persistence of electrical cardiac activity, associated with an effective systemic circulation (i.e., ROSC), is the goal of resuscitation maneuvers. CA rhythms can be separated into two categories with respect to management: arrhythmias that respond to electrical defibrillation or cardioversion (also called shockable rhythms), namely, VF and VT, and arrhythmias that do not respond to defibrillation (nonshockable rhythms), namely, asystole and PEA. Both groups are managed by advanced cardiac life support (ACLS) maneuvers. Evidently, patients with CA presenting with nonshockable rhythms (asystole or PEA) typically have poorer survival rates than those presenting with shockable rhythms (VF or VT) [6, 7]. For this reason, VF and VT have traditionally been considered “good” cardiac arrest rhythms (Table 21.1).
Cardiac Rhythm Transitions During Cardiac Arrest The reported incidence of cardiac re-arrest (defined by the occurrence of any pulseless cardiac rhythm after a ROSC) ranges from 61 to 79 % in different studies [8–10], and the
Table 21.1 Association between first presenting rhythm, rhythm transition, and prognosis following resuscitation of cardiac arrest First detected rhythm during cardiac arrest Shockable rhythm (VF or VT) Nonshockable rhythm (asystole or PEA) Rhythm transition during ongoing cardiac arrest Recurrent shockable rhythm (VT/VF) Transition from shockable to nonshockable Transition from nonshockable to shockable
Prognosisa +++++ ++
++ + +
a The number of + symbols, ranging from 1 to 5, indicates the relative prognosis ranging from poorest to best. Transition from a nonshockable to a shockable rhythm is not associated with an improvement in prognosis (see text for explanation)
transition from a shockable rhythm to a nonshockable rhythm commonly occurs during the CA (Table 21.1). Skogvoll et al. [11], analyzed defibrillator event recordings of 304 cases of CA among adult populations in Norway, Sweden, and the UK. They reported a median of five (range 1–39) rhythm transition states among the four main rhythms of CA during an acute episode, with an increased number of rhythm transitions when the initial rhythm was VF or VT rather than asystole or PEA. Importantly, in all 304 defibrillator recordings, 35 % of patients regained a ROSC during CPR and only 21 % went on to achieve sustained ROSC. In patients initially presenting with VF, the reappearance of VF and/or the appearance of asystole are major risk factors for poorer outcome. PEA is a particularly negative risk factor for resuscitations of longer duration. Knowledge of the transition and timing of different rhythms during CA can provide important information in directing management decisions during CA (Fig. 21.1). Comparable data was demonstrated by Meaney et al. [12], who analyzed 51,919 cases of patients having undergone in-hospital CA occurring in 411 different centers. They found that it was both the presence of a shockable rhythm as well as the temporal sequence in the succeeding shockable and nonshockable rhythms that determined the eventual outcome. Importantly, patients with nonshockable rhythms, such as asystole or PEA, followed by a subsequent shockable rhythm during the resuscitative efforts, had much worse outcomes than those who remained in asystole of PEA. Similarly, but in a cohort of patients with out-of-hospital CA, Hallstrom et al. [13] reported a poorer outcome in patients whose initial rhythm was asystole or PEA that subsequently converted to VF or VT versus patients who remained in asystole or PEA. A recent study by Sacedo et al. [14], on the incidence of re-arrest in a cohort of out-of-hospital CA, demonstrated that the identification of cardiac re-arrest in the acute setting was a few minutes longer than the time it took a competent observer to make the correct diagnosis from the same data. A clear understanding of the dynamic evolution of CA is of paramount importance in prompting well-timed therapeutic intervention.
282 Fig. 21.1 Flow diagram of the potential sequence of arrhythmias and resuscitation efforts during cardiac arrest. The temporal sequence of different cardiac arrhythmias has prognostic significance. Black arrows indicate a worse prognosis than red lines; red arrows indicate a worse prognosis than blue arrows. Abbreviations: PEA pulseless electrical activity, ACLS advanced cardiac life support, ROSC return of spontaneous circulation
R. Proietti et al.
VT/VF
PEA/Asystole
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Defibrillation+ ACLS
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Transient ROSC
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VT/VF Termination of resuscitation efforts
The Impact of Pharmacological Therapy on Arrhythmias During Cardiac Arrest It has been hypothesized that in the dynamic transition between different cardiac arrhythmias during CA, the administered pharmacological therapy could have detrimental effects. Clinical observations suggest that adrenaline, a cornerstone therapy in the current treatment algorithms, can make a cardiac rhythm during CA more dynamic and unstable. Recently, Neset et al. [15] published an analysis of a trial conducted on 223 cases of out-of-hospital CA. Patients were randomized to ACLS with or without the administration of intravenous drugs. Patients receiving intravenous adrenaline presented with more frequent rhythm transitions than patients not receiving intravenous adrenaline. A trend toward shockresistant VF or VT in the adrenaline group was detected. Relapse from ROSC to VF or VT in the no-adrenaline group tended to occur during the first 20 min, whereas the adrenaline group experienced the relapse after more than 20 min. The transition from nonshockable rhythm to VF or VT occurred more frequently in the adrenaline group than in the no-adrenaline group. However, as discussed earlier, this rhythm transition does not necessarily correspond to an improvement in prognosis. Evidence concerning the effect of anti-arrhythmic drugs is incomplete. It has been suggested that amiodarone may play a role in the treatment of CA to prevent VF or VT recurrence, but this effect has not been thoroughly studied and its contribution to rhythm transition has not yet been assessed.
Beta-blockers may have a benefit during CA from VT due to their effect on decreasing oxygen demand. Improvements in long-term prognosis of patients treated with beta-blockers has been shown [16]. However, concerns have arisen regarding beta-blocker effects on reduction of myocardial contractility which causes hypotension in patients with CA.
Cardiac Rhythm Preceding Sudden Death in Patients with Implantable Cardioverter Defibrillators and Impact of Electrical Therapy Over the last decade, important new insights into the mechanisms of cardiac rhythm transition during CA have emerged as a result of follow-up of patients with implantable cardioverter defibrillators (ICDs). Approximately 25 % of patients with ICDs present with sudden cardiac death despite the presence of an ICD [17–20]. Incessant VF or VT as well as shock failure account for 26 and 18 %, respectively, of sudden cardiac death mechanisms in patients with functioning ICDs. Mitchell et al. [21] interrogated more than 317 patients ICDs and described an electromechanical dissociation after repeated defibrillator discharge as the mechanism responsible for sudden cardiac death in up to 29 %. In these patients, two or more shocks were required to convert the VF or VT, but this was followed by cardiac mechanical deterioration leading to death. The short temporal sequence between
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shock and mechanical dysfunction excludes necrosis as the instigating mechanism, but supports a potential deleterious effect of the shock on the molecular and electrical functioning of the heart, which could last from minutes to hours. These functional changes have only thus far been demonstrated in animal models [22, 23]; therefore, the clinical impact is still to be determined. Recently, Tsuji et al. [24, 25] have demonstrated in an animal model of electrical storm that repeated defibrillation can affect the activity of membrane protein handling calcium cell homeostasis (mainly calcium/calmodulin-protein kinase II). The upregulation of this protein can lead to intracellular calcium overload which may be responsible for mechanical dysfunction and arrhythmia recurrence. Finally, even the electrical therapy used for cardioversion at the time of CA can be proarrhythmic [26, 27]. In some circumstances, when the energy delivered by the shock is not adequate and the myocardium is more vulnerable, delivery of a shock can result in re-initiation of VF instead of halting its propagation.
Impact of Cooling on Arrhythmias After Cardiac Arrest In recent years, therapeutic hypothermia has been introduced as a treatment to reduce neurological damage in survivors of CA due to an initial shockable rhythm [28]. The rationale underlying this therapy is to reduce cerebral metabolic demands and minimize cellular brain damage produced by reperfusion. Due to the significantly better neurological outcomes shown in trials [29, 30], therapeutic hypothermia has largely become adopted for patients resuscitated from CA. The patient is sedated, paralyzed, and rapidly cooled to a temperature of 32–34 °C for 12–24 h. Following the adoption of hypothermia therapy, a wide spectrum of electrocardiographic abnormalities have been detected among patients monitored in the intensive care unit. An alteration commonly described is a prolongation of the QTc interval from 47 to 80.3 ms longer than the baseline QTc interval [31–33]. The incidence of ventricular arrhythmias is very rare, and if present, is associated with more severe hypothermia (below 32 °C) [33]. Cases of torsades de pointes [34], idioventricular rhythms [35], and VF [36] after QT prolongation have been described. The pharmacological management of cardiac effects during therapeutic hypothermia is currently under debate. The effect of hypothermia on defibrillation threshold in patients with ICDs is also unclear [37]. Conclusion
In the management of CA, great attention has been paid to the initial presenting rhythm and to ROSC after resuscitation. This is a consequence of the efforts of the cardiology
community to attempt to address the challenge posed by CA. However, what is not sufficiently emphasized in the current approach to CA is the dynamic evolution of different cardiac rhythms during the event. The temporal sequence of different cardiac arrhythmias has prognostic significance. Moreover, the pharmacologic and electrical management during the resuscitation process may themselves result in secondary adverse cardiac arrhythmias. An appropriate knowledge of this dynamic evolution of cardiac rhythm constitutes a challenge to the current management of CA.
References 1. The European resuscitation Council Guidelines for resuscitation. 2010. Available from: http://resuscitation-guidlines.articlesmotion. com/resource-center. 2. Nichol G, Stiell IG, Laupacis A, Pham B, De Maio VJ, Wells GA. A cumulative meta-analysis of the effectiveness of defibrillatorcapable emergency medical services for victims of out-of-hospital cardiac arrest. Ann Emerg Med. 1999;34(4 Pt 1):517–25. 3. Grasner JT, Meybohm P, Fischer M, Bein B, Wnent J, Franz R, et al. A national resuscitation registry of out-of-hospital cardiac arrest in Germany-a pilot study. Resuscitation. 2009;80(2): 199–203. 4. Grmec S, Krizmaric M, Mally S, Kozelj A, Spindler M, Lesnik B. Utstein style analysis of out-of-hospital cardiac arrest–bystander CPR and end expired carbon dioxide. Resuscitation. 2007;72(3): 404–14. 5. Chugh SS, Reinier K, Teodorescu C, Evanado A, Kehr E, Al Samara M, et al. Epidemiology of sudden cardiac death: clinical and research implications. Prog Cardiovasc Dis. 2008;51(3): 213–28. 6. Cummins RO, Chamberlain D, Hazinski MF, Nadkarni V, Kloeck W, Kramer E, et al. Recommended guidelines for reviewing, reporting, and conducting research on in-hospital resuscitation: the inhospital ‘Utstein style’. American Heart Association. Circulation. 1997;95(8):2213–39. 7. Eisenberg MS, Cummins RO, Damon S, Larsen MP, Hearne TR. Survival rates from out-of-hospital cardiac arrest: recommendations for uniform definitions and data to report. Ann Emerg Med. 1990;19(11):1249–59. 8. Martens PR, Russell JK, Wolcke B, Paschen H, Kuisma M, Gliner BE, et al. Optimal Response to Cardiac Arrest study: defibrillation waveform effects. Resuscitation. 2001;49(3):233–43. 9. White RD, Russell JK. Refibrillation, resuscitation and survival in out-of-hospital sudden cardiac arrest victims treated with biphasic automated external defibrillators. Resuscitation. 2002;55(1): 17–23. 10. van Alem AP, Post J, Koster RW. VF recurrence: characteristics and patient outcome in out-of-hospital cardiac arrest. Resuscitation. 2003;59(2):181–8. 11. Skogvoll E, Eftestol T, Gundersen K, Kvaloy JT, Kramer-Johansen J, Olasveengen TM, et al. Dynamics and state transitions during resuscitation in out-of-hospital cardiac arrest. Resuscitation. 2008;78(1):30–7. 12. Meaney PA, Nadkarni VM, Kern KB, Indik JH, Halperin HR, Berg RA. Rhythms and outcomes of adult in-hospital cardiac arrest. Crit Care Med. 2010;38(1):101–8. 13. Hallstrom A, Rea TD, Mosesso Jr VN, Cobb LA, Anton AR, Van Ottingham L, et al. The relationship between shocks and survival in
284
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24. 25.
R. Proietti et al. out-of-hospital cardiac arrest patients initially found in PEA or asystole. Resuscitation. 2007;74(3):418–26. Salcido DD, Stephenson AM, Condle JP, Callaway CW, Menegazzi JJ. Incidence of rearrest after return of spontaneous circulation in outof-hospital cardiac arrest. Prehosp Emerg Care. 2010;14(4):413–8. Neset A, Nordseth T, Kramer-Johansen J, Wik L, Olasveengen TM. Effects of adrenaline on rhythm transitions in out-of-hospital cardiac arrest. Acta Anaesthesiol Scand. 2013;57(10):1260–7. Bourque D, Daoust R, Huard V, Charneux M. beta-Blockers for the treatment of cardiac arrest from ventricular fibrillation? Resuscitation. 2007;75(3):434–44. Pires LA, Hull ML, Nino CL, May LM, Ganji JR. Sudden death in recipients of transvenous implantable cardioverter defibrillator systems: terminal events, predictors, and potential mechanisms. J Cardiovasc Electrophysiol. 1999;10(8):1049–56. Luceri RM, Habal SM, Castellanos A, Thurer RJ, Waters RS, Brownstein SL. Mechanism of death in patients with the automatic implantable cardioverter defibrillator. Pacing Clin Electrophysiol. 1988;11(11 Pt 2):2015–22. Kelly PA, Cannom DS, Garan H, Mirabal GS, Harthorne JW, Hurvitz RJ, et al. The automatic implantable cardioverter-defibrillator: efficacy, complications and survival in patients with malignant ventricular arrhythmias. J Am Coll Cardiol. 1988;11(6):1278–86. Mercando AD, Furman S, Johnston D, Frame R, Brodman R, Kim SG, et al. Survival of patients with the automatic implantable cardioverter defibrillator. Pacing Clin Electrophysiol. 1988;11 (11 Pt 2):2059–63. Mitchell LB. Use of the implantable cardioverter-defibrillator in patients with coronary artery spasm as the apparent cause of spontaneous life-threatening ventricular tachycardia or ventricular fibrillation: crossing the spasm sudden death chasm. J Am Coll Cardiol. 2012;60(10):914–6. Van Vleet JF, Tacker Jr WA, Geddes LA, Ferrans VJ. Acute cardiac damage in dogs given multiple transthoracic shocks with a trapezoidal wave-form defibrillator. Am J Vet Res. 1977;38(5):617–26. Tedeschi CG, White Jr CW. A morphologic study of canine hearts subjected to fibrillation, electrical defibrillation and manual compression. Circulation. 1954;9(6):916–21. Tsuji Y. Electrical storm and calcium signaling: a review. J Electrocardiol. 2011;44(6):725–9. Tsuji Y, Hojo M, Voigt N, El-Armouche A, Inden Y, Murohara T, et al. Ca(2+)-related signaling and protein phosphorylation
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
abnormalities play central roles in a new experimental model of electrical storm. Circulation. 2011;123(20):2192–203. Lesigne C, Levy B, Saumont R, Birkui P, Bardou A, Rubin B. An energy-time analysis of ventricular fibrillation and defibrillation thresholds with internal electrodes. Med Biol Eng. 1976;14(6): 617–22. Chen PS, Shibata N, Dixon EG, Martin RO, Ideker RE. Comparison of the defibrillation threshold and the upper limit of ventricular vulnerability. Circulation. 1986;73(5):1022–8. Oku K, Kuboyama K, Safar P, Obrist W, Sterz F, Leonov Y, et al. Cerebral and systemic arteriovenous oxygen monitoring after cardiac arrest. Inadequate cerebral oxygen delivery. Resuscitation. 1994;27(2):141–52. Hypothermia after Cardiac Arrest Study G. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002;346(8):549–56. Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, et al. Treatment of comatose survivors of out-ofhospital cardiac arrest with induced hypothermia. N Engl J Med. 2002;346(8):557–63. Lebiedz P, Meiners J, Samol A, Wasmer K, Reinecke H, Waltenberger J, et al. Electrocardiographic changes during therapeutic hypothermia. Resuscitation. 2012;83(5):602–6. Riaz A, Hieb H, Foley B, Mulvihill N, Crean P, Murphy RT, et al. Safety of therapeutic hypothermia in post VF/VT cardiac arrest patients. Ir Med J. 2013;106(2):55–6. Piktel JS, Jeyaraj D, Said TH, Rosenbaum DS, Wilson LD. Enhanced dispersion of repolarization explains increased arrhythmogenesis in severe versus therapeutic hypothermia. Circ Arrhythm Electrophysiol. 2011;4(1):79–86. Huang CH, Tsai MS, Hsu CY, Chen WJ. Images in cardiovascular medicine. Therapeutic hypothermia-related torsade de pointes. Circulation. 2006;114(14):e521–2. Wu ET, Huang SC, Chi NH, Lin MT, Ko WJ, Wang SS, et al. Idioventricular rhythm induced by therapeutic hypothermia. Resuscitation. 2008;76(3):471–3. Richter S, Ehrlich JR, Fassbender S, Fichtlscherer S. Malignant Osborn waves during therapeutic hypothermia. Europace. 2009;11(5):668–9. Khan JN, Prasad N, Glancy JM. QTc prolongation during therapeutic hypothermia: are we giving it the attention it deserves? Europace. 2010;12(2):266–70.
Electrical Storm: Recent Advances
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Mitsunori Maruyama and Teppei Yamamoto
Abstract
Electrical storm is a life-threatening syndrome that is defined by three or more sustained episodes of ventricular tachycardia or ventricular fibrillation within a relatively short period of time. Electrical storm typically leads to a poor outcome and its management is challenging. Electrical storm can occur in various conditions, and the effective management of electrical storm requires an understanding of the mechanisms underlying the recurrent arrhythmia. Here, we present a review of recent advances in the approach and management of electrical storm including pharmacological and non-pharmacological therapies. Keywords
Electrical storm • Mechanisms • Prognosis • Treatment
Electrical storm refers to a state of cardiac electrical instability manifested by multiple episodes of ventricular tachycardia (VT) or ventricular fibrillation (VF) within a relatively short period of time. Although implantable cardioverter/ defibrillator (ICD) significantly improves survival in patients with VT/VF, electrical storm is still associated with high mortality and morbidity [1]. Electrical storm is generally defined as the occurrence of three or more sustained episodes of VT or VF during a 24-h period, requiring intervention to terminate the episode. The episodes of VT/VF must be separate, implying that the persistence of VT/VF following failed cardioversion/defibrillation is not considered as a second episode. A sustained VT/VF that resumes immediately after (≥1 sinus cycle and within 5 min) successful cardioversion/defibrillation is regarded as a severe form of electrical storm (Fig. 22.1). In more than half of the patients, intervals between VT/VF episodes are less than 1 h with the shortest interval <1 min [2].
M. Maruyama, MD, PhD (*) • T. Yamamoto, MD Cardiovascular Center, Chiba-Hokusou Hospital, Nippon Medical School, 1715 Kamakari, Inzai, Chiba 2701694, Japan e-mail:
[email protected] A.S. Kibos et al. (eds.), Cardiac Arrhythmias, DOI 10.1007/978-1-4471-5316-0_22, © Springer-Verlag London 2014
Etiology Patients who present with electrical storm often have a structural heart disease [3], while functional electrical abnormalities also provoke electrical storm in patients with a structurally normal heart. Underlying conditions that cause electrical storm are listed in Table 22.1. Risk factors for electrical storm include advanced age, male sex, a low left ventricular ejection fraction, and New York Heart Association functional class III or IV heart failure [23]. Antiarrhythmic agents can provoke electrical storm [24]. Electrical storm is often the initial manifestation of myocardial ischemia. In electrical storm, polymorphic VT is most often associated with acute ischemic syndromes; however, polymorphic VT also occurs in the absence of organic heart disease [25].
Incidence Several studies were carried out to determine the incidence of electrical storm in ICD recipients. Great variability in the incidence was reported in the various studies probably because the definition of electrical storm was not homogeneous in the studies examined. When electrical storm is defined as three defibrillator interventions during 285
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M. Maruyama and T. Yamamoto Shock
*
*
** ** Shock
*
* *
*
Fig. 22.1 An example of monitor ECG during electrical storm. Electrical shocks (downward arrows) successfully terminated the VF, followed by immediate recurrence of VF. Asterisks show intervening sinus or ectopic beats between the VFs
Table 22.1 Causes of electrical storm Structural heart diseases Ischemic heart diseases With acute myocardial infarction [4, 5] Without acute myocardial infarction Nonischemic cardiomyopathy Dilated cardiomyopathy [6] Hypertrophic cardiomyopathy [7] Arrhythmogenic right ventricular dysplasia/cardiomyopathy [8] Valvular heart diseases [9] Corrected congenital heart diseases Myocarditis [10] Chagas disease [11] Metastatic cardiac tumor [12] Abnormal electrical substrate (structurally normal hearts) Primary causes Idiopathic [13] Brugada syndrome [14–16] Early repolarization syndrome [16, 17] Long QT syndrome [18] Catecholaminergic polymorphic ventricular tachycardia [19] Secondary causes Electrolyte abnormalities Toxic/drug related [20] Perioperative [21] Iatrogenic (T wave pacing) [22]
24 h, the incidence of electrical storm ranges between 10 and 28 % in patients with secondary preventive indication for ICD [6, 26, 27] and 4 % in patients with primary ICD indication [28].
Prognostic Significance Electrical storm might be an independent risk factor for cardiac death. In the AVID study [27], patients with electrical storm displayed a 2.4-fold higher risk of all-cause mortality. In the MADIT-II substudy [28], patients with electrical storm had a 7.4-fold higher risk of death than patients without electrical storm. Both studies showed that the risk of death was highest within the first 3 months after the electrical storm. Recurrent episodes of VT or VF can lead to an increase in intracellular Ca2+ and exacerbation of heart failure [29]. In addition, an electric shock itself may cause myocardial injury [30]. Nevertheless, it is unclear whether electrical storm contributes directly to a poor outcome or is simply an epiphenomenon of advanced structural heart diseases [23, 26].
Pathophysiology Electrical storm is the result of multiple interactions between a predisposing electrophysiological substrate and alterations in the autonomous nervous system and cellular milieu. The mechanisms for recurrences of VT and VF after DC shocks for cardioversion/defibrillation vary according to conditions in which the electrical storm occurs. From a clinical point of view, determining the pathophysiology of electrical storm is critical, because treatment must target the underlying mechanism. In structural heart diseases, reentry is the mechanism for a majority of cases with sustained VT. Conduction and repolarization abnormalities lie within heterogeneous areas of scarred myocardium caused by fibrosis and collagen
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Electrical Storm: Recent Advances
deposition of various etiologies (Table 22.1). Bundles of surviving myofibrils around the border of the scar provide an anatomical substrate for conduction pathways allowing for an electrically stable reentry. Myocardial ischemia is a common trigger of electrical storm, which causes abnormal automaticity with an altered membrane potential or triggered activity leading to repetitive inductions of reentrant VT. In animal models of acute ischemia, the initial VT beats were recorded from Purkinje fibers situated close to the ischemic border zone of the myocardial infarction [31]. In the subacute phase of myocardial infarction, the survived Purkinje fibers in the border zone show abnormal Ca2+ handling by which spontaneous Ca2+ release from the sarcoplasmic reticulum (SR) via the ryanodine receptor occurs [32]. The spontaneous SR Ca2+ release activates inward membrane currents sensitive to intracellular Ca2+, which cause delayed afterdepolarization (DAD) and triggered activity. A recent experimental study has shown that beta-adrenergic stimulation due to sympathetic activation which generally follows hemodynamically unstable VT/VF contributes to VT recurrence by the DAD mechanism [33]. Beta-adrenergic stimulation enhances intracellular Ca2+ overload secondary to rapid activation during VT/VF and induces post-shock VT (Fig. 22.2a) [33]. Ca2+-/ calmodulin-dependent protein kinase II activation may promote the Ca2+-handling abnormality during electrical storm [34]. The genesis of DAD requires a high membrane responsiveness to changes in intracellular Ca2+ (i.e., high intracellular Ca2+-membrane voltage coupling gain) [33], and it is known that the Ca2+-voltage coupling gain increases in failing hearts by downregulation of inward rectifier K+ current (IK1) and upregulation of Na+-Ca2+ exchange current [35]. In fact, heart failure is one of the major risk factors of electrical storm [23]. Since IK1 density is small in Purkinje cells [36], Purkinje fibers can serve as an arrhythmogenic source of the post-shock VT [33]. In addition, heart failure facilitates acute shortening of action potential duration (APD) immediately after termination of VF [37]. In this case, persistent elevation of intracellular Ca2+ due to Ca2+ overload following VF activates inward Ca2+-sensitive currents during late phase 3 of the action potential which induce triggered activity and spontaneous VF (i.e., late phase 3 early afterdepolarization (EAD) [38] (Fig. 22.2b)). This arrhythmogenic post-shock APD shortening after defibrillation of VF occurs in heart failure by upregulation of apamin-sensitive small-conductance K+ current in failing hearts [39]. Sympathetic stimulation also accelerates the post-shock APD shortening, late phase 3 EAD, and VF recurrences [40]. Catecholaminergic polymorphic VT (CPVT) is an inherited disorder of intracellular Ca2+ handling, which can cause electrical storm [19]. Abnormal SR Ca2+ release from defective ryanodine receptors develops DAD, triggered activity in the Purkinje system, which is proposed as the mechanism of polymorphic VT in CPVT patients [41].
Shock
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c Phase 2 EAD
d
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Long APD 1
Electrotonic depolarization
3
2 Short APD
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e
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Endo Epi
Endo Epi
Fig. 22.2 Schematic representation of pathophysiology of recurrent ventricular arrhythmias in electrical storm. The red and black lines depict intracellular Ca2+ (Cai) and membrane voltage (Vm), respectively. (a) Delayed afterdepolarization (DAD). (b) Late phase 3 early afterdepolarization (EAD). (c) Phase 2 EAD. (d) Phase 3 EAD (classical-type). (e) Phase 2 reentry
In long QT conditions, triggered activity due to EAD leads to polymorphic VT including torsades de pointes. Recent studies showed that spontaneous SR Ca2+ release as well as reactivation of L-type Ca2+ current (ICa,L) plays a role in the genesis of phase 2 EAD (Fig. 22.2c) [42, 43]. Furthermore, heterogeneous prolongation of APD sets the stage for reentry and phase 3 EAD caused by electrotonic reexcitation at the sites with a steep repolarization gradient (Fig. 22.2d) [42]. Brugada syndrome is characterized by a unique J point and ST segment elevation in the right precordial leads of ECG and occurrence of VF in structurally normal hearts. Early repolarization syndrome, also known as J wave syn-
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drome, is a novel clinical entity which shows a J point elevation, notching or slurring of the terminal portion of the R wave (J wave) in the inferior or lateral leads of ECG and VF in otherwise healthy patients. Brugada syndrome and early repolarization syndrome are thought to have similar mechanisms underlying the genesis of VF, although etiology and genetics of each syndrome seem different. The transient outward current (Ito) expression is more profound in the epicardium than in the endocardium, resulting in a more prominent action potential notch in the epicardium. When the ionic balance during the early repolarization phase is altered, APD can be greatly shortened only in the epicardium due to loss of the action potential dome, thereby markedly enhancing transmural voltage gradient creating the electric source of prominent J wave and ST segment elevation on surface ECG. This allows the action potential dome at adjacent sites to be electrotonically conducted to the site with loss of the action potential dome (phase 2 reentry), giving rise to polymorphic VT/VF (Fig. 22.2e).
Management Management of electrical storm is challenging and requires an approach tailored to the underlying cause. A patient with electrical storm should be managed in an intensive care unit. The electrical storm with hemodynamic collapse is an accepted indication for an intra-aortic balloon pumping, percutaneous left ventricular assist device, or extracorporeal life support. These devices help stabilize hemodynamics and may suppress VT/VF recurrences. If pro-arrhythmic triggers are present (e.g., electrolyte disturbances, myocardial ischemia), treating those triggers may reverse the electrical instability of the myocardium. In some cases, emergent revascularization is necessary to control the electrical storm.
Pharmacological The physical and emotional stress that patients undergo in association with electrical storm activates the sympathetic nervous system. In addition to elevation of endogenous catecholamines [44], the use of epinephrine or vasopressin that is recommended by the current clinical guidelines for pulseless VT or VF further stimulates beta-adrenergic receptor of the heart. This deteriorates Ca2+ overload and elicits DAD and late phase 3 EAD. To alleviate the burden of the electrical storm and multiple electric shocks, all storm-patients should be adequately sedated. Short-acting anesthetics such as propofol, benzodiazepines, and some agents of general anesthesia have been associated with the suppression of electrical storm [45]. Since beta-adrenergic stimulation greatly enhances Ca2+ overload that plays an important role in the genesis of
M. Maruyama and T. Yamamoto
electrical storm [33, 34, 40], beta-adrenergic blockade is a key intervention in the management of electrical storm. Nademanee et al. [4] compared the efficacy of sympathetic blockade to conventional treatment according to the Advanced Cardiac Life Support (ACLS) guidelines at that time including lidocaine, procainamide, and bretylium therapy in patients with electrical storm associated with recent myocardial infarction. The sympathetic blockade was achieved by propranolol, esmolol, or left stellate ganglionic blockade. Although the trial was non-randomized, sympathetic blockade provided a marked survival advantage (1 week and 1 year mortality rate, 78 and 67 % in sympathetic blockade group vs. 18 and 5 % in ACLS guideline group, respectively). Similarly, thoracic (T1–T2) epidural anesthesia has suppressed electrical storm that was refractory to multiple antiarrhythmic agents and a beta-blocker [46]. This therapeutic approach directly targets nerve fibers that innervate the myocardium and reduces adrenergic tone selectively in the heart with minimal effects on hemodynamics. Sympathetic blockade is also the mainstay treatment of CPVT, since beta-adrenergic stimulation is the most important trigger of CPVT which is caused by DAD due to abnormal SR Ca2+ release. Non-dihydropyridine Ca2+ channel blocker has an additional preventive effect on CPVT in case of electrical storm related to CPVT [19]. A recent study has shown that flecainide has a direct effect on ryanodine receptor as well as on Na+ channel and prevents CPVT [47], but its usefulness on electrical storm remains to be confirmed. Lidocaine is an antiarrhythmic agent which used to be wildly given to prevent recurrences of VT/VF in the emergency care setting. However, the ALIVE trial has revealed that intravenous amiodarone significantly improved survival compared with intravenous lidocaine in patients with shockresistant out-of-hospital VT/VF (survival to hospital admission, 23 % vs. 12 %) [48]. Lidocaine preferentially binds to fast sodium channels in ischemic myocytes with a reduced pH and a reduced membrane potential. Outside the setting of ischemia, lidocaine has relatively weak antiarrhythmic properties: conversion rates from VT to sinus rhythm range from 8 to 30 % [24]. The 2006 American College of Cardiology/ American Heart Association guidelines for treating ventricular arrhythmias [49] gave class IIb recommendation (“usefulness is less well established”) for intravenous lidocaine only in the treatment of polymorphic VT that is associated with ischemia. Currently, amiodarone has replaced lidocaine as first-line therapy for electrical storm. Amiodarone has little negative inotropic effects and is safe in patients who have poor systolic function. In the ARREST trial, amiodarone improved survival to hospital admission rates compared with placebo in patients who had electrical storm [50]. In storm-patients with a long QT interval, intravenous magnesium sulfate is highly effective for suppression of
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Electrical Storm: Recent Advances
polymorphic VT, irrespective of serum magnesium levels [51]. Experimental studies have shown that magnesium sulfate suppressed EAD and triggered activity [52]. The exact mechanism of magnesium in preventing EAD is not clear, but a modulator effect of magnesium on intracellular Ca2+ may be responsible since Ca2+ handling is now recognized as an important element in the genesis of EAD [42, 43]. Since APD prolongation and heterogeneity of the APD are exaggerated at slower heart rates, temporary transvenous cardiac pacing at rates around 100 beats/min is another highly effective measure to prevent polymorphic VT in long QT conditions [53]. In instances of bradycardia or heart block, isoproterenol therapy can be used to increase the heart rate before placement of temporary cardiac pacing. However, isoproterenol may promote induction of polymorphic VT if the heart rate response to isoproterenol is not high enough; caution should therefore be exercised especially during the early period after isoproterenol is initiated. If the cause of the QT prolongation is known as congenital, sympathetic blockade is a good option for preventing polymorphic VT. Further, if the congenital long QT syndrome is associated with a mutation of cardiac Na+ channel gene, SCN5A, Na+ channel blockers such as lidocaine and mexiletine are expected to have an additional prophylactic effect [54]. Obviously, when there are offending factors such as electrolyte imbalances (hypokalemia, hypocalcemia, or hypomagnesemia) and the use of medications that are known to prolong the QT interval, correction of the electrolyte abnormalities and withdrawal of those medications are crucial first steps in the prevention of polymorphic VT. In Brugada syndrome, management of electrical storm is very different from most other conditions. Antiarrhythmic agents including beta-blockers, lidocaine, mexiletine, sotalol, amiodarone, and magnesium are unreliable in preventing recurrent VF or can even worsen the situation [14]. In contrast, beta-adrenergic stimulation with isoproterenol infusion is highly effective to control electrical storm in Brugada patients [15]. Beta-adrenergic stimulation increases ICa,L and decreases Ito by accelerating the heart rate, which helps restore the epicardial action potential dome and a normal transmural voltage gradient, resulting in normalization of ST segment elevation and suppression of electrical storm. Most class I antiarrhythmic agents are contraindicated in Brugada patients because Na+ channel blockade can provoke a loss of the action potential dome. However, quinidine has been reported to suppress recurrent VF in Brugada patients by blocking the Ito [14, 55]. Hence, quinidine is a recommended therapy for refractory cases of electrical storm caused by Brugada syndrome. As noted above, early repolarization syndrome appears to share common underlying electrophysiological abnormalities with Brugada syndrome. It was reported that
289
electrical storms were also inhibited by isoproterenol infusion or quinidine treatment in patients with early repolarization syndrome [16].
Non-pharmacological Patients who have episodes of electrical storm despite pharmacological therapies can be candidates for radiofrequency catheter ablation (RFCA). Myocardial substrates for reentrant VT and/or the origin of focal VT is the target in patients with VT storm, and a trigger initiating VF is the target in patients with VF storm. Although ablating multiple and unstable VT is challenging, modern computerized mapping and catheter navigation technologies enable us to treat them with a substantial success rate [56, 57]. When the hemodynamics during VT is stable enough to map the VT, a RFCA target can be localized with the conventional criteria of activation and entrainment mapping for VT [58]. When targeted VTs are unmappable due to hemodynamic instability, difficulty with induction, or unstable morphology in response to attempted entrainment pacing, substrate mapping during sinus rhythm with the assistance of electroanatomical mapping system is the choice of treatment [59]. Substrate modification with several RFCA strategies [60] can make the unmappable VTs non-inducible and suppress the VT storm. VF storm can be suppressed by RFCA aiming at premature ventricular complexes which trigger VF. Interestingly, those ventricular triggers often originate in the distal Purkinje system (Fig. 22.3) in patients with recent myocardial infarction [5] and without structural heart diseases [13], although the working myocardium (typically in the right ventricular outflow tract) also serves as an arrhythmogenic trigger in some cases. RFCA of those triggers can eliminate future VF episodes. This strategy of ablating the Purkinje or myocardial triggers might also be effective to control electrical storm in patients with Brugada and long QT syndrome [61] and CPVT [62]. Electrical storm in patients with ICD implantation may receive multiple shocks. Since the shock itself can exert harmful effects including myocardial electric injury [30] and sympathetic activation due to painful shocks, it is important to avoid unnecessary shocks by proper programming of ICD. Programming ICD to deliver antitachycardia pacing for fast VT can reduce the need for shocks. In the PainFree Rx II trial [63], antitachycardia pacing effectively treated fast VT (188–250 beats/min). This resulted in 70 % fewer shocks than did conventional ICD programming and improved the patients’ quality of life. The PREPARE investigators [64] evaluated the effect of extending the VT detection intervals that were needed to trigger ICD shocks to prevent repeated shocks for non-sustained VT. The PREPARE study patients were less likely to receive a shock in the first year compared with control patients (9 % vs. 17 %) without increasing arrhythmic syncope.
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M. Maruyama and T. Yamamoto 200ms I II V1 A
V
V
d - 200ms
CS
p p
0.93cm
His
HBE
His d
PP
PP I
ABL1-2
II III aVR aVL
ABL uni
aVF ABL3-4
V1 V2 V3
SR
PVC
V4 V5
400 ms
V6 SR
SR
Fig. 22.3 Radiofrequency catheter ablation of a trigger of electrical storm guided by distal Purkinje potential. Spontaneous VFs were initiated repeatedly by the same premature ventricular contraction (PVC) with a right bundle branch block pattern and superior axis. Intracardiac electrogram recorded at the left ventricular inferoseptum (red arrow)
PVC
V-fib
800 ms
using the ablation catheter (ABL1-2) exhibits Purkinje potential (PP) that follows His bundle electrogram during sinus rhythm (SR) and precedes the QRS onset of the PVC triggering the VF. RF application at this site prevented the VF recurrences
22
Electrical Storm: Recent Advances
Conclusions
A wide variety of pathophysiology can be responsible for electrical storm. A rapid and correct understanding of its etiology is essential for controlling electrical storm. Despite the insufficient clinical evidence, the specific therapy based on the underlying mechanism should provide a better outcome in the management of this lifethreating condition.
References 1. Israel CW, Barold SS. Electrical storm in patients with an implanted defibrillator: a matter of definition. Ann NoninvasiveElectrocardiol. 2007;12:375–82. 2. Wood MA, Simpson PM, Stambler BS, Herre JM, Bernstein RC, Ellenbogen KA. Long-term temporal patterns of ventricular tachyarrhythmias. Circulation. 1995;91:2371–7. 3. Villacastin J, Almendral J, Arenal A, Albertos J, Ormaetxe J, Peinado R, Bueno H, Merino JL, Pastor A, Medina O, Tercedor L, Jimenez F, Delcan JL. Incidence and clinical significance of multiple consecutive, appropriate, high-energy discharges in patients with implanted cardioverter-defibrillators. Circulation. 1996;93:753–62. 4. Nademanee K, Taylor R, Bailey WE, Rieders DE, Kosar EM. Treating electrical storm: sympathetic blockade versus advanced cardiac life support-guided therapy. Circulation. 2000;102:742–7. 5. Bansch D, Oyang F, Antz M, Arentz T, Weber R, Val-Mejias JE, Ernst S, Kuck KH. Successful catheter ablation of electrical storm after myocardial infarction. Circulation. 2003;108:3011–6. 6. Bansch D, Bocker D, Brunn J, Weber M, Breithardt G, Block M. Clusters of ventricular tachycardias signify impaired survival in patients with idiopathic dilated cardiomyopathy and implantable cardioverter defibrillators. J Am Coll Cardiol. 2000;36:566–73. 7. Ueda A, Fukamizu S, Soejima K, Tejima T, Nishizaki M, Nitta T, Kobayashi Y, Hiraoka M, Sakurada H. Clinical and electrophysiological characteristics in patients with sustained monomorphic reentrant ventricular tachycardia associated with dilated-phase hypertrophic cardiomyopathy. Europace. 2012;14:734–40. 8. Strohmer B, Schernthaner C, Pichler M. Multiple appropriate and spurious defibrillator shocks in a patient with right ventricular cardiomyopathy. Int J Cardiol. 2005;102:363–6. 9. Li YG, Gronefeld G, Israel C, Hohnloser SH. Catheter ablation of frequently recurring ventricular fibrillation in a patient after aortic valve repair. J Cardiovasc Electrophysiol. 2004;15:90–3. 10. Kozluk E, Gaj S, Kiliszek M, Lodzinski P, Piatkowska A, Opolski G. Efficacy of catheter ablation in patients with an electrical storm. Kardiol Pol. 2011;69:665–70. 11. Flores-Ocampo J, Nava S, Marquez MF, Gomez-Flores J, Colin L, Lopez A, Celaya M, Trevino E, Gonzalez-Hermosillo JA, Iturralde P. Clinical predictors of ventricular arrhythmia storms in chagas cardiomyopathy patients with implantable defibrillators. Arch Cardiol Mex. 2009;79:263–7. 12. Yudi M, Batra R. A case of aborted sudden cardiac death and consequent extreme electrical storm secondary to a metastatic cardiac tumor. Pacing Clin Electrophysiol. 2013;36:e125. 13. Haissaguerre M, Shoda M, Jais P, Nogami A, Shah DC, Kautzner J, Arentz T, Kalushe D, Lamaison D, Griffith M, Cruz F, de Paola A, Gaita F, Hocini M, Garrigue S, Macle L, Weerasooriya R, Clementy J. Mapping and ablation of idiopathic ventricular fibrillation. Circulation. 2002;106:962–7. 14. Maury P, Hocini M, Haissaguerre M. Electrical storms in Brugada syndrome: review of pharmacologic and ablative therapeutic options. Ind Pac Electr J. 2005;5:25–34.
291 15. Ohgo T, Okamura H, Noda T, Satomi K, Suyama K, Kurita T, Aihara N, Kamakura S, Ohe T, Shimizu W. Acute and chronic management in patients with Brugada syndrome associated with electrical storm of ventricular fibrillation. Heart Rhythm. 2007;4:695–700. 16. Nam GB, Ko KH, Kim J, Park KM, Rhee KS, Choi KJ, Kim YH, Antzelevitch C. Mode of onset of ventricular fibrillation in patients with early repolarization pattern vs. Brugada syndrome. Eur Heart J. 2010;31:330–9. 17. Takeuchi T, Sato N, Kawamura Y, Takahashi F, Sato M, Kikuchi K, Akasaka N, Go K, Fujimoto K, Hasebe N. A case of a short-coupled variant of torsades de pointes with electrical storm. Pacing Clin Electrophysiol. 2003;26:632–6. 18. Saxon LA, Shannon K, Wetzel GT, Endler LK, Klitzner TS. Familial long QT syndrome: electrical storm and implantable cardioverter device therapy. Am Heart J. 1996;131:1037–9. 19. Fagundes A, DE Magalhaes LP, Russo M, Xavier E. Pharmacological treatment of electrical storm in cathecolaminergic polymorphic ventricular tachycardia. Pacing Clin Electrophysiol. 2010;33:e27–31. 20. Srivatsa UN, Ebrahimi R, El-Bialy A, Wachsner RY. Electrical storm: case series and review of management. J Cardiovasc Pharmacol Ther. 2003;8:237–46. 21. Schmidt TD, Muir AJ. A case of electrical storm in a liver transplant patient. Transplant Proc. 2003;35:1437–8. 22. Jaoude SA, Salame E, Azar R, Kassab R. T wave pacing inducing electrical storm and multiple shocks in an ICD-recipient: a novel complication of the automatic gain control function. J Interv Card Electrophysiol. 2003;9:401–3. 23. Gatzoulis KA, Andrikopoulos GK, Apostolopoulos T, Sotiropoulos E, Zervopoulos G, Antoniou J, Brili S, Stefanadis CI. Electrical storm is an independent predictor of adverse long-term outcome in the era of implantable defibrillator therapy. Europace. 2005;7:184–92. 24. Eifling M, Razavi M, Massumi A. The evaluation and management of electrical storm. Tex Heart Inst J. 2011;38:111–21. 25. Viskin S, Belhassen B. Polymorphic ventricular tachyarrhythmias in the absence of organic heart disease: classification, differential diagnosis, and implications for therapy. Prog Cardiovasc Dis. 1998;41:17–34. 26. Credner SC, Klingenheben T, Mauss O, Sticherling C, Hohnloser SH. Electrical storm in patients with transvenous implantable cardioverter-defibrillators: incidence, management and prognostic implications. J Am Coll Cardiol. 1998;32:1909–15. 27. Exner DV, Pinski SL, Wyse DG, Renfroe EG, Follmann D, Gold M, Beckman KJ, Coromilas J, Lancaster S, Hallstrom AP. Electrical storm presages nonsudden death: the antiarrhythmics versus implantable defibrillators (AVID) trial. Circulation. 2001;103:2066–71. 28. Sesselberg HW, Moss AJ, McNitt S, Zareba W, Daubert JP, Andrews ML, Hall WJ, McClinitic B, Huang DT. Ventricular arrhythmia storms in postinfarction patients with implantable defibrillators for primary prevention indications: a MADIT-II substudy. Heart Rhythm. 2007;4:1395–402. 29. Zaugg CE, Wu ST, Barbosa V, Buser PT, Wikman-Coffelt J, Parmley WW, Lee RJ. Ventricular fibrillation-induced intracellular Ca2+ overload causes failed electrical defibrillation and post-shock reinitiation of fibrillation. J Moll Cell Cardiol. 1998;30:2183–92. 30. Joglar JA, Kessler DJ, Welch PJ, Keffer JH, Jessen ME, Hamdan MH, Page RL. Effects of repeated electrical defibrillations on cardiac troponin I levels. Am J Cardiol. 1999;83:270–2, A276. 31. Janse MJ, Cinca J, Morena H, Fiolet JW, Kleber AG, de Vries GP, Becker AE, Durrer D. The “border zone” in myocardial ischemia. An electrophysiological, metabolic, and histochemical correlation in the pig heart. Circ Res. 1979;44:576–88. 32. Boyden PA, Barbhaiya C, Lee T, ter Keurs HE. Nonuniform Ca2+ transients in arrhythmogenic Purkinje cells that survive in the infarcted canine heart. Cardiovasc Res. 2003;57:681–93. 33. Maruyama M, Joung B, Tang L, Shinohara T, On YK, Han S, Choi EK, Kim DH, Shen MJ, Weiss JN, Lin SF, Chen PS. Diastolic
292
34. 35.
36. 37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
M. Maruyama and T. Yamamoto intracellular calcium-membrane voltage coupling gain and postshock arrhythmias: role of Purkinje fibers and triggered activity. Circ Res. 2010;106:399–408. Tsuji Y. Electrical storm and calcium signaling: a review. J Electrocardiol. 2011;44:725–9. Pogwizd SM, Schlotthauer K, Li L, Yuan W, Bers DM. Arrhythmogenesis and contractile dysfunction in heart failure: roles of sodium-calcium exchange, inward rectifier potassium current, and residual beta-adrenergic responsiveness. Circ Res. 2001;88:1159–67. Cordeiro JM, Spitzer KW, Giles WR. Repolarizing K+ currents in rabbit heart Purkinje cells. J Physiol. 1998;508(Pt 3):811–23. Ogawa M, Morita N, Tang L, Karagueuzian HS, Weiss JN, Lin SF, Chen PS. Mechanisms of recurrent ventricular fibrillation in a rabbit model of pacing-induced heart failure. Heart Rhythm. 2009;6:784–92. Burashnikov A, Antzelevitch C. Late-phase 3 EAD. A unique mechanism contributing to initiation of atrial fibrillation. Pacing Clin Electrophysiol. 2006;29:290–5. Chua S-K, Chang P-C, Maruyama M, Turker I, Shinohara T, Shen M, Chen Z, Shen C, Rubart M, Lopshire J, Ogawa M, Weiss J, Lin S-F, Ai T, Chen P-S. Small-conductance calcium-activated potassium channel and recurrent ventricular fibrillation in failing rabbit ventricles. Circ Res. 2011;108:971–9. Maruyama M, Chua S-K, Ai T, Park H-W, Lee Y-S, Shen MJ, Chang P-C, Lin S-F, Chen P-S. Mechanisms of recurrent spontaneous ventricular fibrillation in a rabbit model of electrical storm. Circulation. 2011;124:A8784. Cerrone M, Noujaim SF, Tolkacheva EG, Talkachou A, O’Connell R, Berenfeld O, Anumonwo J, Pandit SV, Vikstrom K, Napolitano C, Priori SG, Jalife J. Arrhythmogenic mechanisms in a mouse model of catecholaminergic polymorphic ventricular tachycardia. Circ Res. 2007;101:1039–48. Maruyama M, Lin S-F, Xie Y, Chua S-K, Joung B, Han S, Shinohara T, Shen MJ, Qu Z, Weiss JN, Chen P-S. Genesis of phase-3 early afterdepolarizations and triggered activity in acquired long QT syndrome. Circ Arrhythm Electrophysiol. 2011;4:103–11. Choi BR, Burton F, Salama G. Cytosolic Ca2+ triggers early afterdepolarizations and torsade de pointes in rabbit hearts with type 2 long QT syndrome. J Physiol. 2002;543:615–31. Kern KB, Elchisak MA, Sanders AB, Badylak SF, Tacker WA, Ewy GA. Plasma catecholamines and resuscitation from prolonged cardiac arrest. Crit Care Med. 1989;17:786–91. Burjorjee JE, Milne B. Propofol for electrical storm; a case report of cardioversion and suppression of ventricular tachycardia by propofol. Can J Anaesth. 2002;49:973–7. Mahajan A, Moore J, Cesario DA, Shivkumar K. Use of thoracic epidural anesthesia for management of electrical storm: a case report. Heart Rhythm. 2005;2:1359–62. Watanabe H, Chopra N, Laver D, Hwang HS, Davies SS, Roach DE, Duff HJ, Roden DM, Wilde AA, Knollmann BC. Flecainide prevents catecholaminergic polymorphic ventricular tachycardia in mice and humans. Nat Med. 2009;15:380–3. Dorian P, Cass D, Schwartz B, Cooper R, Gelaznikas R, Barr A. Amiodarone as compared with lidocaine for shock-resistant ventricular fibrillation. N Engl J Med. 2002;346:884–90. Zipes DP, Camm AJ, Borggrefe M, Buxton AE, Chaitman B, Fromer M, Gregoratos G, Klein G, Moss AJ, Myerburg RJ, Priori SG, Quinones MA, Roden DM, Silka MJ, Tracy C, Smith Jr SC, Jacobs AK, Adams CD, Antman EM, Anderson JL, Hunt SA, Halperin JL, Nishimura R, Ornato JP, Page RL, Riegel B, Blanc JJ, Budaj A, Dean V, Deckers JW, Despres C, Dickstein K, Lekakis J, McGregor K, Metra M, Morais J, Osterspey A, Tamargo JL, Zamorano JL. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: A report of the American college of cardiology/American heart association task force and the European society of cardiology committee for practice guidelines (writing committee to develop guidelines for
50.
51.
52.
53. 54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
management of patients with ventricular arrhythmias and the prevention of sudden cardiac death). J Am Coll Cardiol. 2006;48: e247–346. Kudenchuk PJ, Cobb LA, Copass MK, Cummins RO, Doherty AM, Fahrenbruch CE, Hallstrom AP, Murray WA, Olsufka M, Walsh T. Amiodarone for resuscitation after out-of-hospital cardiac arrest due to ventricular fibrillation. N Engl J Med. 1999;341:871–8. Tzivoni D, Banai S, Schuger C, Benhorin J, Keren A, Gottlieb S, Stern S. Treatment of torsade de pointes with magnesium sulfate. Circulation. 1988;77:392–7. Bailie DS, Inoue H, Kaseda S, Ben-David J, Zipes DP. Magnesium suppression of early afterdepolarizations and ventricular tachyarrhythmias induced by cesium in dogs. Circulation. 1988;77:1395–402. Khan IA. Long QT, syndrome: diagnosis and management. Am Heart J. 2002;143:7–14. Wang DW, Crotti L, Shimizu W, Pedrazzini M, Cantu F, De Filippo P, Kishiki K, Miyazaki A, Ikeda T, Schwartz PJ, George Jr AL. Malignant perinatal variant of long-QT syndrome caused by a profoundly dysfunctional cardiac sodium channel. Circ Arrhythm Electrophysiol. 2008;1:370–8. Mok NS, Chan NY, Chiu AC. Successful use of quinidine in treatment of electrical storm in Brugada syndrome. Pacing Clin Electrophysiol. 2004;27:821–3. Carbucicchio C, Santamaria M, Trevisi N, Maccabelli G, Giraldi F, Fassini G, Riva S, Moltrasio M, Cireddu M, Veglia F, Della Bella P. Catheter ablation for the treatment of electrical storm in patients with implantable cardioverter-defibrillators: Short- and longterm outcomes in a prospective single-center study. Circulation. 2008;117:462–9. Kozeluhova M, Peichl P, Cihak R, Wichterle D, Vancura V, Bytesnik J, Kautzner J. Catheter ablation of electrical storm in patients with structural heart disease. Europace. 2011;13:109–13. Stevenson WG, Sager P, Nademanee K, Hassan H, Middlekauff HR, Saxon LA, Wiener I. Identifying sites for catheter ablation of ventricular tachycardia. Herz. 1992;17:158–70. Schreieck J, Zrenner B, Deisenhofer I, Schmitt C. Rescue ablation of electrical storm in patients with ischemic cardiomyopathy: a potential-guided ablation approach by modifying substrate of intractable, unmappable ventricular tachycardias. Heart Rhythm. 2005;2:10–4. Haqqani HM, Marchlinski FE. Electrophysiologic substrate underlying postinfarction ventricular tachycardia: characterization and role in catheter ablation. Heart Rhythm. 2009;6:S70–6. Haissaguerre M, Extramiana F, Hocini M, Cauchemez B, Jais P, Cabrera JA, Farre G, Leenhardt A, Sanders P, Scavee C, Hsu LF, Weerasooriya R, Shah DC, Frank R, Maury P, Delay M, Garrigue S, Clementy J. Mapping and ablation of ventricular fibrillation associated with long-QT and Brugada syndromes. Circulation. 2003;108:925–8. Szumowski L, Walczak F, Przybylski A, Maryniak A, Szufladowicz E, Derejko P, Bieganowska K, Bodalski R, Orczykowski M, Sterlinski M, Miszczak-Knecht M, Szwed A. Ablation of a catecholaminergic polymorphic VT and VF originating from Purkinje fibers–a case report. Kardiol Pol. 2007;65:319–26. Wathen MS, DeGroot PJ, Sweeney MO, Stark AJ, Otterness MF, Adkisson WO, Canby RC, Khalighi K, Machado C, Rubenstein DS, Volosin KJ. Prospective randomized multicenter trial of empirical antitachycardia pacing versus shocks for spontaneous rapid ventricular tachycardia in patients with implantable cardioverterdefibrillators: pacing fast ventricular tachycardia reduces shock therapies (PainFree RxII) trial results. Circulation. 2004;110:2591–6. Wilkoff BL, Williamson BD, Stern RS, Moore SL, Lu F, Lee SW, Birgersdotter-Green UM, Wathen MS, Van Gelder IC, Heubner BM, Brown ML, Holloman KK. Strategic programming of detection and therapy parameters in implantable cardioverterdefibrillators reduces shocks in primary prevention patients: results from the PREPARE (primary prevention parameters evaluation) study. J Am Coll Cardiol. 2008;52:541–50.
Electrical Storm: Clinical Management
23
Sofia Metaxa, Spyridon Koulouris, and Antonis S. Manolis
Abstract
Electrical storm (ES) is defined as three or more sustained episodes of ventricular tachycardia (VT), ventricular fibrillation (VF), or appropriate implantable cardioverter-defibrillator (ICD) therapies during a period of 24 h. Electrical storm is a life-threatening situation presenting during the acute phase of myocardial infarction or in patients with various forms of ischemic or nonischemic cardiomyopathy. It requires hospitalization to ensure management of hemodynamically unstable patients and optimization of pharmacologic or non-pharmacologic therapy. Certain triggers or risk factors have been identified for patients presenting with ES, and, in general, ES has been associated with increased mortality and might be an independent risk factor for cardiac death. The cornerstone of ES treatment is the reduction of elevated sympathetic tone by maximizing the dose of beta-blockers, usually in combination with amiodarone and other antiarrhythmic drugs or invasive adrenergic blockade and implantation of an intra-aortic balloon pump. The implantation of ICDs for primary and secondary prevention reduces mortality in patients at high risk for arrhythmic death, yet the rate of ES recurrences is high during follow-up, probably due to advanced structural heart disease. Advances in technology and in our understanding of ventricular tachycardia substrates have led to suppression of malignant arrhythmias by catheter ablation therapy and resynchronization therapy, with acceptable efficacy and safety.
Definition The term “electrical storm” (ES) was introduced in the 1990s to describe a life-threatening cardiac syndrome involving incessant or frequently recurrent ventricular fibrillation (VF) or hemodynamically destabilizing ventricular tachycardia (VT) [1, 2]. It is an emergency medical condition associated with increased mortality, requiring electrical cardioversion or defibrillation and treatment of underlying causes in the intensive care unit. Electrical storm is defined as three or more separate sustained episodes of VT, VF, or appropriate implantable cardioverter-defibrillator (ICD) electrical therapies (antitachycardia pacing and/or shocks) during a period of 24 h [3–5]. Nowadays, with the availability and proven efficacy of ICDs for primary and secondary prevention of sudden cardiac S. Metaxa, MD • S. Koulouris, MD • A.S. Manolis, MD (*) Department of Cardiology, Evagelismos General Hospital of Athens, Athens, Greece e-mail:
[email protected] A.S. Kibos et al. (eds.), Cardiac Arrhythmias, DOI 10.1007/978-1-4471-5316-0_23, © Springer-Verlag London 2014
death (SCD), ES does not necessarily imply hemodynamic instability since antitachycardia pacing (ATP) or shock delivered by the ICD device may prevent the hemodynamic compromise of these patients. An inappropriate intervention of the ICD does not count for the episodes defining an ES. On the other hand, the episodes of VT/VF should be intermittent (Fig. 23.1), meaning that the persistence of the ventricular arrhythmia after an unsuccessful intervention of the ICD is not regarded as a second episode. Moreover, when sustained VT resumes immediately (≥1 sinus cycle and within 5 min) after a technically successful therapy, it is regarded as a severe form of ES, while repetitive VTs within the first week after ICD implantation should not be considered as an ES [6].
Incidence, Triggers, Risk Factors, and Prognosis Over the last decades, several studies, which have been carried out to determine the incidence, triggers, and risk factors of ES in various populations, reported highly variable results 293
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Fig. 23.1 Electrical storm in an ICD patient with ischemic cardiomyopathy
(Table 23.1). Electrical storm tends to develop in the presence of myocardial ischemia or worsening heart failure, and it is estimated to occur in 10–20 % of ICD recipients, depending mainly on the duration of the observational study period. The reported incidence of ES in the ICD patients varies from 4 % (primary prevention) to 10–28 % (secondary prevention) [20–22]. Approximately 50–70 % of ICD patients receive appropriate device-based therapies within 2 years following ICD implantation, and the onset of ES after an ICD implan-
tation varies according to myocardial substrate, pharmacologic treatment, and indications for device implantation. A number of well-known precipitating factors increase the electrical instability of the heart, e.g., myocardial ischemia, electrolyte disturbances, decompensation of heart failure, fever, hyperthyroidism, and proarrhythmic side effects of antiarrhythmic drugs. Although frequently undetectable, transient aberrations in the electrophysiological substrate of affected patients may occur. Credner et al. [5] demonstrated
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Electrical Storm: Clinical Management
Table 23.1 Incidence of electrical storm Author (ref) Arya et al. [7] Brigadeau et al. [8] Bansch et al. [9] Credner et al. [5] Exner et al. [4] Fries et al. [10] Gasparini et al. [11] Gatzoulis et al. [12] Greene et al. [13] Hohnloser et al. [14] Sesselberg et al. [15] Stuber et al. [16] Verma et al. [17] Villacastin et al. [18] Wood et al. [19]
Patients 126 307 106 136 457 119 631 169 222 633 719 214 2,028 80 31
Definition (VT/VF) >3 >2 >3 >3 >3 >2 >3 >3 >3 >3 >3 >3 >2 >2 >3
that triggers for ES can be identified in 26 % of patients, and Hohnloser et al. [14] (SHIELD trial) found that ES was precipitated by new or worsened congestive heart failure in 9 % and by electrolyte disturbances in 4 % of patients. Nevertheless, certain trials report that triggers are identifiable in 65 % or even 71 % of patients presenting with an ES [9, 13], underlying the role of adrenergic activation (increased incidence during daytime hours, patients with reduced baroreflex sensitivity), emotional stress, and seasonal occurrence (winter and summer preponderance). Apart from conflicting results about triggers, risk factors for ES are also difficult to identify. Brigadeau et al. [8] reported that patients predisposed to ES are those with severely compromised left ventricular ejection fraction (LVEF), chronic renal failure (CRF), older age, VT as presenting arrhythmia, and absence of lipid-lowering drugs. Ventricular fibrillation as presenting arrhythmia and, surprisingly enough, diabetes mellitus appears more frequently in the ES-free patients, although such a paradoxical effect of diabetes was argued in the SCDHeFT study [23]. The relation of CRF with ES has also been demonstrated in patients admitted in the coronary care unit by Soman et al. [24]; a relative risk 2.07 of sustained VT was found for patients with CRF compared with patients with normal renal function, while patients with CRF and prior myocardial infarction had a higher arrhythmic mortality. Patients experiencing ES have a poor outcome, suggesting that ES might be an independent risk factor for cardiac death. In the AVID trial, patients with ES had an increased risk of sudden noncardiac death, and in the MADIT-II sub-study, patients with ES had a 7.4-fold higher risk of death during the first 3 months after the ES than patients without ES [20]. It is unclear whether ES contributes directly to a poor outcome or it is simply an epiphenomenon of advanced structural heart disease; shocks may provoke myocardial damage, inflammation, and remodeling leading to progression of heart failure.
Follow-up (months) 14.3 ± 10 28 ± 10 33 ± 23 13 ± 7 31 ± 13 36 ± 18 19 ± 11 33 ± 26 34 ± 31 2–12.3 48 39.6 ± 26.4 22 ± 5 21 ± 19 7.5 ± 6.1
Incidence (%) 14 40 28 10 20 60 7 19 18 23 4 24 10 20 10
On the other hand, malignant arrhythmias may constitute the initial manifestation of irreversible heart failure [21].
Clinical Characteristics and Electrocardiographic Classification of Electrical Storm Electrical storm has been described during the acute phase of myocardial infarction (MI), in patients with postinfarction coronary artery disease and in various other forms of cardiomyopathy, valvular disease, surgically corrected congenital heart disease, and genetically determined cardiac diseases, e.g., Brugada syndrome [22]. The clinical presentation is often dramatic, involving cardiac arrest or major symptoms like palpitations, dizziness, and often syncope. Admission to the hospital is the most important step in the care of ES patients (required in approximately 80 % of patients, 100 % for patients with >3 shocks) [9] to ensure critical care management of a compromised airway, post-shock bradycardia, hypotension, ischemia, and defibrillation of symptomatic or hemodynamically unstable patients. Patients who are hemodynamically stable can be treated with antiarrhythmic medications, while patients with poor LVEF or rapid VT may require multiple electrical cardioversions or defibrillations. According to the surface electrocardiogram (ECG), ES can present with one of the three following major morphologies: monomorphic VT (86–97 %), polymorphic VT, and VF which are unusual cases (1–7 %) [6, 20].
Monomorphic Ventricular Tachycardia Monomorphic VT occurs when ventricular activation sequence is the same without any variation in the QRS
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complexes. It presents in ischemic or nonischemic cardiomyopathy due to electrical wave front reentry around a fixed anatomical barrier, most commonly scar tissue after MI. It does not require active ischemia as a trigger. The burden of ventricular arrhythmias is higher when inadequate reperfusion or large areas of infarction are present. The surface ECG morphology depends upon the location of the scar and the exit site into the ventricle. The clinical presentation of monomorphic VT depends upon ventricular rate, LV function, presence of heart failure, loss of atrioventricular synchrony, and the pattern of ventricular activation [25]. It is usually managed pharmacologically with β-blockers and amiodarone.
Polymorphic Ventricular Tachycardia Polymorphic VT is characterized by beat-to-beat variations in the QRS complexes and is associated with a normal or a prolonged QT interval in sinus rhythm. It usually appears in acute ischemic syndromes (during the first 72 h of ischemia, unless the patient had a previous MI which created a substrate for reentry), acute myocarditis, or hypertrophic cardiomyopathy. It may also occur in the absence of organic heart disease. During an acute MI, various mechanisms (ischemia, altered membrane potential, triggered activity, necrosis, or scar formation) result in polymorphic VT, and the most effective treatment is to abolish ischemia with emergency coronary revascularization, thrombolytic agents, and antiischemic/antiplatelet agents. In addition, the use of betablockers and certain antiarrhythmic agents (lidocaine, amiodarone) has been proven of great value. Patients with polymorphic VT should have their baseline ECG carefully evaluated for a prolonged QT interval. Torsades de pointes is pause-dependent polymorphic VT with a long QT interval associated with certain risk factors like female gender, bradycardia, heart block, QT-prolonging drugs (sotalol, ibutilide, quinidine, haloperidol, methadone, erythromycin, etc.), hypokalemia, hypomagnesemia, and inherited long QT syndrome. In the case of bradycardia or heart block, torsades de pointes should be managed with temporary overdrive pacing and implantation of a permanent pacemaker in refractory cases. Intravenous magnesium administration is a reasonable therapy for polymorphic VT with a long QT interval along with potassium repletion (serum level above 4.5 mmol/L).
Ventricular Fibrillation VF is characterized by chaotic activation on ECG which may recur repeatedly despite defibrillation. When VF presents as ES, mortality rates are high (85–97 %) and ischemia is the
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primary related mechanism. ES associated with Brugada syndrome is a seldom reported, potentially lethal, event. Brugada syndrome accounts for 4 % of all sudden deaths and for 20 % of sudden deaths in those without structural heart disease and is one of the leading causes of sudden death in subjects under the age of 40 years. It is an inherited electrical disorder caused by a defective cardiac sodium-channel gene, diagnosed clinically by its characteristic ECG patterns. It requires aggressive treatment when presented as an ES [26]. In most of the cases, continuous infusion of isoproterenol terminates ES and completely normalizes ST-segment elevation [27]. Oral antiarrhythmic therapy may be required because attempts to wean patients from isoproterenol may result in recurrent VF. Although class I antiarrhythmic agents are potent sodium-channel blockers and are contraindicated in patients with Brugada syndrome, yet quinidine has prevented ventricular arrhythmias in these patients and is a recommended therapy for refractory cases of ES caused by Brugada syndrome [20].
Pharmacologic Therapy for Electrical Storm The clinical management of ES can be very challenging. Various pharmacologic therapies have been proposed, yet mortality remains extremely high.
Adrenergic Blockade The cornerstone of ES treatment is the reduction of elevated sympathetic tone by beta-blockers or non-pharmacologic interventions. It has been known for years that ischemia or infarction and reperfusion can trigger cardiac reflexes (acute inferoposterior MI may result in bradycardia, whereas anterior MI more frequently provokes tachycardia) [28]. Nevertheless, ischemia can also inhibit these reflexes; it has been reported that several minutes after the initiation of transmural myocardial ischemia, sympathetic reflexes become interrupted or attenuated, while non-transmural ischemia attenuates vagal vasodepressor response [29]. Along with ischemia-produced efferent sympathetic denervation, a complex mechanism is responsible for the sympathetic supersensitivity [30]. Sympathetic supersensitivity elicits inhomogeneous autonomic and electrophysiological changes and makes the heart more vulnerable to the induction of ventricular arrhythmias [31]. Experimental studies have shown that beta-blockers increase the fibrillation threshold sixfold under ischemic and nonischemic conditions, and potent nonselective beta-blockers have been proven more effective in decreasing sympathetic outflow, perhaps because β2-receptors prevail in the failing hearts [32]. According to Lombardi et al. [33], sympathetic activity is reflexively increased during myocardial ischemia, resulting in
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decreased VF threshold in the case of coronary artery occlusion, and Schwartz et al. [34] demonstrated that pharmacologic or surgical antiadrenergic interventions prevent sudden cardiac death in high-risk post-MI patients. Nademanee et al. [35] investigated sympathetic blockade (esmolol, propranolol, left stellate ganglion blockade) versus the antiarrhythmic therapy (lidocaine, procainamide, bretylium) recommended by the American Heart Association Advanced Cardiac Life Support (ACLS) guidelines and found that short-term outcome is much better in patients treated with sympathetic blockade (1-week survival 82 % for sympathetic blockade and 22 % for antiarrhythmic therapy), while patients who survived the first week after the onset of ES continued to do well during the 1-year follow-up period (1-year survival 67 % for sympathetic blockade and 5 % for antiarrhythmic therapy). The finding that sympathetic blockade dramatically reduces mortality rates is in accordance with the evidence that beta-blockers prevent ventricular tachyarrhythmias in post-MI patients, while the Beta-Blocker Heart Attack Trial confirmed that the more severe the left ventricular dysfunction, the more beneficial β-blockade is [36, 37]. Various beta-blockers have been studied in the treatment of ES. Metoprolol (oral β1-blocker) inhibits ventricular arrhythmias in patients with acute MI [38, 39] and should be given in high doses (>200 mg/day) [40]. Propranolol, an oral nonselective beta-blocker, has been proved more effective than metoprolol in establishing electrical stability (doses ~400 mg/day) [41] but requires careful monitoring because it can exacerbate heart failure in patients with poor systolic function. Esmolol and landiolol are selective β1-blockers with short plasma half-lives (esmolol 9 min, landiolol 4 min) given intravenously, suitable for emergency medical care of ES [35, 42]. Carvedilol (multi-acting β-blocker that blocks α-receptors) and bisoprolol (pureβ1-blocker) are also appropriate oral beta-blockers for patients in ES [42]. It has been suggested that the combination of a beta-blocker with amiodarone is the mainstay of therapy for patients with ES. Indeed in the OPTIC trial which included high-risk ICD patients, electrical discharges were delivered in 38.5 % of patients on beta-blockers, in 24.3 % of patients on sotalol and in only 10.3 % of patients who were taking beta-blocker combined with amiodarone [20, 35, 42–44].
Antiarrhythmic Agents Amiodarone is widely used in the treatment of ES, for both the termination and the prevention of ES recurrences. The electrophysiological effects of amiodarone are complex. In the acute phase of ES, rapid intravenous administration of amiodarone blocks inward sodium (class I effect) and calcium (class IV effect) currents and has a noncompetitive alpha- and beta-blockade effect (class II effect), while during
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chronic administration, it inhibits outward potassium currents (class III effect), resulting in prolongation of action potential duration and prolongation of the effective refractory period [45]. The ARREST and the ALIVE studies were two randomized clinical trials which demonstrated the efficacy of amiodarone in the termination of ventricular arrhythmias. Amiodarone improved survival-to-hospital admission rates in patients who had an ES (VF or pulseless VT) and resolved ES at approximately 60 % [20, 46, 47]. Levine et al. [48] examined 273 hospitalized patients with ES refractory to lidocaine, procainamide, or bretylium therapy and suggested that when amiodarone was given, 46 % of the patients survived for 24 h without other episodes of VT and 12 % of patients responded to the administration of amiodarone plus another agent. Although certain concern has been expressed regarding the increase in defibrillation threshold due to amiodarone, the combination of amiodarone with beta-blocker and mexiletine (class Ib agent, decreases action potential duration by shortening the repolarization phase) particularly in resistant cases seems to be an alternative and effective therapeutic choice [12, 49, 50]. Apart from amiodarone, sotalol is another class III antiarrhythmic agent (a relatively weak β-blocker as well) used to treat patients with ES as monotherapy or in combination with other antiarrhythmic agents [51, 52]. Sotalol was found to be an effective antiarrhythmic agent in the ESVEM trial [53], but in the SWORD trial [54] d-sotalol was associated with excess mortality for patients surviving MI with left ventricular dysfunction, and thus, its clinical use since then has been rather limited. Nifekalant hydrochloride is a novel class III agent developed in Japan, which has attracted much attention in recent years due to its efficacy in suppressing ventricular tachyarrhythmias without aggravating the patient’s hemodynamic stability. It selectively blocks IKr, can only be used intravenously, has a relatively short half-life, has no negative inotropic effects, and does not affect cardiac conduction. The true functional mechanism of nifekalant is still unclear; in electrophysiological studies nifekalant has been shown to inhibit or prevent reentrant VT in humans and aggravate adrenaline-induced arrhythmias (due to abnormal automaticity and/or triggered activity) [55]. In clinical practice, nifekalant has been proven effective and safe for severe ES cases refractory to amiodarone [56–58]. Azimilide is another class III antiarrhythmic agent, developed for treating both supraventricular and ventricular tachyarrhythmias, that prolongs repolarization in a dosedependent manner by increasing the action potential duration, QT interval, and effective refractory period [59]: in the SHIELD trial, azimilide was proven effective in reducing the incidence of ES in patients with implantable cardioverterdefibrillators (reduction of recurrent ES by 37 % and 55 % in doses of 75 and 125 mg/day, respectively) [14, 60]. Bretylium, a class III antiarrhythmic which blocks K+ channels and the
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release of noradrenaline from nerve terminals, was found effective in the treatment of ES in certain cases, but its use is not currently recommended due to its frequent adverse effects (especially hypotension) [61, 62]. According to the 2006 American College of Cardiology/ American Heart Association guidelines for treating ventricular arrhythmias, intravenous lidocaine (class Ib) has a IIb recommendation for the treatment of polymorphic VT associated with ischemia [63]. On the other hand, procainamide (class Ia), which blocks fast sodium channels and prolongs cardiac action potential, is a reasonable choice for terminating monomorphic VT but may cause hypotension or prolong the width of QRS complex by more than 50 % resulting in the discontinuation of the drug [20]. Although ES is a rare phenomenon in Brugada syndrome, there are data suggesting that isoproterenol or orciprenaline (β-adrenergic stimulators) are effective in terminating ES and improving the electrocardiographic pattern of Brugada syndrome, while quinidine/ hydroquinidine prevent the recurrence of VF during the electrophysiological study [26, 64–66]. Apart from adrenergic blockade and antiarrhythmic treatment, sedation or even general anesthesia/intubation is involved in the treatment of ES due to induction of central inhibition of the cardiac sympathetic drive. The physical and emotional stress experienced during ES often perpetuate arrhythmias; short-acting anesthetics such as propofol, benzodiazepines, and other agents of general anesthesia have been associated with conversion and suppression of ES [67, 68]. Further studies are needed to determine which sedative and anesthetic agents should be used and whether they have direct antiarrhythmic effects.
Non-pharmacologic Therapy for Electrical Storm The suppression of malignant arrhythmias is achieved by various non-pharmacologic measures including the implantable cardioverter-defibrillator, radiofrequency catheter ablation, cardiac resynchronization therapy, intra-aortic balloon pumping, and cardiac sympathetic denervation.
Implantable Cardioverter-Defibrillators Sudden cardiac death (SCD) is a common cause of death throughout the world. The implantation of ICDs for primary prevention of SCD affects two major patient groups: patients whose LVEF is less than or equal to 40 % as a result of prior MI, with spontaneous non-sustained VT and sustained monomorphic VT (SMVT) inducible by EP testing [69], and patients whose LVEF is less than 35 % as a result of MI (which has occurred at least 40 days earlier) with NYHA functional class
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II or III symptoms [23]. For patients experiencing cardiac arrest due to VF (not within the first 48 h of acute MI) or sustained VT, the implantation of an ICD refers to secondary prevention [63]. Although ICDs reduce mortality in patients at high risk for arrhythmic death compared with antiarrhythmic drugs, recurrent arrhythmias occur in 40–60 % of ICD recipients over the initial 3 years of follow-up, and ES ranges from 4 % (primary prevention) to 10–28 % (secondary prevention) [70]. Various studies have demonstrated that ES is not rare in the “real world” population with ICDs [5]. Patients with an ICD have increased risk of developing ES due to their typically impaired left ventricular systolic function or history of previous VT. The rate of ES recurrences is high (50.8 %) within the first year after the initial event and its incidence is 6.6 % during an average follow-up of 4.5 years [70]. Data suggest that VF as the index arrhythmia or a structurally normal heart protect against ES, while dilated cardiomyopathy and old age (patients above the age of 65 years revealed a 2.6-fold higher risk) are independent predictors of ES [70, 71]. Although the development of VT/VF is not associated with increased risk of subsequent death, ES is an important and independent marker of increased mortality, particularly within the first 3 months after its occurrence. Evidence suggests that multiple shocks due to ES lead to elevation of cardiac troponin levels, indicative of minor degrees of myocardial injury, inflammation, and fibrosis which are associated with progressive ventricular dysfunction, cardiac apoptosis, and arrhythmia facilitation contributing to excess mortality [4]. Soon after the occurrence of ES in a patient who carries an ICD, interpretation of stored electrograms should be performed depending on device filters, amplifiers, and compression algorithms in order to determine inappropriate therapies (e.g., supraventricular tachyarrhythmia, noise). In some cases, it is difficult to distinguish VT from VF in the absence of a surface ECG because the type of arrhythmia is mainly classified according to its morphology (monomorphic signals or not) and cycle length. ICD reprogramming is an issue of major importance; data suggest that antitachycardia pacing (ATP) can successfully terminate a significant percentage of fast VTs in a harmless and pain-free way, providing a good quality of life [72]. Nevertheless, subclinical termination of VT by ATP may lead to an underestimate of the true incidence of ES since the patients do not seek medical assistance or hospitalization after such an event. Other safety features of the device should also be reprogrammed; prolongation of the time window (30 s altered to 2–5 min) to allow spontaneous termination of VT has been proposed, according to the DEFINITE trial which supported the concept that many VT episodes do not need to be treated [73]. Moreover, unnecessary right ventricular pacing in ICD patients may have a detrimental impact upon myocardial contractility functioning, acting as a trigger for ES. This could be prevented by using alternative right ventricular pacing sites and appropriate programming [74]. Apart
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Table 23.2 Catheter ablation therapy Della Bella et al. [77] Carbucicchio et al. [78] Peichl et al. [79] Stevenson et al. [81] Tanner et al. [82] Kozeluhova et al. [80]
Patients 218 95 9 231 63 50
Follow-up (months) 17.3 ± 18.2 22 13 ± 7 6 12 ± 3 18 ± 16
from ICD interrogation, a thorough evaluation of the ICD patient should be performed to decide about other therapeutic strategies including catheter ablation.
Catheter Ablation Therapy Episodes of ES are a marker of increased mortality and worsen the quality of life in patients with structural heart disease and ICDs. Advances in technology and in our understanding of VT substrates allow radiofrequency ablation of VTs of various origins and even of hemodynamically unstable ones, with acceptable efficacy and safety. According to the recent EHRA/ HRS guidelines on catheter ablation (CA) of ventricular arrhythmias, ablation of VT (associated with ES) is recommended for symptomatic sustained monomorphic VT or VT terminated by an ICD, despite antiarrhythmic drug therapy or when antiarrhythmic drugs are not tolerated or desired, and sustained monomorphic VT or VT storm not provoked by a transient reversible cause [75]. Prophylactic VT ablation in patients with ICDs (implanted for primary or secondary prevention) is investigational and only rarely performed. Some type of preprocedural imaging is necessary for patients who undergo ablation therapy; echocardiography, CT/ MRI, coronary angiogram, or recent exercise/pharmacologic stress evaluation will be required to exclude reversible causes and define hemodynamic tolerance during VT. When scarrelated VT is suspected, imaging can be used to characterize the location/extent of the myocardial scar that is likely to contain the VT substrate. Transesophageal or intracardiac echocardiography, for operators experienced with their use, is helpful to detect an LV thrombus. Antiarrhythmic drug therapy should be discontinued for four to five half-lives before the procedure for idiopathic VTs, while patients with significant structural heart disease usually undergo catheter ablation under pharmaceutical therapy; in fact, intravenous amiodarone or procainamide may slow the rate of VT and convert pleomorphic to a more stable monomorphic VT. Careful consideration should be taken to lower the significant risks of ablation, which may include cardiac tamponade (1 %), vascular injury (2 %), thromboembolism, air embolism, damage to the conduction system or to coronary arteries, or decompensation of heart failure. In patients with scar-related VT, particularly after
Acute prevention of VT (%) 71.6 89 89 81 81 84
Recurrence of VT/ES (%) 31.4/– 34/8 –/11 47/– 49 –/26
MI, heart failure accounts for more than one-third of mortality during follow-up after ablation and exceeds 10 % per year in some studies [75]. Multiple VT morphologies are usually inducible in the same patient due to multiple reentry circuit pathways complicating mapping and ablation procedure. Selection of the strategies for ablation is based upon the type and severity of the underlying heart disease, characteristics of the VT, and available technologies. The standard approach is endocardial; few experienced centers perform epicardial ablation; only 21 % of the centers apply epicardial approach initially, 62 % use it after failure of the endocardial approach, and 36 % have never performed epicardial approach [76], while surgical ablation of VT and intracoronary ethanol ablation exist as options but are rather rarely used. The most common ablation strategy is substrate mapping and ablation (frequently used by the 63 % of arrhythmia centers), performed by creation of connecting lines (from scar to anatomical boundaries, between scars or within a scar – 75 % of centers) and by targeting late and fractionated potentials around and within scars (70 %). It is reported that 25 % of the centers frequently perform the ablation with conventional catheters, while modern electroanatomical tools (CARTO or NavX systems) are altogether used by 90 % of centers and noncontact mapping or remote navigation are used only by a minority of them [76]. Different centers report varying outcomes of ablation therapy (Table 23.2) depending on disease severity, stability of VTs for mapping, methods for mapping, and ablation or ablation endpoints [77–79]. Kozeluhova et al. [80] found that catheter ablation was effective in suppression of ES in 84 % of cases but repeated procedures were necessary in 13 out of 50 patients. They defined several predictors of adverse outcome within the first 6 months after the procedure, including severely depressed LVEF, significantly dilated LV, renal insufficiency, and ES recurrence after previous ablation procedure although they underlined that testing of VT inducibility after the procedure is not predictive of ES recurrences during follow-up. The Multicenter Thermocool Ventricular Tachycardia Ablation Trial enrolled 231 patients with recurrent VT for ablation with the use of an electroanatomical mapping system using substrate and/or entrainment mapping approaches [81]; ablation abolished at least one VT in 81 % of patients and all VTs in 49 % of patients, while 47 % of
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patients had recurrent VT during the following 6 months. In 142 patients with an ICD, >75 % reduction of the VT episodes was demonstrated in 67 % of patients. During a 1-year follow-up period, mortality was 15 % (38 % due to ventricular arrhythmias and 35 % due to heart failure). The Euro-VT Study performed catheter ablation in 63 patients with a median of 17 VT episodes in the 6 months prior to ablation and found that the mean number of ICD therapies was decreased from 60 ± 70 prior to ablation to 14 ± 15 6 months after the procedure [82]. According to the findings of the Substrate Mapping and Ablation in Sinus Rhythm to Halt Ventricular Tachycardia (SMASH-VT) multicenter study, 33 % of the control group but only 12 % of the ablation group received appropriate ICD therapy for VT or VF during an average follow-up period of 23 months [83]. Although catheter ablation can be immediately lifesaving for patients with ES, it is not indicated prophylactically; nevertheless, it has been suggested that sustained ST-segment elevation and abnormal Q waves could be a risk factor for ES in patients with structural heart disease leading to empiric ablation, but further studies are needed to confirm such a report [84].
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CRT programming possibly changes activation around the scar, modifies the substrate, and suppresses the arrhythmia. Nordbeck et al. [91] analyzed the incidence of ES in 561 ICD patients and 168 consecutive patients with a CRT-D device with a mean follow-up period of 41 months and concluded that ES was much less common in CRT-D patients than in ICD patients (0.6 % vs 7 %; P < 0.01). They also found that the risk for clustered shocks was clearly elevated for ICD patients with concomitant severe heart failure, but this risk was not elevated for patients treated with CRT-D. Similarly, the TOVA trial demonstrated that class III HF is an important predictor, along with LVEF, of appropriate device discharges in ICD patients [92]. According to Kowal et al. [93] chronic biventricular pacing (BiV) results in reduced incidence of ventricular arrhythmias due to its beneficial electrophysiological properties; 18 patients with coronary artery disease were randomized to right ventricular (RV) versus biventricular (BiV) programmed electrical stimulation (PES), and BiV-PES was found to be associated with a significant reduction in the induction of monomorphic VT but with no significant effect on VF induction.
Intra-aortic Balloon Pump (IABP) Cardiac Resynchronization Therapy Cardiac resynchronization therapy (CRT) has been recommended as a class IA indication by both heart failure (HF) and pacing guidelines for advanced HF patients (NYHA III/ IV) with QRS ≥120 ms, ejection fraction (EF) ≤ 35 %, and sinus rhythm refractory to optimal pharmaceutical treatment [85]. Cardiac resynchronization therapy improves symptoms, exercise capacity, functional class, ventricular function, and ventricular geometry in patients with moderate-to-severe congestive heart failure and ventricular conduction system abnormalities, while the combination of CRT with an ICD (CRT-D) reduces all-cause mortality [86]. Decompensation of heart failure has been identified as a trigger for ES in certain studies but electrophysiological effects of CRT are still poorly understood and need to be further clarified. Some studies demonstrate a decreased incidence of VTs after CRT, but several case reports underline the occurrence of VT, VF, or ES after biventricular pacing managed by conventional therapy or temporary discontinuation of left ventricular pacing. Nevertheless the incidence is low, between 3.4 and 4 %, mainly in patients with ischemic cardiomyopathy, and occurs more frequently within the first hours or days of biventricular pacing [87–89]. Combes et al. [90] presented a case of severe ES after CRT-D implantation treated with atrioventricular delay optimization that led to suppression of VT without the need to turn off LV pacing; it was suggested that LV pacing reverses the direction of transmural activation of LV wall and modifies input to a reentrant circuit leading to VT. Modification of global LV depolarization by modifying
The suppression of malignant arrhythmias is an acceptable indication for placing an intra-aortic balloon pump (IABP). Intra-aortic balloon pumping improves coronary flow, reduces myocardial distention, stabilizes hemodynamic status, and relieves the ischemic substrate and thus potentially influences ventricular irritability by direct and indirect effects [94]. Mechanical support is of potential benefit in patients with end-stage heart failure who poorly tolerate negative inotropic agents and patients under hemodynamic compromise due to the arrhythmia itself or the administration of antiarrhythmic agents. The mechanism by which IABP helps control ES is unclear, but several possible effects have been suggested. Augmentation of coronary blood flow and myocardial oxygen supply reduces the potential for ischemia which contributes to arrhythmogenesis; hemodynamic support reduces adrenergic stimulation and its proarrhythmic effects; and numerous studies in both isolated tissue and intact animal hearts have shown that alterations in preload and afterload result in arrhythmogenesis, leading to the concept of mechanoelectrical feedback [95]. In concordance with such a concept, implantation of a left ventricular assist device was performed successfully as alternative salvage technique for ES caused by an open heart surgery in a 38-year-old man [96].
Invasive Adrenergic Blockade Cardiac sympathetic denervation (CSD) decreases the incidence of ventricular arrhythmias. In humans left CSD may
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be ineffective promoting thus the bilateral CSD which is nevertheless very rarely performed and its safety is largely unknown. Ajijola et al. [97] reviewed six cases undergoing bilateral CSD and observed complete response in 66.7 % of patients, partial response in 16.7 %, and no response in 16.7 %, but serious postoperative complications were observed in two patients (heart failure and poor tolerance of single-lung ventilation during surgery). Left stellate ganglion blockade, a safe and effective procedure used for a variety of chronic pain and vascular syndromes, has been documented as an alternative treatment for drug-resistant ES; apart from decreasing sympathetic activity, it also shortens QTc interval, thus reduces the risk of cardiac arrhythmias [98, 99]. Renal sympathetic denervation, a novel catheter-based technology for treatment of refractory arterial hypertension, has been shown to reduce whole body norepinephrine spillover by 42 % and efferent muscle sympathetic nerve activity by 66 % [100]. Uneka et al. [101] studied two patients who underwent renal denervation leading to reduction of ventricular arrhythmias without any apparent hemodynamic complications, but obviously, only randomized and controlled trials would justify such a promising strategy for clinical use. Conclusion
Electrical or arrhythmic storm is a very challenging and life-threatening clinical event, which presents a daunting array of problems in clinical management. It is characterized by the occurrence of three or more sustained episodes of ventricular tachyarrhythmias or appropriate electrical therapies from an ICD clustering within 24 h. It can occur in the setting of an acute coronary syndrome and in patients who have underlying structural heart disease or an ICD or in those who are afflicted by an inherited syndrome of primary electrical disease. ES has typically a poor prognosis, mostly related to the degree of underlying left ventricular dysfunction and clinical status or progression of heart failure. The initial therapeutic approach aims at electrical cardioversion or use of amiodarone for termination and/or prevention of ES but also at identifying and correcting underlying causes and triggers, including ischemia, decompensation of heart failure, electrolyte imbalances, and blocking the sympathetic nervous system by betablockers. In patients with ICDs, device reprogramming is important with an aim to achieve pain-free electrical therapy such as effective antitachycardia pacing rather than delivering painful shocks. For recurring or drug-refractory VT, transcatheter ablation may be an effective and/or lifesaving therapy to control ES. After the acute phase, the focus is shifted towards optimizing anti-ischemic treatment (including revascularization as needed), heart failure therapy (including applying or upgrading to cardiac resynchronization when appropriate), ICD device programming, and antiarrhythmic drug treatment.
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References 1. Kowey PR. An overview of anti-arrhythmic drug management of electrical storm. Can J Cardiol. 1996;12(Suppl B):3B–8. 2. Dorian P, Cass D. An overview of the management of electrical storm. Can J Cardiol. 1997;13(Suppl A):13A–7. 3. Zipes DP, Camm AJ, Borggrefe M, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College Of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management Of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death). J Am Coll Cardiol. 2006;48:e247–346. 4. Exner DV, Pinski SL, Wyse G, et al. Electrical storm presaged nonsudden death. The antiarrhythmics versus implantable defibrillators (AVID) Trial. Circulation. 2001;103:2066–71. 5. Credner SC, Klingenheben T, Mauss O, Sticherling C, Hohnloser SH. Electrical storm in patients with transvenous implantable cardioverter-defibrillators. J Am Coll Cardiol. 1998;32:1909–15. 6. Israel CW, Barold SS. Electrical storm in patients with an implanted defibrillator: a matter of definition. Ann Noninvasive Electrocardiol. 2007;12:375–82. 7. Arya A, Haghjoo M, Dehghani MR, et al. Prevalence and predictors of electrical storm in patients with implantable cardioverter defibrillators. Am J Cardiol. 2006;97:389–92. 8. Brigadeau F, Kouakam C, Klug D, et al. Clinical predictors and prognostic significance of electrical storm in patients with implantable cardioverter defibrillators. Eur Heart J. 2006;27:700–7. 9. Bansch D, Bocker D, Brunn J, Weber M, Breithardt G, Block M. Clusters of ventricular tachycardia signify impaired survival in patients with idiopathic dilated cardiomyopathy and implantable cardioverter defibrillators. J Am Coll Cardiol. 2000;36:566–73. 10. Fries R, Heisel A, Huwer H, et al. Incidence and clinical significance of short-term recurrent ventricular tachyarrhythmias in patients with implantable cardioverter-defibrillator. Int J Cardiol. 1997;59:281–4. 11. Gasparini M, Lunati M, Landolina M, et al. Electrical storm in patients with biventricular implantable cardioverter defibrillator: incidence, predictors and prognostic implications. Am Heart J. 2008;156:847–54. 12. Gatzoulis KA, Andrikopoulos GK, Apostolopoulos T, et al. Electrical storm is an independent predictor of adverse long-term outcome in the era of implantable defibrillator therapy. Europace. 2005;7:184–92. 13. Greene M, Newman D, Geist M, Paquette M, Heng D, Dorian P. Is electrical storm in ICD patients the sign of a dying heart? Outcome of patients with clusters of ventricular tachyarrhythmias. Europace. 2000;2:263–9. 14. Hohnloser SH, Al-Khalidi HR, Pratt CM, et al., SHock Inhibition Evaluation with AzimiLiDe (SHIELD) Investigators. Electrical storm in patients with an implantable defibrillator: incidence, features and preventive therapy: insights from a randomized trial. Eur Heart J. 2006;27:3027–32. 15. Sesselberg HW, Moss AJ, McNitt S, et al. Ventricular arrhythmia storms in postinfarction patients with implantable defibrillators for primary prevention indications: a MADIT-II substudy. Heart Rhythm. 2007;4:1395–402. 16. Stuber T, Eigenmann C, Delacretaz E. Characteristics and relevance of clustering ventricular arrhythmias in defibrillator recipients. Pacing Clin Electrophysiol. 2005;28:702–7. 17. Verma A, Kilicaslan F, Marrouche NF, et al. Prevalence, predictors and mortality significance of the causative arrhythmia in patients with electrical storm. J Cardiovasc Electrophysiol. 2004;15:1265–70.
302 18. Villacastin J, Almendral J, Arenal A, et al. Incidence and clinical significance of multiple consecutive, appropriate, high-energy discharges in patients with implanted cardioverter-defibrillators. Circulation. 1996;93:753–62. 19. Wood MA, Simpson PM, Stambler BS, Herre JM, Bernstein RC, Ellenbogen KA. Long-term temporal patterns of ventricular tachyarrhythmias. Circulation. 1995;91:2371–7. 20. Eifling M, Razavi M, Massumi A. The evaluation and management of electrical storm. Tex Heart Inst J. 2011;38:111–21. 21. Proietti R, Sagone A. Electrical storm: incidence, prognosis and therapy. Indian Pacing Electrophysiol J. 2011;11:34–42. 22. Gatzoulis K, Sideris S, Kallikazaros I, Stefanadis C. Electrical storm: a new challenge in the age of implantable defibrillators. Hellenic J Cardiol. 2008;49:86–91. 23. Bardy GH, Lee KL, Mark DB, et al., Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) Investigators. Amiodarone or an implantable cardioverter defibrillator for congestive heart failure. N Engl J Med. 2005;352:225–37. 24. Soman SS, Sandberg KR, Borzak S, Hudson MP, Yee J, McCullough PA. The independent association of renal dysfunction and arrhythmias in critically ill patients. Chest. 2002; 122:669–77. 25. Saksena S, Ciccone JM, Craelius W, Pantopoulos D, Rothbart ST, Werres R. Studies on left ventricular function during sustained ventricular tachycardia. J Am Coll Cardiol. 1984;4:501–8. 26. Schweizer PA, Becker R, Katus HA, Thomas D. Successful acute and long-term management of electrical storm in Brugada syndrome using orciprenaline and quinine/quinidine. Clin Res Cardiol. 2010;99:467–70. 27. Ohgo T, Okamura H, Noda T, et al. Acute and chronic management in patients with Brugada syndrome associated with electrical storm of ventricular fibrillation. Heart Rhythm. 2007;4:695–700. 28. Robertson D, Hollister AS, Forman MB, Robertson RM. Reflexes unique to myocardial ischemia and infarction. J Am Coll Cardiol. 1985;5:99B–104. 29. Barber MJ, Mueller TM, Davies BG, Gill RM, Zipes DP. Interruption of sympathetic and vagal-mediated afferent responses by transmural myocardial infarction. Circulation. 1985;72:623–31. 30. Inoue H, Zipes DP. Results of sympathetic denervation in the canine heart: supersensitivity that may be arrhythmogenic. Circulation. 1987;75:877–87. 31. Zipes DP. Influence of myocardial ischemia and infarction on autonomic innervation of heart. Circulation. 1990;82:1095–105. 32. Anderson JL, Rodier HE, Green LS. Comparative effects of betaadrenergic blocking drugs on experimental ventricular fibrillation threshold. Am J Cardiol. 1983;51:1196–202. 33. Lombardi F, Verrier RL, Lown B. Relationship between sympathetic neural activity, coronary dynamics and vulnerability to ventricular fibrillation induced by myocardial ischemia and reperfusion. Am Heart J. 1983;105:958–65. 34. Schwartz PJ, Motolese M, Pollavini G, et al., The Italian Sudden Death Prevention Group. Prevention of sudden cardiac death after a first myocardial infarction by pharmacologic or surgical antiadrenergic interventions. J Cardiovasc Electrophysiol. 1992;3:2–16. 35. Nademanee K, Taylor R, Bailey WE, Rieders DE, Kosar EM. Treating electrical storm: sympathetic blockade versus advanced cardiac life support-guided therapy. Circulation. 2000;102:742–7. 36. Gottlieb SS, McCarter RJ, Vogel RA. Effect of beta-blockade on mortality among high-risk and low-risk patients after myocardial infarction. N Engl J Med. 1998;339:489–97. 37. Chadda K, Goldstein S, Byington R, Curb JD. Effects of propranolol after acute myocardial infarction in patients with congestive heart failure. Circulation. 1986;73:503–10. 38. Ryden L, Ariniego R, Arnman K, et al. A double-blind trial of metoprolol in acute myocardial infarction. Effects on ventricular tachyarrhythmias. N Engl J Med. 1983;308:614–8.
S. Metaxa et al. 39. The MIAMI Trial Research Group. Metoprolol in acute myocardial infarction. Arrhythmias. Am J Cardiol. 1985;56:35G–8. 40. Yu JB, Yang B, Xu DJ, et al. Impact of metoprolol use in the treatment of patients with electrical storm after cardioverter defibrillators implantation. Zhonghua Xin Xue Guan Bing Za Zhi. 2011;39:717–20. 41. Tsagalou EP, Kanakakis J, Rokas S, Anastasiou-Nana MI. Suppression by propranolol and amiodarone of an electrical storm refractory to metoprolol and amiodarone. Int J Cardiol. 2005; 99:341–2. 42. Miwa Y, Ikeda T, Mera H, et al. Effects of landiolol, an ultra-shortacting β1-selective blocker, on electrical storm refractory to class III antiarrhythmic drugs. Circ J. 2010;74:856–63. 43. Pinter A, Dorian P. Approach to antiarrhythmic therapy in patients with ICDs and frequent activations. Curr Cardiol Rep. 2005; 7:376–81. 44. Connoly ST, Dorian P, Roberts RS, Gent M, Bailin S, Fuin ES. Comparison of b-blockers, amiodarone plus b-blockers or sotalol for prevention of shocks from implantable cardioverter defibrillators: the OPTIC study: a randomized trial. JAMA. 2006;295:165–71. 45. Van Herendael H, Dorian P. Amiodarone for the treatment and prevention of ventricular fibrillation and ventricular tachycardia. Vasc Health Risk Manag. 2010;6:465–72. 46. Kudenchuk PJ, Cobb LA, Copass MK, et al. Amiodarone for resuscitation after out-of-hospital cardiac arrest due to ventricular fibrillation. N Engl J Med. 1999;341:871–8. 47. Dorian P, Cass D, Shwartz B, et al. Amiodarone as compared with lidocaine for shock resistant ventricular fibrillation. N Engl J Med. 2002;346:884–90. 48. Levine JH, Massumi A, Scheinman MM, et al. Intravenous amiodarone for recurrent sustained hypotensive ventricular tachyarrhythmias. Intravenous Amiodarone Multicenter Trial Group. J Am Coll Cardiol. 1996;27:67–75. 49. Manolis AG, Katsivas AG, Vassilopoulos C, Tsatiris CG. Electrical storms in an ICD-recipient with 429 delivered appropriate shocks: therapeutic management with antiarrhythmic drug combination. J Interv Card Electrophysiol. 2002;6:91–4. 50. Waleffe A, Mary-Rabine L, Legrand V, Demoulin JC, Kulbertus HE. Combined mexiletine and amiodarone treatment of refractory recurrent ventricular tachycardia. Am Heart J. 1980;100:788–93. 51. Fuchs T, Groysman R, Meilichov I. Use of a combination of class III and class Ic antiarrhythmic agents in patients with electrical storm. Pharmacotherapy. 2008;28:14–9. 52. Furushima H, Chinushi M, Okamura K, et al. Effect of dl-sotalol on mortality and recurrence of ventricular tachyarrhythmias: ischemic compared to nonischemic cardiomyopathy. Pacing Clin Electrophysiol. 2007;30:1136–41. 53. Mason JW. A comparison of seven antiarrhythmic drugs in patients with ventricular tachyarrhythmias: Electrophysiologic Study versus Electrocardiographic Monitoring Investigators. N Engl J Med. 1993;329:452–8. 54. Waldo AL, Camm AJ, deRuyter H, et al. Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction: the SWORD Investigators (Survival With Oral d-Sotalol). Lancet. 1996;348:7–12. 55. Isomoto S, Konoe A, Centurion OA, et al. Electrophysiological effects of MS-551 in humans: a class III antiarrhythmic agent. Pacing Clin Electrophysiol. 1995;18:2022–7. 56. Washizuka T, Chinushi M, Watanabe H, et al. Nifekalant hydrochloride suppresses severe electrical storm in patients with malignant ventricular tachyarrhythmias. Circ J. 2005;69:1508–13. 57. Sahara M, Sagara K, Yamashita T, Iinuma H, Fu LT, Watanabe H. Nifekalant hydrochloride, a novel class III antiarrhythmic agent, suppressed postoperative recurrent ventricular tachycardia in a patient undergoing coronary artery bypass grafting and the Dor approach. Circ J. 2003;67:712–4.
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Electrical Storm: Clinical Management
58. Kurisu K, Hisahara M, Onitsuka H, et al. Nifekalant hydrochloride terminated electrical storms after coronary surgery. Ann Thorac Surg. 2010;89:1637–9. 59. VerNooy RA, Mangrum JM. Azimilide, a novel oral class III antiarrhythmic for both supraventricular and ventricular arrhythmias. Curr Drug Targets Cardiovasc Haematol Disord. 2005;5:75–84. 60. Dorian P, Borggrefe M, Al-Khalidi HR, et al., SHock Inhibition Evaluation with AzimiLiDe (SHIELD) investigators. Placebocontrolled, randomized clinical trial of azimilide for prevention of ventricular tachyarrhythmias in patients with an implantable cardioverter defibrillator. Circulation. 2004;110:3646–54. 61. Kowey PR, Levine JH, Herre JM, et al. Randomized, double-blind comparison of intravenous amiodarone and bretylium in the treatment of patients with recurrent, hemodynamically destabilizing ventricular tachycardia or fibrillation. Circulation. 1995;92:3255–63. 62. Kapoor JR, Batsford WP, Foody JM. Refractory electrical storm suppression by bretylium. Int J Cardiol. 2006;113:E111–2. 63. European Heart Rhythm Association, Heart Rhythm Society, Zipes DP, Camm AJ, Borggrefe M, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention Of Sudden Cardiac Death). J Am Coll Cardiol. 2006;48:e247–346. 64. Jongman JK, Jepkes-Bruin N, RamdatMisier AR, et al. Electrical storms in Brugada syndrome successfully treated with isoproterenol infusion and quinidine orally. Neth Heart J. 2007;15:151–5. 65. Kyriazis K, Bahlmann E, van der Schalk H, Kuck KH. Electrical storm in Brugada syndrome successfully treated with orciprenaline; effect of low-dose quinidine on the electrocardiogram. Europace. 2009;11:665–6. 66. Sharif-Kazemi MB, Emkanjoo Z, Tavoosi A, et al. Electrical storm in Brugada syndrome during pregnancy. Pacing Clin Electrophysiol. 2011;34:e18–21. 67. Burjorjee JE, Milne B. Propofol for electrical storm: a case report of cardioversion and suppression of ventricular tachycardia by propofol. Can J Anaesth. 2002;49:973–7. 68. Mahajan A, Moore J, Cesario DA, Shivkumar K. Use of thoracic epidural anesthesia for management of electrical storm: a case report. Heart Rhythm. 2005;2:1359–62. 69. Buxton AE, Lee KL, Fisher JD, Josephson ME, Prystowsky EN, Hafley G. A randomized study of the prevention of sudden death in patients with coronary artery disease. Multicenter Unsustained Tachycardia Trial Investigators. N Engl J Med. 1999;341:1882–90. 70. Streitner F, Kuschyk J, Veltmann C, et al. Predictors of electrical storm recurrences in patients with implantable cardioverterdefibrillators. Europace. 2011;13:668–74. 71. Song PS, Kin JS, Shin DH, et al. Electrical storms in patients with an implantable cardioverter defibrillator. Yonsei Med J. 2011; 52:26–32. 72. Wathen MS, DeGroot PJ, Sweeney MO, et al., PainFREE Rx II Investigators. Prospective randomized multicenter trial of empirical antitachycardia pacing versus shocks for spontaneous rapid ventricular tachycardia in patients with implantable cardioverterdefibrillators: Pacing Fast Ventricular Tachycardia Reduces Shock Therapies (PainFREE Rx II Investigators) trial results. Circulation. 2004;110:2591–6. 73. Ellenbogen KA, Levine JH, Berger RD, et al. Are implantable cardioverter defibrillator shocks a surrogate for sudden cardiac death in patients with nonischemic cardiomyopathy? Circulation. 2006;113:776–82. 74. Wilkoff BL, Cook JR, Epstein AE, et al., Dual Chamber and VVI Implantable Defibrillator Trial Investigators. Dual-chamber pacing
303
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
87.
88.
or ventricular backup pacing in patients with an implantable defibrillator: the Dual Chamber and VVI Implantable Defibrillator (DAVID) Trial. JAMA. 2002;288:3115–23. Aliot EM, Stevenson WG, Almendral-Garrote JM, et al., EHRA/ HRS Expert Consensus on Catheter Ablation of Ventricular Arrhythmias. Developed in a partnership with the European Heart Rhythm Association (EHRA), a Registered Branch of the European Society of Cardiology (ESC), and the Heart Rhythm Society (HRS); in collaboration with the American College of Cardiology (ACC) and the American Heart Association. Europace. 2009;11:771–817. Dagres N, Cantu F, Geelen P, Lewalter T, Proclemer A, BlomstromLundqvist C. Current practice of ventricular tachycardia ablation in patient with implantable cardioverter-defibrillators. Europace. 2012;14:135–7. Della Bella P, Brugada J, Zeppenfeld K, et al. Epicardial ablation for ventricular tachycardia: a European multicenter study. Circ Arrhythm Electrophysiol. 2011;4:653–9. Carbucicchio C, Santamaria M, Trevisi N, et al. Catheter ablation for the treatment of electrical storm in patients with implantable cardioverter-defibrillators: short- and long-term outcomes in a prospective single-center study. Circulation. 2008;117:462–9. Peichl P, Cihak R, Kozeluhova M, Wichterle D, Vancura V, Kautzner J. Catheter ablation of arrhythmic storm triggered by monomorphic ectopic beats in patients with coronary artery disease. J Interv Card Electrophysiol. 2010;27:51–9. Kozeluhova M, Peichl P, Cihak R, et al. Catheter ablation of electrical storm in patients with structural heart disease. Europace. 2011;13:109–13. Stevenson WG, Wilber DJ, Natale A, et al. Irrigated radiofrequency catheter ablation guided by electroanatomic mapping for recurrent ventricular tachycardia after myocardial infarction: the Multicenter Thermocool Ventricular Tachycardia Ablation Trial. Circulation. 2008;118:2773–82. Tanner H, Hindricks G, Volkmer M, et al. Catheter ablation of recurrent scar-related ventricular tachycardia using electroanatomical mapping and irrigated ablation technology: results of the prospective multicenter Euro-VT-Study. J Cardiovasc Electrophysiol. 2010;21:47–53. Tung R, Josephson ME, Reddy V, Reynolds MR, SMASH-VT Investigators. Influence of clinical and procedural predictors on ventricular tachycardia ablation outcomes: an analysis from the substrate mapping and ablation in Sinus Rhythm to Halt Ventricular Tachycardia Trial (SMASH-VT). J Cardiovasc Electrophysiol. 2010;21:799–803. Furushima H, Chinushi M, Iijima K, et al. Is the coexistence of sustained ST-segment elevation and abnormal Q waves a risk factor for electrical storm in implanted cardioverter defibrillator patients with structural heart disease? Europace. 2012;14(5):675–81. Dickstein K, Vardas PE, Auricchio A, et al. 2010 Focused Update of ESC Guidelines on device therapy in heart failure. An update of the 2008 guidelines for the diagnosis and treatment of acute and chronic heart failure and the 2007 ESC guidelines for cardiac and resynchronization therapy. Developed with the special contribution of the Heart Failure Association and the European Heart Rhythm Association. Europace. 2010;31:2677–87. Bristow MR, Saxon LA, Bochmer J, et al. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med. 2004;350:2140–50. Guerra JM, Wu J, Miller JM, Groh WJ. Increase in ventricular tachycardia frequency after biventricular implantable cardioverter defibrillator upgrade. J Cardiovasc Electrophysiol. 2003;14:1245–7. Kantharia BK, Patel JA, Nagra BS, Ledley GS. Electrical storm of monomorphic ventricular tachycardia after a cardiac-resynchronization therapy-defibrillator upgrade. Europace. 2006; 8:625–8.
304 89. Shukla G, Chaudhry GM, Orlov M, Hoffmeister P, Haffajee C. Potential proarrhythmic effect of biventricular pacing: fact or myth? Heart Rhythm. 2005;2:951–6. 90. Combes N, Marijon E, Boveda S, Albenque JP. Electrical storm after CRT implantation treated by AV delay optimization. J Cardiovasc Electrophysiol. 2010;21:211–3. 91. Nordbeck P, Seidl B, Bauer WR, Ritter O. Effect of cardiac resynchronization therapy on the incidence of electrical storm. Int J Cardiol. 2010;143:330–6. 92. Whang W, Mittleman MA, Rich DQ, et al., TOVA Investigators. Heart failure and the risk of shocks in patients with implantable cardioverter defibrillators: results from the Triggers Of Ventricular Arrhythmias (TOVA) study. Circulation. 2004;109:1386–91. 93. Kowal RC, Wasmund SL, Smith ML, et al. Biventricular pacing reduces the induction of monomorphic ventricular tachycardia: a potential mechanism for arrhythmia suppression. Heart Rhythm. 2004;1:295–300. 94. Fotopoulos GD, Mason MJ, Walker S, et al. Stabilization of medically refractory ventricular arrhythmia by intra-aortic balloon counterpulsation. Heart. 1999;82:96–100. 95. Hansen DE, Grig CS, Hondenghem LM. Stretch-induced arrhyth-
S. Metaxa et al.
96.
97.
98.
99.
100.
101.
mias in the isolated canine ventricle. Evidence for the importance of mechano-electrical feedback. Circulation. 1990;81:1094–105. Ryu YG, Baek MJ, Kim HJ. Alternative salvage technique during postcardiotomy electrical storm. Thorac Cardiovasc Surg. 2010;58:311–2. Ajijola O, Lellouche N, Bourke T, et al. Bilateral cardiac sympathetic denervation for the management of electrical storm. J Am Coll Cardiol. 2012;59:91–2. Mine JR, Ward DE, Spurrell RA, Camm AJ. The long QT syndrome; effects of drugs and left stellate ganglion block. Am Heart J. 1982;104:194–8. Patel RA, Priore DL, Szeto WY, Slevin KA. Left stellate ganglion blockade for the management of drug-resistant electrical storm. Pain Med. 2011;12:1196–8. Krum H, Schlaich M, Whitbourn R, et al. Catheter-based renal sympathetic denervation for resistant hypertension: a multicenter safety and proof-of-principle cohort study. Lancet. 2009;361:932–4. Ukena C, Bauer A, Mahfoud F, et al. Renal sympathetic denervation for treatment of electrical storm: first-in-man experience. Clin Res Cardiol. 2012;101:63–7.
Cellular Pharmacology of Cardiac Automaticity and Conduction: Implications in Antiarrhythmic Drug Assessment
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Gary Aistrup
Abstract
Cardiac automaticity (the spontaneous or automatic generation of cardiac impulses) and conduction (propagation of cardiac impulses) are fundamental to the underlying periodicity and rhythmicity of heartbeats. Cardiac arrhythmias occur when the normal succession of impulse generation and/or its propagation becomes disrupted. Significant abnormalities in the cardiac conduction system, whether inherited or acquired structural/functional, if not successfully remedied will predispose to arrhythmias acutely (e.g., sudden cardiac death) and/or chronically (e.g., atrial fibrillation), the latter of which then predispose to various cardiovascular diseases. Advancements in pharmacogenomics have enabled considerable delineation of the molecular/cellular players underlying both normal and abnormal automaticity and conduction. This has, for example, in the sinoatrial node (SAN), led to the realization of intricate workings of the ensemble of ion channels, exchangers, and pumps constituting a coupled sarcolemmal membrane and calcium cycling clock that provide for a robust yet tunable normal intrinsic impulse generation and likewise has led to the realization of how myocardial injury, disease, and channelopathies affect such molecular/cellular ensembles and give rise to automaticity and conduction abnormalities responsible for life disparaging or life-threatening arrhythmias. Increased understanding via drug-target interaction mechanisms and multiple experimental animal models has enabled detailed investigations into the various cellular signaling systems involved in modulating automaticity, and conduction has vastly expanded “drugable” targets. Accordingly expanded is the potential for developing novel antiarrhythmic drugs that are more regionally specific, can effectively target ensembles rather than single players involved in aberrant automaticity/conduction by acting upstream, and can attenuate or possibly even reverse the remodeling processes that produce arrhythmogenic substrates. This chapter will detail how these recent advancements in cellular/molecular basis of cardiac automaticity and conduction as well as their physiological and pathophysiological modulation now lend itself to improved antiarrhythmic drug assessment and therapies. Keywords
Automaticity • Conduction • Cellular pharmacology • Antiarrhythmic drugs • Ion channels • G-protein signaling • Micro RNAs
Introduction G. Aistrup, PhD Feinberg Cardiovascular Research Institute, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA e-mail:
[email protected] A.S. Kibos et al. (eds.), Cardiac Arrhythmias, DOI 10.1007/978-1-4471-5316-0_24, © Springer-Verlag London 2014
Cardiac automaticity (the spontaneous or automatic generation of cardiac impulses) and conduction (propagation of cardiac impulses) are fundamental to the underlying periodicity and rhythmicity of heartbeats, which need to occur 305
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~2.5 billion times over the average human lifespan. To beget a heartbeat, a cardiac impulse must (1) be generated via automaticity (typically) in the sinoatrial node (SAN); then (2) propagate out the SAN, where it encounters and overcomes the SAN—working right atrium current source–current sink (“source–sink”) mismatch—i.e., the small source depolarization from SAN impulse vs. the large repolarized sink of the working atria; then (3) quickly spread as an unbroken excitation wavefront throughout the rest of the atria to initiate atrial contraction, as well as (4) invade the AVN, wherein it must be delayed for sufficient time to allow for the atria to finish contracting and fill the ventricles; then (5) propagate to and accelerate through the His bundle/bundle branches and the more extensive Purkinje fibers; then (6) overcome the Purkinje fiber, working ventricles source–sink mismatch; and then (7) quickly spread as an unbroken excitation wavefront throughout the ventricles to initiate ventricular contraction. This highly ordered/sequential cardiac impulse generation and propagation involving multiple spatiotemporal changes in its region-to-region conduction collectively described the cardiac conduction system. Cardiac arrhythmias occur when the normal succession of impulse generation (automaticity) and/or its propagation (intercellular conduction) is disrupted. Indeed, enhanced or suppressed automaticity, triggered activity, and reentry are responsible for pathogenesis of any arrhythmia. Significant abnormalities/disorders in the cardiac conduction system, whether inherited (e.g., ion channelopathies) or acquired structural/functional (e.g., myocardial infarctions, extensive fibrosis, ischemia, hypertension), if not successfully remedied will predispose to arrhythmias acutely (e.g., sudden cardiac death) and/or chronically (e.g., atrial fibrillation); and chronic arrhythmias such as atrial fibrillation (AF) predispose to stroke, pathological cardiac hypertrophy (CH), and heart failure (HF). Hence, there is certainly a need in this new millennium to understand or at least be familiar with the current state of pharmacological/drug therapies available to remedy disorders in automaticity and conduction. To do so requires well-versed and up-to-date knowledge of the cellular/molecular basis of normal intrinsic automaticity and conduction along with their physiological modulation (e.g., autonomic influences), in order to understand how abnormal automaticity and conduction arise and lead to arrhythmias. Such knowledge is essential to antiarrhythmic drug development and assessment, as drugs are developed against one or more molecular targets believed to be involved in either initiating or maintaining arrhythmias and are assessed according to their remedy effectiveness and safety—i.e., lack of significant side effects. The importance of this precept is well exemplified by well-known outcomes of the studies such as AFFIRM, CAST, and SWORD, wherein it was found that
G. Aistrup
most antiarrhythmic drugs clinically used actually result in an increase in overall mortality directly related to antiarrhythmic drug side effects (e.g., proarrhythmia (precipitation of potentially lethal torsade de pointes [1]), toxicity, and worsening of comorbidities such as HF). It therefore should not be surprising that while antiarrhythmic drug therapy is still nominally the mainstay, it has become increasingly supplanted by more invasive surgical/catheter ablation and ICD alternatives— ICDs are in fact the only effective mortality-decreasing therapy for ventricular arrhythmias. But surgical/catheter/ICD therapies treat the complications of arrhythmias, not their basis; and as with any invasive therapy, they come with their own set of inherent risks, particularly when arrhythmias are comorbid with heart disease (which is often the case, as such morbidities are often underlie arrhythmogenesis). Thus, there is obviously still much to be learned in effectively preventing arrhythmias long-term using antiarrhythmic drug therapy. Despite the present shortcomings of antiarrhythmic drug therapy, newly acquired knowledge from drug-target interaction mechanisms (e.g., ion channel state-dependent drug action) and multiple experimental animal models enabling detailed investigations into the various signaling systems involved in modulating the ensembles of ion channels/ exchangers/pumps (C/X/Ps) in different types of cardiomyocytes (e.g., nodal vs. working) and how these changes in heart disease pathologies that predispose to arrhythmogenesis have come a long way in recent years. Thus, the potential for “drugable” targets in antiarrhythmic drug therapy is now vastly expanded and must be embraced notwithstanding the increased complexity in terms of discovering/developing novel effective antiarrhythmic drugs that are more heart region and/or cardiomyocyte type specific, multimolecular and/or upstream/modulatory-molecule targeting, and arrhythmogenic substrate remodeling targeting. The integration of these issues is the objective of this chapter, wherein discussions will detail how the most recent findings regarding the cellular/molecular basis for cardiac automaticity and conduction as well as their physiological and pathophysiological modulation lend themselves to improved antiarrhythmic drug assessment.
Cellular Basis of Cardiac Impulse Generation/Automaticity Automaticity is defined as property of cells to generate spontaneous action potentials (APs)—the cellular manifestation of the myocardial impulse—repetitively without external input/stimulation. Cardiac APs reflect the summation of the movement of ions according to electrical and chemical gradients across the cardiac cell (cardiomyocyte) membrane
24
Cellular Pharmacology of Cardiac Automaticity and Conduction: Implications in Antiarrhythmic Drug Assessment Early repolarization (1) Plateau (2) to Ks NCX
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Fig. 24.1 (Top) Composite cardiac action potential showing characteristics of working cardiomyocytes that have a stable resting membrane potential, as well as automatic (e.g., SAN) myocytes that have a pacemaker potential; (Middle) inward and outward movement of ions across the sarcolemma during the action potential (as aligned); (Bottom) ensemble of ion channel and exchanger currents that underlie/contribute to each phase of the action potential (as aligned)—green inward current, blue outward current, orange pacemaker current. Numerals are the respective phase of the action potential (Portions adapted from Michael et al. [2] and Ruan et al. [3] with permissions)
(sarcolemma) via the activity of ensembles of sarcolemmal ion channels, exchangers, and pumps therein (Fig. 24.1). The morphology of cardiac APs vary according to the specific heart region from which they are generated (Fig. 24.2) (for
307
a much more detailed/accurate description of the cardiac conduction system, see Boyett [5]), which reflects the specific types of cardiomyocytes and its particular ensemble of resident ion channels/exchangers/pumps constituting each specific myocardial region [6–13] (Table 24.1). Normal generation of spontaneous cardiac APs (normal cardiac automaticity) is an inherent property of pacemaker cardiomyocytes in the sinoatrial node (SAN), the atrioventricular node (AVN), and specialized ventricular fast-conducting cardiomyocytes in the common His bundle and bundle branches and Purkinje fibers (His–Purkinje system) of the ventricles. The SAN usually generates the highest intrinsic pacing rate and thus is the primary pacemaker, overriding the successively slower intrinsic pacing rates of the AVN and His–Purkinje system. The AVN and His–Purkinje system (in successive order) can provide pacing when the SAN fails to generate and/or propagate impulses (such “failures” can be due to intrinsic or drug-induced abnormalities). Spontaneous slow diastolic depolarization—spontaneous phase 4 depolarization, in cardiac AP terminology (Fig. 24.2)—underlies automaticity in pacemaker cells and thus is often referred to as the pacemaker potential. In accordance with SAN myocytes providing primary pacemaking, the pacemaker potential is best exemplified by focal inspection of a typical SAN AP and the particular ensemble of channels/exchangers/pumps constituting it [8–10, 14] as illustrated in Figs. 24.3a, b also shows examples of how cellular pharmacological block can delineate the role particular currents have therein. The decay of the repolarizing outward K+ current, primarily that of the delayed rectifiers, IKr and/ or IKs, together with the onset of depolarizing small, slow inward Na+ and/or Ca2+ current—If, ICaL-D, ICaT(-G?), INCX, (TTXRINa ,fast only in perinodal myocytes [10, 20–22])—underlies the development of pacemaker potential. The indication of “Ca Sparks” and “RyR recovery” in Fig. 24.3 refers to rhythmic calcium cycling consisting of type 2 (and type 3 in SAN myocytes [10]) ryanodine receptor (RyR2/3)-mediated Ca2+ release from sarcoplasmic reticulum (SR, a specialized intracellular Ca2+ storage organelle) either spontaneously [23] or triggered by ICaT [24]and/or ICaL-D [25], some of which is subsequently extruded from the cell by the sarcolemmal Na+– Ca2+ exchanger (NCX1) in forward mode, which extrudes 1 Ca2+ while bringing in 3 Na+ and thus generates an inward current (INCX) contributing to spontaneous diastolic depolarization, recently referred to as the “coupled clock system” [26] (Fig. 24.4). As is evident in the representative SAN/ AVN APs in Figs. 24.2 and 24.3, SA and compact AV nodal myocytes do not exhibit a “resting” membrane potential (Vm,rest) but rather a transitory maximum diastolic potential (MDP). The lack of a Vm,rest is of course essential to automaticity, and the molecular signature of primary pacemaker
308
G. Aistrup
Aorta Action potential SA node Superior vena cava Atrial muscle AV node LAF
Sinoatrial node
Common bundle
Internodal pathways
Bundle branches
Atrioventricular node
Purkinje fibers
Bundle of His Right bundle branch Ventricular muscle Purkinje system
Epicardium
Midmyocardium
Endocardium
Left posterior fascicle
ECG
T
P QRS 0.2 0.4 Time (s)
U 0.6
Fig. 24.2 Differential action potential morphology through the various regions of the heart (Portions adapted from Ganong [4] with permission)
cells is the absence of the strong inward-rectifier potassium current, IK1—a unique potassium current, carried by Kir2.1/2.3/2.2 channels. Kir2.x|IK1 activates at well-negative hyperpolarizing membrane potentials but upon membrane depolarization exhibits strongly voltage-dependent decrease of K+ conductance (inward K+ rectification, Fig. 24.5) that in effect acts to stabilize the membrane to Vm,rest near the K+ equilibrium potential [29] (~ −85 mV in cardiomyocytes). The presence of Kir2.x|IK1 in all other cardiomyocytes is key to their function in properly following and conducting the SAN-generated impulse throughout the rest of the heart to coordinate contraction, which depends on the ability to remain quiescent until stimulated by SAN-generated impulse. Working ventricular myocytes actually do have the capacity (i.e., IKs, IKr, SRICa-RyR2, INCX) to generate a diastolic depolarization (as can occur as discussed below), albeit less reliably periodic, if Kir2.x|IK1 was taken out of the profile. Despite accruement of rather detailed knowledge regarding normal automaticity, the exact nature of the
pacemaker potential arising is still intensely debated [8, 30–33] and seems to undergo constant revision, particularly concerning when and how much HCN|If and RyR2/3|SRICaRyR → NCX1|INCX, Cav3.x|ICaT, Cav1.3ICaL-D and Ist contribute to the initiation of diastolic depolarization [10, 12, 15, 34–37]. The recent addition to the cellular pharmacological tool kit of ivabradine [38], a very selective inhibitor of HCN|If, has helped to quell some factions of such debate, but it still remains incompletely unresolved due largely to inadequately selective/efficacious pharmacological agents targeting the other major contributors to automaticity—i.e., NCX1, Cav1.3, Cav3.x, and obviously Ist and its unknown molecular basis (it has been suggested to be a novel, Na+selective Cav1.? subtype, as it exhibits L-type Ca2+ channel pharmacology [39–41]). This becomes of practical concern when devising adequate remedies for abnormal automaticity (discussed below) when it arises. Hence, there is still relevant need for continued cellular pharmacological advancements in furthering a complete understanding of automaticity.
(Ca ) ∞ If (Na+, K+) ∞?, ϕ? ITRPM4 (Na+, K+) ∞? ITRPC3 (Na+, K+, Ca2+) ∞, ψ INCX,fm (3Na+ in, 1Ca2+ out) Repolarizing ϕ,ψ IK1 (K+) ϕ IKur (K+) ϕ IKr (K+) ϕ IKs (K+) ϕ,ψ Ito,f
2+
∞, ϕ? Ni-S ICaT-H
(Ca2+)
∞,ϕ? Ni-R ICaT-G
ICaL-D (Ca2+)
∞
Current (ion selectivity) Depolarizing ϕ TTX-R INa,fast (Na+) ϕ TTX-S INa,fast (Na+) ∞ Ist (Na+) ψ ICaL-C (Ca2+)
Kir2.1/2.3/2.2 Kv1.5 Kv11.1 (hERG1) Kv7.1 Kv4.2/4.3
?
Kv11.1 (hERG1)
Kv7.1
?
Cav3.2/α1H-TTCC [↑ in diseased heart] HCN4/2/1 [↑ in diseased heart] TrpM4 [↑ in diseased heart?] TrpC3 [↑ in diseased heart] NCX1 [↑ in diseased heart]
Cav3.1/α1G-TTCC [↑ in diseased heart]
? [in diseased heart?]
−
NCX1
TrpC3
TrpM4
HCN4/2/1
Cav1.2/α1c-LTCC (↓SAN center, ↑SAN periphery) Cav1.3/α1D-LTCC (↑SAN center, ↓SAN periphery) Cav3.1/α1G-TTCC (in SAN center, ↑SAN periphery) ?
Nav1.5
Nav1.5 (only in SAN periphery) Nav1.1 (only in SAN periphery) (novel Cav1. Subtype?) Nav1.1 (only in T-tubules) − [in diseased heart?] Cav1.2/α1c-LTCC
Working atria
SAN
?
Kv7.1
Kv11.1 (hERG1)
?
−
NCX1
TrpC3
HCN4/2/1 ↑nodal cells, ↓perinodal cells) TrpM4
Cav3.2/α1H-TTCC
Cav3.1/α1G-TTCC
Cav1.3/α1D-LTCC (↑nodal cells, ↓perinodal cells)
Cav1.2/α1c-LTCC (↓nodal cells, ↑perinodal cells)
Nav1.5 (only in AV perinodal cells) Nav1.1 (only in AV perinodal cells) (novel Cav1. Subtype?)
AVN
Protein subunit(s), if present (Δ distribution) [Δ pathological expression]
Kv11.1 (hERG1) (↑His bundles, ↓Purkinje cells) Kv7.1 (↑His bundles, ↓Purkinje cells) Kv4.2/4.3
?
Kir2.1/2.3/2.2
NCX1
TrpC3
HCN4/2/1 (↑His bundles, ↓Purkinje cells) TrpM4
Cav3.2/α1H-TTCC
Cav3.1/α1G-TTCC
Cav1.3/α1D-LTCC
Cav1.2/α1c-LTCC (↓His bundles, ↑Purkinje cells)
Nav1.1 (at Z-lines, intercalated disks) (novel Cav1. Subtype?)
Nav1.5, Nav1.8
His–Purkinje
Table 24.1 Cardiac ion channel/exchanger/pump currents and their molecular basis and expression profiles (if known)
Kv11.1 (hERG1) (↑epi|mid, ↓endo) Kv7.1 (↑epi, ↓mid|endo) Kv4.2/4.3
−
Kir2.1/2.3/2.2
Cav3.2/α1H-TTCC [↑ in diseased heart] HCN4/2/1 [↑ in diseased heart] TrpM4 [↑ in diseased heart?] TrpC3 [↑ in diseased heart] NCX1 [↑ in diseased heart]
Cav3.1/α1G-TTCC [↑ in diseased heart]
? ?[in diseased heart]?
Nav1.1 (only in T-tubules) − [in diseased heart?] Cav1.2/α1c-LTCC
Nav1.5
Working ventricle
Cellular Pharmacology of Cardiac Automaticity and Conduction: Implications in Antiarrhythmic Drug Assessment (continued)
KChIP2, MiRP1, MiRP2, Kvβ1-5, DPP6
minK, Kvβ1-5
MiRP1, Kvβ1-5
Kvβ1-5, PIP2
PIP2
PIP2, PLM, TrpM4?, TrpC3?
DAG, PIP2, NCX?
PIP2, NCX?
PIP2, MiRP1(HCN2?)
Cavα2δ2
Cavα2δ2, Cavγ6 (?)
‘’
Cavβ1,2, Cavα2δ1
?
‘’
Navβ1-4
Cofactors
24 309
KCa2.1-3(SK1-3) Na+K+ATPase-α1-3β1
NCX1 [↑ in diseased heart]
KCa2.2(SK2)
Na+K+ATPase-α1-3β1
NCX1
∞
IP3R2
SERCA2
(↓SAN center), (↑SAN center) [↑leak in diseased heart] SERCA2 [↓ in diseased heart] IP3R2 [↑ in diseased heart]
[↑leak in diseased heart]
IP3R2
SERCA2
(↓ AV nodal), (↑AV nodal) [↑leak in diseased heart]
RyR2, RyR3
NCX1
Na+K+ATPase-α1-3β1
KCa2.2(SK2)
Kir6.1/6.2
Kir3.1/3.4
?
AVN
important for automaticity, ϕ important in conduction, ψ important in E-C coupling (inotropy)
(Ca2+)
∞?, ψ? SR ICa-IP3R
(Ca2+)
∞, ψSR ICa-SERCA
(Ca2+)
RyR2
Kir6.1/6.2
Kir6.1/6.2
RyR2, RyR3
Kir3.1/3.4
Kir3.1/3.4
IK-ACh(Ado) (K+) IK-ATP (K+) ISK-Ca (K+) ϕ,ψ INaK (3Na+ out, 2K+ in) ψ INCX,rm (3Na+ out, 1Ca2+ in) Intracellular
∞, ψSR ICa-RyR
Kv1.4 [↓ in diseased heart]
[↓ in diseased heart]
Working atria
?
SAN
Protein subunit(s), if present (Δ distribution) [Δ pathological expression]
Ito,s (K+)
ϕ,ψ
Current (ion selectivity) (K+)
Table 24.1 (continued)
SERCA2 [↓ in diseased heart?] IP3R2
[↑leak in diseased heart]
RyR2
NCX1
Na+K+ATPase-α1-3β1
KCa2.1-3(SK1-3)
Kir6.1/6.2
(↓His bundles, ↑Purkinje cells) [↓ in diseased heart] Kv1.4 (↓His bundles, ↑Purkinje cells) [↓ in diseased heart] Kir3.1/3.4
His–Purkinje
‘’
PLM
Ca2+, ?
SUR1/SUR2, ATP, PIP2
ACh, Ado, PIP2
KChIP2, Kvβ1-5
Cofactors
Calstabin2, CaM, CaMKII, PKA-aKAP, [↑leak in diseased heart] PP1-spinophilin, PP2A-PR130, junctin, triadin, calsequestrin, HRC, sorcin, Homer SERCA2 PLB, sarcolipin (atria) [↓ in diseased heart] [↓ in diseased heart] IP3R2 PIP2 [↑ in diseased heart]
RyR2
NCX1 [↑ in diseased heart]
Na+K+ATPase-α1-3β1
KCa2.1-3(SK1-3)
Kir6.1/6.2
Working ventricle (↑epi|mid, ↓endo) [↓ in diseased heart] Kv1.4 (↓epi|mid, ↑endo) [↓ in diseased heart] Kir3.1/3.4
310 G. Aistrup
24
Cellular Pharmacology of Cardiac Automaticity and Conduction: Implications in Antiarrhythmic Drug Assessment
Fig. 24.3 (a) Ion channel, exchanger, and pump currents that contribute to the pacemaker potential and thus intrinsic automaticity in SAN myocytes; (b) effects of “selective” block of particular currents on SAN action potential (Panel a adapted from Lipsius and Bers [8] with permission; panel b adapted from Refs. [15–19] with permissions)
311
a +40 +20 0 −20 −40
l
potentia Pacemaker
−60
ICa,L-C
↓IK If
ICaL-D’ICa T
RyR recovery Ca Sparks INa/Ca INa ISustained
b
Block of If Cs+
Block of ICaT
Control
Ni2+
Block of INa
Block of ICaL
100 nm TTX 30 μM TTX
Nifedipine Control
Inhibition of SR Ca2+ release
2 μM ryanodine
G. Aistrup
312 K+
1) IKr,IKs ( Kv11.1 ,Kv7.1)
1) If
Ca2+
(HCN4/2/1)
2,3 and 5) INCX NCX1 Na+K+
4) ICaL-C (Cav1.2)
3Na+ Ca2+
-Na+ Ca2+
2,3) ICaL-D (Cav1.3) 2,3) ICaT (Cav3.1)
2,3 and 4) Ryanodine 5)SERCA2 receptor + Sarcoplasmic (RyR2) reticulum
Ca2+ 5) SOCC (TrpC1,3,6,7 Channels?)
Ca2+-induced Ca2+ release
Fig. 24.4 Coupled clock system in SAN myocytes. During the pacemaker potential, there is (1) a voltage-dependent decay of delayed outward K+ current (IKr&IKs) and (2) a voltage-dependent activation of at least three inward currents, If (funny current), and also or a bit later (2, 3) ICa,L-D (Cav1.3), then also Cav3.1, and INCX,fm in response to a spontaneous (or ICaL-D/ICaT triggered) release of Ca2+ from the sarcoplasmic reticulum via the ryanodine receptor (RyR2); then (4) during the final phase of the pacemaker potential, ICaL-C (Cav1.2) activates and initiates the phase 0 SAN myocyte AP upstroke, which then triggers RyR2s
Negative slope conductance
Cellular Basis of Cardiac Impulse/AP Propagation
2 I 1
Ek
−120
−100 Vm
Outward current −80
−60
−40
−20 −1
20 Inward current
−2 Inward current Non-rectifier (ohmic)
again via Ca2+-induced Ca2+ release from the sarcoplasmic reticulum causing a large global Ca2+ release (the cellular Ca2+ transient) that activates contraction (excitation–contraction coupling); and finally (5) the sarcoplasmic reticulum is replenished with Ca2+ by reuptake of Ca2+ into the sarcoplasmic reticulum via SERCA2 (perhaps SR replenishing is aided by sarcolemmal store-operated Ca2+ channels—SOCC, possibly in part via TrC channels), and again Ca2+ entering through ICa is extruded via NCX1|INCX (Adapted from Monfredi et al. [27] with permissions)
−3
−4
Fig. 24.5 Strong inward rectification of Kir2.x|IK1 that gives rise to and maintains a stable Vm,rest (Adapted from Dhamoon and Jalife [28] with permission)
Impulse propagation in myocardium is manifest as intercellular cardiomyocyte-to-cardiomyocyte AP conduction realized through cardiomyocyte electrotonic coupling—i.e., cardiomyocytes are electrically (and physically) interconnected via large transjunctional “gap junction” (GJ) ion channels formed via the bridging of two connexons (the assembly of six transmembrane connexin (Cx) proteins as hemichannels) across the extracellular gap between cardiomyocytes that provide for intercellular ion flow (and exchange of other small molecules) [42] (Fig. 24.6). Three major Cx isoforms are expressed in the human heart—Cx40, Cx43, and Cx45—and can form various homomeric or heteromeric Cx connexons, of which one type of connexon from one cardiomyocyte can connect to the same or different type of connexon from another cardiomyocyte, thus forming homotypic and/or heterotypic GJ channels (Fig. 24.6b), all of which exhibit different conductance properties and regionally distinct expression profiles [43–46] (Table 24.2) that impart distinct differential tuning of the cardiac impulse
24
Cellular Pharmacology of Cardiac Automaticity and Conduction: Implications in Antiarrhythmic Drug Assessment Cx subunits constituent to connexon hemichannels
a
Myocyte 1 cytosol
Myocyte 1 sarcolemma Extracellular space (gap) Myocyte 2 sarcolemma
Myocyte 2 cytosol
Gap junction Channel Connexon Connexon from from Myocyte 1 Myocyte 2
b Heteromeric Homotypic
Cx43 Heteromeric Hetrotypic
Homomeric Hetrotypic
Cx40
Homomeric Homotypic Connexin
Connexon
Gap junctions
Fig. 24.6 (a) Gap junction channels: six connexins (Cx—subunit integral-membrane proteins) assemble to form connexon hemichannels, which upon two from adjacent myocytes interconnect, the form extracellular gap-spanning intercellular channels—i.e., gap junctions channels (GJs). (b) Different Cx subunits can assemble to homo- or hetero-connexons and then via various homo- and hetero-connexon interconnections form the indicated Xmeric–Xtypic GJs (Portions adapted from Mese et al. [42] with permission)
propagation velocity in each region (Fig. 24.7). GJs are normally concentrated at the myocyte ends, with only sparse presence on the edges, near or integral to the intercalated disks (complex concentration of adhesion proteins that provide strong physical interconnections between adjoining cardiomyocytes [48]), thus promoting AP propagation parallel to the longitudinal (more so than the transverse) axis of interconnected cardiomyocytes.
313
So, electrotonic coupling does enable the current underlying the “source” depolarization of an AP in one cardiomyocyte to be rapidly conducted via GJ channels (Igj) to adjoining cardiomyocytes (Fig. 24.8). But successful intercellular propagation of the AP is contingent upon the amount of Igi conducted from the “source” cardiomyocytes being sufficient to provide enough initial depolarization to overcome the “sink” repolarized adjoining cardiomyocytes and trigger an AP therein [49–52] (e.g., a rough comparison: “source” current from contact pacing electrodes must attain a sufficient magnitude before it electrically captures “sink” intact myocardium). So in addition to GJ-mediated electrotonic coupling, AP propagation depends on inherent excitability of each particular cardiomyocyte—i.e., how easily can an AP be triggered therein—which is determined by their Vm,rest vs. the strength/rapidity of the phase 0 upstroke of their APs. SA and compact AV nodal myocytes represent the extreme case of excitability (Fig. 24.2, left; Fig. 24.3)—i.e., no stable Vm,rest (no Kir2.x|IK1) but rather the aforementioned spontaneous diastolic depolarization (automaticity), which trumps their slow (~5 V · s−1 for inner SAN; ~10 s−1for compact AVN) diffuse phase 0 AP upstrokes consequent primarily to the underlying Cav1.2|ICaL-Cwith its typically moderate amplitude and relatively slow activation at moderately hyperpolarized threshold membrane potentials (~−35 mV). However, the ICaL-C-mediated slow phase 0 AP upstroke combined with sparse, dispersed GJs containing almost exclusively low-conductance Cx45 in SA and AV nodal myocytes equates to slow conduction velocity in the SAN and AVN (Fig. 24.8; Table 24.2)—underscoring impulse propagation being determined by both excitability and electrotonic coupling (not to mention integral tissue architecture). Obviously slow conduction velocity is a necessity for the impulse delay function of compact AV nodal myocytes (the complex tissue architecture of the entire AV junction also contributes to the delay [5, 53]). But slow conduction velocity is also important in the SAN—i.e., inherent prominent automaticity of SA nodal myocytes essentially eliminates source–sink issues within the SAN, and AP propagation between adjoining SAN pacemaker cardiomyocytes primarily serves as a means for synchronizing their automaticity. This synchronized automaticity (which would likely be disseminated by fast conduction) effectively engenders a large enough “source” depolarization to enable the SAN-generated impulse to overcome the formidable surrounding repolarized “sink” right atrium (having a Vm,rest ≈ −80 mV) and propagate out into it [54] (the SAN is also insulated from the large electrotonic influence of the surrounding right atrium by a separating layer of connective tissue, and a small restricted zone at the
314
G. Aistrup
Table 24.2 Regionally distinct gap junction connexin expression and homomeric–homotypic and homomeric–heterotypic GJ channel properties Cx isoform 40
SAN Atria Compact AVN ± ++++ − (dispersed) 43 ± ++++ − (dispersed in periphery) 45 +++ + +++ (dispersed) (dispersed) Homomeric–homotypic GJ channels Cx40–Cx40 Cx43–Cx43 Cx45–Cx45 198pS 89pS 32pS Homomeric–heterotypic GJ channels Cx40–Cx43 Cx40– Cx45 Cx40cell(-) Cx43cell(-) Cx40cell(-) 60pS 100pS 30pS ↑Igj ↓Igj ↓Igj
His bundle ++++
Bundle branches ++++
Purkinje fibers ++++
Ventricles −
++
+++
++++
++++
++
+
+
±
Cx45cell(-) 40pS ↑Igj
Cx43–Cx45 Cx43cell(-) ~40pS ↑Igj
Cx45cell(-) ~40pS ↓Igj
Scale: ++++ very abundant, ± nominally detectable, − not detectable (-) cell hyperpolarized, ↑↓ increase/decrease Fig. 24.7 Differential Cx expression throughout the heart and corresponding differential conduction velocity (CV) therein (Adapted from Severs et al. [47] with permissions)
Left atrium Cx43, Cx40 CV ≈ 0.5 m/s SA node Cx45 (CV ≤ 0.05 m/s)
Upper bundle branches Cx45, Cx40 (CV ≈ 2 m/s)
Right atrium Cx43, Cx40 CV ≈ 0.5 m/s
Lower bundle branches Cx40,Cx45, Cx43 (CV ≈ 3 m/s)
AV node Cx45(CV ≈ 0.05m/s) His bundle Cx45, Cx40 (CV ≈ 2 m/s)
Left ventricle Cx43(CV ≈ 0.5 m/s)
Right ventricle Cx43(CV ≈ 0.05 m/s)
SAN|crista terminalis border containing both Cx45 and intermediate-conductance Cx43 may be an “exit route” out into the right atrium [55]). His–Purkinje myocytes [56] display quite prominent excitability (Fig. 24.2)—i.e., while having a Vm,rest ≈ −90 mV, they also have some inherent automaticity and exhibit the strongest/fastest phase 0 AP upstroke (~600 V · s−1) as a consequence of the considerable presence of Nav1.5/1.8|INa,fast that activates extremely fast at well-hyperpolarized threshold membrane potentials (~ −70 mV). Hence, only moderate
Purkinje fibres Cx40,Cx45, Cx43(CV ≈ 4 m/s)
initial depolarization is needed to trigger in AP His–Purkinje myocytes, which indeed should be sufficiently provided for by their being electronically coupled via predominantly high-conductance Cx40 (and varying amounts of Cx43 and Cx45)-containing GJs (Fig. 24.8). This all correlates well with His–Purkinje myocytes being specialized for fast conduction velocity. Working atrial and ventricular myocytes both exhibit moderate (though not quite equivalent) excitability (Fig. 24.2, right; Fig. 24.6)—i.e., both have Vm,rest (≈ −80 mV in atrial;
24
Cellular Pharmacology of Cardiac Automaticity and Conduction: Implications in Antiarrhythmic Drug Assessment
Fig. 24.8 Cellular ion channel-mediated excitation and gap junction-mediated intercellular conduction govern action potential propagation
Ito
Iks Ikr
Ik1
Igj
Igj
INa,fast
≈ −90 mV in ventricular, have higher density Kir2.x|IK1) with no inherent automaticity, and both exhibit strong/fast phase 0 AP upstrokes (~150 V · s−1) resultant to considerable presence of Nav1.5|INa,fast. Hence, again only moderate initial depolarization is needed to trigger in APs in atrial and ventricular myocytes, although the excitability of atrial myocytes is somewhat greater in accordance with their being electronically couple via Cx40- and Cx43-containing GJs, whereas ventricular myocytes are electronically coupled with nearly exclusively Cx43-containing GJs (Fig. 24.8). The potentially higher conduction velocity attained by mixed Cx40/Cx43 GJs in the atria may well correlate with it having to propagate SAN-generated impulses to the AVN with nominal efficiency, albeit at the expense of causing some heterogeneity in impulse spread and thus contraction across the rest of the atria. The near homogeneity of Cx43 GJs in the ventricles would maximize smooth impulse spread and thus contractions across the ventricles. Note that this is all uncannily optimal, credit being due to millions of years of evolution.
Upstream Modulation of Automaticity and Conduction The ability of the heart to adapt to changes in physiological conditions is manifest by changes in heart rate (chronotropy), excitability (bathmotropy), conduction velocity (dromotropy), contractility (inotropy), and relaxation (lusitropy). Thus, any discussion concerning cardiac automaticity would be remiss without some attention given to chronotropy, and likewise any discussion concerning cardiac conduction would be remiss without some attention given to bathmotropy and dromotropy (not to mention that chronotropic and/ or bathmotropy/dromotropic modulations typically affect inotropy and lusitropy). Arguably the predominant modulation of both automaticity and conduction is exerted by the autonomic nervous system [57], the cardiac innervation of which is minimally
315
ICa-L
Sympathetic gaglia chains Parasympatheic vagus nerves
S-A node
Sympathetic nerves
A-V node
Sympathetic nerves
Fig. 24.9 Autonomic innervation of the heart (Adapted from Guyton and Hall [58] with permission)
illustrated in Fig. 24.9. Sympathetic postganglionic cardiac plexus nerve endings release norepinephrine (NE), which activate myocardial β1–3 -adrenergic receptors (β-ARs)—having overall expression densities of β1>β2>>>β3 (circulating epinephrine released by the adrenal medulla also activates β-ARs), hence the basis for “beta-blocker” drug therapy. Parasympathetic–vagal cardiac plexus nerve endings release acetylcholine (ACh), which activates myocardial muscarinic Μ1–5-cholinergic receptors (Μ-CRs)—having overall expression densities of Μ2>>Μ1,3,4>>Μ5. All β-ARs and Μ-CRs are G-protein-coupled receptors (GPCRs)—i.e., their activation is transduced via functionally coupled intracellular heterotrimeric (αβγ) guanine nucleotide (GDP/GTP)-binding proteins, (Gαβγ)-proteins, that upon GPCR stimulation causes the exchange of GDP for GTP bound to the Gα (GTPase) subunit followed by dissociation and mobilization of Gα and βγ, which go on to evoke particular signaling cascades that modulate the function of various downstream target
316
G. Aistrup NE,EPI
ACh
β1ARs
M2CRs chronotropy Bathmotropy Dromotropy Inotropy Lusitropy Cardiomyocyte
Fig. 24.10 Autonomic modulation of cardiac ion channels (IK-ACh, IKur only in atria). “+” functional increase, “−” functional decrease, the relative size of which equates to the relative magnitude of change; “⦸” inhibition/ablation (Portions adapted from Taggart and Lambiase [59] and Klabunde [60] with permissions)
proteins. β1, 2-ARs couple (though not equivalently) to Gαsβγ and instigate stimulation (hence Gα“s”) of adenylate cyclase (AC)|cyclic adenosine monophosphate (cAMP)|protein kinase-A (PKA) signaling, whereas Μ2, 4-CRs couple to Gαi/oβγ and instigate inhibition/attenuation (hence Gα“i”) of AC|cAMP|PKA signaling and additionally activate via Gi/oβγ the G-protein-coupled inwardly rectifying potassium channel (GIRK3.1/3.4—i.e., Kir3.1/3.4) current IK-ACh(Ado) in SAN, AVN, His–Purkinje, and working atrial myocytes. Gαsβγ signaling alters the function of multiple ion channels/exchangers/pumps and/or their associated cofactors via PKA-mediated phosphorylation (via cAMP binding, in the case of HCN), of which the aggregate effect is dramatic positive chronotropy, bathmotropy, and dromotropy (as well as positive inotropy and lusitropy) (Fig. 24.10). Accordingly, Gαi/oβγ signaling opposes or counteracts the latter, thus causing dramatic negative chronotropy, bathmotropy, and dromotropy (as well as negative inotropy and lusitropy). This sympathetic vs. parasympathetic modulation of automaticity is clearly manifest in the acceleration vs. deceleration of the pacemaker potential and somewhat more depolarized MDP vs. somewhat more hyperpolarized MPD in SAN myocytes that result in increased vs. decreased heart rate (Fig. 24.11).
Ctrl
NA
ACh
0 mV
0 mV
20 mV 200 ms
Fig. 24.11 Autonomic-mediated changes in SAN AP and rate (Adapted from Verkerk et al. [61] with permission)
24
Cellular Pharmacology of Cardiac Automaticity and Conduction: Implications in Antiarrhythmic Drug Assessment
In terms of changes in conduction, β1, 2-AR|Gs and Μ2, 4-CR|Gi/o signaling accelerates and decelerates, respectively, impulse propagation in the AVN wherein the signaling detailed in Fig. 24.11 aggregates to increase (via β1, 2-AR|Gs) or decrease (via Μ2, 4-CR|Gi/o) the excitability of AVN myocytes—i.e., more depolarized/hyperpolarized MDP and accelerated/decelerated ICaL-mediated phase 0 upstroke of AVN APs. Thus, the dromotropic effects of sympathetic and parasympathetic in the AVN may largely be consequent from the underlying bathmotropic effects thereof. However, we now know the situation is not that simple, as β2-ARs also couple, varyingly depending on physiological/pathophysiological conditions, to Gαiβγ signaling [53], as do β3-ARs [62, 63], but β3-AR|Gαiβγ coupling in cardiomyocytes is compartmentalized to activate nitric oxide synthase (NOS)|guanosine cyclase(GC)|cGMP|protein kinase G (PKG) signaling rather than ↓AC|↓cAMP|↓PKA signaling, the former of which typically attenuates the latter but under certain circumstances the former can potentiate the latter [64, 65]. Additionally, Μ1- and Μ3-CRs, as well as α1Aand α1B-ARs, couple to Gαqβγ-protein stimulation of phospholipase-C (PLC)|phosphatidylinositol-4,5-bisphosphate (PIP2)|diacylglycerol (DAG)|inositol-1,4,5-triphosphate (IP3)|TrpC3/6/7|protein kinase C (PKC) signaling [66, 67] and nominally to Gαi/oβγ signaling [68, 69]. Cardiac-relevant autocoids—angiotensin II and endothelin-1—also couple to Gαqβγ signaling [70] and nominally to Gαi/oβγ signaling [71–74]. In particular to Gαqβγ signaling, note that PIP2, a lipid essential for Gαqβγ signaling, is a necessary cofactor for many cardiac ion channels/exchangers/pumps (see Table 24.1), the importance of which is still to be revealed [75]. Moreover, because Ca2+ is a second messenger common to Gs, Gi/o, and Gq signaling, in some way intertwined with Ca2+|calmodulin(CaM)|type-II Ca2+/calmodulin-dependent kinase (CaMKII) signaling [76] as well (this is minimally illustrated in Fig. 24.12). Note the addition of transient receptor potential channels (TrpM4|ITrpM4 and TrpC3|ITrpC3) [78–80] and small conductance Ca2+-activated K+ channels ((KCa2.1–3/ SK1–3)|ISK-Ca) [81], which via Gq and Ca2+ signaling seem to contribute more significantly to modulation of automaticity and conduction than previously realized. Moreover, intercellular conduction via GJs is variably modulated by Gs|↑PKA (generally enhances GJ coupling), Gi|↑NOS|↑PKG (generally uncouples GJs), Gq|↑PKC (enhances GJ coupling or uncouples GJs depending on PKC isoform—i.e., PKCα generally enhances GJ coupling, whereas PKCε generally uncouples GJs), and ↑Ca2+|↑CaM (generally uncouples GJs) signaling [82–85]. (See Table 24.3 for G-protein-mediated effects on ion channels/exchangers/pump involved in cardiac automaticity and conduction/repolarization.) Beyond G-protein signaling, now gaining attention is the role microRNAs (miRNAs) [86] play in modulating cardiac automaticity and conduction, particularly that of miR-1 and
317
miR-133. miRNAs are short (22–26 nucleotides) noncoding RNAs that regulate gene expression at the posttranscriptional level by binding particular 3’ untranslated regions of target mRNAs where they direct an RNA-induced silencing complex protein complex, thus causing suppression and/or induce degradation of the targeted mRNA [87]. Tissues/cells have characteristic miRNA expression profiles, or “miRNomes,” wherein at the very least miR-1, miR-133, and miR29 have now been repeatedly identified as key regulators of various components of cardiac automaticity and conduction as [88, 89]. Normal expression of miRNA-1 and -133 contributes to controlling/modulating automaticity, repolarization (and thus excitability), and conduction by keeping in check the expression of HCN4/2|If, Kv11.1(ERG)|IKr, Kv7.1/minK(KCNQ1/KCNE1)|IKs, Kir2.1(KCNJ2)|IK1, Iroquois protein-regulated Kv4.2(KCND2)|Ito, and Cx43(GJA1)|Igj-Cx43. The role of miR-29 in modulating conduction is consequent to it regulating various interstitial extracellular matrix protein genes that maintain myocardium architecture integrity, thus intracellular conduction integrity. More on such regulation is yet to come, as many (if not all) cardiac ion channels/exchangers/pumps mRNA transcripts have been either experimentally determined to be or otherwise predicted (via sequence matching) to be regulated by various miRNAs [90, 91] (as listed in Table 24.3). It goes without saying that these “other” signaling systems introduce multiple layers of complexity concerning modulation of cardiac automaticity and conduction, and while their modulatory effects on automaticity and conduction under normal conditions may not be as apparent as that byβ1-AR|Gs and Μ2-CR|Gi/o signaling, they do become more apparent under cardiopathic conditions. Indeed, Gαiβγ|NOS|cGMP signaling, Gαqβγ signaling, Ca2+|CaM signaling, and miRNA expression profiles dramatically change and play significant roles in oxidative stress, acute myocardial ischemia (AMI)/ reperfusion, hypertension, fibrogenesis, AF, CH, and HF [90–94]—all pathological conditions relevant in arrhythmogenic automaticity and conduction. Exemplifications of this include recent findings indicating that Gq-protein family members, G12/13-proteins, are activated via coupling to purinergic P2Y6 receptors (yet additional G-protein signaling) stimulated by extracellular nucleotides released from cardiomyocytes through pannexin-1 hemi-channel induced by mechanical stretch, which initiates the induction of increased cardiac fibrogenesis through a reactive oxygen species (ROS)-dependent pathway [95]; and accumulative findings that posttranscription regulation of cardiac ion channels/exchangers/pumps by miRNAs is indeed not static but in fact changes under the stresses of various pathological insults [96, 97], including cardiac pathologies such as acute myocardial AMI, CH/HF, and oxidative stress (OS) [91, 98]. AMI-/CH-/HF-/OS-mediated changes in miRNA expression profiles lead to automaticity, conduction, and repolarization
318
G. Aistrup Na+Ca2+ TRPC3
Receptor γ β
–
Ca2+
αq GDP
NCX
– GRK
Na+Ca2+
Arrestin –
GTP
Many Others
RGS +
Receptor γ β
–
αq
PIP2
GDP +
PLC
+
DAG
IP3 γ β
+
K+ Channel K+
K+
CaM
Phospholamban
–
+
SK+ Channel K+
+
Ca2+
+
cAMP
αs
CREB – NFAT-3
+ AC
+
+
+
+ –
αs GDP
+
HDAC 4/5
Ca2+
+
Receptor
Calcineurin +
RyR
CaMKIV
+
+
Ca2+
+ TRPM4
+
Ca2+
PKA-R Na+
Ca2+ CaM
Ca2+ PKA-C
MAPK Pathway
+ Ca2+
Na+
Na+
+
SERCA
Ca2+
?
Many Others
–
CaMKII +
Ca2+
+
γ β
+
Ca2+
Ca2+ Channel
Na+ Channel
Many Others
+
PDE
IP3R
+
K+
PKC
Ca2+
+
Ca2+
Na+
+
+
– Ca2+
Na+
GTP
αq
–
–
Ca2+ +
+
αi
–
Na+
Transcription
TnC GTP
ATP
+ MCIP-1
+
+
+
Contraction
Hypertrophy
Fig. 24.12 GPCR|G-protein, Ca2+-CaM|CaMKII integrated/crosstalk signaling (Adapted from Mike Berridge et al. [77] with permission)
changes that predispose to arrhythmogenesis, which, as with respect to miR-1 and miR-133, are illustrated in Fig. 24.13 [91]. Note the encompassment of sarcolemmal ion channel, intracellular Ca2+ cycling, and GJs in just these two miRNAs, hence the potential for pharmacological antiarrhythmic therapy.
Notwithstanding such complexity, when all this is looked at from the perspective of cellular pharmacology, drug development, and/or assessment concerning abnormal and/or arrhythmogenic automaticity and conduction, the potential for novel more selective and specific agents becomes tremendous, albeit certainly challenging.
24
Cellular Pharmacology of Cardiac Automaticity and Conduction: Implications in Antiarrhythmic Drug Assessment
319
Table 24.3 “Typical” modulation of cardiac ion channel/exchanger/pump currents by neurohormonal/autocoid-mediated G-protein signaling and miRNAs Current Sodium
Gs signaling Gi/o signaling Gq signaling Ca2+|CaM|CaMKII effect effect effect effect Gene ↑
↓
↓
INa,late↑
∞I st
↑
↓
↑
Calcium ICaL-C
↑
↓
↓
TTX-R INa,fast
?
SCN5A SCN1A ?
miR-26, miR-let-7 ? ?
↓CaM ↑CaMKII
CACNA1C CACNA1D CACNB1(Cavβ1) CACNB2(Cavβ2) NACNA1G
miR-26, miR-30, miR-92, miR-320, miR-328 ? miR-16, miR-24, miR-125, miR-195 miR-26, miR-27, miR-30, miR-145 miR-150
TTX-S INa,fast
ICaL-D
↔ ICaT-G ICaT-H Intracellular SR ↑ ICa-RyR2
↔
↑
↑
↓
↑
↑
↑ SR ↑ ICa-IP3R Potassium channels ↓ IK1
↓ ↓
↑ ↑
↑ ↓
↑
↓
↑a↓c
SR
ICa-SERCA
PP2A(assoc. phosphatase) RyR3
?
↓
↑
KCNJ8(Kir6.1)
miR-20
↓
↓
↑
miR-1, miR-27, miR-125, miR-185 miR-1, miR-92, miR-133 miR-1, miR-27, miR-30, miR-185, miR-214 miR-29, miR-30, miR-185 miR-185, miR-199a
↑
↓
?
IKs
↑
↓
↓
↑
IKur
↑
↓
↓
?
Ito,f Ito,s
↓
↑
↓
↑a↓c
IK-ACh(Ado)
↑
↓
IK-ATP
↑
↑ (but primary means of activation) ↓ (↑ via PKG)
INCX
↔↑
↔↓
↓
?
HCN4 HCN2 SLC8A1
INaK IGJ,Cx40
↑ ↑
↓ ↓
↑ ↓ ↔ ↑
↓ ↓
ATP1B1 GJA5
IGJ,Cx43 IGJ,Cx45 ITrpM4 ITrpC
↔A ↑C ↓ ↑ ↓
↔A ↓C ↑ ↑ ↑
↔ ↑ ↑ ↓
GJA1 GJC1
A acutely, C chronically
miR-367 ? ?
KCNJ12 KCNH2 KCNAB2(Kvβ2) KCNQ1 KCNE1(mink) KCNAB2(Kvβ2) KCNA5 KCNAB2(Kvβ2) KCND2(Kv4.2) KCNiP2(KChIP2) KCNA4 KCNAB2(Kvβ2) KCNJ3(Kir3.1)
↓
KCNJ2
miR-1, miR-133
miR-1, miR-16, miR-26, miR-195, miR-208 miR-29, miR-30, miR-145 miR-133 miR-324 miR-133 miR-1 miR-324 miR-1 miR-324 miR-1 mkR-29 miR-145 miR-324 miR-30, miR-92
IKr
Mixed cation ↑ If
miRNAs (non-diseased, adult)
↑ ↑
miR-1, miR-20, miR-23, miR-30, miR-125 miR-let-7, miR-20, miR-125, miR-150 ? ?
320
AMI
CH/HF
Cell–cell coupling interruption
Membrane depolarization
OS
Conduction slowing
Ischaemic Arrhythmias
Gap junction Kir2.1 (IK1) miR-133
Cx43
Fig. 24.13 Consequence of deregulation of microRNAs miR-1 and miR-133 by acute myocardial ischemia (AMI), cardiac hypertrophy and/or heart failure (CH/HF), and oxidative stress (OS) that causes de-suppression of the expression of multiple ion channels involved in automaticity and conduction/ repolarization, and therefore predisposes to arrhythmogenesis during these pathologies (Adapted from Yang et al. [93] with permission)
G. Aistrup
miR-1
HERG (IKr) HCN2 (If)
HCN4 (If)
KCNE1 (IKs)
HCN2/HCN4 expression Cytoplasmic membrane
Ectopic excitation
Arrhythmias
Arrhythmogenic Automaticity Sick Sinus Syndrome/Enhanced Automaticity Arrhythmogenic intrinsic automaticity can be manifest as severe sinus bradycardia, sinus pauses or arrest, sinus node exit block, chronic atrial tachyarrhythmias, alternating periods of atrial bradyarrhythmias and tachyarrhythmias, and inappropriate responses of heart rate during exercise or stress inappropriate for physiological requirements that result from functional or structural abnormalities in impulse generation in the SAN. These abnormalities are aggregately referred to as “sick sinus syndrome” [27, 99]; and subspecific to tachyarrhythmic abnormal automaticity, also referred to as “enhanced automaticity” [100]. Mutations in the Nav1.5 gene (SCN5A) associate with bradycardia and bradytachycardia phenotypes [101, 102]; mutations in the HCN4 gene associate with bradycardia as well as long QT and ventricular tachycardia phenotypes [103, 104]; and mutations in calsequestrin—a SR Ca2+-binding/Ca2+buffering protein important in Ca2+ cycling—associate with catecholaminergic polymorphic ventricular tachycardia and SAN dysfunction [105], the latter suggesting interference with the SAN calcium clock [106] (see above). Ischemia consequent to coronary artery disease is estimated to be responsible for ~33 % of sick sinus syndromes [107]; and extreme physical training, aging, and AF and HF associate
HCN2 (If)
KCNQ1 (IKs)
EAD APD ERP QT ERP
Anti-arrhythmic
TA
Proarrhythmias
with increased incidence of sick sinus syndrome [108–111], likely consequent to chronic aberrant modulatory influences causing remodeling in the SAN.
Triggered Activity In addition to abnormal intrinsic automaticity in the SAN, abnormal automaticity referred to as “triggered activity” can arise under particular conditions (below) in latent pacemaker and non-pacemaker cardiomyocytes from slow depolarizations following an AP—afterdepolarizations, either occurring before complete membrane repolarization, typically arising from the AP plateau and so referred to as early afterdepolarizations (EADs); or occurring after the full membrane repolarization after the AP arising from Vm,rest and so referred to as delayed afterdepolarizations (DADs)—that upon attaining sufficient amplitude trigger a subsequent AP (Fig. 24.14). Although afterdepolarizations resemble slow spontaneous diastolic depolarizations, they are dependent on the occurrence of and are “triggered” by the AP itself and do not occur in the absence of an AP. Thus, triggered activity is distinct in its underlying. EADs (Fig. 24.14, left) arise via a decrease in outward repolarizing currents (e.g., reduced availability of Kv11.1|IKr and/or Kv7.1|IKs), an increase in inward depolarizing current (e.g., increased availability of Cav1.2|ICaL-C, increased NCX1|INCX,fm, and/or increased persistent/late Nav1.5|INa,late),
24
Cellular Pharmacology of Cardiac Automaticity and Conduction: Implications in Antiarrhythmic Drug Assessment
Fig. 24.14 Example depictions of early afterdepolarization (EAD) and delayed afterdepolarization (DAD)-evoked triggered activity. See text for details (Adapted from Chen and Antzelevich [112] with permission)
321
Triggered activity EAD-evoked Phase 2 EAD-
Phase 3 EAD-induced triggered extrasystole
DAD-evoked Late phase 3 EAD-induced triggered extrasystole
DAD-induced triggered extrasystole
Normal Prolonged
Phase 3 EAD
or a combination of both during phases 2 and 3 of the AP that compromise the ability of myocytes to repolarize expediently [113–116]. The complex dynamics and overlapping of ionic fluxes during phases 2 and 3 of the AP make it difficult to pinpoint the impact individual current alterations have on these AP phases (except in the cases of congenital long QT syndromes where specific ion channelopathies enable such pinpointing [117]), but the balance shifts to inward depolarizing current that prolongs phases 2 and/or 3 of the AP. Under such conditions, any mechanism that progressively increases net inward current can then potentially reverse repolarization, but in the voltage range spanning phases 2–3 of the AP, ICaL and INCX,fm are the major currents that fit such criteria. ICaL fits this criteria via its window current (−35–0 mV, where ICa-L steady-state activation and inactivation relationships overlap and the Ca 1.2 channel population dynamically equilibrates among open, closed, and inactivated states, resulting in a steady-state current [118]), which can self-amplify and generate an EAD if repolarization through this voltage range is too slow. The EAD if large enough can completely reverse repolarization and trigger an ICa-L-mediated extra AP/ extrasystole. INCX,fm fits the criteria because intracellular Ca2+ is elevated during phases 2–3 of the AP, and thus INCX,fm thereby opposes repolarization. But INCX,fm cannot by itself reverse repolarization, because upon depolarization, at constant Ca2+ and Na+ concentrations, it becomes smaller. Yet if intracellular Ca2+ increases further, either via ICaL reactivation or via spontaneous SR Ca2+ release (spontaneous SRICa-RyR) consequent to Ca2+ overload conditions, INCX,fm can synergistically with reactivated ICaL generate an EAD, which again if large enough triggers an extra AP. Whatever the case, EADs are primarily bradycardia-dependent consequent to time-dependent K+ currents, such as IKs, entering more deeply closed states from which subsequent activation requires more time [119]. But EADs can occur during accelerated heart rates if repolarization reserve is reduced sufficiently—e.g., upon drug-induced K+ current block [120, 121], in conjunction with LQT syndromes [122, 123]; or during conditions of ischemia, HF, and/ or AF that lead to abnormal increases in late Nav1.5 current (INa,late)—as this depolarizing current persists and opposes repolarization throughout the phases 2–3 of the AP [124, 125].
Late phase 3 EAD
DADs
Late-phase 3 EADs (Fig. 24.14, right) represent a mechanism of EAD formation that is unique to atrial myocytes and dependent on dramatic AP abbreviation, tachycardia, and strong normal—not spontaneous—SR Ca2+ release [126, 127]. (Actually, atrial myocytes seem only to be able to produce phase 3 EADs, ventricular myocytes only phase 2 EADs, and Purkinje fiber myocytes both phases 2 and 3 EADs [128].) This three conditions combined to greatly accentuate INCX,fm consequent to peak of the intracellular Ca2+ transient occurring during late-phase 3 of the AP where the membrane potential is ~−70 mV and is likely to be responsible for reinitiating paroxysmal AF immediately after its termination and possibly the initiation of AF due to unbalanced interaction of sympathetic and parasympathetic input [128]. DADs arise via a Ca2+-dependent transient inward depolarizing current (ITI) evoked by sudden increases in cytosolic Ca2+ from extraordinary spontaneous SR Ca2+ release (i.e., spontaneous SRICa-RyR) that occurs upon cellular and consequently SR Ca2+ overload. Cellular Ca2+ overload can be induced by various conditions including (1) adrenergic stress, i.e., extensive or hyperactivation of cardiomyocyte β-adrenergic|Gs signaling-mediated (see above) increase ICaL and SRICa-SERCA resulting in extended durations of high SR Ca2+ load; (2) AMI/acidosis–reperfusion, i.e., increased intracellular Na+ via increase forward-mode sodium-proton exchanger (NHE-1) current (INHE,fm) [129] or via increased INa,late [130, 131] leading to reverse-mode NCX (3Na+ out, 1Ca2+ in) current (INCX,rm) and thus increased intracellular Ca2+/SR Ca2+; and (3) CH and early-stage HF, i.e., increased intracellular Na+ via increased INa,late and/or decrease Na+–K+ ATPase (3Na+ out, 2 K+ in) current (INaK) [114, 115, 132] leading again to increased INCX,rm and thus increased intracellular Ca2+/SR Ca2+. ITI is not a single current, although INCX,fm is considered to be its major component, with minor components being attributable to Ca2+-activated chloride current [133] (molecular basis unknown) and Ca2+-activated nonselective cation current—the prime candidate for this being the transient receptor potential channel, TrpM4 [78, 134]. Not to digress, but while a lesser component of ITI, TrpM4 is expressed throughout the heart [135], including in SAN myocytes [136], which when taken together with its impaired
322
G. Aistrup
endocytosis being associated with human progressive familial heart block type 1 [137] is indicative of playing roles in both automaticity and conduction. In any case, DADs are promoted by tachycardia, as tachycardia exacerbates spontaneous SRICa-RyR → ITI from already Ca2+-overloaded SR. It is interesting to note here that the mechanisms underlying triggered activity and the couple-clock system of SAN automaticity actually share striking similarities; the difference, again, merely being that SAN automaticity arises automatically.
(i.e., attenuate excitation and/or intercellular impulse propagation) in the segment of the circuit susceptible to a block may induce a block and terminate the circuit movement. If the excitatory gap is short, prolonging the refractory period (i.e., attenuate repolarization) of the traveling wavefront in the circuit may terminate reentry when the head approaches the tail of the circuit.
Arrhythmogenic Conduction
Traditional antiarrhythmic drug development/assessment has largely been guided by the one-drug–one-target strategy, and the targets have, with the exception of β-ARs, been sarcolemmal ion channels (e.g., Table 24.4). This is exemplified by the still entrenched Vaughan-Williams classification of antiarrhythmic drugs, which given the current molecular/cellular knowledge is woefully inadequate. The Sicilian Gambit classification—which is actually not a classification but rather a guide to treating various vulnerable parameters that underlie particular arrhythmias—is an improvement but as of yet has not found a broad audience, largely because it not as simple. But perhaps it is time to dispense with simplicity in favor of competency, particularly when considering the rather dismal track record of antiarrhythmic drug therapy (i.e., poor efficacy as well as iatrogenicity), not to mention the multiple forms of arrhythmias, as outlined in Fig. 24.15, all of which have multiplicities of underlying mechanisms—some shared, some divergent. In fact it is becoming quite apparent that newer more effective antiarrhythmic drugs actually do fit well into the Vaughan-Williams classification—e.g., even though amiodarone is categorized as a Class III antiarrhythmic, it exhibits actions consistent with all four Vaughan-Williams Classes—although a “Class V” was added to include “other” antiarrhythmics, which is where most if not all new antiarrhythmics should be classified, thus essentially precluding this type of classification. Indeed, newer antiarrhythmic drugs are emerging that are selective to specific channels expressed only in the region of arrhythmia origin (e.g., pacemaker channels in the SAN/AVN/His–Purkinje system, atrial-predominant Kv1.5|IKur and Kir3.1/4|IK-ACh) and multichannel blockers (e.g., amiodarone, ranolazine, vernakalant), act on disease-specific targets upstream to ion channels (e.g., GPCRs|G-proteins|immediate downstream effectors—i.e., protein kinases, microRNAs), and/or act as antiarrhythmogenic substrate re-remodeling agents (e.g., antifibrotic agents, microRNAs). It is these newer concept antiarrhythmic drugs that will now be discussed in terms of assessing their effectiveness if clinically available or potential effectiveness if still only investigation.
Repetitive excitation of the heart can also result from circus movement of excitation with reentry. But sustained circus movement/reentry is dependent on abnormally slow conduction velocity within its circuit and does not depend on spontaneous depolarization; hence, it is a manifestation of abnormal conduction, not abnormal automaticity. Reentry occurs when a propagating impulse persists after sinus activation of the heart and re-excites cardiac tissue after the expiration of its refractory (inexcitable) period. The most common forms of reentry-based arrhythmia leading to a high risk of cardiac morbidity and mortality are AF and ventricular tachycardia/fibrillation (VT/VF)— although these arrhythmias may be initiated via abnormal automaticity. Other reentry-based rhythm disorders result mostly from unique mechanisms such as intra AVN reentry or accessory pathways. Reentrant-based arrhythmia is dependent on abnormally slow conduction velocity within its circus movement circuit(s), which is due either to structural (infarct scars, excessive fibrosis) or functional barriers (ischemic/stunned depolarized myocytes, GJ closure) to the propagation of the cardiac impulse. In either case, the path of the circus movement must be longer than the wavelength of the excitatory impulse as determined by effective refractory period (ERP) and conduction velocity (CV). Differences in the ERP can be as small as 16 ms can sustain micro-reentry in atria [138], which also can occur in ventricle via amplification of spatial dispersion of refractoriness in ventricular myocardium consequent to augmentation of transmural dispersion of repolarization (see Fig. 24.2, differences in the AP of ventricular epicardium, midmyocardium, and endocardium) in AMI/reperfusion, hypertrophic and dilated cardiomyopathies, as well as various ion channelopathies (i.e., long QT, short QT, and Brugada syndromes, as well as catecholaminergic VT). Whether macro- or micro-reentry, an excitatory gap is considered to be present in the reentry circuit(s) if an external stimulus can enter the circuit(s) and elicit an excitatory response. If the excitatory gap is long, depressing conduction further
Drug Assessment for Arrhythmogenic Automaticity and Conduction
24
Cellular Pharmacology of Cardiac Automaticity and Conduction: Implications in Antiarrhythmic Drug Assessment
323
Table 24.4 Pharmacology of cardiac ion channel/exchanger/pump currents potentially involved in abnormal automaticity and/or conduction/ repolarization vs. their targeting clinical antiarrhythmics if available Current Sodium
Example “selective” experimental cellular Rx agents
Targeting clinical antiarrhythmic drug
TTX-R INa,fast
JZTX-III, TTX(μM), STX, veratridine TTX(nM), STX, veratridine ATX-II Cd2+, dihydropyridines, phenylalkylamines, benzothiazeines, ?Ibutilide?
Class I antiarrhythmics Class I antiarrhythmics Ranexa (ranolazine), Cordarone (amiodarone), Brinavess (vernakalant) ?Corvert (ibutilide)?
Cd2+, dihydropyridines, phenylalkylamines, benzothiazeines Same as for Cav1.2 (some dihydropyridines less potent?) R(-)-efonidipine, NNC 55-0396, ML218 Ni2+(low μM), NNC 55-0396, ML218
Class IV antiarrhythmics Class IV antiarrhythmics NA NA
Ranolazine, Flecanide (but also Class I agent), JTV519 (but has multiple cellular targets) Thapsigargin, cyclopiazonic acid (CPA), 2,5-di-[t-butyl]-1,4-hydroquinone (BHQ), tetrabromobisphenol A (TBBPA), mastoparan, peptide M391, calmidazolium, istaroxime Xestospongin C, heparin
Tambocor/Almarytm/Apocard/Ecrinal/Flécaine (flecanide) NA
TTX-S INa,fast
INa,late Ist Calcium ICaL-C ICaL-D ICaT-G ICaT-H Intracellular SR
SR
SR
ICa-RyR
ICa-SERCA2
ICa-IP3R
Potassium IK1 IKr
Adenosine, BaCl2, AMP579 E-4031, quinidine, clomiphene, ketanserin, ketoconazole, ziprasidone, A-934142, ICA-105574, KB130015, NS1643, NS3623, PD-118057, PD-307243, RPR260243 IKs Chromanol-293B, ephedrine, ginsenoside RE, phenylboronic acid, resveratrol, R-L3, tanshinone IIA Cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate, nordihydroguaiaretic acid, IKur citalopram, DPO-1, LY294002, BMS-394136, KVI-0201, XEN-D0103 Ito Heteropoda spider toxins, adenosine, AMP579 Tertiapin-Q, NIP-151, NTC-801, XEN-R0702, JTV-519(K201), KB130015, IK-ACh(Ado) U73122/U73343 IK-ATP Verrucotoxin, HMR 1098, HMR 1883, nicorandil, 3-pyridyl pinacidil, A-312110, BMS-191095, P1705 Mixed cation (see Table 24.1) Alinidine, falipamil, UL-FS49, ZD7288 ivabradine If KB-R7943, SEA0400, SN-6, XIP, ranolazine INCX Cariporide, eniporide, zoniporide, BIIB 513 INHE INaK Oubain, bufalin, rostafuroxin Palmitoleic acid, carbenoxolone peptides: AAP, AAP10, HP-5, IGJ ZP123(rotigaptide) GAP-134, CyRP-71 ITrpM4 9-phenanthrol, BPT2 (activator at [nM]) BPT2 (inhibitor at [μM]), Pyr3 ITrpC3
NA Class III antiarrhythmics Class III antiarrhythmics
Class III antiarrhythmics Class III antiarrhythmics, Brinavess (vernakalant) Class III antiarrhythmics, Brinavess (vernakalant) Class III antiarrhythmics, Brinavess (vernakalant) Class III antiarrhythmics
Procoralan (ivabradine) NA Cariporide, eniporide Digoxin NA ? ?
Activators are italicized NA none available
Regionally/Origin-Selective Ion Channel Antiarrhythmic Drug Development/ Assessment The impetus for developing heart region/origin-selective drugs relies on the presumption that such targeting would not only be more effective in alleviating automaticity and/or conduction disorder(s) underlying particular arrhythmia(s) that
often occur in a particular heart region but would decrease proarrhythmia risks induced by antiarrhythmic drugs in other heart regions as well as extra-cardiac side effects/toxicity. This entails two strategies that may or may not be amenable to be combined: (1) utilizing drugs that selectively target ion channels whose modulation would be not only be antiarrhythmic but also whose expression is nominally limited to the heart region where a particular arrhythmia occurs and/or
324 Fig. 24.15 Some common cardiac arrhythmias associated with abnormal automaticity and conduction
G. Aistrup Mechanisms of cardiac arrhythmias Abnormal impulse formation (automaticity)
Abnormal impulse propagation (conduction)
Sick Sinus Syndrome/enhanced automaticity Sinus tachycardia Sinus bradycardia Sinus brady- tachycardia Atrial tachycardia Atrial fibrillation Accelerated AV junctional tachycardia Accelerated idioventricular rhythm Right ventricular outflow track tachycardia
Reentrant Sinus node reentry Atrial tachycardia Atrial flutter Atrial fibrillation AV nodal reentry tachycardia AV reentry tachycardia Ventricular tachycardia Ventricular fibrillation Torsades de pointes
Triggered activity (EADs and DADs) Atrial tachycardia Multifocal atrial tachycardia Ventricular tachycardia ventricular tachycardia Right ventricular outflow track tachycardia Catecholaminergic polymorphic ventricular tachycardia Torsades de pointes
(2) delivery of less selective antiarrhythmic agents targeted and restricted to heart region where the arrhythmia occurs— i.e., therapeutic peptide/RNAi/microRNA transgene vector delivery in vivo, a very promising technique which is progressing steadily [139–141]. In terms of altering abnormal intrinsic automaticity in the SAN (or the AVN and/or His–Purkinje system) using such strategy, selective drug targets are HCN|If, Cav1.3|ICaL-D, and Cav3.1|ICaT-G, as these targets are unique or at least more so particular to intrinsic automaticity and not involved in the primary function of working cardiomyocytes. But to date, only one drug is clinically available that selectively targets one of these ion channels—the selective HCN blocker, ivabradine [142]. Indeed, ivabradine is a good example of the process of drug assessment—i.e., it was originally approved for slowing heart rate in alleviation of angina pectoris (as angina is pain due to global cardiac ischemia, decreasing heart rate equates to less demand for oxygen, thus angina relief) but, in recent clinical trials assessing the prospective of reducing heart rate in HF, is accruing very respectable safety and efficacy profiles [143], but it would obviously be contraindicative in cases of comorbid bradyarrhythmia wherein it would exacerbate the latter. Bradyarrhythmia therapy in this context awaits selective activators of HCN|If, Cav1.3|ICaL-D, Cav3.1|ICaT-G. Moreover, gene ablation of either HCN4|If or Cav1.3|ICaL-D causes ~50 % reduction in heart rate [36, 144, 145] and that of Cav3.1|ICaT-G causes ~35 % reduction in heart rate [146], but their pharmacological block results in much more modest reductions [99]. Thus for more control of more severe tachyarrhythmia, a more potent HCN inhibitor and/or augmentation by a selective Cav1.3|ICaL-D or Cav3.1|ICaT-Ginhibitor would seem to be warranted. Cav1.3|ICaL-D- and/or Cav3.1|ICaT-G-selective inhibitors may also demonstrate an effective alleviation of accelerated
AV junctional tachycardias, as Cav1.3|ICaL-D may be the predominant ICaL in the AVN and wherein Cav3.1|ICaT-G is more abundantly expressed [37]. The exclusive atrial expression of Kir3.1/4|IK-ACh(Ado) and Kv1.5|IKur makes them attractive targets for reducing sustainability of reentrant atrial arrhythmias like AT/AFL/AF [147]. Selective inhibition of Kir3.1/4|IK-ACh(Ado) (which is constitutively active in chronic and paroxysmal AF [148, 149]) would be expected to increase AP duration/atrial effective refractory period (AERP) via prolonging terminal repolarization and would eliminate Kir3.1/4|IK-ACh(Ado) contribution (together with IK1) to Vm,rest and cause it to be less hyperpolarized, which in turn would likely reduce Nav1. x|INa,fast availability and increase post-repolarization refractoriness (PRR)—i.e., decreased atria excitability and reduced automaticity, thus, and unsustainability of AF reentrant rotors. Actually, such IK-ACh(Ado) inhibitory properties would provide for both termination and prevention of AF. However, inhibition of Kir3.1/4|IK-ACh(Ado) may lead to enhanced and/or more variable intrinsic automaticity, and expression of Kir3.x channels in the CNS could lead to neurological side effects, but these have not been indicated by the clinical trials thus far undertaken with several IK-ACh(Ado)-selective inhibitors (e.g., NIP-151, NTC-801, XEN-R0702) [147]. Similarly, Kv1.5|IKur inhibition would only be expected to increase AP duration/ AERP, though via prolonging early repolarization and without affecting Vm,rest or PRR (i.e., no indirect attenuation of INa,fast); thus Kv1.5|IKur inhibitors may be effective in preventing reoccurrence of atrial arrhythmias, but less effective in terminating them. The effectiveness and tolerance of Kv1.5|IKur-selective drugs (e.g., BMS-394136, KVI-0201, XEN-D0103) awaits recently undertaken clinical trials [147]. These atrial-selective drugs hold definite promise for improved treatment of supraventricular arrhythmias.
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Cellular Pharmacology of Cardiac Automaticity and Conduction: Implications in Antiarrhythmic Drug Assessment
Changes in GJs have been variably implicated in conduction slowing in AMI/reperfusion injuries [150, 151] and AF [152], which predisposes to reentrant arrhythmia susceptibility. And because the origins of AMI/reperfusion-initiated reentrant arrhythmias are typically localized to discrete regions of the heart, enhancement of GJ conduction in the regions/origins of risk has the potential to be antiarrhythmic. Thus, ideally the delivery of GJ-enhancing antiarrhythmics would be targeted and restricted to the area of risk surrounding the AMI/reperfusion injury site or at least to the working atria, as enhanced GJs elsewhere could be predisposed to overly enhanced conduction that, for instance, in the SAN could predispose to less reliable SAN impulse generation or in the AVN to improper impulse delay. However, enhanced myocardial GJ conduction via systemic administration of rotigaptide, a peptide that results in Cx43/45-selective conduction enhancement and reduced AP duration dispersion [153, 154], prevents AMI and/or AMI-/reperfusion-induced atrial and ventricular reentrant tachycardias without significant side effects and toxicity [150]. This was indicative that such antiarrhythmic strategy can work and that in this case “globally” enhanced Cx43/45 GJ conduction is not overtly a problem. Such antiarrhythmic action appears to be constrained to reentrant arrhythmias, as rotigaptide did not prevent/suppress not focal arrhythmias [155]—i.e., arrhythmias caused by most likely triggered activity due to injury currents flowing between the ischemic and the normal area can play a role in arrhythmia initiation/reinitiation under such conditions. In terms of supraventricular arrhythmias such as AF, rotigaptide improved conduction in multiple animal models of AF but suppressed AF only under conditions of acute ischemia substrate [156]. However, AF was effectively suppressed by delivering Cx40- and/or Cx43-expressing transgene vectors to atria in a persistent AF development model [157], wherein targeted-restricted atrial delivery of transgene vectors is prerequisite, even if only for practicalities. There are more examples of potential region/originselective drug development/assessment (e.g., inhibition of TrpM4 most prevalently expressed in the His–Purkinje system as a strategy against AV/bundle branch-based triggered and/or reentrant arrhythmias [158]), but with the discussion of just these few examples, it should be evident that there is reasonable potential for increased efficacy and safety in regionally/origin-selective antiarrhythmic pharmacological therapy with or without targeted-restricted agent delivery.
Multichannel Antiarrhythmic Drug Development/Assessment Despite the attraction and perceived eloquence of selectivetarget drug development/assessment, one cannot escape the realization that the most effective antiarrhythmic drugs
325
appear to be those that target multiple ion channels/exchangers/pumps, particularly for the most common, most mechanistically complex AT/AFL/AF and VT/VF arrhythmias. Amiodarone has already been exemplified in this regard— which blocks INa,fast,INa,late,ICa in a use- and voltage-dependent manner; IK-ACh(Ado),IKr, IKs, and IK-ATP; as well as INCX and αand β-ARs (all of which also exemplifies its toxicity propensity) yet exhibits little proarrhythmic propensity (likely due to its effect to reduce QT dispersion) [159]. Actually, this may be no misnomer given that physiological regulation of automaticity and conduction does not occur via monotypic modulation but rather multitypic modulation—e.g., β-AR|Gs signaling modulates nearly all the cardiac channels involved in automaticity and conduction (recall Fig. 24.11). But continued drug development/assessment is revealing more examples—albeit even if the initial goal was supposed to be selective-target agents. Interestingly, dronedarone, an modified structurally modified analogue of amiodarone with a much better toxicity profile, seems to gain the latter with the cost of lower antiarrhythmic efficacy vs. amiodarone [160]. Ranolazine/Ranexa® (CV Therapeutics, acquired by Gilead Sciences) has emerged as a potentially powerful antiarrhythmic drug [161–163]. Initially developed and considered relatively selective for blocking INa,late, thus reducing Na+-induced Ca2+ overload (as discussed above), ranolazine was approved as an antianginal agent (not an antiarrhythmic). But because INa,late likely contributes to triggered activity, particularly as INa,late is increased not only in ischemia/ AMI but also in CH, HF, OS, and AF (as well as in LQT-III syndrome), ranolazine was soon examined for antiarrhythmic potential. Such investigations revealed that ranolazine, at its therapeutic concentrations (2–8 μM) of blocking late INa,late, also inhibits IKr, peak atrial INa,fast (more atrial Nav1.5 channels are in the inactivated state—more negative V½,inact and less negative Vm,rest—compared to that in the ventricle, and ranolazine is a use-dependent Nav1.5 inactivated-state blocker [164] and may explain atrial selectivity of amiodarone and vernakalant), and ICa-L,late [162]; and now recently, ranolazine has been shown to reduce the open probability and desensitize Ca2+-dependent activation of RyR2s [165]. The latter further exemplifies its antiarrhythmic effectiveness, particularly in suppressing triggered activity and torsade de pointes despite IKr inhibition (and would ranolazine be effective in treating catecholaminergic polymorphic ventricular tachycardia, given flecainide achieves this via block of both Nav1.5 and RyR2 inhibition [166]?). Indeed, numerous animal and clinical studies have shown significant antiarrhythmic efficacy of ranolazine in treating AT/AF and VT/ VF [161, 162] (one showing ranolazine to be more effective than amiodarone [167]) without proarrhythmia or severe toxicity and without contraindication in comorbid MI, CH, or HF. Still, realizing the true potential of ranolazine awaits more robust clinical trial testing.
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Vernakalant/Brinavess™ (Cardiome Pharma), a drug recently approved in Europe for the conversion of recentonset AF [168], has both multichannel targets and is largely atrial selective [169]. Vernakalant blocks IKur, IK-ACh(Ado), Ito, and to a lesser extent IKr and INa,fast; but at rapid heart rates and/or more depolarizing Vm,rest, inhibition of INa,fast as well as INa,late becomes significantly more prominent [170, 171] (i.e., prominent use- and voltage-dependent Nav1.5 block, like ranolazine and amiodarone). Such properties would explain its effectiveness in terminating and preventing acute reoccurances of AF (indeed it was shown to be effective against torsades de pointes induced by Class III antiarrhythmics [171]) without significant proarrhythmia risk or severe toxicity. Oddly, though, vernakalant was ineffective in converting AFL [172], which points to nontrivial differences in AFL and AF maintenance mechanisms. To this latter point, the Class III agent ibutilide/Corvert® (Pfizer), the only intravenous drug approved for acute AF conversion in the USA, actually has greater efficacy rate for acute conversion of AFL than AF [173, 174]. Interestingly, while ibutilide primarily blocks IKr and thus significantly prolongs the AP duration (and is proarrhythmic), it also uniquely activates a slow inward Na+ current that can be blocked by nifedipine [175], which actually is a similar profile to that of Ist (see discussion above and Table 24.1); hence, thorough antiarrhythmic drug assessment can provide positively feedback to the basic science of delineating specific components in automaticity and/ or conduction. How this plays into differential AFL vs. AF therapy awaits further investigation. Given the apparent success of multichannel-targeting antiarrhythmics, it is quite likely that there will be more to come—e.g., HIB-3000 (HUYA Bioscience Int’l), which again blocks IKR, peak INa,fast, and ICa-L but more dominantly inhibits INa,late, and suppressed EADs in failing ventricular myocytes as well as EADs induced by Class III agents [176]. There obviously is a trend towards mixed outward and inward current block portending effective antiarrhythmic without proarrhythmia, but the devil is in the mechanistic details, as another mixed INa, ICa, and IK blocker, terfenadine [177, 178], is proarrhythmic (causes torsade de pointes leading to VF) [179, 180].
Upstream Modulator-Targeting Antiarrhythmic Drug Development/ Assessment The idea behind targeting upstream modulators of ion channels/exchangers/pumps is that while all pathologies that predispose to arrhythmogenic automaticity and/or conduction entail multiple molecular players (including ion channels/exchangers/pumps), their aberrant modulation stems from one or a few common aberrant upstream
G. Aistrup
entity—i.e., G-protein|protein kinases, Ca2+-CaM|CaMKII, and/or miRNAs. Thus, selective attenuation (or potentiation) of such upstream targets (or their more immediate downstream effectors) or miRNAs associated with the arrhythmogenic pathologies could potentially effectively attenuate (or potentiate) all of the downstream effectors as well. Of course given the overt modulation of automaticity by the autonomic system, such concept is not new, as evidenced by well-established clinical use of β-blockers (antagonists of β1,2-AR|Gs|↑cAMP|↑PKA signaling) to alleviate sinus tachycardia and right ventricular outflow tract tachycardia and atropine (antagonist of Μ2,4-CR|Gαi/ oβγ|↑Kir3.1/4|↓cAMP|↓PKA signaling) to acutely reverse AV block. Relatedly, though conversely to the latter, by virtue of type 1 adenosine (Ado) receptors (A1-AdoRs) coupling to Gαi/oβγ|↑Kir3.1/4(IK-ACh(Ado))|↓cAMP|↓PKA signaling [181] (as do Μ2,4-CRs), Ado is well suited to acutely terminate AVN reentry-based paroxysmal supraventricular tachycardias with minor side effects due to fast half-life and nominal ventricular action compared to Cav1.x|ICaL also used for this purpose (e.g., verapamil), particularly in cases of comorbid left ventricular dysfunction, as nonselective ICaL blockers like verapamil also inhibit Cav1.2|ICaL-C channels essential for E-C coupling in working myocardium [182]. However, if AVN-based arrhythmias persist and/or if supraventricular arrhythmia is not AVN based, adenosine can be proarrhythmic owing to its (like ACh’s) action to active Kir3.1/4|IK-ACh(Ado) in working atria to dramatically reduce AERP, thus predisposing to reentrant arrhythmias—indeed, as discussed above, considerable effort has recently been put into developing Kir3.1/4|IK-ACh(Ado)-selective inhibitory drugs. Ca2+/CaM|CaMKII, as discussed above, is also heavily intertwined in modulating automaticity and, given that CaMKIIδC overactivation leads to arrhythmogenic leaky RyR2s in HF, yet in and of itself only nominally decreases in SR Ca2+ and contraction and relaxation [183], selectively inhibiting CaMKIIδC should and has recently been shown to be antiarrhythmogenic at the investigational level (using the CaMKII inhibitor KN93 in a AMI/reperfusion—triggered activity—model [184] and using transgenic expression of the selective CaMKIIδC inhibitory peptide AC3-I in a transgenic calcineurin-induced ventricular dysfunctional arrhythmogenic hypertrophic heart [185]). Interestingly, AC3-I inhibition of oxidized (activated) CaMKII prevents SAN dysfunction consequent to increased circulating AngII signaling in hypertension and HF [186]. On a similar note, KN93 as well as another CaMKII-inhibitory peptide, AIP, attenuated EAD, and DAD formation induced by enhanced ICa-L and INa,late consequent to OS-generated reactive oxygen species (ROS) as induced by H2O2 or AngII [187, 188] and ROS-activated CamKIIδC is apparently required for enhanced INa,late, which can lead to Na+ and Ca2+ overload
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Cellular Pharmacology of Cardiac Automaticity and Conduction: Implications in Antiarrhythmic Drug Assessment
(and thus DADs and possibly EADs and triggered activity), but was reversed by KN93 or AIP administration [189]. The latter may be particularly significant in CH/HF arrhythmia susceptibility, as both ROS and CaMKII are increased in CH/ HF. Clearly more examination into the potential of CaMKII as an upstream antiarrhythmic drug target is warranted by such findings but also indicative was crosstalk between Ca2+-CaM|CaMKII signaling and Gq signaling (recall AngII couples via AT1Rs to Gαqβγ) as well as to OS-generated reactive oxygen species (ROS), thus signifying the potential for attenuating Gq signaling and/or ROS generation (e.g., via NADPH oxidase inhibition [188]) as upstream antiarrhythmic targets. Indeed, Gq-induced atrial remodeling (i.e., CH, left atrial dilation, extensive fibrosis, slowed conduction) and arrhythmogenesis (both ventricular and atrial tachyarrhythmias, including AF) was prevented by degenerating DAG (a primary second messenger in Gq signaling) with DAG kinaseζ [190, 191]. Again, there are many more recent examples demonstrating the potential and feasibility of targeting upstream modulators of abnormal automaticity and conduction as a novel basis for antiarrhythmic pharmacotherapy. The most recent strategy in this regard is the extrinsic manipulation of microRNA posttranscriptional regulation of cardiac automaticity, conduction, and repolarization (discussed above). But while techniques to manipulate microRNA expression, such as anti-miR oligonucleotides to inhibit miR action, and miR mimics to augment miR action are available [192], much more needs to be garnered in terms of better identifying/ validating and characterizing miRNAs important in regulating cardiac automaticity and conduction, optimizing miR specificity/efficacy/toxicity, and further developing and optimizing miRNA oligonucleotide and mimic delivery strategies [193]—i.e., heart region/myocyte type target-restricted delivery—as may well be the case for many other antiarrhythmic pharmacotherapeutics that target upstream modulators discussed herein given that such agents are often not amiable to systemic delivery. Notwithstanding, progress is being made in this and with it additional novel antiarrhythmic drug development and assessment.
Concluding Remarks Drug development/assessment has been slow even seemingly reluctant to embrace the recent advancements made in molecular/cellular basis for cardiac automaticity and conduction and the underlying basis for associated arrhythmogenic abnormalities, no doubt largely due to the realized complexities. But it should also be realized that while cardiac automaticity and conduction are complex processes, their successful physiological modulation is accomplished only by equally complex processes that exert exquisitely
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selective control of various molecular constituents of intrinsic automaticity and conduction. Thus, advances can be and are being made by devising new approaches to antiarrhythmic drug development, and assessment based on the acknowledgement and continued delineation of the underlying complexities of automaticity and conduction abnormalities is embraced accordingly.
Abbreviations: Proteins Nav NCX1 Cav LTCC TTCC HCN NCX Kir Kv hERG ATPase MiRP1 minK KChiP2 DPP6 SUR RyR2 SERCA PLB PLM AC PKA aKAP PP1 PP2A PR130 HRC PLC PKC CaM CaMKII
Voltage-dependent Na+ channel Type 1 Na+-Ca2+ exchanger Voltage-dependent Ca2+ channel L-type Ca2+ channel (older nomenclature) T-type Ca2+ channel (older nomenclature) Hyperpolarization-activated channel Na+-Ca2+ exchanger Inwardly rectifying K+ current Voltage-dependent K+ current Human ether-a-go-go-related channel Adenosinetriphosphase MinK-related channel subunit-1 Minimal K+ channel subunit Kv-channel interacting subunit-2 Diaminopeptidyltransferase-like protein 6 Sulfonylurea receptor subunit Type-2 ryanodine receptor SR Ca2+ release channel Sarco-endoplasmic reticulum Ca2+-ATPase Phospholamban Phospholemman Adenylate cyclase Protein kinase A A-kinase anchoring protein Protein phosphatase type 1 Protein phosphatase type A2 Phosphatase recruiting/regulatory protein Histidine-rich Ca2+-binding protein Phospholipase-C Protein kinase C Calmodulin Ca2+/calmodulin-dependent kinase type-II
Currents ICaL-C ICaL-D ICaT-G ICaT-H
α1C-LTCC current α1D-LTCC current α1G-TTCC current α1H-TTCC current
328
If Ist INCX,fm IK1 IKur IKr IKs Ito,f Ito,s IK-ACh(Ado) IK-ATP INaK SR INCX,rm SR ICa-RyR2 SR ICa-SERCA2
G. Aistrup
”Funny” current ”Sustained” current Forward-mode NCX current Inward-rectifier K+ current Ultrarapid component of delayed-rectifier K+ current Rapid component of delayed-rectifier K+ current Slow component of delayed-rectifier K+ current Transient outward K+ current, fast component Transient outward K+ current, slow component Acetylcholine(or adenosine)-activated inwardly rectifying K+ current Adenosine triphosphate-inhibited K+ current Na+/K+ ATPase pump current Sarcoplasmic reticulum Reverse-mode NCX current RyR2-mediated SR Ca2+-release current SERCA2-mediated SR Ca2+-reuptake current.
Other CAMP PIP2 DAG TTX Epi Mid Endo
Cyclic adenosine monophosphate Phosphatidylinositol-4,5-bisphosphate Diacylglycerol Tetrodotoxin Ventricular epicardium Ventricular midmyocardium Ventricular endocardium
References 1. Tamargo J. Drug-induced torsade de pointes: from molecular biology to bedside. Jpn J Pharmacol. 2000;83(1):1–19. 2. Michael G, Xiao L, Qi X-Y, Dobrev D, Nattel S. Remodelling of cardiac repolarization: how homeostatic responses can lead to arrhythmogenesis. Cardiovasc Res. 2009;81(3):491–9. doi:10.1093/ cvr/cvn266. 3. Ruan Y, Liu N, Priori SG. Sodium channel mutations and arrhythmias. Nat Rev Cardiol. 2009;6(5):337–48. 4. Ganong WF. Review of medical physiology. 22nd ed. New York: McGraw-Hill; 2005. 5. Boyett MR. ‘And the beat goes on’ the cardiac conduction system: the wiring system of the heart. Exp Physiol. 2009;94(10):1035–49. doi:10.1113/expphysiol.2009.046920. 6. Shih HT. Anatomy of the action potential in the heart. Tex Heart Inst J. 1994;21(1):30–41. 7. Schram G, Pourrier M, Melnyk P, Nattel S. Differential distribution of cardiac ion channel expression as a basis for regional specialization in electrical function. Circ Res. 2002;90(9):939–50. 8. Lipsius SL, Bers DM. Cardiac pacemaking: if vs. Ca2+, is it really that simple? J Mol Cell Cardiol. 2003;35(8):891–3. 9. Satoh H. Sino-atrial nodal cells of mammalian hearts: ionic currents and gene expression of pacemaker ionic channels. J Smooth Muscle Res. 2003;39(5):175–93.
10. Tellez JO, Dobrzynski H, Greener ID, Graham GM, Laing E, Honjo H, et al. Differential expression of Ion channel transcripts in atrial muscle and sinoatrial node in rabbit. Circ Res. 2006;99(12):1384– 93. doi:10.1161/01.res.0000251717.98379.69. 11. Mangoni ME, Couette B, Marger L, Bourinet E, Striessnig J, Nargeot J. Voltage-dependent calcium channels and cardiac pacemaker activity: from ionic currents to genes. Prog Biophys Mol Biol. 2006;90(1–3):38–63. doi:10.1016/j.pbiomolbio.2005.05.003. 12. Greener ID, Tellez JO, Dobrzynski H, Yamamoto M, Graham GM, Billeter R, et al. Ion channel transcript expression at the rabbit atrioventricular conduction axis//CLINICAL PERSPECTIVE. Circ Arrhythm Electrophysiol. 2009;2(3):305–15. doi:10.1161/ circep.108.803569. 13. Gaborit N, Le Bouter S, Szuts V, Varro A, Escande D, Nattel S, et al. Regional and tissue specific transcript signatures of ion channel genes in the non-diseased human heart. J Physiol. 2007;582(2):675–93. doi:10.1113/jphysiol.2006.126714. 14. Mangoni ME, Nargeot J. Genesis and regulation of the heart automaticity. Physiol Rev. 2008;88(3):919–82. doi:10.1152/physrev.00018.2007. 88/3/919 [pii]. 15. Hagiwara N, Irisawa H, Kameyama M. Contribution of two types of calcium currents to the pacemaker potentials of rabbit sino-atrial node cells. J Physiol. 1988;395(1):233–53. 16. Denyer JC, Brown HF. Pacemaking in rabbit isolated sino-atrial node cells during Cs + block of the hyperpolarization-activated current if. J Physiol. 1990;429(1):401–9. 17. Lei M, Jones SA, Liu J, Lancaster MK, Fung SS-M, Dobrzynski H, et al. Requirement of neuronal- and cardiac-type sodium channels for murine sinoatrial node pacemaking. J Physiol. 2004;559(3):835– 48. doi:10.1113/jphysiol.2004.068643. 18. Kodama I, Nikmaram MR, Boyett MR, Suzuki R, Honjo H, Owen JM. Regional differences in the role of the Ca2+ and Na + currents in pacemaker activity in the sinoatrial node. Am J Physiol Heart Circ Physiol. 1997;272(6):H2793–806. 19. Rigg L, Terrar D. Possible role of calcium release from the sarcoplasmic reticulum in pacemaking in guinea-pig sino-atrial node. Exp Physiol. 1996;81(5):877–80. 20. Nathan RD. Two electrophysiologically distinct types of cultured pacemaker cells from rabbit sinoatrial node. Am J Physiol Heart Circ Physiol. 1986;250(2):H325–9. 21. Muramatsu H, Zou AR, Berkowitz GA, Nathan RD. Characterization of a TTX-sensitive Na+ current in pacemaker cells isolated from rabbit sinoatrial node. Am J Physiol Heart Circ Physiol. 1996;270(6):H2108–19. 22. Yoo S, Dobrzynski H, Fedorov VV, Xu S-Z, Yamanushi TT, Jones SA, et al. Localization of Na+ channel isoforms at the atrioventricular junction and atrioventricular node in the rat. Circulation. 2006;114(13):1360–71. doi:10.1161/circulationaha.106.613182. 23. Bogdanov KY, Vinogradova TM, Lakatta EG. Sinoatrial nodal cell ryanodine receptor and Na(+)-Ca(2+) exchanger: molecular partners in pacemaker regulation. Circ Res. 2001;88(12):1254–8. 24. Huser J, Blatter LA, Lipsius SL. Intracellular Ca2+ release contributes to automaticity in cat atrial pacemaker cells. J Physiol. 2000;524(Pt 2):415–22. 25. Torrente A, Mesirca P, Neco P, Sinegger-Brauns M, Striessnig J, Nargeot J, et al. Cav1.3 L-type calcium channels-mediated ryanodine receptor dependent calcium release controls heart rate. Biophys J. 2011;100(3, Supplement):567a. doi:10.1016/j.bpj.2010.12.3289. 26. Lakatta EG, Maltsev VA, Vinogradova TM. A coupled SYSTEM of intracellular Ca2+ clocks and surface membrane voltage clocks controls the timekeeping mechanism of the heart’s pacemaker. Circ Res. 2010;106(4):659–73. doi:10.1161/CIRCRESAHA.109.206078. 106/4/659 [pii]. 27. Monfredi O, Dobrzynski H, Mondal T, Boyett MR, Morris GM. The anatomy and physiology of the sinoatrial node—a contemporary review. Pacing Clin Electrophysiol. 2010;33(11):1392–406. doi:10.1111/j.1540-8159.2010.02838.x.
24
Cellular Pharmacology of Cardiac Automaticity and Conduction: Implications in Antiarrhythmic Drug Assessment
28. Dhamoon AS, Jalife J. The inward rectifier current (IK1) controls cardiac excitability and is involved in arrhythmogenesis. Heart Rhythm. 2005;2(3):316–24. doi:10.1016/j.hrthm.2004.11.012. 29. Anumonwo JMB, Lopatin AN. Cardiac strong inward rectifier potassium channels. J Mol Cell Cardiol. 2010;48(1):45–54. doi:10.1016/j.yjmcc.2009.08.013. 30. Lakatta EG, DiFrancesco D. What keeps us ticking: a funny current, a calcium clock, or both? J Mol Cell Cardiol. 2009;47(2):157– 70. doi:10.1016/j.yjmcc.2009.03.022. 31. DiFrancesco D, Noble D. Rebuttal: “the funny current in the context of the coupled clock pacemaker cell system”. Heart Rhythm. 2012;9(3):457–8. doi:10.1016/j.hrthm.2011.09.023. 32. Lakatta EG, Maltsev VA. Rebuttal: what if the shoe doesn’t fit? “the funny current has a major pacemaking role in the sinus node”. Heart Rhythm. 2012;9(3):459–60. doi:10.1016/j.hrthm.2011.09.024. 33. Rosen MR, Nargeot J, Salama G. The case for the funny current and the calcium clock. Heart Rhythm. 2012;9(4):616–8. doi:10.1016/j. hrthm.2011.10.008. 34. Mangoni ME, Couette B, Bourinet E, Platzer J, Reimer D, Striessnig J, et al. Functional role of L-type Cav1.3 Ca2+ channels in cardiac pacemaker activity. Proc Natl Acad Sci. 2003;100(9):5543–8. 35. Ono K, Iijima T. Cardiac T-type Ca2+ channels in the heart. J Mol Cell Cardiol. 2010;48(1):65–70. doi:10.1016/j.yjmcc.2009.08.021. 36. Baig SM, Koschak A, Lieb A, Gebhart M, Dafinger C, Nurnberg G, et al. Loss of Cav1.3 (CACNA1D) function in a human channelopathy with bradycardia and congenital deafness. Nat Neurosci. 2011;14(1):77–84. doi:http://www.nature.com/neuro/journal/v14/ n1/abs/nn.2694.html#supplementary-information. 37. Marger L, Mesirca P, Alig J, Torrente A, Dubel S, Engeland B, et al. Functional roles of Ca(v)1.3, Ca(v)3.1 and HCN channels in automaticity of mouse atrioventricular cells: insights into the atrioventricular pacemaker mechanism. Channels (Austin). 2011;5(3):251–61. 15266 [pii]. 38. DiFrancesco D. Funny channels in the control of cardiac rhythm and mode of action of selective blockers. Pharmacol Res. 2006;53(5):399–406. doi:10.1016/j.phrs.2006.03.006. 39. Guo J, Ono K, Noma A. A sustained inward current activated at the diastolic potential range in rabbit sino-atrial node cells. J Physiol. 1995;483(Pt 1):1–13. 40. Mitsuiye T, Shinagawa Y, Noma A. Sustained inward current during pacemaker depolarization in mammalian sinoatrial node cells. Circ Res. 2000;87(2):88–91. doi:10.1161/01.res.87.2.88. 41. Zhang H, Holden AV, Boyett MR. Sustained inward current and pacemaker activity of mammalian sinoatrial node. J Cardiovasc Electrophysiol. 2002;13(8):809–12. 42. Mese G, Richard G, White TW. Gap junctions: basic structure and function. J Invest Dermatol. 2007;127(11):2516–24. 43. Davis LM, Rodefeld ME, Green K, Beyer EC, Saffitz JE. Gap junction protein phenotypes of the human heart and conduction system. J Cardiovasc Electrophysiol. 1995;6(10 Pt 1):813–22. 44. Vozzi C, Dupont E, Coppen SR, Yeh H-I, Severs NJ. Chamberrelated differences in connexin expression in the human heart. J Mol Cell Cardiol. 1999;31(5):991–1003. doi:10.1006/jmcc.1999.0937. 45. Desplantez T, Halliday D, Dupont E, Weingart R. Cardiac connexins Cx43 and Cx45: formation of diverse gap junction channels with diverse electrical properties. Pflugers Arch. 2004;448(4):363–75. 46. Rackauskas M, Neverauskas V, Skeberdis VA. Diversity and properties of connexin gap junction channels. Medicina (Kaunas). 2010;46(1):1–12. 1001-01 [pii]. 47. Severs NJ, Bruce AF, Dupont E, Rothery S. Remodelling of gap junctions and connexin expression in diseased myocardium. Cardiovasc Res. 2008;80(1):9–19. 48. Swietach P, Spitzer KW, Vaughan-Jones RD. Modeling calcium waves in cardiac myocytes: importance of calcium diffusion. Front Biosci. 2010;15:661–80. 3639 [pii]. 49. Shaw RM, Rudy Y. Ionic mechanisms of propagation in cardiac tissue : roles of the sodium and L-type calcium currents during
50.
51.
52.
53.
54.
55.
56. 57.
58. 59. 60. 61.
62.
63.
64.
65.
66. 67.
68.
329
reduced excitability and decreased gap junction coupling. Circ Res. 1997;81(5):727–41. doi:10.1161/01.res.81.5.727. Jalife J, Morley GE, Vaidya D. Connexins and impulse propagation in the mouse heart. J Cardiovasc Electrophysiol. 1999;10(12): 1649–63. KLÉBER AG, RUDY Y. Basic mechanisms of cardiac impulse propagation and associated arrhythmias. Physiol Rev. 2004;84(2): 431–88. doi:10.1152/physrev.00025.2003. Jansen JA, van Veen TAB, de Bakker JMT, van Rijen HVM. Cardiac connexins and impulse propagation. J Mol Cell Cardiol. 2010;48(1):76–82. doi:10.1016/j.yjmcc.2009.08.018. Bernstein D, Fajardo G, Zhao M. The role of β-adrenergic receptors in heart failure: differential regulation of cardiotoxicity and cardioprotection. Prog PediatrCardiol. 2011;31(1):35–8. doi:10.1016/j. ppedcard.2010.11.007. Li Q, O’Neill Stephen C, Tao T, Li Y, Eisner D, Zhang H. Mechanisms by which cytoplasmic calcium wave propagation and alternans Are generated in cardiac atrial myocytes lacking T-tubules—insights from a simulation study. Biophys J. 2012;102(7):1471–82. doi:10.1016/j.bpj.2012.03.007. Coppen SR, Kodama I, Boyett MR, Dobrzynski H, Takagishi Y, Honjo H, et al. Connexin45, a major connexin of the rabbit sinoatrial node, is co-expressed with connexin43 in a restricted zone at the nodal-crista terminalis border. J Histochem Cytochem. 1999;47(7):907–18. Dun W, Boyden PA. The Purkinje cell; 2008 style. J Mol Cell Cardiol. 2008;45(5):617–24. doi:10.1016/j.yjmcc.2008.08.001. Shibata EF, Brown TLY, Washburn ZW, Bai J, Revak TJ, Butters CA. Autonomic regulation of voltage-gated cardiac Ion channels. J Cardiovasc Electrophysiol. 2006;17:S34–42. doi:10.1111/j.1540-8167.2006.00387.x. Guyton C, Hall JE. Textbook of medical physiology. 11th ed. Philadelphia: W.B. Saunders (Elsevier, Moser, Saunders); 2006. Taggart P, Lambiase P. Anger, emotion and mental stress: from brain to heart. Front Physiol. 2011;2. doi:10.3389/fphys.2011.00067. Klabunde RE. Cardiovascular physiology concepts. 2nd ed. Philadelphia: Lippincott & Wilkins; 2011. Verkerk AO, Geuzebroek GSC, Veldkamp MW, Wilders R. Effects of acetylcholine and noradrenalin on action potentials of isolated rabbit sinoatrial and atrial myocytes. Front Physiol. 2012;3. doi:10.3389/fphys.2012.00174. Rozec B, Noireaud J, Trochu JN, Gauthier C. Place of beta 3-adrenoceptors among other beta-adrenoceptor subtypes in the regulation of the cardiovascular system. Arch Mal Coeur Vaiss. 2003;96(9):905–13. Gauthier C, Rozec B, Manoury B, Balligand JL. Beta-3 adrenoceptors as new therapeutic targets for cardiovascular pathologies. Curr Heart Fail Rep. 2011;8(3):184–92. doi:10.1007/ s11897-011-0064-6. Stangherlin A, Gesellchen F, Zoccarato A, Terrin A, Fields LA, Berrera M, et al. CGMP signals modulate cAMP levels in a compartment-specific manner to regulate catecholamine-dependent signaling in cardiac myocytes/novelty and significance. Circ Res. 2011;108(8):929–39. doi:10.1161/circresaha.110.230698. Hammond J, Balligand J-L. Nitric oxide synthase and cyclic GMP signaling in cardiac myocytes: from contractility to remodeling. J Mol Cell Cardiol. 2012;52(2):330–40. doi:10.1016/j. yjmcc.2011.07.029. Hubbard KB, Hepler JR. Cell signalling diversity of the Gq [alpha] family of heterotrimeric G proteins. Cell Signal. 2006;18(2):135–50. Salazar NC, Chen J, Rockman HA. Cardiac GPCRs: GPCR signaling in healthy and failing hearts. Biochim Biophys Acta. 2007;1768(4):1006–18. Hool LC, Oleksa LM, Harvey RD. Role of G proteins in α1-adrenergic inhibition of the β-adrenergically activated chloride current in cardiac myocytes. Mol Pharmacol. 1997;51(5): 853–60.
330 69. Kim JH, Shin SY, Nam JH, Hong E-K, Chung Y-S, Jeong JY, et al. Adrenergic regulation of the intracellular [Ca2+] and voltageoperated Ca2+ channel currents in the rat prostate neuroendocrine cells. Prostate. 2003;57(2):99–110. doi:10.1002/pros.10277. 70. Zhu Y-C, Zhu Y-Z, Lu N, Wang M-J, Wang Y-X, Yao T. Role of angiotensin AT1 and AT2 receptors in cardiac hypertrophy and cardiac remodelling. Clin Exp Pharmacol Physiol. 2003;30(12):911– 8. doi:10.1111/j.1440-1681.2003.03942.x. 71. Lu HK, Fern RJ, Luthin D, Linden J, Liu LP, Cohen CJ, et al. Angiotensin II stimulates T-type Ca2+ channel currents via activation of a G protein, Gi. Am J Physiol Cell Physiol. 1996;271(4):C1340–9. 72. Maturana AD, Casal AJ, Demaurex N, Vallotton MB, Capponi AM, Rossier MF. Angiotensin II negatively modulates L-type calcium channels through a pertussis toxin-sensitive G protein in adrenal glomerulosa cells. J Biol Chem. 1999;274(28):19943–8. doi:10.1074/jbc.274.28.19943. 73. Tomić M, Van Goor F, He M-L, Zivadinovic D, Stojilkovic SS. Ca2+ - mobilizing endothelin-a receptors inhibit voltage-gated Ca2+ influx through Gi/oSignaling pathway in pituitary lactotrophs. Mol Pharmacol. 2002;61(6):1329–39. doi:10.1124/mol.61.6.1329. 74. Hilal-Dandan R, He H, Martin JL, Brunton LL, Dillmann WH. Endothelin downregulates SERCA2 gene and protein expression in adult rat ventricular myocytes: regulation by pertussis toxinsensitive Gi protein and cAMP. Am J Physiol Heart Circ Physiol. 2009;296(3):H728–34. doi:10.1152/ajpheart.00584.2008. 75. Suh B-C, Hille B. PIP2 is a necessary cofactor for Ion channel function: How and Why? Annu Rev Biophys. 2008;37(1):175–95. doi:10.1146/annurev.biophys.37.032807.125859. 76. Mohler PJ, Hund TJ. Role of CaMKII in cardiovascular health, disease, and arrhythmia. Heart Rhythm. 2011;8(1):142–4. doi:10.1016/j.hrthm.2010.07.029. 77. Mike Berridge BC, Jim Stull, Shaun Couglin, Gil R. Sambrano, Roger Sunahara. Calcium signaling in cardiac myocytes. 2012. http://cmbi.bjmu.edu.cn/cmbidata/cgf/CGF_reviews/cell/www. cellularsignaling.org/csmap/calcium.html. 78. Guinamard R, Demion M, Chatelier A, Bois P. Calcium-activated nonselective cation channels in mammalian cardiomyocytes. Trends Cardiovasc Med. 2006;16(7):245–50. doi:10.1016/j. tcm.2006.04.007. 79. Eder P, Probst D, Rosker C, Poteser M, Wolinski H, Kohlwein SD, et al. Phospholipase C-dependent control of cardiac calcium homeostasis involves a TRPC3-NCX1 signaling complex. Cardiovasc Res. 2007;73(1):111–9. doi:10.1016/j.cardiores.2006.10.016. 80. Vassort G, Alvarez J. Transient receptor potential: a large family of new channels of which several are involved in cardiac arrhythmia this article is one of a selection of papers from the NATO advanced research workshop on translational knowledge for heart health (published in part 1 of a 2-part special issue). Can J Physiol Pharmacol. 2009;87(2):100–7. doi:10.1139/y08-112. 81. Tuteja D, Xu D, Timofeyev V, Lu L, Sharma D, Zhang Z, et al. Differential expression of small-conductance Ca2+ -activated K+ channels SK1, SK2, and SK3 in mouse atrial and ventricular myocytes. Am J Physiol Heart Circ Physiol. 2005;289(6):H2714–23. doi:10.1152/ajpheart.00534.2005. 82. Peracchia C. Chemical gating of gap junction channels: roles of calcium, pH and calmodulin. Biochim Biophys Acta. 2004;1662(1– 2):61–80. doi:10.1016/j.bbamem.2003.10.020. 83. Xu Q, Kopp RF, Chen Y, Yang JJ, Roe MW, Veenstra RD. Gating of Connexin43 Gap junctions by a cytoplasmic loop calmodulin binding domain. Am J Physiol Cell Physiol. 2012. doi:10.1152/ ajpcell.00319.2011. 84. Salameh A, Dhein S. Pharmacology of Gap junctions. New pharmacological targets for treatment of arrhythmia, seizure and cancer? Biochim Biophys Acta. 2005;1719(1–2):36–58. doi:10.1016/j. bbamem.2005.09.007.
G. Aistrup 85. Salameh A, Dhein S. Adrenergic control of cardiac gap junction function and expression. Naunyn-Schmiedeberg’s Arch Pharmacol. 2011;383(4):331–46. doi:10.1007/s00210-011-0603-4. 86. Bauersachs J, Thum T. Biogenesis and regulation of cardiovascular MicroRNAs. Circ Res. 2011;109(3):334–47. doi:10.1161/ circresaha.110.228676. 87. Fabian MR, Sonenberg N, Filipowicz W. Regulation of mRNA translation and stability by microRNAs. Annu Rev Biochem. 2010;79(1):351–79. doi:10.1146/annurev-biochem-060308-103103. 88. Latronico MVG, Condorelli G. RNA silencing: small RNA-mediated posttranscriptional regulation of mRNA and the implications for heart electropathophysiology. J Cardiovasc Electrophysiol. 2009;20(2):230–7. doi:10.1111/j.1540-8167.2008.01357.x. 89. Small EM, Olson EN. Pervasive roles of microRNAs in cardiovascular biology. Nature. 2011;469(7330):336–42. 90. Cheng H-J, Zhang Z-S, Onishi K, Ukai T, Sane DC, Cheng C-P. Upregulation of functional β3-adrenergic receptor in the failing canine myocardium. Circ Res. 2001;89(7):599–606. doi:10.1161/ hh1901.098042. 91. Wang Z. The role of microRNA in cardiac excitability. J Cardiovasc Pharmacol. 2010;56(5):460–70. doi:10.1097/ FJC.0b013e3181edb22c. 92. Mishra S, Ling H, Grimm M, Zhang T, Bers DM, Brown JH. Cardiac hypertrophy and heart failure development through Gq and CaM kinase II signaling. J Cardiovasc Pharmacol. 2010;56(6):598–603. doi:10.1097/FJC.0b013e3181e1d263. 93. Yang B, Lu Y, Wang Z. Control of cardiac excitability by microRNAs. Cardiovasc Res. 2008;79(4):571–80. doi:10.1093/cvr/ cvn181. 94. Kukreja RC, Yin C, Salloum FN. MicroRNAs: new players in cardiac injury and protection. Mol Pharmacol. 2011;80(4):558–64. doi:10.1124/mol.111.073528. 95. Nishida M. Roles of heterotrimeric GTP-binding proteins in the progression of heart failure. J Pharmacol Sci. 2011. advpub:1108050596-. 96. Gommans WM, Berezikov E. Controlling miRNA regulation in disease. Methods Mol Biol. 2012;822:1–18. doi:10.1007/978-1-61779-427-8_1. 97. Mendell Joshua T, Olson EN. MicroRNAs in stress signaling and human disease. Cell. 2012;148(6):1172–87. doi:10.1016/j. cell.2012.02.005. 98. Luo X, Zhang H, Xiao J, Wang Z. Regulation of human cardiac Ion channel genes by microRNAs: theoretical perspective and pathophysiological implications. Cell Physiol Biochem. 2010;25(6):571–86. 99. Dobrzynski H, Boyett MR, Anderson RH. New insights into pacemaker activity. Circulation. 2007;115(14):1921–32. doi:10.1161/ circulationaha.106.616011. 100. Sampson KJ, Kass RS. Chapter 29: Anti-arrhythmic drugs. In: Brunton L, Chabner B, Knollmann B, editors. Goodman & Gilman’s the pharmacological basis of therapeutics. 12 ed. New York: McGraw-Hill; 2011. 101. Benson DW, Wang DW, Dyment M, Knilans TK, Fish FA, Strieper MJ, et al. Congenital sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A). J Clin Invest. 2003;112(7):1019–28. doi:10.1172/JCI18062. 112/7/1019 [pii]. 102. Smits JP, Koopmann TT, Wilders R, Veldkamp MW, Opthof T, Bhuiyan ZA, et al. A mutation in the human cardiac sodium channel (E161K) contributes to sick sinus syndrome, conduction disease and Brugada syndrome in two families. J Mol Cell Cardiol. 2005;38(6):969–81. doi:10.1016/j.yjmcc.2005.02.024. S0022-2828(05)00061-1 [pii]. 103. Ueda K, Nakamura K, Hayashi T, Inagaki N, Takahashi M, Arimura T, et al. Functional characterization of a trafficking-
24
104.
105.
106.
107.
108.
109.
110.
111.
112.
113.
114.
115. 116.
117.
118.
119.
120.
121.
Cellular Pharmacology of Cardiac Automaticity and Conduction: Implications in Antiarrhythmic Drug Assessment defective HCN4 mutation, D553N, associated with cardiac arrhythmia. J Biol Chem. 2004;279(26):27194–8. doi:10.1074/ jbc.M311953200. M311953200 [pii]. Schulze-Bahr E, Neu A, Friederich P, Kaupp UB, Breithardt G, Pongs O, et al. Pacemaker channel dysfunction in a patient with sinus node disease. J Clin Invest. 2003;111(10):1537–45. doi:10.1172/JCI16387. Ueda K, Nakamura K, Hayashi T, Inagaki N, Takahashi M, Arimura T, et al. Functional characterization of a traffickingdefective HCN4 mutation, D553N, associated with cardiac arrhythmia. J Biol Chem. 2004;279(26):27194–8. Joung B, Chen P-S, Lin S-F. The role of the calcium and the voltage clocks in sinoatrial node dysfunction. Yonsei Med J. 2011;52(2):211–9. Shaw DB, Linker NJ, Heaver PA, Evans R. Chronic sinoatrial disorder (sick sinus syndrome): a possible result of cardiac ischaemia. Br Heart J. 1987;58(6):598–607. Estes 3rd NA, Link MS, Cannom D, Naccarelli GV, Prystowsky EN, Maron BJ, et al. Report of the NASPE policy conference on arrhythmias and the athlete. J Cardiovasc Electrophysiol. 2001;12(10):1208–19. Stein R, Medeiros CM, Rosito GA, Zimerman LI, Ribeiro JP. Intrinsic sinus and atrioventricular node electrophysiologic adaptations in endurance athletes. J Am Coll Cardiol. 2002;39(6):1033– 8. S0735109702017229 [pii]. Elvan A. Sinoatrial remodeling caused by persistent atrial fibrillation: what is the relationship between postcardioversion sinus node dysfunction and increased atrial vulnerability? J Cardiovasc Electrophysiol. 2001;12(7):807–8. doi:10.1046/j.1540-8167.2001.00807.x. Sanders P, Kistler PM, Morton JB, Spence SJ, Kalman JM. Remodeling of sinus node function in patients with congestive heart failure. Circulation. 2004;110(8):897–903. doi:10.1161/01. cir.0000139336.69955.ab. Chen P, Antzelevich C. Mechanisms of cardiac arrhythmias and conduction disturbances. In: Fuster V, Walsh RA, editors. Hurst’s the heart. 13th ed. New York: McGraw-Hill; 2011. January C, Riddle J. Early afterdepolarizations: mechanism of induction and block. A role for L-type Ca2+ current. Circ Res. 1989;64(5):977–90. doi:10.1161/01.res.64.5.977. Volders PGA, Vos MA, Szabo B, Sipido KR, de Groot SHM, Gorgels APM, et al. Progress in the understanding of cardiac early afterdepolarizations and torsades de pointes: time to revise current concepts. Cardiovasc Res. 2000;46(3):376–92. doi:10.1016/ s0008-6363(00)00022-5. Pogwizd SM, Bers DM. Cellular basis of triggered arrhythmias in heart failure. Trends Cardiovasc Med. 2004;14(2):61–6. Weiss JN, Garfinkel A, Karagueuzian HS, Chen P-S, Qu Z. Early afterdepolarizations and cardiac arrhythmias. Heart Rhythm. 2010;7(12):1891–9. doi:10.1016/j.hrthm.2010.09.017. Kramer DB, Zimetbaum PJ. Long-QT syndrome. Cardiol Rev. 2011;19(5):217–25. doi:10.1097/CRD.0b013e3182203504. 00045415-201109000-00001 [pii]. Hirano Y, Moscucci A, January C. Direct measurement of L-type Ca2+ window current in heart cells. Cir Res. 1992;70(3):445–55. doi:10.1161/01.res.70.3.445. Silva J, Rudy Y. Subunit interaction determines IKs participation in cardiac repolarization and repolarization reserve. Circulation. 2005;112(10):1384–91. doi:10.1161/circulationaha.105.543306. Patterson E, Scherlag BJ, Szabo B, Lazzara R. Facilitation of epinephrine-induced afterdepolarizations by class III antiarrhythmic drugs. J Electrocardiol. 1997;30(3):217–24. doi:10.1016/ s0022-0736(97)80007-6. Burashnikov A, Antzelevitch C. Acceleration-induced action potential prolongation and early afterdepolarizations. J Cardiovasc
122.
123. 124.
125.
126.
127.
128.
129.
130.
131.
132.
133.
134.
135.
136.
137.
138. 139.
331
Electrophysiol. 1998;9(9):934–48. doi:10.1111/j.1540-8167.1998. tb00134.x. Huffaker R, Lamp ST, Weiss JN, Kogan B. Intracellular calcium cycling, early afterdepolarizations, and reentry in simulated long QT syndrome. Heart Rhythm. 2004;1(4):441–8. doi:10.1016/j. hrthm.2004.06.005. Roden DM. Long-QT syndrome. N Engl J Med. 2008;358(2):169– 76. doi:10.1056/NEJMcp0706513. Undrovinas A, Maltsev VA. Late sodium current is a new therapeutic target to improve contractility and rhythm in failing heart. Cardiovasc Hematol Agents Med Chem. 2008;6(4):348–59. Wu L, Ma J, Li H, Wang C, Grandi E, Zhang P, et al. Late sodium current contributes to the reverse rate-dependent effect of IKr inhibition on ventricular repolarization/clinical perspective. Circulation. 2011;123(16):1713–20. doi:10.1161/ circulationaha.110.000661. Burashnikov A, Antzelevitch C. Reinduction of atrial fibrillation immediately after termination of the arrhythmia is mediated by late phase 3 early afterdepolarization–induced triggered activity. Circulation. 2003;107(18):2355–60. doi:10.1161/01. cir.0000065578.00869.7c. Patterson E, Po SS, Scherlag BJ, Lazzara R. Triggered firing in pulmonary veins initiated by in vitro autonomic nerve stimulation. Heart Rhythm. 2005;2(6):624–31. doi:10.1016/j. hrthm.2005.02.012. S1547-5271(05)00224-9 [pii]. Burashnikov A, Antzelevitch C. Late-phase 3 EAD. A unique mechanism contributing to initiation of atrial fibrillation. Pacing Clin Electrophysiol. 2006;29(3):290–5. doi:10.1111/j.1540-8159.2006.00336.x. Karmazyn M, Sawyer M, Fliegel L. The Na+/H+ exchanger: a target for cardiac therapeutic intervention. Curr Drug Targets Cardiovasc Hematol Disord. 2005;5(4):323–35. Noble D, Noble PJ. Late sodium current in the pathophysiology of cardiovascular disease: consequences of sodium–calcium overload. Heart. 2006;92 suppl 4:iv1–5. doi:10.1136/hrt.2005.078782. Zaza A, Belardinelli L, Shryock JC. Pathophysiology and pharmacology of the cardiac “late sodium current”. Pharmacol Ther. 2008;119(3):326–39. doi:10.1016/j.pharmthera.2008.06.001. Sipido KR. Calcium overload, spontaneous calcium release, and ventricular arrhythmias. Heart Rhythm. 2006;3(8):977–9. doi:10.1016/j.hrthm.2006.01.013. Duan D-y, Liu LLH, Bozeat N, Huang ZM, Xiang SY, Wang G-l, et al. Functional role of anion channels in cardiac diseases. Acta Pharmacol Sin. 2005;26(3):265–78. Guinamard R, Chatelier A, Demion M, Potreau D, Patri S, Rahmati M, et al. Functional characterization of a Ca2+ -activated non-selective cation channel in human atrial cardiomyocytes. J Physiol. 2004;558(1):75–83. doi:10.1113/jphysiol.2004.063974. Watanabe H, Murakami M, Ohba T, Ono K, Ito H. The pathological role of transient receptor potential channels in heart disease. Circ J. 2009.advpub:0902040259-. Demion M, Bois P, Launay P, Guinamard R. TRPM4, a Ca2+activated nonselective cation channel in mouse sino-atrial node cells. Cardiovasc Res. 2007;73(3):531–8. doi:10.1016/j. cardiores.2006.11.023. Kruse M, Schulze-Bahr E, Corfield V, Beckmann A, Stallmeyer B, Kurtbay G, et al. Impaired endocytosis of the ion channel TRPM4 is associated with human progressive familial heart block type I. J Clin Invest. 2009;119(9):2737–44. Antzelevitch C. Basic mechanisms of reentrant arrhythmias. Curr Opin Cardiol. 2001;16(1):1–7. Katz MG, Swain JD, White JD, Low D, Stedman H, Bridges CR. Cardiac gene therapy: optimization of gene delivery techniques in vivo. Hum Gene Ther. 2010;21(4):371–80. doi:10.1089/ hum.2009.164.
332 140. Ishikawa K, Tilemann L, Fish K, Hajjar RJ. Gene delivery methods in cardiac gene therapy. J Gene Med. 2011;13(10):566–72. doi:10.1002/jgm.1609. 141. Katz MG, Swain JD, Tomasulo CE, Sumaroka M, Fargnoli A, Bridges CR. Current strategies for myocardial gene delivery. J Mol Cell Cardiol. 2011;50(5):766–76. doi:10.1016/j. yjmcc.2010.09.003. 142. Speranza L, Franceschelli S, Riccioni G. The biological effects of ivabradine in cardiovascular disease. Molecules. 2012;17(5):4924– 35. doi:10.3390/molecules17054924. molecules17054924 [pii]. 143. Vizzardi E, Bonadei I, D’Aloia A, Del Magro F, Piovanelli B, Bontempi L, et al. The importance of reducing heart rate in cardiovascular diseases: effects of ivabradine. Minerva Med. 2011;102(5):373–9. R10113207 [pii]. 144. Baruscotti M, Bucchi A, Viscomi C, Mandelli G, Consalez G, Gnecchi-Rusconi T, et al. Deep bradycardia and heart block caused by inducible cardiac-specific knockout of the pacemaker channel gene Hcn4. Proc Natl Acad Sci. 2011;108(4):1705–10. doi:10.1073/pnas.1010122108. 145. Platzer J, Engel J, Schrott-Fischer A, Stephan K, Bova S, Chen H, et al. Congenital deafness and sinoatrial node dysfunction in mice lacking class D L-type Ca2+ channels. Cell. 2000;102(1):89–97. doi:10.1016/s0092-8674(00)00013-1. 146. Mangoni ME, Traboulsie A, Leoni A-L, Couette B, Marger L, Le Quang K, et al. Bradycardia and slowing of the atrioventricular conduction in mice lacking CaV3.1/α1G T-type calcium channels. Circ Res. 2006;98(11):1422–30. 147. Milnes JT, Madge DJ, Ford JW. New pharmacological approaches to atrial fibrillation. Drug Discov Today. 2012. doi:10.1016/j. drudis.2012.02.007. 148. Dobrev D, Friedrich A, Voigt N, Jost N, Wettwer E, Christ T, et al. The G protein–gated potassium current IK, ACh is constitutively active in patients with chronic atrial fibrillation. Circulation. 2005;112(24):3697–706. doi:10.1161/circulationaha.105.575332. 149. Voigt N, Trausch A, Knaut M, Matschke K, Varro A, Van Wagoner DR, et al. Left-to-right atrial inward rectifier potassium current gradients in patients with paroxysmal versus chronic atrial fibrillation. Circ Arrhythm Electrophysiol. 2010;3(5):472–80. doi:10.1161/CIRCEP.110.954636. CIRCEP.110.954636 [pii]. 150. Kjølbye AL, Haugan K, Hennan JK, Petersen JS. Pharmacological modulation of Gap junction function with the novel compound rotigaptide: a promising New principle for prevention of arrhythmias. Basic Clin Pharmacol Toxicol. 2007;101(4):215–30. doi:10.1111/j.1742-7843.2007.00123.x. 151. Wit AL, Peters NS. The role of gap junctions in the arrhythmias of ischemia and infarction. Heart Rhythm. 2012;9(2):308–11. doi:10.1016/j.hrthm.2011.09.056. 152. Kato T, Iwasaki Y-k, Nattel S. Connexins and atrial fibrillation. Circulation. 2012;125(2):203–6. doi:10.1161/ circulationaha.111.075432. 153. Dhein S, Manicone N, Muller A, Gerwin R, Ziskoven U, Irankhahi A, et al. A new synthetic antiarrhythmic peptide reduces dispersion of epicardial activation recovery interval and diminishes alterations of epicardial activation patterns induced by regional ischemia. A mapping study. Naunyn Schmiedeberg’s Arch Pharmacol. 1994;350(2):174–84. 154. Kjolbye AL, Holstein-Rathlou NH, Petersen JS. Anti-arrhythmic peptide N-3-(4-hydroxyphenyl)propionyl Pro-Hyp-Gly-AlaGly-OH reduces dispersion of action potential duration during ischemia/reperfusion in rabbit hearts. J Cardiovasc Pharmacol. 2002;40(5):770–9. 155. Xing D, Kjølbye AL, Petersen JS, Martins JB. Pharmacological stimulation of cardiac gap junction coupling does not affect ischemia-induced focal ventricular tachycardia or triggered activity in dogs. Am J Physiol Heart Circ Physiol. 2005;288(2):H511– 6. doi:10.1152/ajpheart.00720.2004.
G. Aistrup 156. Shiroshita-Takeshita A, Sakabe M, Haugan K, Hennan JK, Nattel S. Model-dependent effects of the Gap junction conduction–enhancing antiarrhythmic peptide rotigaptide (ZP123) on experimental atrial fibrillation in dogs. Circulation. 2007;115(3):310–8. doi:10.1161/circulationaha.106.665547. 157. Igarashi T, Finet JE, Takeuchi A, Fujino Y, Strom M, Greener ID, et al. Connexin gene transfer preserves conduction velocity and prevents atrial fibrillation /clinical perspective. Circulation. 2012;125(2):216–25. doi:10.1161/circulationaha.111.053272. 158. Simard C, Sallé L, Rouet R, Guinamard R. Transient receptor potential melastatin 4 inhibitor 9-phenanthrol abolishes arrhythmias induced by hypoxia and re-oxygenation in mouse ventricle. Br J Pharmacol. 2012;165(7):2354–64. doi:10.1111/j.1476-5381.2011.01715.x. 159. Doggrell SA. Amiodarone – waxed and waned and waxed again. Expert Opin Pharmacother. 2001;2(11):1877–90. doi:10.1517/14656566.2.11.1877. 160. Kozlowski D, Budrejko S, Lip GYH, Mikhailidis DP, Rysz J, Raczak G, et al. Dronedarone: an overview. Ann Med. 2011;44(1):60–72. doi:10.3109/07853890.2011.594808. 161. Sossalla S, Maier LS. Role of ranolazine in angina, heart failure, arrhythmias, and diabetes. Pharmacol Ther. 2012;133(3):311–23. 162. Antzelevitch C, Burashnikov A, Sicouri S, Belardinelli L. Electrophysiologic basis for the antiarrhythmic actions of ranolazine. Heart Rhythm. 2011;8(8):1281–90. doi:10.1016/j. hrthm.2011.03.045. 163. Vizzardi E, D’Aloia A, Quinzani F, Bonadei I, Rovetta R, Bontempi L, et al. A focus on antiarrhythmic properties of ranolazine. J Cardiovasc Pharmacol Ther. 2012. doi:10.1177/1074248412442000. 164. Burashnikov A, Di Diego JM, Zygmunt AC, Belardinelli L, Antzelevitch C. Atrium-selective sodium channel block as a strategy for suppression of atrial fibrillation. Circulation. 2007;116(13):1449–57. doi:10.1161/circulationaha.107.704890. 165. Parikh A, Mantravadi R, Kozhevnikov D, Roche MA, Ye Y, Owen LJ, et al. Ranolazine stabilizes cardiac ryanodine receptors: a novel mechanism for the suppression of early afterdepolarization and torsades de pointes in long QT type 2. Heart Rhythm. 2012;9(6):953–60. doi:10.1016/j.hrthm.2012.01.010. 166. Watanabe H, Steele DS, Knollmann BC. Mechanism of antiarrhythmic effects of flecainide in catecholaminergic polymorphic ventricular tachycardia. Circ Res. 2011;109(6):712–3. doi:10.1161/circresaha.111.251322. 167. Miles RH, Passman R, Murdock DK. Comparison of effectiveness and safety of ranolazine versus amiodarone for preventing atrial fibrillation after coronary artery bypass grafting. Am J Cardiol. 2011;108(5):673–6. doi:10.1016/j.amjcard.2011.04.017. 168. Dagres N, Sommer P, Anastasiou-Nana M, Hindricks G. Treating arrhythmias: an expert opinion. Expert Opin Pharmacother. 2011;12(9):1359–67. doi:10.1517/14656566.2011.555397. 169. Fedida D. Vernakalant (RSD1235): a novel, atrial-selective antifibrillatory agent. Expert Opin Investig Drugs. 2007;16(4):519–32. doi:10.1517/13543784.16.4.519. 170. Fedida D, Orth PMR, Chen JYC, Lin S, Plouvier B, Jung G, et al. The mechanism of atrial antiarrhythmic action of RSD1235. J Cardiovasc Electrophysiol. 2005;16(11):1227–38. doi:10.1111/j.1540-8167.2005.50028.x. 171. Orth PMR, Hesketh JC, Mak CKH, Yang Y, Lin S, Beatch GN, et al. RSD1235 blocks late INa and suppresses early afterdepolarizations and torsades de pointes induced by class III agents. Cardiovasc Res. 2006;70(3):486–96. doi:10.1016/j. cardiores.2006.01.026. 172. Pratt CM, Roy D, Torp-Pedersen C, Wyse DG, Toft E, Juul-Moller S, et al. Usefulness of vernakalant hydrochloride injection for rapid conversion of atrial fibrillation. Am J Cardiol. 2010;106(9):1277–83. doi:10.1016/j.amjcard.2010.06.054.
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Cellular Pharmacology of Cardiac Automaticity and Conduction: Implications in Antiarrhythmic Drug Assessment
173. Ellenbogen KA, Stambler BS, Wood MA, Sager PT, Wesley Jr RC, Meissner MD, et al. Efficacy of intravenous ibutilide for rapid termination of atrial fibrillation and atrial flutter: a dose–response study. J Am Coll Cardiol. 1996;28(1):130– 6. doi:10.1016/0735-1097(96)00121-0. 174. Murray KT. Ibutilide. Circulation. 1998;97(5):493–7. doi:10.1161/01.cir.97.5.493. 175. Lee KS, Lee EW. Ionic mechanism of ibutilide in human atrium: evidence for a drug-induced Na+ current through a nifedipine inhibited inward channel. J Pharmacol Exp Ther. 1998;286(1):9–22. 176. Guo D, Liu Q, Liu T, Elliott G, Gingras M, Kowey PR, et al. Electrophysiological properties of HBI-3000: a new antiarrhythmic agent with multiple-channel blocking properties in human ventricular myocytes. J Cardiovasc Pharmacol. 2011;57(1):79–85. doi:10.1097/FJC.0b013e3181ffe8b3. 177. Crumb WJ, Wible B, Arnold DJ, Payne JP, Brown AM. Blockade of multiple human cardiac potassium currents by the antihistamine terfenadine: possible mechanism for terfenadine-associated cardiotoxicity. Mol Pharmacol. 1995;47(1): 181–90. 178. Lu Y, Wang Z. Terfenadine block of sodium current in canine atrial myocytes. J Cardiovasc Pharmacol. 1999;33(3):507–13. 179. Koh KK, Rim MS, Yoon J, Kim SS. Torsade de pointes induced by terfenadine in a patient with long QT syndrome. J Electrocardiol. 1994;27(4):343–6. 180. Smith SJ. Cardiovascular toxicity of antihistamines. Otolaryngol Head Neck Surg. 1994;111(3 Pt 2):348–54. a56717 [pii]. 181. Mubagwa K, Mullane K, Flameng W. Role of adenosine in the heart and circulation. Cardiovasc Res. 1996;32(5):797–813. doi:10.1016/s0008-6363(96)00140-x. 182. Garratt CJ, Malcolm AD, Camm AJ. Adenosine and cardiac arrhythmias. BMJ. 1992;305(6844):3–4. 183. Maier LS. Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) in the heart. Adv Exp Med Biol. 2012;740:685–702. doi:10.1007/978-94-007-2888-2_30. 184. Bell JR, Curl CL, Ip WTK, Delbridge LMD. Ca2+/calmodulindependent protein kinase inhibition suppresses post-ischemic
185.
186.
187.
188.
189.
190.
191.
192.
193.
333
arrhythmogenesis and mediates sinus bradycardic recovery in reperfusion. Int J Cardiol. (0). doi:10.1016/j.ijcard.2011.02.038. Khoo MSC, Li J, Singh MV, Yang Y, Kannankeril P, Wu Y, et al. Death, cardiac dysfunction, and arrhythmias Are increased by calmodulin kinase II in calcineurin cardiomyopathy. Circulation. 2006;114(13):1352–9. doi:10.1161/circulationaha.106.644583. Swaminathan PD, Purohit A, Soni S, Voigt N, Singh MV, Glukhov AV, et al. Oxidized CaMKII causes cardiac sinus node dysfunction in mice. J Clin Invest. 2011;121(8):3277–88. Xie L-H, Chen F, Karagueuzian HS, Weiss JN. Oxidative stress–induced afterdepolarizations and calmodulin kinase II signaling. Circ Res. 2009;104(1):79–86. doi:10.1161/ circresaha.108.183475. Zhao Z, Fefelova N, Shanmugam M, Bishara P, Babu GJ, Xie L-H. Angiotensin II induces afterdepolarizations via reactive oxygen species and calmodulin kinase II signaling. J Mol Cell Cardiol. 2011;50(1):128–36. doi:10.1016/j.yjmcc.2010.11.001. Wagner S, Ruff HM, Weber SL, Bellmann S, Sowa T, Schulte T, et al. Reactive oxygen species–activated Ca/calmodulin kinase IIδ is required for late INa augmentation leading to cellular Na and Ca overload/novelty and significance. Circ Res. 2011;108(5):555–65. doi:10.1161/circresaha.110.221911. Hirose M, Takeishi Y, Niizeki T, Shimojo H, Nakada T, Kubota I, et al. Diacylglycerol kinase [zeta] inhibits G[alpha] q-induced atrial remodeling in transgenic mice. Heart Rhythm. 2009;6(1):78–84. Hirose M, Takeishi Y, Niizeki T, Nakada T, Shimojo H, Kashihara T, et al. Diacylglycerol kinase [zeta] inhibits ventricular tachyarrhythmias in a mouse model of heart failure: roles of canonical transient receptor potential (TRPC) channels. Circ J. 2011;75(10):2333–42. Latronico MV, Condorelli G. Therapeutic use of microRNAs in myocardial diseases. Curr Heart Fail Rep. 2011;8(3):193–7. doi:10.1007/s11897-011-0068-2. Thum T. MicroRNA therapeutics in cardiovascular medicine. EMBO Mol Med. 2012;4(1):3–14. doi:10.1002/emmm.201100191.
Biophysical and Molecular Targets
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Mark Slevin, Michael Carroll, Chris Murgatroyd, and Garry McDowell
Abstract
Cardiac arrhythmia is the leading cause of death in the Western world despite significant therapeutic improvements by surgical, interventional, and pharmacological approaches in the last decade. This chapter reviews the latest research in identifying drugs and targets with the aim of preventing the arrhythmia. We discuss the therapeutic regulation of ion channels which are important targets that are modulated by a range of currently prescribed drugs. Next we review efficacies of upstream therapies, such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, statins, n-3 polyunsaturated fatty acids, and calcium channel blockers in preventing specific mechanisms of arrhythmias. We conclude with the current knowledge about microRNAs in cardiovascular diseases which are emerging as interesting new drug targets. The potential advantages of pharmacological antiarrhythmic agents motivate continued efforts to identify novel therapeutic means to restore and maintain cardiac rhythm. This review provides a succinct overview of some of the current investigational or recently approved strategies for improving efficacy and safety of antiarrhythmic therapies. Keywords
Cardiac arrhythmia • microRNA • Ion channels • n-3 Polyunsaturated fatty acids • ACE inhibitors • Statins • CaMKII
Cardiac Arrhythmias Cardiac arrhythmias represent a large heterogeneous collection of heart abnormalities characterized by the presence of electrical dysfunction caused by abnormalities in the conduction of
M. Slevin, PhD, FRCPath (*) SBCHS, Manchester Metropolitan University, Chester Street, Manchester, UK School of Healthcare Science, Manchester Metropolitan University, Manchester, UK e-mail:
[email protected] M. Carroll, PhD • C. Murgatroyd, PhD School of Healthcare Science, Manchester Metropolitan University, Manchester, UK G. McDowell, PhD, FRCPath Health and Biomedical Science, University of Edgehill, Ormskirk, Liverpool, UK A.S. Kibos et al. (eds.), Cardiac Arrhythmias, DOI 10.1007/978-1-4471-5316-0_25, © Springer-Verlag London 2014
nerve signals. In these cases, the heart either beats irregularly, too fast, or too slowly. Arrhythmia of the heart can have both acute and chronic long-term life-threatening effects including cardiac arrest, stroke, embolism, and increased propensity for development of atherosclerosis and unstable plaques susceptible to thrombosis. While historical fact types of arrhythmia and epidemiology of this group of diseases have been covered in detail by other authors, it is worth reiterating the importance of identifying and treating this complex group of disorders that can account for a large proportion of both asymptomatic and symptomatic disease following acute myocardial infarction (46 %) [18], with high-degree atrioventricular block associated with a very high degree of cardiac death. While currently available implantable cardioverter-defibrillator therapy is now considered to be the most effective against malignant arrhythmias, this is in fact only effective at treating some kinds of arrhythmia and is extremely expensive, making the search for more effective and specific pharmaceuticals imperative. 335
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Defining Potential Drug Targets
Cardiac Ion Channels
Identification and use of optimal/novel drugs and targets with the aim of preventing the arrhythmia is complicated by both the number of and classification of arrhythmias and the numbers of drug classes currently available. Nearly every antiarrhythmic drug has the potential to act as a proarrhythmic, and so accurate diagnosis is crucial. An increase in our understanding of the molecular mechanisms associated with development of these arrhythmias as well as their relationship to protein expression and ion-channel abnormalities has allowed us to introduce more targeted therapies based on regulation of specific biomolecular components. Classic antiarrhythmic drugs for atrial fibrillation (AF) are of limited effectiveness and may increase the risk of ventricular tachycardia (VT) and/or ventricular fibrillation (VF), may have systemic toxicity, and may increase defibrillation threshold. In the last 30 years, very few new and effective antiarrhythmic drugs have been identified and successfully passed through clinical trials, mainly due to safety concerns or limited benefits in comparison to existing therapy. Similarly, other drug classes (e.g., beta-blockers, ACE inhibitors, and statins) have shown their ability to reduce cardiac mortality, suggesting a need to examine upstream signalling pathways related to the ion channels. The original classifications of drugs describing a “one drug for one molecular target” scenario appear too restrictive in light of current knowledge of molecular and cellular mechanisms [56, 59]. As the data below will demonstrate, there are new drugs and multifocal targeted approaches including upstream therapy and anti-remodelling drugs that should form the future of our therapeutic efforts (Fig.25.1):
Drugs targeting ion channels have been the original focus of antiarrhythmatic drugs primarily since it was first realized that the electrical activity of the heart is closely linked to their currents [23]. Both inherited and acquired cardiac syndromes have been linked with pathological changes in the late component of the cardiac Na+ current [40]. Blocking Na+ current slows conduction and can block arrhythmias by converting unidirectional blocks into bidirectional ones. Pathological prolongation of the QT interval has been associated with a number of gene mutations that code for proteins within many of the ion channel complexes and structural anchoring proteins including ankyrin and caveolin [2]. The recently highlighted hypothesis suggesting a strong genetic link or predisposition to development of arrhythmias offers major potential diagnostic advantages over conventional testing. One of the earlier studies demonstrated this examined complications of VT, VF, and other abnormalities associated with Brugada syndrome (previously linked to SCN5A gene mutations which encode the α-subunit of cardiac voltagegated sodium channel hNav1.5 subsequently expressed as a protein product in cell membranes with multiple β-subunits and initiating the action potential in cardiac cells [24]). They showed that a missense mutation of SCN5A was also associated with an arrhythmic electrical storm during an episode of myocardial infarction (MI) and that VT and VF episodes were associated with ST-segment changes concomitant with G400A mutation and H558R polymorphism on the same gene allele. Resulting functional expression of TSA201 induced a loss of function of the sodium channel. Hence, a subclinical mutation of SCN5A may predispose patients
Cardiac ion channels
Up-stream targets
Na2+ Ca2+ Ryanodine receptors
ACE inhibitors Angiotensin II receptor blockers Statins CaMKII inhibition
Micro RNAs
Fig. 25.1 Biophysical and molecular targets for cardiac arrhythmias
Biomarkers Molecular targets
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Biophysical and Molecular Targets
with acute MI to increased risk of mortality in the days and weeks following the primary event and could be considered for use as a diagnostic/prognostic indicator. Since the sodium current flux within the heart is in fact a mix of currents, it does not exhibit mono-exponential decay, and this may be as a result of complex kinetics associated with several distinct available sodium channels. For example, one component, the INaP although normally constituting about 1 % of the peak transient current (INaT), increases dramatically during hypoxia and therefore following MI. This change is known to contribute to ischemic damage and reperfusion and predisposition to development of several types of arrhythmia. In this situation, therapeutic agents that can effectively block INaP such as ranolazine either alone or in combination with other channel blockers may be beneficial for the treatment of atrial arrhythmias as well as potentially alleviating the symptoms of angina [16]. Increases in the late component of the Na(+) current, I(NaL), also associated with acquired or inherited disease, trigger arrhythmia (mainly ventricular) by disruption of cellular repolarization. As mentioned above, current drugs (lidocaine, amiodarone, etc.) are largely unsuccessful in treatment due to pharmacological toxicity and a lack of discrimination between peak current components responsible for single-cell excitability and propagation in coupled tissue and I(Na)L. Novel drugs such as ranolazine, which is selective for the late peak Na+ current, seem to protect against enhanced I(NaL) in LQT3 and heart failure, suggesting a greater knowledge of the pathophysiological mechanisms associated with these conditions will help to make significant advances in their treatment. Calcium (Ca2+) release from the sarcoplasmic reticulum and operating through the calcium release channel is also essential for normal heart contraction. Pathological release of Ca2+ via the ryanodine receptors (RyR2) originating from changes in RyR2 activity (through point mutations/genetic defects, drug use, heart failure, etc.) can result in calcium overloading-induced damage of cardiomyocytes and subsequent arrhythmogenesis in both inherited arrhythmia syndrome (catecholaminergic polymorphic ventricular tachycardia) and acquired heart disease such as atrial fibrillation [10]. Mutant RyR2 channels also give rise to spontaneous release of Ca2+ from the sarcoplasmic reticulum during systole related to an incomplete closure of the RyR2 channel [16]. However, although RyR2 drug inhibitors such as JTV519 and flecainide can block ventricular arrhythmia by reducing intracellular Ca2+ leak, chronic use is associated with side effects (slight increase in rate of death and increased risk of occurrence of new arrhythmias) [19]. New insights into the structural-functional relationships of the RyR2 receptor and the molecular basis of channel dysfunction demonstrate multiple synergisms of several cellular components involved in Ca+ signalling, and a fuller understanding
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of the interactions between these molecules should pave the way for the introduction of more specific and effective therapeutics [53]. Pathological modulation of potassium channels are also involved intimately during arrhythmias such as atrial fibrillation, for example, Kv1.5 mediation of the ultrarapid current I(Kur) which ultimately controls the atrial action potential duration. Martens and colleagues have studied ion channel trafficking with a focus on Kv1.5 and highlighted novel and specific effects of drugs such as quinidine, which indicated that the pleiotropic effects of antiarrhythmic drugs could be separated [54]. Selective manipulation of ion channel surface density thus overcomes the present limitations of proarrhythmic side effects [48]. Many of the typically used class III drugs as well as pharmaceuticals used in other treatment (antihistamines, macrolides, etc.) prolong the QT interval through hERG K+ blockade, leading to increased likelihood of polymorphous ventricular arrhythmia, associated syncope, and further degeneration into ventricular fibrillation [67]. New and potential antiarrhythmic drugs must be screened to ensure they do not increase the prevalence of this pathology.
Upstream Therapies for Management and Prevention of Arrhythmias Research into molecular mechanisms of cardiac arrhythmias and enhanced understanding of processes involved in the initiation and maintenance of arrhythmias have transformed the approach to its management. This has lead to interventions (upstream therapies) that reduce or prevent arrhythmogenic remodelling or structural remodelling. Alterations in cardiac structure and function can lead to acquired cardiac arrhythmias where remodelling-induced abnormalities in cardiac structure and electrical function bestow a predisposition to atrial fibrillation (AF) and ventricular fibrillation (VF) [41]. Structural remodelling comprise of several pathological changes, which include interstitial fibrosis, fibroblast proliferation, dilation, hypertrophy, and pathological collagen accumulation [12, 42]. The antiarrhythmic potential of upstream therapies, such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers (ARBs), statins, n-3 (v-3) polyunsaturated fatty acids, and calcium channel blockers, has all been implicated in preventing specific mechanisms of arrhythmias [50, 51]. The involvement of the renin-angiotensin-aldosterone system (RAAS) in the initiation and perpetuation of AF has been reported for over a decade. Tachycardia-induced atrial fibrosis is a feature of AF-induced structural remodelling, and studies using animal models have shown that atrial fibrosis plays an important role in the induction and perpetuation of
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AF [30]. Atrial fibrosis causes intra- and interatrial inhomogeneity in conduction, thus creating a substrate for local reentry and contributing to the progressive nature of AF [7]. Among the many identified fibrogenic factors, the RAAS, especially angiotensin II (AngII), has been shown to play an important role in the development of cardiac remodelling during AF. Recently, He et al. has persuasive in vivo and in vitro experimental evidence that tachycardia during AF may activate the AngII/AT1 receptor/TGF-β1 and ERK/Smads signalling pathways and AT1 receptor-specific downregulation of the I-Smads (Smad7) may serve as a key mechanism for the AF-induced atrial fibrosis [22]. These results may provide new insights into the understanding of the mechanisms for AF-induced atrial fibrosis and myocardial remodelling and valuable information for novel therapeutic targets of AF. Previous studies have suggested that angiotensinconverting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) could prevent AF onset or recurrence, and small clinical studies or retrospective analyses in selected patient cohorts have been positive; however, larger prospective RCTs have yielded controversial, mostly negative, results [50, 51]. More recently, one study reviewed all published prospective, randomized versus placebo or no-treatment studies concerning the effect of ACEIs and ARBs in the prevention of AF recurrences. Four ACEIs studies accounting for a total of 355 patients and six ARBs studies consisting of 4,040 patients were analyzed. The authors of this meta-analysis suggested that a publication bias may result in an overestimation of the treatment effect, and they concluded that there is no role for ARBs and ACEIs in the prevention of AF [14]. Previous studies have indicated a role of oxidative stress in AF-associated remodelling [25]. Tissue oxidation can alter ion-channel function, thus contributing to tissue fibrosis, and antioxidant interventions may have a role in preventing atrial remodelling [49]. The mechanism by which electrophysiological remodelling occurs is poorly understood, though evidence increasingly supports the role of oxidative stress as the key mediator in this process [29]. Oxidative stress results from excessive reactive oxygen species (ROS), chemically reactive, oxygen-containing ions and small molecules. They are involved in a variety of pathological processes such as DNA damage, apoptosis, and cellular hypertrophy as well as signal pathway intonation. The short half-life of free radicals and complexity of available techniques make their measurement in humans difficult [25]. However, a number of substitute markers are used to assess levels of oxidative stress. Peroxynitrite is a free radical that leads to oxidation of cellular lipids, proteins, and DNA, which can therefore affect protein and enzyme structure and function and cell death [9, 27]. In one study myofibrillar proteins were examined for evidence of oxidative posttranslational protein modification. It was found that the atrial biopsy
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of patients with AF had increased levels of nitrotyrosine and protein carbonyls, markers of peroxynitrite and hydroxyl radical protein interaction, respectively. In addition, there was evidence of a direct interaction of peroxynitrite with creatinine kinase, causing oxidative damage associated with atrial myofibrillar energetic impairment [38]. The pathophysiological link between oxidative stress and AF is unclear. It has been postulated that derangement of ion-channel regulatory mechanisms by oxidative stress may be responsible. Activity of the sodium channel is particularly linked with the development of AF, and the slowly inactivating sodium currents are reduced by oxidative stress [4]. More recently, it has been reported that mechanical stretch and oxidative stress have been shown to prolong action potential duration (APD) and produce early afterdepolarizations (EADs), and it has been suggested that this mechanism may contribute to the increased propensity to arrhythmias seen in cardiomyopathies, where the myocardium stretch and oxidative stress generally coexist [61]. There is accumulating evidence reported surrounding the use of antioxidant vitamins for the primary and secondary prevention of AF [39], and a study recently carried out to examine the role antioxidant vitamins C and E in the prevention of AF discovered that these vitamins, through their reactive oxygen species (ROS)-scavenging effect, have shown a role in AF prevention in both animal and small clinical studies [49]. There is not enough available evidence, however, to support recommendations for the use of antioxidants in the wider patient population. Larger-scale clinical studies are required to confirm these preliminary results [21, 47]. Both tissue oxidation and inflammation can alter ionchannel function and contribute to tissue fibrosis, and antioxidant interventions might prevent atrial remodelling. Inflammation can play an important role in the development of some forms of AF [58], and it has been suggested that antiinflammatory drugs such as glucocorticoids can prevent atrial remodelling and the recurrence of clinical AF [13, 26]. Recently, several studies have suggested therapeutic benefit of statins for prevention of AF. Statins (3-hydroxy3-methylglutaryl-coenzyme A [HMG-CoA] reductase inhibitors) have been shown to suppress cholesterol biosynthesis and to reduce cardiovascular pathology significantly in patients who are at risk of developing atherosclerotic disease. Furthermore, these cholesterol-lowering statin drugs have antioxidant and anti-inflammatory properties and are also effective in preventing atrial remodelling [1]. The activity of these statins, which are responsible for the prevention of AF, has not been established. However, it is believed to be the overall benefit derived from the improvement of lipid metabolism and prevention of the process of atherosclerosis, antiinflammatory, and antioxidant actions and prevention of endothelial dysfunction and neurohormonal activation, altered membrane fluidity, and ion-channel conductance [17].
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In a recent meta-analysis of 13 short-term trials, it was shown that statin treatment reduced the risk of getting an AF by 39 %. However, they also showed that among 22 longerterm trials of statin treatment versus control, there was no significant association between satin treatment and the reduction in AF. They have found that the suggested beneficial effect of statins on atrial fibrillation from shorter-term studies is not supported by a comprehensive review of published and unpublished evidence from larger-scale trials [45]. More recently, another meta-analysis demonstrated that statin therapy was significantly associated with a decreased risk of the incidence of recurrence of AF. The benefit of statin therapy was more noticeable in AF population (i.e., those who had coronary surgery or electrical cardioversion) than in the non-AF population [28]. To establish if statin therapy is a therapeutic option for the management of AF, further large-scale randomized clinical trials are required. Emerging evidence suggests that abnormal intracellular Ca2+ signalling is a significant contributor to focal firing, substrate evolution, and atrial remodelling during AF. Consequently, identification of the underlying atrial Ca2+handling abnormalities will lead to novel mechanistically based therapeutic targets. Abnormalities in intracellular Ca2+ handling occur in a range of arrhythmogenic conditions, and given the fundamental role intracellular calcium plays in contractile function, calcium-mediated alternans may represent an important mechanistic link between mechanical dysfunction and electrical instability. Increased intracellular calcium [Ca2+]i concentrations and abnormalities in [Ca2+]i handling have been linked to initiation of AF by promoting delayed and late phase III early afterdepolarizations sufficient to initiate ectopic activation [44]. Cardiac alternans refer to either mechanical (contractile) or electrical (repolarization) oscillations that occur on an every-other-beat basis. These calcium transient alternans are coupled to repolarization alternans that form a substrate for reentrant excitation. Abnormal intracellular calcium cycling, either impaired release or impaired reuptake of sarcoplasmic reticulum calcium, is a cellular mechanism of calcium transient alternans. Therefore, cardiac alternans is an important mechanistic link between mechanical dysfunction, arrhythmias, and sudden cardiac death [32]. Ca2+ handling is a crucial and complex cardiomyocyte function, and any Ca2+-handling abnormalities can lead to atrial and ventricular fibrillation. Effective contraction requires rapid increases in free cytoplasmic Ca2+concentration, but for successful relaxation, rapid restoration of low Ca2+concentrations is required in diastole (the relaxed phase of the cardiac cycle). Efficient Ca2+handling is maintained by a complex set of intracellular Ca2+ stores, transporters, and channels [63]. As there are many membrane electrical functions regulated by Ca2+, abnormalities in Ca2+ handling can be highly
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arrhythmogenic. Key components of the Ca2+ −handling machinery include the sarcoplasmic reticulum (SR) Ca2+ release channel or ryanodine receptor (RyR2), the RyR2binding molecule calstabin-2, the SR Ca2+-ATPase (SERCA2A), and the SERCA2A-regulatory molecule phospholamban [33]. They have proposed that RyR2-mediated diastolic SR Ca2+ leak triggers VT and sudden cardiac death. They demonstrated that calstabin-2-deficient mice display diastolic SR Ca2+ leak, monophasic action potential alternans, and bidirectional VT. Additionally they showed that calstabin-deficient cardiomyocytes exhibited SR Ca2+ leakinduced aberrant transient inward currents in diastole consistent with delayed afterdepolarizations. Thus, calstabin-2 is a crucial modulator of RyR2 function, and calstabin-2 deficiency is a critical mediator of triggers that initiate cardiac arrhythmias [62]. Moreover, it has been shown that a derivative of 1,4-benzothiazepine (JTV519) increased the affinity of calstabin-2 for RyR2, which stabilized the closed state of RyR2 and thus prevented the Ca2+ leak that triggers arrhythmias. Therefore, enhancing the binding of calstabin-2 to RyR2 has great potential as a therapeutic strategy for common ventricular arrhythmias [15]. Another potential upstream target is calcium-/calmodulindependent kinase II (CaMKII). CaMKII increases L-type Ca2+ channel open probability, potentially facilitating channel reactivation. CaMKII inhibition therefore constitutes a potential novel antiarrhythmic strategy, and several studies have suggested that CaMKII inhibition may provide an effective treatment strategy for heart diseases [3]. It has been shown that CaMKII plays a key role in modulating cardiac function and regulating hypertrophy development. Moreover, CaMKII activity has been found elevated in the failing hearts from human patients and animal models. Therefore, inhibition of CaMKII activity has been shown to mitigate hypertrophy, prevent functional remodelling, and reduce arrhythmogenic activity [3]. The development of drugs that stabilize the Ca2+ release channel and prevent diastolic Ca2+ leak may produce valuable new upstream treatments for the prevention and treatment of arrhythmic conditions. The newly emerging nontraditional approaches, such as upstream therapies, are providing promising potential. However, further investigations and broader clinical trials are required if these are to be utilized in the mainstream.
Understanding MicroRNAs and Their Potential as Biomarkers/Blueprints of Specific Arrhythmias The regulation of gene expression in the development and function of the heart is complex, with individual genes controlled by multiple enhancers that direct very specific
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Table 25.1 Targets and binding sites of miRNAs associated with arrhythmia miRNA miR-1
Targets Connexin 43
Gene symbol Alternative names CX43 GJA1
Potassium channel inwardly rectifying, subfamily J, member 2
KCNJ2
Protein phosphatase PP2A regulating subunit B56a
PP2A
miR-1-2
Iroquois homeobox protein
Irx5
miR-133
Potassium channel KCNH2 voltage-gated, subfamily H, member 2
HERG, ERG1
Potassium channel voltage-gated, KQT-like subfamily, member 1 Potassium channel voltage-gated, ISK-related, subfamily member 1 Protein phosphatase PP2A regulating subunit B56a
KCNQ1
KVLQT1, KCNA9, KCNA8
KCNE1
ISK, MINK
Calcium channel voltage-dependent L-type alpha-1C subunit Calcium channel voltage-dependent beta-1 subunit
CACNA1C
CaV1.2, CACH2
CACNB1
CCHLB1, CCHLB, CACNLB1
miR-328
HHIRK1, IRK1, KIR2.1
IRXB2
PP2A
expression patterns. By adding another layer of regulation at the posttranscriptional level, microRNAs (miRNAs) are now reshaping our view of how cardiac gene expression is regulated (for review see [43]). The implications of miRNAs in the pathological process of the cardiovascular system have being been recognized, and research on miRNAs in relation to cardiovascular disease has now become a rapidly evolving field. Importantly, recent studies are highlighting miRNAs as important in cardiac excitability by fine-tuning expression of ion channels, transporters, and cellular proteins that determine arrhythmogenicity in many conditions. Briefly, miRNAs are a family of small nonprotein-coding RNAs that have emerged as important regulators in cardiac and vascular developmental and pathological processes, including cardiac arrhythmia, fibrosis, hypertrophy and ischemia, heart failure, and vascular atherosclerosis. Precursor
Function Gap junction protein associated with enhanced arrhythmic risk, atrioventricular septal defect, Hallermann-Streiff syndrome, hypoplastic left heart syndrome, oculodentodigital dysplasia, autosomal recessive oculodentodigital dysplasia Potassium channel active in muscles and associated with long familial atrial fibrillation, long QT syndrome-7, and short QT syndrome-3 Phosphotyrosyl phosphatase activator of the dimeric form of protein phosphatase-2A. Attenuates cardiac response to LPS-induced sepsis in mice Represses potassium voltage-gated channel member 2 (KCND2) and causes cardiac arrhythmias in mice Pore-forming subunit of a rapidly activatingdelayed rectifier potassium channel, associated with long QT syndrome-2 and short QT syndrome-1 A voltage-gated potassium channel associated with familial atrial fibrillation, Jervell and Lange-Nielsen syndrome, long QT syndrome-1, and short QT syndrome-2 A voltage-gated potassium channel associated with Jervell and Lange-Nielsen syndrome-2, Romano-Ward syndrome, and long QT syndrome-5 Phosphotyrosyl phosphatase activator of the dimeric form of protein phosphatase-2A. Attenuates cardiac response to LPS-induced sepsis in mice Calcium channel subunit, associated with Brugada syndrome 3, Timothy syndrome, and long QT syndrome Calcium channel subunit, associated with a lack of excitation-contraction coupling in mice
Reference Yang et al. [66]
Yang et al. [66]
Belevych et al. [5]
Zhao et al. [68]
Xiao et al. [65]
Luo et al. [36]
Luo et al. [36]
Belevych et al. [5]
Lu et al. [35]
Lu et al. [35]
microRNAs, following processing by the enzyme Dicer, can act as an adaptor for the RNA-induced silencing complex (RISC). These recognize their target mRNAs by base-pairing interactions between nucleotides 2 and 8 of the miRNA and complementary nucleotides in the 3′-untranslated region of mRNAs, and miRISCs subsequently inhibit gene expression by targeting mRNAs for translational repression or cleavage (Table 25.1). The crucial importance of miRNAs to cardiac development and function is demonstrated through genetic disruption of pathways involved in miRNA biosynthesis. Ubiquitous disruption of Dicer in mice is embryonic lethal. However, cardiac-specific deletion of Dicer from E8.5, during heart patterning and differentiation, using Cre recombinase expressed under the control of endogenous Nkx2.5 regulator elements, resulted in embryos showing a variety of
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Biophysical and Molecular Targets
cardiac developmental defects, including pericardial edema and underdevelopment of the ventricular myocardium [52]. Importantly, Dicer activity is also required for normal functioning of the mature heart with the loss of Dicer in the myocardium of adult mice causing cardiac hypertrophy and reactivation of the fetal cardiac gene program [11]. Musclespecific deletion of another component of the miRNA biogenesis pathway, DiGeorge syndrome critical region gene 8 (DGCR8), leads to phenotypic outcomes similar to the cardiac-specific Dicer-deficient mice, showing a critical role for miRNAs in maintaining cardiac function in mature cardiomyocytes [46]. The growing number of miRNAs being reported in the literature includes several that are muscle specific and expressed in the heart. The most abundant cardiac miRNAs are miR-1 and miR-133 [34]. These two species, in addition to miR-208 and miR-499, have been demonstrated to be involved in heart development and hypertrophy and are dysregulated in hearts from individuals with coronary artery disease [66], myocardial infarction [6], and heart failure [57]. One recent study analyzing the miRNA transcriptome found a distinct miRNA expression signature in atrial fibrillation patients with alterations in the expression of 136 and 96 miRNAs and in mitral stenosis patients with or without atrial fibrillosis, respectively, when compared to controls [64]. The importance of miRNAs in heart development and function is further supported by studies in animal models. A study using experimental atrial fibrillation to some extent supported the previously mentioned clinical study [64], revealing relatively wide effects on the miRNA transcriptome with upregulations of miR-223, miR-328, and miR-664 and downregulation of miR-101, miR-320, and miR-499 [35]. In support of causal mechanisms, overexpression of miR-328 enhanced atrial fibrillation vulnerability, diminished L-type Ca2+ current, and shortened atrial action potential duration while reducing of miR-328 levels dampened atrial fibrillation vulnerability [61]. Further miRNA overexpression studies have revealed roles of miR-133 to improve diastolic function in pressureoverload hypertrophy [37], while a 2-fold increase of miR208 was sufficient to induce hypertrophy and arrhythmia [8]. A number of important targets for miRNAs related to cardiac excitation have been implicated in arrhythmogenesis. One target of miR-1-2 is the cardiac transcription factor iroquois homeobox (Irx)5, which represses potassium voltagegated channel, Shal-related subfamily, member 2 (KCND2), a potassium channel subunit (Kv4.2) responsible for transient outward K+ current (Ito) by use of a targeted deletion technique [68]. Cardiac ion-channel genes that have been confirmed experimentally to be targets of miR-1 or miR-133 include gap junction protein Connexin 43 (CX43) [66]; potassium channel inwardly rectifying, subfamily J, member 2 (KCNJ2) [20, 66]; potassium voltage-gated channel, subfamily H, member 2 (KCNH2) [65]; potassium voltage-gated
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channel, KQT-like subfamily, member 1 (KCNQ1) [36]; and potassium voltage-gated channel, Isk-related family, member 1 (KCNE1) [36]. CACNA1C and CACNB1, which encode cardiac L-type Ca2+ channel α1c- and β1 subunits, respectively, are further targets for miR-328 [35]. Terentyev and colleagues [5] have demonstrated that the protein phosphatase PP2A regulating subunit B56a is potentially an important target for miR-1 and miR-133 in the heart, and through translational inhibition of this mRNA, miR-1 caused calmodulin kinase II (CAMKII)-dependent hyperphosphorylation of the ryanodine receptor (RyR2) and enhanced RyR2 activity, consequently promoting arrythmogenic sarcoendoplasmic reticulum Ca2+ release. Though it should be cautioned that previously mentioned studies suggest wide miRNA dysregulation in arrhythmia, and considering the inherent capacity of miRNAs to target a broad range of proteins, the suggestion that altered expression of key miRNAs, such as miR1, might deregulate expression of cardiac ion channels that direct links to arrhythmia is far from clear, and more miRNAs and targets may be involved. Interestingly, some miRNAs appear to show sex differences in expression. For example, evidence suggests that lower expression of miR-1 in female cardiomyocytes may be responsible for the sex difference in cardiac CX43 expression in under pathological conditions [55]. It would therefore be important to determine whether such regulations might underlie wellestablished gender differences in occurrences of heart and ventricular arrhythmia [31]. Finally, what are the potentials of miRNAs serving as biomarkers and could cardiomyocyte alterations in miRNAs associated with arrhythmia be detected in the blood? A recent study by Wang et al. [60] measured miR-133 and miR-328 levels in blood from patients with acute myocardial infarction and found that the circulating levels in acute myocardial infarction patients were significantly increased compared to those in control subjects, suggesting that miRNAs might prove promising biomarkers. Though the mechanisms surrounding such miRNA alterations and what role these might have in the pathology remain unclear, this study does open the possibility that levels of specific miRNAs might serve to as markers for pathological heart defects and diseases.
References 1. Adam O, Neuberger HR, et al. Prevention of atrial fibrillation with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Circulation. 2008;118:1285–93. 2. Antzelevitch C. Genetic basis of Brugada syndrome. Heart Rhythm. 2007;4:756. 3. Bányász T, Szentandrássy N. Cardiac calmodulin kinase: a potential target for drug design. Curr Med Chem. 2011;18:3707–13. 4. Barrington PL, Martin RL, Zhang K. Slowly inactivating sodium currents are reduced by exposure to oxidative stress. J Mol Cell Cardiol. 1997;29:3251–65.
342 5. Belevych AE, Sansom SE, et al. MicroRNA-1 and −133 increase arrhythmogenesis in heart failure by dissociating phosphatase activity from RyR2 complex. PLoS One. 2011;6:e28324. 6. Bostjancic E, Zidar N, et al. MicroRNAs miR-1, miR-133a, miR133b and miR-208 are dysregulated in human myocardial infarction. Cardiology. 2010;115:163–9. 7. Burstein B, Nattel S. Atrial fibrosis: mechanisms and clinical relevance in atrial fibrillation. J Am Coll Cardiol. 2008;51:802–9. 8. Callis TE, Pandya K, et al. MicroRNA-208a is a regulator of cardiac hypertrophy and conduction in mice. J Clin Invest. 2009;119:2772–86. 9. Carnes CA, Chung MK, et al. Ascorbate attenuates atrial pacinginduced peroxynitrite formation and electrical remodeling and decreases the incidence of postoperative atrial fibrillation. Circ Res. 2001;89:E32–8. 10. Chelu MG, Wehrens XH. Sarcoplasmic reticulum calcium leak and cardiac arrhythmias. J Mol Cell Cardiol. 2011;50:214–22. 11. da Costa Martins PA, Bourajjaj M, et al. Conditional dicer gene deletion in the postnatal myocardium provokes spontaneous cardiac remodeling. Circulation. 2008;118:1567–76. 12. De Jong AM, Maass AH, et al. Mechanisms of atrial structural changes caused by stretch occurring before and during early atrial fibrillation. Cardiovasc Res. 2011;89:754–65. 13. Dernellis J, Panaretou M. Relationship between C-reactive protein concentrations during glucocorticoid therapy and recurrent atrial fibrillation. Eur Heart J. 2004;25:1100–7. 14. Disertori M, Barlera S, et al. Systematic review and meta-analysis: renin-Angiotensin system inhibitors in the prevention of atrial fibrillation recurrences. An unfulfilled hope. Cardiovasc Drugs Ther. 2012;26:47–54. 15. Dobrev D. Atrial Ca2+ signaling in atrial fibrillation as an antiarrhythmic drug target. Naunyn Schmiedebergs Arch Pharmacol. 2010;381:195–206. 16. Dulhunty AF, Casarotto MG, Beard NA. The ryanodine receptor: a pivotal Ca2+ regulatory protein and potential therapeutic drug target. Curr Drug Targets. 2011;12:709–23. 17. Fang WT, Li HJ, et al. The role of statin therapy in the prevention of atrial fibrillation: a meta-analysis of randomized controlled trials. Br J Clin Pharmacol. 2012. doi:10.1111/j.1365-2125.2012.04258.x. 18. Federman J, Whitford JA, et al. Incidence of ventricular arrhythmias in first year after myocardial infarction. Br Heart J. 1998;40:1243–50. 19. George CH, Lai FA. Developing new anti-arrhythmics: clues from the molecular basis of cardiac ryanodine receptor (RyR2) Ca + − release channel dysfunction. Biochem Soc Trans. 2007;35:952–6. 20. Girmatsion Z, Biliczki P, et al. Changes in microRNA-1 expression and IK1 up-regulation in human atrial fibrillation. Heart Rhythm. 2009;6:1802–9. 21. Harling L, Rasoli S, et al. Do antioxidant vitamins have an antiarrhythmic effect following cardiac surgery? A meta-analysis of randomised controlled trials. Heart. 2011;97:1636–42. 22. He X, Gao X, et al. Atrial fibrillation induces myocardial fibrosis through angiotensin II type 1 receptor-specific Arkadia-mediated downregulation of Smad7. Circ Res. 2011;108:164–75. 23. Hodgkin AL, Huxley AF. Currents carried by sodium and potassium ions through the membrane of the giant axon of Loligo. J Physiol. 1952;116:449–72. 24. Hu D, Viskin S, et al. Genetic predisposition and cellular basis for ischemia-induced ST-segment changes and arrhythmias. J Electrocardiol. 2007;40:S26–9. 25. Huang CX, Liu Y, et al. Oxidative stress: a possible pathogenesis of atrial fibrillation. Med Hypotheses. 2009;72:466–7. 26. Issac TT, Dokainish H, Lakkis NM. Role of inflammation in initiation and perpetuation of atrial fibrillation: a systematic review of the published data. J Am Coll Cardiol. 2007;50:2021–8. 27. Kim YM, Guzik TJ, et al. A myocardial Nox2 containing NAD(P) H oxidase contributes to oxidative stress in human atrial fibrillation. Circ Res. 2005;97:629–36.
M. Slevin et al. 28. Komatsu T, Tachibana H, et al. Long-term efficacy of upstream therapy with lipophilic or hydrophilic statins on antiarrhythmic drugs in patients with paroxysmal atrial fibrillation: comparison between atorvastatin and pravastatin. Int Heart J. 2011;52:359–65. 29. Korantzopoulos P, Kolettis TM, et al. The role of oxidative stress in the pathogenesis and perpetuation of atrial fibrillation. Int J Cardiol. 2007;115:135–43. 30. Kumagai K, Nakashima H, et al. Effects of angiotensin II type 1 receptor antagonist on electrical and structural remodeling in atrial fibrillation. J Am Coll Cardiol. 2003;41:2197–204. 31. Lampert R, McPherson CA, et al. Gender differences in ventricular arrhythmia recurrence in patients with coronary artery disease and implantable cardioverter-defibrillators. J Am Coll Cardiol. 2004;43:2293–9. 32. Laurita KR, Rosenbaum DS. Cellular mechanisms of arrhythmogenic cardiac alternans. Prog Biophys Mol Biol. 2008;97:332–47. 33. Lehnart SE, Terrenoire C, et al. Stabilization of cardiac ryanodine receptor prevents intracellular calcium leak and arrhythmias. Proc Natl Acad Sci U S A. 2006;103:7906–10. 34. Liu N, Williams AH, et al. An intragenic MEF2-dependent enhancer directs muscle-specific expression of microRNAs 1 and 133. Proc Natl Acad Sci U S A. 2007;104:20844–9. 35. Lu Y, Zhang Y, et al. MicroRNA-328 contributes to adverse electrical remodeling in atrial fibrillation. Circulation. 2010;122:2378–87. 36. Luo X, Xiao J, et al. Transcriptional activation by stimulating protein 1 and post-transcriptional repression by muscle-specific microRNAs of IKs-encoding genes and potential implications in regional heterogeneity of their expressions. J Cell Physiol. 2007;212:358–67. 37. Matkovich SJ, Wang W, et al. MicroRNA-133a protects against myocardial fibrosis and modulates electrical repolarization without affecting hypertrophy in pressure-overloaded adult hearts. Circ Res. 2010;106:166–75. 38. Mihm MJ, Yu F, et al. Impaired myofibrillar energetics and oxidative injury during human atrial fibrillation. Circulation. 2001;104:174–80. 39. Mohammed KS, Kowey PR, Musco S. Adjuvant therapy for atrial fibrillation. Future Cardiol. 2010;6:67–81. 40. Moreno JD, Clancy CE. Pathophysiology of the cardiac late Na current and its potential as a drug target. J Mol Cell Cardiol. 2012;52:608–19. 41. Nattel S, Maguy A, et al. Arrhythmogenic ion-channel remodeling in the heart: heart failure, myocardial infarction, and atrial fibrillation. Physiol Rev. 2007;87:425–56. 42. Nattel S, Shiroshita-Takeshita A, et al. Mechanisms of atrial remodeling and clinical relevance. Curr Opin Cardiol. 2005;20:21–5. 43. Ono K, Kuwabara Y, Han J. MicroRNAs and cardiovascular diseases. FEBS J. 2011;278:1619–33. 44. Priori SG, Chen SR. Inherited dysfunction of sarcoplasmic reticulum Ca2+ handling and arrhythmogenesis. Circ Res. 2011;108:871–83. 45. Rahimi K, Emberson J, et al. Executive effect of statins on atrial fibrillation: collaborative meta-analysis of published and unpublished evidence from randomised controlled trials. BMJ. 2011;16:342. 46. Rao PK, Toyama Y, et al. Loss of cardiac microRNA-mediated regulation leads to dilated cardiomyopathy and heart failure. Circ Res. 2009;105:585–94. 47. Rasoli S, Kakouros N, et al. Antioxidant vitamins in the prevention of atrial fibrillation: what is the evidence? Cardiol Res Pract. 2011;2011:164078. 48. Recanatini M, Poluzzi E, et al. QT prolongation through hERG K + channel blockade: current knowledge and strategies for the early prediction during drug development. Med Res Rev. 2005;25:133–66. 49. Rodrigo R, Vinay J, et al. Use of vitamins C and E as a prophylactic therapy to prevent postoperative atrial fibrillation. Int J Cardiol. 2010;138:221–8.
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50. Savelieva I, Kakouros N, et al. Upstream therapies for management of atrial fibrillation: review of clinical evidence and implications for European Society of Cardiology guidelines. Part I: primary prevention. Europace. 2011;13:308–28. 51. Savelieva I, Kakouros N, et al. Upstream therapies for management of atrial fibrillation: review of clinical evidence and implications for European Society of Cardiology guidelines. Part II: secondary prevention. Europace. 2011;13:610–25. 52. Saxena A, Tabin CJ. MiRNA-processing enzyme Dicer is necessary for cardiac outflow tract alignment and chamber septation. Proc Natl Acad Sci U S A. 2010;107:87–91. 53. Schumacher SM, McEwen DP, et al. Antiarrhythmic drug-induced internalization of the atrial-specific K + channel Kv1.5. Circ Res. 2009;104:1390–8. 54. Schumaker SM, Martens JR. Ion channel trafficking: a new therapeutic horizon for atrial fibrillation. Heart Rhythm. 2010;7:1309–15. 55. Stauffer BL, Sobus RD, Sucharov CC. Sex differences in cardiomyocyte connexin43 expression. J Cardiovasc Pharmacol. 2011;58:32–9. 56. Thireau J, Pasquie JL, et al. New drugs vs. old concepts: a fresh look at antiarrhythmics. Pharmacol Ther. 2011;132:125–45. 57. Thum T, Galuppo P, et al. MicroRNAs in the human heart: a clue to fetal gene reprogramming in heart failure. Circulation. 2007;116:258–67. 58. Van Wagoner DR. Oxidative stress and inflammation in atrial fibrillation: role in pathogenesis and potential as a therapeutic target. J Cardiovasc Pharmacol. 2008;52:306–13. 59. Vaughan Williams EM. Subgroups of class 1 antiarrhythmic drugs. Eur Heart J. 1984;5:96–8.
343 60. Wang Y, Joyner RW, et al. Stretch-activated channel activation promotes early afterdepolarizations in rat ventricular myocytes under oxidative stress. Am J Physiol Heart Circ Physiol. 2009;296:1227–35. 61. Wang R, Li N, et al. Circulating MicroRNAs are promising novel biomarkers of acute myocardial infarction. Intern Med. 2011;50:1789–95. 62. Wehrens XH, Lehnart SE, et al. Protection from cardiac arrhythmia through ryanodine receptor-stabilizing protein calstabin2. Science. 2004;304:292–6. 63. Wilson LD, Rosenbaum DS, et al. Targeting ryanodine receptors for anti-arrhythmic therapy. Acta Pharmacol Sin. 2011;32: 749–57. 64. Xiao J, Liang D, et al. MicroRNA expression signature in atrial fibrillation with mitral stenosis. Physiol Genomics. 2011;43:655–64. 65. Xiao J, Luo X, et al. MicroRNA miR-133 represses HERG K+ channel expression contributing to QT prolongation in diabetic hearts. J Biol Chem. 2007;282:12363–7. 66. Yang B, Lin H, et al. The muscle-specific microRNA miR-1 regulates cardiac arrhythmogenic potential by targeting GJA1 and KCNJ2. Nat Med. 2007;13:486–91. 67. Yap YG, Camm AJ. Drug induced QT prolongation and torsades de pointes. Heart. 2003;89(11):1363–72. 68. Zhao Y, Ransom JF, et al. Dysregulation of cardiogenesis, cardiac conduction, and cell cycle in mice lacking miRNA-1-2. Cell. 2007;129:303–17.
Proarrhythmia (Secondary)
26
Debabrata Dash
Abstract
Proarrhythmia is defined as the generation of new or worsened arrhythmias with drug therapy. Specific proarrhythmia syndromes, each with distinct mechanism and approach to therapy, have been described. The recognized examples are digitalis intoxication, proarrhythmia associated with sodium-channel block, and torsade de pointes (TdP) occurring during QT-prolonging therapies. In addition, because proarrhythmia often seems to develop in the absence of clear risk predictors, a role for genetics in predisposing to this reaction has been postulated. Acquired long QT syndromes (LQTSs) describe pathologic excessive prolongation of the QT interval, with risk for TdP upon exposure to drug therapy. The wide array of drugs with potential for QT prolongation, the large number of patients exposed to such drugs, the difficulty in predicting the risk, and the potentially fatal outcome make acquired LQTS an important public health problem. The best approach to therapy is to identify the patients at risk, to recognize proarrhythmia, to withdraw the offending agents, and to use specific therapies when available. Keywords
Proarrhythmia • Sodium-channel block • Torsade de pointes
Introduction Proarrhythmia is defined as the generation of new or worsened arrhythmias with drug therapy. It represents an extreme example of the phenomenon that drug effects vary widely among individuals. Studies of mechanisms leading to proarrhythmia have had important implications for understanding arrhythmogenesis, rational use of antiarrhythmic therapies, selection of patients for specific therapies, and even drug development. In addition, as proarrhythmia often seems to develop in the absence of clear risk factors, a role for genetics in modulating drug action has been postulated. A major D. Dash, MD, DM, FICC, FCCP, FSCAI, FAPSC Department of Cardiology, S.L. Raheja (a Fortis Associate) Hospital, Mumbai, MH, India e-mail:
[email protected],
[email protected]
A.S. Kibos et al. (eds.), Cardiac Arrhythmias, DOI 10.1007/978-1-4471-5316-0_26, © Springer-Verlag London 2014
obstacle to widespread use of drugs to manage cardiac arrhythmias has been the relatively high incidence of side effects, especially as drugs are considered for long-term therapy. From a basic science and drug development point of view, these adverse effects, and in particular the phenomenon of proarrhythmia, demonstrate the need for further refinement in our understanding of molecular targets at which antiarrhythmic drugs should be aimed [1]. It is now quite clear that the general phenomenon of proarrhythmia can arise from a number of electrophysiologically distinct and identifiable mechanisms. Here the author reviews the well-recognized proarrhythmia syndrome: arrhythmias due to digitalis and sodium-channel block and drug-induced torsade de pointes. These syndromes serve to illustrate gene-drug interaction that mediates proarrhythmia risk (Table 26.1) [2].
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Table 26.1 Factors mediating proarrhythmia risk
Digitalis toxicity Torsade de pointes
Sodium channel
Pharmacokinetic Gene Potential effect MDRI Polymorphisms linked to increases in blood level CYP2D6
Pharmacodynamic Gene RYR2 CASQ2 PM at increased risk for thioridazineANK2 related TdP KCNQ1 KCNH2(HERG) KCNEI PM at increased risk for flecainide-related SCN5A adverse effects: ultrarapid metabolizer at SCN5A S1102Y increased risk for encainide-related SCN5A toxicity
Proarrhythmias Due to Digitalis The phenomenon of proarrhythmia was probably first recognized when digitalis glycosides were found to provoke arrhythmias. Virtually any arrhythmia can result from digitalis intoxication; the common manifestations include ventricular arrhythmias such as ventricular bigeminy, atrial tachycardia, and various degrees of suppression of sinuses and atrioventricular function. Rare digitalis-induced arrhythmias include bidirectional ventricular tachycardia (VT), a regular VT in which alternating beats have different axes, and, with very high digitalis concentrations associated with suicidal overdose, cardiac standstill [3]. Digitalis undergoes renal and biliary excretion via a drug-efflux pump, P-glycoprotein. P-glycoprotein function is inhibited by various drugs, including amiodarone, quinidine, itraconazole, cyclosporine, and verapamil, and each one elevates serum digoxin concentrations and can result in digitalis toxicity through this mechanism [4]. Polymorphisms in the MDR1 gene encoding P-glycoprotein have been described and have been associated with variability in digoxin concentrations, although the extent to which they contribute risk for digitalis toxicity is unknown [5, 6]. Its molecular target is the sodiumpotassium ATPase pump, and downstream physiologies that are modulated by pump inhibition include sodium-calcium exchange and other systems involved in intracellular calcium homeostasis. Therefore, candidate genes in which variants may modulate digitalis effects include those encoding sodium-potassium ATPase, the sodium-calcium exchanger, and those regulating intracellular calcium control. Accordingly, congenital diseases altering intracellular calcium control, including catecholaminergic polymorphic VT [7, 8] and the ankyrin-B-linked form of the long QT syndrome [9], may predispose to digitalis toxicity. Mild cases of digitalis toxicity (e.g., slightly elevated serum digoxin concentrations with asymptomatic premature ventricular complexes or bradyarrhythmias) can frequently be managed by discontinuation of the drug, cautious
Potential effect Loss of function variants may predispose to digitalis_mediated arthymias Subclinical congenital long QT syndrome mutations predispose to TdP
Y allele confers increased risk AfricanAmericans VF during drug challenge in patients with Brugada syndrome
potassium supplementation, and observation. A number of antiarrhythmic drugs (e.g., phenytoin) have been proposed as therapies for life-threatening arrhythmia related to digitalis intoxication, but they have been largely supplanted by antidigoxin antibodies. A “vagal” onset of atrial fibrillation (AF) occurs in some patients, usually in young healthy subjects who develop episodes of AF during times of increased vagal tone such as sleep or after meals or exertion. Digitalis can actually increase the frequency of episodes in such patients, presumably by its vagotonic effects, which probably shorten action potentials by activating acetylcholine-sensitive potassium current. This represents another example of proarrhythmia syndrome with a specific underlying mechanism. The management is to avoid digitalis [10].
Proarrhythmias Due to Sodium-Channel Block Sodium-channel block is the common mechanism underlying many well-described proarrhythmia syndromes: slowing of atrial flutter with the potential for 1:1 AV conduction, development of incessant slow VT in patients with myocardial scarring, and increased risk of death following myocardial infarction (as in the CAST [Cardiac Arrhythmias Suppression Trial] study) [11] and in patients in whom the Brugada ECG phenotype (and rarely ventricular fibrillation) is elicited by administration of a sodium-channel-blocking drug [12].
Atrial Flutter with 1:1 Atrioventricular Conduction In patients with AF or atrial flutter receiving sodium-channelblocking drugs, conduction slowing due to sodium-channel block can result in prolongation of flutter cycle length. If the flutter cycle length prolongs sufficiently, 1:1 atrioventricular
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Proarrhythmia (Secondary)
transmission becomes possible, with resultant paradoxical increase in ventricular response. Because conduction slowing by sodium-channel blockers is rate dependent, the rapidly conducted QRS complexes are markedly prolonged and may display intraventricular conduction defects [13]. Thus this arrhythmia may be difficult to distinguish from VT [14]. Atrial flutter with 1:1 conduction occurs with quinidine, flecainide, and propafenone. This form of proarrhythmia may also occur in patients receiving the drug therapy for AF (who frequently also have episodes of atrial flutter). If the diagnosis is suspected and simple maneuvers (monitoring long rhythm strips, carotid sinus massage) do not uncover atrial flutter, a trial of adenosine is worth attempting to establish the diagnosis. Treatment consists of withdrawal of offending drug and control of ventricular response (e.g., with intravenous calcium-channel blocker or B-blocker)
“Incessant” Slow VT In this entity, patients with actual or potential circuits for reentrant VT develop incessant VT upon exposure to sodiumchannel-blocking drug, often flecainide or propafenone. Occasionally, the rhythm in patients with incessant VT of this type degenerates into a “slow” ventricular fibrillation (VF) pattern [15, 16]. This arrhythmia is often very resistant to cardioversion and can be lethal. High doses of quinidine in AF cause death due to VF, presumably through a similar mechanism [17].
Altered Defibrillation and Pacing Threshold The situations in which substantial sodium-channel block is present at slow rates (e.g., during therapy with drugs such as flecainide, propafenone, or quinidine) are particularly prone to increase pacing threshold [18]. Extensive sodium-channel block can also impair ventricular defibrillation and has occasionally rendered implantable cardioverter-defibrillators (ICDs) ineffective [19, 20].
Drug-Induced Torsade De Pointes Introduction Prolongation of the QT interval and the concomitant risk for polymorphic VT, torsade de pointes (TdP), is the hallmark of the congenital long QT syndromes (LQTSs). Acquired LQTS describes pathologic excessive prolongation of the QT interval, with risk for TdP, upon exposure to an environmental stressor, the most common being drug therapy. Indeed, the risk of acquired LQTS is the most common
347 Table 26.2 Examples of drug with case reports on drug-induced torsade de pointes Antiarrhythmic drugs Amiodarone, disopyramide, dofetilide, flecainide,ibutilide, procainamide, quinidine, sotalol Antihistamines Astemizole, diphenhydramine, terfenadine Antimicrobials Chloroquine, clarithromycin, grepafloxacin, erythromycin, halofantrine, ketoconazole, pentamidine Antipsychotics Chlorpromazine, desipramine, doxepin, droperidol, haloperidol, imipramine, lithium, maprotiline, pimozide, sertindole, thioridazine Cholinergic antagonists Cisapride
cause of withdrawal of restriction of drugs that have already been marketed. Initial reports of QT-interval-prolonging drugs, which are very effective at blocking reentrant tachycardias but simultaneously prolong cardiac repolarization and, therefore, may induce TdP. It is estimated that more than 1 % of the patients receiving these drugs may develop TdP [21]. Later, many drugs from structurally unrelated chemical classes were also associated with LQTS, including antibiotic, antihistamine, and antipsychotic drugs (Table 26.2) [22]. The electrocardiographic features of TdP include typical pause-dependent onset, marked QT prolongation (particularly in the beat(s) just before or just after an episode of tachycardia), and prominent U waves that display beat-tobeat lability. TdP is usually self-limiting, and the typical symptom is syncope. Death due to TdP is usually caused by its degeneration to VF.
Mechanisms of Drug-Induced QT Prolongation QT prolongation entails action potential prolongation in at least some portions of the ventricle. Action potential prolongation, in turn, results from a net decrease in repolarizing current – either by increased inward current or by reduced outward current. Almost all drugs which cause acquired LQTS target specific potassium current; the rapid component of the delayed rectifier, Ikr [23], is generated by potassium flow through proteins encoded by the human ether-a-go-go-related gene (HERG, now termed KCNH2). Structural features unique to this channel may explain why it is particularly susceptible to a block by a wide array of different drugs [24]. Pharmacologic rescue has recently been shown as a novel mechanism resulting in a drug-induced LQTS phenotype [25]. Cisapride administration resulted in the LQTS phenotype by rescue of the abnormal SCN5A protein, in addition to Ikr block.
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Mechanisms of Proarrhythmia While most drugs that block Ikr result in QT prolongation, which is a requisite for TdP, QT prolongation alone is not sufficient to result in TdP. TdP from amiodarone is exceedingly rare even if it results in significant QT prolongation [26]. Heterogeneity of repolarization across cell types within ventricular myocardium is recognized as one explanation for the lack of direct correlation between QT prolongation and proarrhythmia [27]. The normal myocardium contains at least three types of cells, epicardial, endocardial, and midmyocardial (M) cells, each with action potentials that differ in morphology and duration. The action potential in each cell type responds in different degrees to pharmacologic agents and changes in heart rate. This difference across the ventricular wall, or transmural dispersion of repolarization, is physiologic but, if exaggerated, has been associated with the risk of TdP. While amiodarone prolongs repolarization in all three cell types, the transmural dispersion is reduced, reducing the likelihood of TdP. The interval from the peak to the end of the T wave correlates with transmural dispersion of repolarization [28] and may represent a more specific ECG indicator of risk for TdP in the setting of long QT interval. T-wave alternans has been observed in LQTS as a precursor to TdP [29]. It results from alteration of the M-cell APD, leading to exaggeration of transmural dispersion of repolarization during alternate beats and thus the potential for development of TdP [30]. Another emerging indicator of risk for TdP is beat-to-beat QT variability [31]. A wide variety of drugs can result in prolongation of the action potential, predominantly through direct Ikr block. Action potential prolongation can lead to early afterdepolarizations (EADs), oscillations in the membrane potential during repolarization. These EADs result from reopening either L-type calcium channels or sodium channels and may result in ectopic beats if occurring in large region of the heart. Triggered upstrokes from EADs are likely initiating mechanism for TdP. Thus, the proarrhythmia results indirectly from Ikr block, which enables activation or reactivation of inward currents underlying EADs. Role of Ca-/calmodulindependent protein kinase II in the genesis of TdP has recently been demonstrated.
Risk Factors for Drug-Induced Long QT Syndrome In order to predict the occurrence of acquired LQTS in the clinic, a lot of attention has been focused over recent years (Table 26.3). People with structural heart disease are more prone to drug-induced TdP than healthy individuals.
D. Dash Table 26.3 Major risk factors for acquired long QT syndrome Nongenetic Gender (female) Electrolyte disturbances(hypokalemia) Other heart diseases (myocardial infarction, bradycardia, congestive heart failure, conversion atrial fibrillation) QT-prolonging drugs (overdose, interactions) Genetic Congenital long QT syndrome mutation LQTS gene polymorphisms Drug-metabolizing enzyme gene polymorphisms
Ischemic, valvular, hypertensive heart disease and bradycardia may contribute to triggering TdP [32]. A lower expression level and altered function of the LQTS ion-channel genes might contribute to the increased risk for acquired LQTS in these patients [33, 34]. Hypokalemia has also been reported in individual TdP case reports [35, 36]. Upon removal of extracellular K+, the magnitude of outward HERG current amplitude is reduced, which may lead to prolongation of ventricular repolarization [37]. In combination with a drug that blocks HERG channel, hypokalemia may exaggerate this effect [38]. It is logical that concomitant administration of more than one drug which prolongs repolarization would increase the risk of drug-induced LQTS. In some cases, the mechanism of increased risk is due to drug-drug interactions altering metabolism, rather than by simple additive effects on Ikr. Many drugs are metabolized by the cytochrome P450 in superfamily of proteins, and CYP3A is the predominant cytochrome P450 in human adult liver. Several drugs which are substrates for CYP3A are also Ikr blockers, including erythromycin and terfenadine [39]. While addition of oral erythromycin to terfenadine therapy results in further QT prolongation, it also increases terfenadine concentrations due to competitive inhibition of CYP3A by erythromycin [40]. Indeed, coadministration of CYP3A inhibitors with erythromycin is associated with a doubling of the risk of sudden cardiac death, likely due to increased concentrations of erythromycin [41].
Genetics and Drug-Induced Long QT Syndrome Similarities to the congenital LQTS suggest a genetic component to the risk of drug-induced LQTS. Although the QT and QTc intervals prolonged similarly, the peak to end of the T wave increased significantly only in the relatives of patients with drug-induced LQTS [42]. This study demonstrated greater prolongation of terminal repolarization in the relatives of patients with drug-induced LQTS, suggesting a genetic predisposition to this. Variations in several classes of genes have been associated with drug-induced LQTS.
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Generally, QT prolongation is increased at higher concentrations of drug: thus genetic variations that alter drug metabolism resulting in higher than normal drug concentration predispose to drug-induced LQTS. One example is CYP2D6, which metabolizes thioridazine. In 7–10 % of the population, this enzyme is nonfunctional due to the loss of function genetic variants; these poor metabolizers are at increased risk of TdP from thioridazine.
Management of Torsade De Pointes Management of torsade de pointes involves the following: (1) identifying patients at risk, (2) recognizing arrhythmia when it occurs, and (3) aiming treatment at the underlying cellular mechanism. Once the arrhythmia is recognized, any offending drug should be withdrawn, serum potassium replenished to the high-normal range (4.5–5 mEq/L), and 1–2 g magnesium sulfate administered intravenously. Increased extracellular potassium both increases outward potassium current (especially Ikr) [38] and hence hastens repolarization. Magnesium, in anecdotal studies, prevents episodes of torsade de pointes [43]. If the arrhythmia occurs despite these maneuvers, the next step is to increase heat rate, which directly shortens the QT interval and early afterdepolarizations and triggered activity. This can be accomplished by isoproterenol, which increases not only the heat rate but also QT interval at any given rate. Cardiac pacing is an alternative to isoproterenol if frequent episodes of torsade de pointes occur or if the drug is contraindicated. Conclusions
Serious proarrhythmia is a rare, but well-recognized, complication of therapy with antiarrhythmic drugs and occasionally “non-cardiovascular” agents. Drug-induced proarrhythmia is a growing challenge shared by the pharmaceutical industry and prescribing clinicians. The recognition that proarrhythmia can arise from multiple electrophysiologic mechanisms had led to delineation of specific proarrhythmic syndromes. Each of these has distinct clinical features and specific therapies. The relationship between a drug or class of drugs, the QT interval, and the development of TdP is complicated, and in some cases, it may be unpredictable that the idea of a pharmacogenetic contribution, through pharmacokinetic or pharmacodynamic mechanisms, has some appeal. Indeed, important variants in the molecules of drug disposition, in drug targets, and in modulators of the drug-target interaction have now been well described in individual cases of proarrhythmia. However, the need for newer and more effective antiarrhythmic drugs is ongoing, as is the need for new agents in all areas of medicine. Because of its relative ease of measurement compared with other indices,
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the QT interval will remain as a clinical surrogate for proarrhythmia liability. Its measurement could be improved by sampling a large number of QT intervals and refining methods for accurate, precise, and reproducible measurement of the QT interval. Better surrogates are needed for preclinical screening of the proarrhythmic liability of new compounds [44]. A unifying framework to understand drug-induced LQTS is the concept of reduced repolarization reserve. In the example of the LQTS, a single severe abnormality in a major repolarization current can elicit an abnormal phenotype. More commonly, one or more preexisting minor abnormalities of repolarization results in a subclinical phenotype, which is not apparent until superimposition of a drug that blocks Ikr results in drug-induced LQTS. However, the challenge lies in identifying which patients in which settings and with which drugs or combinations of drugs will develop drug-induced LQTS and avoiding the combination of factors that promote TdP.
References 1. Roden DM. Clinical features of arrhythmia aggravation by antiarrhythmic drugs and their implications for basic mechanism. Drug Dev Res. 1990;19:153–72. 2. Darbar D, Rosen DM. Pharmacogenetics antiarrhythmic therapy. Expert Opin Pharmacother. 2006;7(12):1583–90. 3. Taboulet P, Baud FJ, Bismuth C, et al. Acute digitalis intoxication- is pacing still appropriate? J Toxicol Clin Toxicol. 1993;31:261–73. 4. Fromn MF, Kim RB, Stein CM, et al. Inhibition of P-glycoproteinmediated drug transport: a unifying mechanism to explain the interaction between digoxin and quinidine. Circulation. 1999;99:552–7. 5. Hoffmeyer S, Burk O, von Richter O, et al. Functional polymorphism of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci U S A. 2009;97:3473–8. 6. Kim RB, Leake BF, Choo EF, et al. Identification of functionally variant MDR 1 alleles among European Americans and African Americans. Clin Phrmacol Ther. 2001;70:189–99. 7. Postma AV, Denjoy I, Hoornje TM, et al. Absence of calsequestrin 2 causes severe forms of catecholaminergic polymorphic ventricular tachycardia. Circ Res. 2002;91:E21–6. 8. Priori SG, Napolitano C, Memmi M, et al. Clinical and molecular characterization of patients with catecholaminergic polymorphic ventricular tachycardia. Circulation. 2002;106:69–74. 9. Mohler PH, Schott JJ, Gramolini AO, et al. Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death. Nature. 2003;421:634–9. 10. Coumel P. Autonomic influences in atrial tachyarrhythmias. J Cardiovasc Electrophysiol. 1996;7:999–1077. 11. THE CARDIAC ARRHYTHMIA SUPPRESSION TRIAL (CAST) INVESTIGATORS. Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. N Engl J Med. 1989;321:406–12. 12. Brugada R, Brugada J, Antzelevitch C, et al. Sodium channel blockers identify the risk for sudden death in patients with ST segment elevation and right bundle branch but structurally normal hearts. Circulation. 2000;101:510–5.
350 13. Crijns HJ, van Gelder IC, Lie KI. Supraventricular tachycardia mimicking ventricular tachycardia during flecainide treatment. Am J Cardiol. 1988;62:1303–6. 14. Flak RH. Flecainide-induced ventricular tachycardia and fibrillation in patients treated for atrial fibrillation. Ann Intern Med. 1989;111:107–11. 15. Oetgen WJ, Tibbits PA, Abt MEO, et al. Clinical and electrophysiologic assessment of oral flecainide acetate for recurrent ventricular tachycardia: evidence for exacerbation of electrical instability. Am J Cardiol. 1983;52:746–50. 16. Winkle RA, Mason JW, Griffin JC, et al. Malignant ventricular tachyarrhythmias associated with use of encainide. Am Heart J. 1981;102:857–64. 17. Wetherbee DG, Holzman D, Brown MG. Ventricular tachycardia following the administration of quinidine. Am Heart J. 1951;42:89–96. 18. Greene HL. Interactions between pharmacologic and nonpharmacologic antiarrhythmic therapy. Am J Cardiol. 1996;78(suppl):61–6. 19. Echt DS, Black JN, Barbey JT, et al. Evaluation of antiarrhythmic drugs on defibrillation energy requirements in dogs: sodium channel block and action potential prolongation. Circulation. 1989;79:1106–17. 20. Marinchak RA, Friehling TD, Kiline RA, et al. Effect of antiarrhythmic drugs on defibrillation threshold: case report of an adverse effect of mexiletine and review of the literature. Pacing Clin Electrophysiol. 1988;11:7–12. 21. Viskin S. Long QT syndromes and torsade de pointes. Lancet. 1999;354:1625–33. 22. Jeroen A, Aimee DC, et al. Pharmacogenomics and acquired long QT syndrome. Pharmacogenomics. 2005;6(3):259–70. 23. Roden DM, Viswanathan PC. Genetics of acquired long QT syndrome. J Clin Invest. 2005;115:2025–32. 24. Sanguinetti MC, Tristani-Firouzi M. HERG potassium channels and cardiac arrhythmia. Nature. 2006;440:463–9. 25. Liu K, Yang T, Viswanathan PC, et al. New mechanism contributing to drug-induced arrhythmia. Circulation. 2005;112:3239–46. 26. Lazzara R. Amiodarone and torsade de pointes. Ann Intern Med. 1989;111:549–51. 27. Antzeivitch C. Role of transmural dispersion of repolarization in the genesis of drug-induced torsade de pointes. Heart Rhythm. 2005;2:S9–15. 28. Xia Y, Liang Y, Kongstad O, et al. In vivo validation of the coincidence of the peak and end of the T wave with full repolarization of the epicardium and endocardium in swine. Heart Rhythm. 2005;2: 162–9. 29. Grabowski M, Karpinski G, Filipiak KJ, et al. Images in cardiovascular medicine: drug induced long- QT syndrome with macroscopic T wave alternans. Circulation. 2004;24(110):e459–60.
D. Dash 30. Shimizu W, Antzeivitch C. Cellular and ionic basis for T-wave alternans under long QT conditions. Circulation. 1999;99:1499–507. 31. Thomsen MB, Derduyn SC, Stengl M, et al. Increased short term variability of repolarization predicts d-sotalol induced torsade de pointes in dogs. Circulation. 2004;110:2453–9. 32. Shimizu W, Tanaka K, Suennaga K, et al. Bradycardia-dependent early after depolarization in a patient with QTU prolongation and torsade de pointes in association with marked bradycardia and hypokalemia. Pacing Clin Electrophysiol. 1999;14: 1105–11. 33. Voders PG, Sipido KR, Vos MA, et al. Down regulation of delayed rectifier (K+) currents in dogs with chronic complete atrioventricular block and acquired torsade de pointes. Circulation. 1999;100: 2455–61. 34. Ramakers C, Vos MA, Dovendans PA, et al. Coordinated downregulation of KCNQI and KCNE 1expression contributes to reduction of I(ks) in canine hypertrophied hearts. Cardiovasc Res. 2003;57:486–96. 35. Marinella MA, Burdette SD. Visual diagnosis in emergency medicine. Hypokalemia- induced QT interval prolongation. J Emerg Med. 2000;19:375–6. 36. Nosworthy A. Images in clinical medicine. Hypokalemia. N Engl J Med. 2003;349:2116. 37. Sanguinetti MC, Jurkiewicz NK. Role of external Ca2+ and K + in gaiting of cardiac delayed rectifier K + currents. Pflugers Arch. 1992;420:180–6. 38. Yang T, Roden DM. Extracellular potassium modulation of drug block of Ikr. Implications for torsade de pointes and reverse usedependence. Circulation. 1996;93:407–11. 39. Morissette P, Hreiche R, Turgeon J. Drug-induced long QT syndrome and torsade de pointes. Can J Cardiol. 2005;21:857–64. 40. Hong PK, Woosley RL, Zamani K, et al. Changes in the pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine with concomitant administration of erythromycin. Clin Pharmacol Ther. 1992;52:231–8. 41. Ray WA, Murray KT, Meredith S, et al. Oral erythromycin and the risk of sudden death from cardiac causes. N Engl J Med. 2004;351:1089–96. 42. Kannankenil PJ, Roden DM, Norris KJ, et al. Genetic susceptibility to acquired long QT syndrome: pharmacologic changes in firstdegree relatives. Heart. 2005;2:134–40. 43. Tzivoni D, Banai S, Schugar C, et al. Treatment of torsade de pointes with magnesium sulfate. Circuation. 1988;77:392–7. 44. Hondelghem LM. Thorough QT/QTc not so thorough: removes torsadogenic predictors from the T wave, incriminates safe drugs, and misses profibrillatory drugs. J Cardiovasc Electrophysiol. 2006;17: 337–40.
Connexin-43 Expression: A Therapeutic Target for the Treatment of Ventricular Tachycardia
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Craig Steven McLachlan, Zakaria Ali Moh Almsherqi, Brett Hambly, and Mark McGuire
Abstract
Gap junctions (Gj) form conduits between adjacent cells that are composed of coannexin (Cx) protein subunits and allow direct intercellular communication. Specifically gap-junctional channels permit intercellular transfer of small molecules including second messengers and metabolites and allow for intercellular propagation of current-carrying ions between excitable cardiac myocytes. Pathological stimuli can cause cellular stress that affects intercellular communication by altering the abundance of functional gap junction channels. Significant changes in gap junction function may alter the velocity or anisotropy of cardiac conduction. The number of gap junctions (expressed Cx) per intercalated disk length and the number of cells connected by intercalated disks to a single myocyte are decreased within the acute myocardial infarct (MI) border zone as a result of ischemia. The gap junction surface area in hearts subjected to chronic hypertrophy is significantly decreased in both human and translational animal models. The concept of heterogeneity for connexin-43 expression across the ventricular myocardial wall is explored in the current chapter. MI ventricular remodeling increases connexin heterogeneity and the propensity for ventricular arrhythmias. Drug targets that alter the expression and function of connexin-43 post-MI are reviewed. A particular emphasis is placed on the role of nitric oxide modulation on connexin-43 expression. Keywords
Connexin 43 • Ventricular tachycardia • Gap-junctional modulation
It is difficult to overstate the importance of maintenance of normal gap junction function in the prevention of arrhythmias and maintenance of health – Gordon F. Tomaselli [1]. C.S. McLachlan, PhD (*) Rural Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia e-mail:
[email protected] Z.A.M. Almsherqi, MD, PhD Department of Physiology, National University of Singapore, Singapore, Singapore B. Hambly, MBBS, PhD, DipAnt Department of Pathology, University of Sydney, Darlington, NSW 2050, Australia M. McGuire, MBBS, PhD, FRACP Department of Cardiology, Royal Prince Alfred Hospital, Missenden Rd, Camperdown, NSW 2050, Australia
A.S. Kibos et al. (eds.), Cardiac Arrhythmias, DOI 10.1007/978-1-4471-5316-0_27, © Springer-Verlag London 2014
Myocardial gap junctions are transmembrane channels that transmit electrical impulses via direct transfer of cytosolic ions, metabolites, and small intracellular messengers between neighboring cells (Fig. 27.1). Gap-junctional coupling will itself be determined by a number of factors, including the amount and types of connexin (Cx) expressed, the size and distribution of gap-junctional plaques, the proportion of each Cx assembled into functional junctions, and the gating and specific Cx makeup of individual gap-junctional channels [2]. The predominant function of these channels in the heart is to allow a more efficient propagation of the action potential from cell to cell [3].
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a
Channel formed by pores in each membrane
b
Open
Closed
Extracelluar space 6 connexins = 1 connexon
Fig. 27.2 Ventricular mid-myocardial immunohistochemical expression of Cx43. Note that Cx43 expression is positive (brown staining) at gap junctions located at the terminal ends of longitudinally arranged cardiac myocytes. Gap junctions are concentrated at intercalated disks, discrete regions of cardiomyocyte-cardiomyocyte coupling in the heart, where they interact intimately with adherens junctions (With permission from McLachlan et al. [11])
Extracelluar side
Cytoplasmic side
Bob Crimi
Fig. 27.1 Six connexin molecules complex to form a connexon hemichannel, which, when inserted into the plasma membrane, can bind with a hemichannel on an opposing cell, creating a conduit that connects the cytoplasms of both cells
The general classification of cardiac ventricular arrhythmias assumes that all disturbances of rhythm result from either an abnormality in impulse initiation or an abnormality in impulse propagation; importantly both may coexist [4]. Various factors determine impulse propagation throughout the heart, the key factors being membrane excitability via fast Na + channels, intercellular coupling, and tissue architecture (i.e., myocyte size, collagen, and fiber orientation) [5–7]. The interaction between these factors is necessary for proper impulse propagation. Abnormalities in impulse initiation are associated particularly with triggered activity and/or abnormal automaticity, whereas impulse conduction with conduction block and reentry [4]. Over the last two decades, there is significant experimental evidence, to be taken as fact, that intercellular electrical coupling and communication are mediated by connexin (Cx). That is, the function of Cx’s through the formation of gap-junctional channels can significantly influence conduction velocity, and those alterations in Cx distribution and/or defective cell-to-cell coupling contribute to slowing of conduction [6]. It is also recognized that altered Cx expression or gap channel opening can act as substrate facilitating the development of reentrant arrhythmias such as ventricular tachycardia. Therefore, it is now logical to test the concept that compounds modifying gap function may have antiarrhythmic actions [8, 9]. The normal propagation of the activation wave front is related to the subcellular distribution of the gap-junctional
channels, which are located at the terminal ends (poles) in the intercalated disks with only small amounts of Cx protein expressed at the lateral borders of the cardiac myocyte [2]. In principle, an action potential propagates along the fiber by activating the sodium current, so that the propagation velocity along the fiber axis mainly depends on the sodium channel availability [7, 10]. At the end of a cardiac myocyte, the action potential is transferred to the next cell via the gapjunctional channels located in the intercalated disk. Gap junctions exist as plaques of hexameric arrays containing hundreds to thousands of Cx polypeptide channels spanning the lipid bilayers of adjacent cells (see Fig. 27.1). To date, over 20 connexin genes have been described in the human genome [2], of which connexin 43 (Cx43) is the primary isoform expressed in gap junctions of the cardiac ventricle (Fig. 27.2). Within cardiomyocytes, Cx43 is also present in the nucleus and in mitochondria [12]. Synthesis, transport, half-life, and degradation of Cx43 determine the number of connexins expressed, whereas intracellular pH, calcium, and/or adenosine triphosphate concentrations regulate the conductance and permeability of Cx43-formed channels [13].
Connexin-43 Expression and Conduction Velocity In mice, significant reductions in Cx43 expression result in slowed mapped surface ventricular conduction [14]. Normal cardiac conduction is anisotropic and conduction velocity in the direction of the fibers—around two times faster than transverse conduction velocity [15]. Conduction velocity of the activation front is approximately 0.5 m/s in the left ventricular myocardium. In mice, conduction velocity is slightly lower in
27 Connexin-43 Expression: A Therapeutic Target for the Treatment of Ventricular Tachycardia Non inducible
a
Inducible
Cx43
GAPDH
b
*P < 0.05
Cx43 total (a.u.)
4
3
2 *
1
0 Non inducible
Inducible
Fig. 27.3 Western blots showing the relative amounts of Cx43 expression in the mouse ventricular myocardium. The amount of total Cx43 is considerably less in those hearts with induced ventricular tachycardia (With permission from Xiao et al. [20])
the right ventricular wall. On the other hand in response to Na+ channel blockade, the right ventricular wall responds with more conduction slowing than the left ventricular wall [10]. Thus suggesting in mice, with relatively little known Cx43 expression compared to other animal species [16], Cx43 in the left ventricle may play a critical role in maintaining conduction velocity [17]. In selectively bred Cx43 knockout mice, a 59 % reduction in Cx43 does not alter propagation velocity or susceptibility to arrhythmia, but when the Cx43 reduction reaches 18 % of control levels and expression appears heterogeneous across the ventricular wall, propagation velocity is slowed by 50 %, and 80 % of mice are at risk for induced ventricular arrhythmias [18, 19]. Heterogeneity of gap-junctional distribution combined with reduced Cx43 levels appears to act cooperatively to create an arrhythmia substrate at less severe levels of overall gap-junctional reduction than predicted in theoretical models (Fig. 27.3).
Transmural Electrophysiological Gradients The development and maintenance of transmural electrophysiological gradients depend on both ion channel heterogeneities intrinsic to cellular layers, which span the ventricular transmural wall, and the degree of intercellular coupling [3, 21]. That is, electrophysiological gradients are known to be affected by ischemic conditions that alter the regulation of Cx43 hemichannels and gap-junctional
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channels during ischemia [13, 22]. Metabolic inhibition opens Cx43 hemichannels and ischemia induces closure of gap-junctional channels [13, 23]. Increased cytosolic Ca2+ concentration, reduced ATP concentration, changes in phosphorylation of Cx43, and acidification, all occurring during ischemia, close gap-junctional channels [24, 25], whereas a decrease in extracellular Ca2+ concentration has been described to open Cx43 hemichannels [26]. The distribution for Cx43 across the cross-sectional ventricular myocardium is not uniformly expressed [11]. For example, from our own published studies in the healthy adult rabbit, Cx43 expression and distribution across the myocardium (for phosphorylated and non-phosphorylated forms of Cx43) are significantly greater in the mid-myocardium, compared to other cross-sectional ventricular regions (Fig. 27.4) [11]. Similarly, Rosenbaum et al. have previously reported a heterogeneous Cx43 transmural expression pattern in dog cross-sectional ventricles and reported that such a heterogeneous Cx43 expression influences both conduction velocity and associated action potential duration (Fig. 27.4) [21, 27]. The fact that arrhythmias are absent in normal myocardium suggests that ion channel and gap-junctional heterogeneities are carefully balanced to prevent arrhythmogenic circuits. Any disturbance to this system has the potential to enhance already present electrophysiological heterogeneities (Fig. 27.5) [21].
Ventricular Remodeling and Connexin-43 Expression Disrupted gap-junctional structure and decreased expression of Cx43 are common features of cardiac remodeling observed in a variety of animal heart failure models, including pressure overload in guinea pigs, ischemia in dogs, and cardiomyopathic hamsters [28–30]. Heart failure, whether nonischemic or ischemic, is associated with a significant incidence of sudden death, primarily from the development of ventricular tachycardia (VT) degenerating to ventricular fibrillation (VF) [31]. Conduction slowing contributing to a VT substrate could arise from decreased depolarizing currents and/or decreased gapjunctional coupling as already suggested. The degree of slow conduction and conduction block in failing myocardium appears to be out of proportion to the changes in active membrane properties [32]. That is, both delayed afterdepolarizations and automaticity, but not early afterdepolarizations, occur more frequently in myocardium from the failing hearts [33]. Left ventricular (LV) cardiac myocytes from animal models of nonischemic heart failure exhibit markedly decreased gap-junctional conductance [32]. Thus, alterations in intercellular coupling involving cardiac gap junctions may underlie slow conduction in both ischemic and nonischemic heart failure.
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Fig. 27.4 Immunohistochemical expression for Cx43 in the crosssectional rabbit heart; note the dense Cx expression in the mid-myocardium. The cross-sectional rabbit heart represents in red the distribution
of connexin in the normal rabbit heart (With permission from McLachlan et al. [11])
Infarction, Ischemia, and Cx43 Expression
different sites of membrane apposition depending on the type of insult. Similarly, in pacing models of ischemicinduced heart failure, this results in well-described temporal changes in phosphorylated Cx43 expression [39]. Importantly temporal associations are seen in the timing of conduction abnormalities, relative changes in Cx43 isoforms, and mechanical dysfunction. Cx remodeling may contribute to increased anisotropy (with different alterations of conduction velocities in longitudinal versus transverse directions) predisposing to reentrant arrhythmias [40]. Additionally because of rapid reformation of gap junctions, the prevention of internalized gap junctions has been suggested to be an “ideal” intervention [41]. In summary, in the diseased ischemic heart, Cx43 abundance/expression can be variable, with focal areas of reduced expression corresponding to hibernating and ischemic zones [42]. There is evidence from both our lab and others that hibernation (and simulation of this state through starvation) results in internalized Cx43 [43, 44]. The question of whether it is good to target upregulation or downregulation Cx43 post-myocardial infarction has not been adequately addressed. At the present, we believe there is a need to have Cx43 either upregulated or possibly completely downregulated to reduce the incidence of ventricular tachycardia. As has been shown in mice, there is a critical level of Cx43 that can be downregulated before this results in a significant substrate for ventricular tachycardia. A natural programmed response to ischemia is a reduction in Cx43 expression to prevent passive transmission of Ca2+ overload within cardiac myocytes [45].
The loss of Cx43 is one of the earliest changes to occur around the infarct zone after acute myocardial infarction. This natural response for a reduction in Cx43 may help to reduce infarct size and insulate the injured area from its neighbor [34]. Cx43 has a relatively short half-life (1.3 h) in the heart [35], suggesting that tight temporal regulation of its expression levels can rapidly respond to ischemic events. In the evolving infarct, from 4 days onward, the number of gap junctions per intercalated disk length and the number of cells connected by intercalated disks to a single myocyte are decreased in infarct border zones [36, 37]. The estimated gap-junctional content per cell is decreased in ischemic ventricles [2]. Unlike most plasma membrane proteins, connexins remain metabolically unstable even after they have been transported to the cell surface. Decreases in Cx43 are prevented by proteasomal and lysosomal inhibitors. Cytosolic stress facilitates gap-junctional formation in such cells at least in part by slowing the turnover, and thereby raising the number, of Cx43 molecules on the cell surface. This seems to be accomplished not by blocking endocytosis but by inhibiting the delivery of internalized Cx43 to the lysosome [38]. Thus, more Cx43 survives in an intact state to recycle back to the plasma membrane, without a requirement for stress to increase the rate of recycling [38]. Thus, it is very likely that remodeling of cardiac gap junctions during both acute and late infarct healing involves degradation of preexisting gap junctions and their reformation at the same or
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27 Connexin-43 Expression: A Therapeutic Target for the Treatment of Ventricular Tachycardia
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Fig. 27.5 Cx43 expression, quantified by confocal immunofluorescence. Cx43 was significantly lower in subepicardial compared with deeper layers. High-resolution transmural optical mapping of the arterially perfused canine wedge preparation demonstrates transmural conduction velocity with respect to relative Cx43 expression. Importantly, reduced subepicardial Cx43 was associated with
transmural heterogeneities of electrophysiological function as evidenced by selectively reduced subepicardial conduction velocity compared with deeper layers. Therefore, Cx43 expression patterns can potentially contribute to arrhythmic substrates that are dependent on transmural electrophysiological heterogeneities (With permission from Poelzing et al. [21])
Nitric Oxide and Regulation of Cx
donor on Cx43 expression have been detected at several different levels including expression and the functional level by interfering with junctional dye transfer. The regulation of gap junctions by NO has been reported previously in some cell types. Sladek et al. [47] showed that endogenous NO attenuated myometrial Cx43 expression in the rat.
Nitric oxide (NO) and NO via nitric oxide synthase (NOS) appear to directly interact to modulate Cx43 expression [46]. Nitric oxide (NO) is able to enhance both basal and cAMP-elicited Cx43 expression and gap-junctional intercellular communication [46]. The net effects of a NO
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A number of known drugs and compounds such as N(G)nitro-l-arginine methyl ester (L-NAME), omega-3 fatty acids, 17β-estradiol, statins, and ACE inhibitors have all been reported to modify Cx43 expression. There is some support that these drugs may act indirectly to modify Cx43 expression via modulation of nitric oxide (NO) production. For example, vulnerability to ventricular arrhythmia during programmed stimulation in 17β-estradiol-treated postinfarct rats was significantly lower than in non-treated infarct rats [48]. Chronic administration of 17β-estradiol after MI is associated with greater expression of Cx43 in the infarct border zone. The suggested mechanism for 17β-estradiol modifying Cx43 expression is via a NO-dependent pathway via the estrogen receptor [48]. 17β-estradiol increases the level of calcium-dependent NO synthase (NOS) activity in cardiac myocytes [49]. On the other hand, we know from our own unpublished observations that N(G)-nitro-l-arginine methyl ester (L-NAME) which blocks NO production via inhibition of NOS also upregulates Cx43 in ventricular tissues in both normal and hypertrophied mice. It may be that 17beta-estradiol is more complex in that it targets phosphorylation sites of Cx43 rather than expression per se. 17beta-estradiol prevents metabolic inhibition induced via tyrosine phosphorylation of Cx43 in association with the cell signaling from a focal adhesion kinase c-Src [50]. This suggests that 17betaestradiol which can also associate with cardiac caveolin-3 provides a unique compartment for conveying 17betaestradiol-elicited, rapid signaling to regulate connexin-43 phosphorylation during ischemia (see section “Cx43 phosphorylation and heart failure”). Additionally, it has been reported that altered expression of Cx43 protein by a change in the reduced phosphorylated state typically accumulates in the border zone of the myocardial infarct, in dogs treated with estrogens [51]. Cardioprotective effects of estrogen could result from modification of the gap-junctional protein, leading to an inhibition of functional propagation of intercellular signaling and less formation of contraction band necrosis [51]. It also follows that junctional communication can be inhibited despite a relatively normal presence of Cx43; this may explain the reduction in infarct size and increased electrical stability, only if all connexin-associated gap junctions are “switched off.” Elevated NOS activity has been shown to be suppressed in both young and old spontaneously hypertensive hereditary hypertriglyceridemic rats when supplemented with omega-3 PUFA [52]. This reduced NOS activity with omega 3 is associated with an upregulation of Cx43 in the ventricular tissue. It is not clear whether overexpression of inducible NOS might account for downregulation of myocardial Cx43 and upregulation is associated with an increase of endothelial NOS [52]. As mentioned above we have shown in unpublished work that L-NAME (that blocks all isoforms of NOS) also upregulates the expression of cardiac Cx43. We are
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aware of one study that did examine Cx43 expression in iNOS knockout mice that had undergone a previous MI [53]. The findings showed that despite similar infarct size, deficiency in iNOS resulted in significantly lower plasma nitrate/ nitrite levels, better hemodynamic performance, and lower mortality 2 weeks after coronary ligation [53]. Myocardial Cx43, but not Cx45, content was lower in WT mice following ligation. The reduction in Cx43 was less in iNOS(−/−) compared with WT mice. Statins are competitive inhibitors of 3-hydroxy3-methylglutaryl-coenzyme A (HMG-CoA) reductase; this enzyme regulates the synthesis of cholesterol from mevalonic acid by suppressing the conversion of HMG-CoA. Mevalonate is the precursor not only of cholesterol but also of many nonsteroidal compounds; inhibition of HMG-CoA reductase by statins may therefore result in pleiotropic effects including reductions in oxidative stress and inflammation. In the rat MI model, pravastatin increases the expression of Cx43 protein and mRNA [54]. The authors suggested that pravastatin, via a mevalonate-dependent Endothelin-1 (ET-1) pathways, plays an important role in Cx43 expression after infarction. Interestingly, pretreatment with atorvastatin reduces infarct size and increases myocardial expression of phosphorylated endothelial nitric oxide synthase (p-eNOS) and inducible NOS (iNOS) in the rat [55] although teasing out a relationship between iNOS, statins, and Cx43 in the heart has not yet been reported. Cardiac-specific overexpression of ACE in mice results in increased ACE in the atria and ventricles, accompanied by a fourfold increase in the level of AngII in the heart. ACEoverexpressing mice suffer from low-voltage atrial activity, advanced atrioventricular (AV) block, an increased incidence of ventricular tachycardia (VT) during programmed stimulation, and an increased risk of sudden death due to spontaneous VT or ventricular fibrillation (VF) [20]. Additionally, angiotensin II (AngII) can increase Cx43 during short exposures and paradoxically decreases Cx43 during chronically elevated states of AngII [56]. Pharmacological inhibition of excessive renin-angiotensin activity in mice with captopril results in partial reversal of abnormal Cx43 remodeling by increasing the amount and functional recovery of Cx43 and reducing the incidence of VT [57]. Like other compounds that influence Cx43 expression, ACE inhibitors also regulate NOS expression. ACE inhibitors have been shown to upregulate eNOS in both healthy and diseased cardiac tissues [58].
Cx43 Phosphorylation and Heart Failure Cx43 is a phosphoprotein, with multiple phosphorylation sites for both serine/threonine and tyrosine [59]. The regulation of Cx43 by phosphorylation is a complex, with some sites being positive regulators, leading to increased conduc-
27 Connexin-43 Expression: A Therapeutic Target for the Treatment of Ventricular Tachycardia
tance, whereas others negatively regulate or close the channel. Studies have shown that overall Cx43 phosphorylation is decreased in ischemia although Ser368 increases phosphorylation yet is associated with junctional channel closure [60]. The phosphorylation of Cx43 on Ser255 has been shown to cause gap-junctional uncoupling in cultured cell lines [61]. Interestingly Cx43 on Ser255 by p34cdc2 kinase in Rat1 cells has been shown to promote endocytosis and degradation [62]. It may be that translocation and degradation of Cx43 in cardiac cells is the result of phosphorylation of specific residues. Altered expression, organization, and phosphorylation of the Cx43 in ventricular muscle have been demonstrated in human patients as well as animal models of diverse heart diseases, including ischemic, hypertrophic, and tachycardiainduced cardiomyopathy [2]. Remo et al. [63] generated Cx43 germline knock-in mice in which serines 325/328/330 were replaced with phosphomimetic glutamic acids (S3E). The S3E mice were resistant to acute and chronic pathological gap-junctional remodeling and displayed diminished susceptibility to the induction of ventricular arrhythmias. These findings demonstrate a mechanistic link between posttranslational phosphorylation of Cx43 and gap-junctional formation, remodeling, and arrhythmic susceptibility. The significance of these findings, modulation of Cx43 phosphorylation status may be a rational antiarrhythmic strategy. In summary, reduced Cx43 phosphorylation in HF could be attributable to reduced phosphorylation by kinases (e.g., protein kinase A, protein kinase C) and/or to increased dephosphorylation by protein phosphatases. There are compounds that increase gap-junctional conductance by a specific peptide, for example, rotigaptide, can prevent atrial conduction slowing or reentrant ventricular tachycardia in the ischemic heart [64].
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Rotigaptide Rotigaptide (ZP123) is a hexapeptide that specifically augments gap-junctional conductance, improving cell-to-cell coupling without any atrial or ventricular proarrhythmic effects [65]. Gap junction-modifying peptides were first described in the early 1980s and later shown to increase gap-junctional intercellular communication in the absence of changes in membrane conductance or basal current. The clinical development of the original antiarrhythmic peptide (AAP) and later synthetic derivatives (HP-5 and AAP10) has been limited by their instability and very short half-life [34, 66]. Rotigaptide is a rotation-inversion of AAP10 that incorporates the unnatural d-configuration of the amino acids to provide improved proteolytic stability. Rotigaptidemediated increases in GJIC occur without alteration of basal or membrane current, suggesting a direct effect of the compound on gap junctions (Fig. 27.6). Rotigaptide also prevents metabolic stress-induced conduction velocity slowing in rat atrial strips [67] and improves ventricular conduction velocity in the whole guinea pig hearts without affecting cellular repolarization [68]. Previously in ischemic canine hearts, rotigaptide has been shown to reduce the incidence of inducible reentrant ventricular tachycardia, demonstrating the importance of gapjunctional uncoupling as an arrhythmogenic substrate [69]. However, in a more recent study the ability of rotigaptide to improve infarct border zone electrical stability has been questioned [65]. The infarct border zone of healing myocardial infarct is an arrhythmogenic substrate, partly the result of structural and functional remodeling of Cx43. Macia et al. [65] reported that rotigaptide partially reversed the loss of Cx43 in the infarct border zone of 5-day-old infarcts but did not affect the increase in S368 phosphorylation, nor did it
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Fig. 27.6 Serine phosphorylation of Cx43 during ischemia: Serine sites marked in red have been identified as phosphorylated at either nonischemic or ischemic conditions, as indicated by the red arrow. The green stars at Ser297 and Ser368 indicate that phosphorylation of these sites was preserved for 30 min of ischemia by pretreatment with rotigaptide (With permission from Axelsen et al. [64])
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reverse Cx43 lateralization. Rotigaptide did not prevent conduction slowing in the infarct border zone, nor did it decrease the induction of sustained ventricular tachycardia by programmed stimulation, although it did decrease the infarct border zone effective refractory period.
Connexin and Oxidative Stress Recent studies also indicate that the cytoskeleton delivery apparatus for Cx may be a focus for therapeutic interventions aimed at the preservation and enhancement of cardiac gap junction. More specifically microtubules bearing gap-junctional hemichannels (connexons) can be delivered directly to adherens gap junctions [70]. The specificity of this delivery requires the microtubule plus-end tracking protein EB1. The cytoskeleton regulatory proteins in the forward delivery of Cx43 can be modified in the presence of oxidative stress. As discussed previously the failing human ventricular myocardium exhibits a reduction in Cx43. There has also been identified a reduction in the microtubule-capping protein EB1 at intercalated disks in human and experimental models of heart failure [1]. Oxidant stress in the adult mouse heart reduces N-cadherin, EB1, and Cx43 colocalization. In HeLa cells and neonatal mouse ventricular myocytes, peroxide exposure displaces both EB1 from the plus ends of microtubules and results in altered microtubule dynamics. Mutational disruption of the EB1-tubulin interaction simulates the effects of oxidant stress, including a reduction in surface Cx43 expression [1]. These data support the view that regulation of Cx43 at gap junctions can be influenced via oxidative stress and drugs that reduce oxidative stress such as statins [71] may also exert some pharmacological protection over the microtubule-capping protein involved in Cx transport.
In Summary In cardiovascular disease states, such as heart failure and myocardial ischemia, there is reduction in both the expression and function of Cx43 across the cross-sectional ventricular wall. In addition to transcription and translation, posttranslational modifications such as phosphorylation are important for Cx43 trafficking and content at gap junctions [22, 72]. Preexisting therapeutics used routinely in cardiovascular practice today, such as ACE inhibitors, can alter Cx43 expression and function [73]. At present the emerging and overlapping themes for therapeutic modulation of connexins are as follows: reducing oxidative stress, NO modulation of Cx43 expression, and targeting molecular regulation of Cx43 phosphorylation states.
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References 1. Tomaselli GF. Oxidant stress derails the cardiac connexon connection. J Clin Invest. 2010;120(1):87–9. 2. Severs NJ, Bruce AF, Dupont E, Rothery S. Remodelling of gap junctions and connexin expression in diseased myocardium. Cardiovasc Res. 2008;80:9–19. 3. Spach MS, Heidlage JF. The stochastic nature of cardiac propagation at a microscopic level. Electrical description of myocardial architecture and its application to conduction. Circ Res. 1995;76:366–80. 4. Kleber AG, Rudy Y. Basic mechanisms of cardiac impulse propagation and associated arrhythmias. Physiol Rev. 2004;84:431–88. 5. Stein M, van Veen TA, Remme CA, Boulaksil M, Noorman M, van Stuijvenberg L, van der Nagel R, Bezzina CR, Hauer RN, de Bakker JM, van Rijen HV. Combined reduction of intercellular coupling and membrane excitability differentially affects transverse and longitudinal cardiac conduction. Cardiovasc Res. 2009;83(1):52–60. 6. Valderrábano M. Influence of anisotropic conduction properties in the propagation of the cardiac action potential. Prog Biophys Mol Biol. 2007;94(1–2):144–68. 7. Spach MS, Heidlage JF, Dolber PC, Barr RC. Changes in anisotropic conduction caused by remodeling cell size and the cellular distribution of gap junctions and Na(+) channels. J Electrocardiol. 2001;34(Suppl):69–76. 8. De Vuyst E, Boengler K, Antoons G, Sipido KR, Schulz R, Leybaert L. Pharmacological modulation of connexin-formed channels in cardiac pathophysiology. Br J Pharmacol. 2011;163(3):469–83. 9. Dhein S. Pharmacology of gap junctions in the cardiovascular system. Cardiovasc Res. 2004;62:287–98. 10. Boukens BJ, Christoffels VM, Coronel R, Moorman AF. Developmental basis for electrophysiological heterogeneity in the ventricular and outflow tract myocardium as a substrate for lifethreatening ventricular arrhythmias. Circ Res. 2009;104(1):19–31. 11. McLachlan CS, Jusuf PR, Rummery N, Kummerfeld SK, Hambly B, McGuire MA, Turner V. Tyramide signal amplification enhances the detectable distribution of connexin-43 positive gap junctions across the ventricular wall of the rabbit heart. Arch Histol Cytol. 2003;66(4):359–65. 12. Ruiz-Meana M, Rodríguez-Sinovas A, Cabestrero A, Boengler K, Heusch G, Garcia-Dorado D. Mitochondrial connexin43 as a new player in the pathophysiology of myocardial ischaemia-reperfusion injury. Cardiovasc Res. 2008;77(2):325–33. 13. Imanaga I. Pathological remodeling of cardiac gap junction connexin 43-with special reference to arrhythmogenesis. Pathophysiology. 2010;17(2):73–81. 14. Eloff BC, Lerner DL, Yamada KA, Schuessler RB, Saffitz JE, Rosenbaum DS. High resolution optical mapping reveals conduction slowing in connexin43 deficient mice. Cardiovasc Res. 2001;51(4):681–90. 15. Desplantez T, Dupont E, Severs NJ, Weingart R. Gap junction channels and cardiac impulse propagation. J Membr Biol. 2007;218:13–28. 16. Yamada KA, Kanter EM, Green KG, Saffitz JE. Transmural distribution of connexins in rodent hearts. J Cardiovasc Electrophysiol. 2004;15:710–5. 17. Stein M, van Veen TA, Hauer RN, de Bakker JM, van Rijen HV. A 50% reduction of excitability but not of intercellular coupling affects conduction velocity restitution and activation delay in the mouse heart. PLoS One. 2011;6(6):e20310. 18. van Rijen HVM, Eckardt D, Degen J, Theis M, Ott T, et al. Slow conduction and enhanced anisotropy increase the propensity for ventricular tachyarrhythmias in adult mice with induced deletion of connexin43. Circulation. 2004;109:1048–55. 19. Morley GE, Vaidya D, Samie FH, Lo C, Delmar M, Jalife J. Characterization of conduction in the ventricles of normal and
27 Connexin-43 Expression: A Therapeutic Target for the Treatment of Ventricular Tachycardia
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31. 32.
33.
34.
35. 36.
heterozygous Cx43 knockout mice using optical mapping. J Cardiovasc Electrophysiol. 1999;10:1361–75. Xiao HD, Fuchs S, Campbell DJ, Lewis W, Dudley Jr SC, Kasi VS, Hoit BD, Keshelava G, Zhao H, Capecchi MR, Bernstein KE. Mice with cardiac-restricted angiotensin-converting enzyme (ACE) have atrial enlargement, cardiac arrhythmia, and sudden death. Am J Pathol. 2004;165(3):1019–32. Poelzing S, Akar FG, Baron E, Rosenbaum DS. Heterogeneous connexin43 expression produces electrophysiological heterogeneities across ventricular wall. Am J Physiol Heart Circ Physiol. 2004;286:H2001–9. Beardslee MA, Lerner DL, Tadros PN, Laing JG, Beyer EC, Yamada KA, et al. Dephosphorylation and intracellular redistribution of ventricular connexin 43 during electrical uncoupling induced by ischemia. Circ Res. 2000;87:656–62. Saez JC, Berthoud VM, Branes MC, Martinez AD, Beyer EC. Plasma membrane channels formed by connexins: their regulation and functions. Physiol Rev. 2003;83(4):1359–400. Johansen D, Cruciani V, Sundset R, Ytrehus K, Mikalsen SO. Ischemia induces closure of gap junctional channels and opening of hemichannels in heart-derived cells and tissue. Cell Physiol Biochem. 2011;28(1):103–14. Tribulova N, Seki S, Radosinska J, Kaplan P, Babusikova E, Knezl V, Mochizuki S. Myocardial Ca2+ handling and cell-to-cell coupling, key factors in prevention of sudden cardiac death. Can J Physiol Pharmacol. 2009;87(12):1120–9. Schalper KA, Sánchez HA, Lee SC, Altenberg GA, Nathanson MH, Sáez JC. Connexin 43 hemichannels mediate the Ca2+ influx induced by extracellular alkalinization. Am J Physiol Cell Physiol. 2010;299(6):C1504–15. Poelzing S, Rosenbaum DS. Altered connexin43 expression produces arrhythmia substrate in heart failure. Am J Physiol Heart Circ Physiol. 2004;287(4):H1762–70. Wang X, Gerdes AM. Chronic pressure overload cardiac hypertrophy and failure in guinea pigs, III: intercalated disc remodeling. J Mol Cell Cardiol. 1999;31:333–43. Huang XD, Sandusky GE, Zipes DP. Heterogeneous loss of connexin43 protein in ischemic dog hearts. J Cardiovasc Electrophysiol. 1999;10:79–91. Yoshida M, Ohkusa T, Nakashima T, Takanari H, Yano M, Takemura G, Honjo H, Kodama I, Mizukami Y, Matsuzaki M. Alterations in adhesion junction precede gap junction remodelling during the development of heart failure in cardiomyopathic hamsters. Cardiovasc Res. 2011;92(1):95–105. Deo R, Albert CM. Epidemiology and genetics of sudden cardiac death. Circulation. 2012;125(4):620–37. Ai X, Pogwizd SM. Connexin 43 downregulation and dephosphorylation in nonischemic heart failure is associated with enhanced colocalized protein phosphatase type 2A. Circ Res. 2005;96(1): 54–63. Vermeulen JT, McGuire MA, Opthof T, Coronel R, de Bakker JMT, Klopping C, Janse MJ. Triggered activity and automaticity in ventricular trabeculae of failing human and rabbit hearts. Cardiovasc Res. 1994;28:1547–54. Hennan JK, Swillo RE, Morgan GA, Rossman EI, Kantrowitz J, Butera J, Petersen JS, Gardell SJ, Vlasuk GP. GAP-134 ([2S,4R]-1[2-aminoacetyl]4-benzamidopyrrolidine-2-carboxylic acid) prevents spontaneous ventricular arrhythmias and reduces infarct size during myocardial ischemia/reperfusion injury in open-chest dogs. J Cardiovasc Pharmacol Ther. 2009;14(3):207–14. Beardslee MA, Laing JG, Beyer EC, Saffitz JE. Rapid turnover of connexin43 in the adult rat heart. Circ Res. 1998;83(6):629–35. Peters NS, Coromilas J, Severs NJ, Wit AL. Disturbed connexin43 gap junction distribution correlates with the location of reentrant circuits in the epicardial border zone of healing canine infarcts that cause ventricular tachycardia. Circulation. 1997;95(4):988–96.
359
37. Kieken F, Mutsaers N, Dolmatova E, Virgil K, Wit AL, Kellezi A, Hirst-Jensen BJ, Duffy HS, Sorgen PL. Structural and molecular mechanisms of gap junction remodeling in epicardial border zone myocytes following myocardial infarction. Circ Res. 2009;104(9):1103–12. 38. VanSlyke JK, Musil LS. Cytosolic stress reduces degradation of connexin43 internalized from the cell surface and enhances gap junction formation and function. Mol Biol Cell. 2005;16(11): 5247–57. 39. Akar FG, Nass RD, Hahn S, Cingolani E, Shah M, Hesketh GG, DiSilvestre D, Tunin RS, Kass DA, Tomaselli GF. Dynamic changes in conduction velocity and gap junction properties during development of pacing-induced heart failure. Am J Physiol Heart Circ Physiol. 2007;293(2):H1223–30. 40. Hesketh GG, Shah MH, Halperin VL, Cooke CA, Akar FG, Yen TE, Kass DA, Machamer CE, Van Eyk JE, Tomaselli GF. Ultrastructure and regulation of lateralized connexin43 in the failing heart. Circ Res. 2010;106(6):1153–63. 41. Berthoud VM, Minogue PJ, Laing JG, Beyer EC. Pathways for degradation of connexins and gap junctions. Cardiovasc Res. 2004;62(2):256–67. 42. Kaprielian RR, Gunning M, Dupont E, Sheppard MN, Rothery SM, Underwood R, Pennell DJ, Fox K, Pepper J, Poole-Wilson PA, Severs NJ. Downregulation of immunodetectable connexin43 and decreased gap junction size in the pathogenesis of chronic hibernation in the human left ventricle. Circulation. 1998;97(7):651–60. 43. McLachlan CS, Almsherqi ZA, Mossop P, Suzuki J, Leong ST, Deng Y. Down regulation of immuno-detectable cardiac connexin43 in BALB/c mice following acute fasting. Int J Cardiol. 2009;136(1):99–102. 44. Lichtenstein A, Minogue PJ, Beyer EC, Berthoud VM. Autophagy: a pathway that contributes to connexin degradation. J Cell Sci. 2011;124(Pt 6):910–20. 45. Oyamada M, Tsujii E, Tanaka H, Matsushita T, Takamatsu T. Abnormalities in gap junctions and Ca2+ dynamics in cardiomyocytes at the border zone of myocardial infarcts. Cell Commun Adhes. 2001;8(4–6):335–8. 46. Gönczi M, Papp R, Kovács M, Seprényi G, Végh A. Modulation of gap junctions by nitric oxide contributes to the anti-arrhythmic effect of sodium nitroprusside? Br J Pharmacol. 2009;156(5): 786–93. 47. Sladek SM, Westerhausen-Larson A, Roberts JM. Endogenous nitric oxide suppresses rat myometrial connexin 43 gap junction protein expression during pregnancy. Biol Reprod. 1999;61:8–13. 48. Chen CC, Lin CC, Lee TM. 17beta-estradiol decreases vulnerability to ventricular arrhythmias by preserving connexin43 protein in infarcted rats. Eur J Pharmacol. 2010;629(1–3):73–81. 49. Weiner CP, Lizasoain I, Baylis SA, Knowles RG, Charles IG. Induction of calcium-dependent nitric oxide synthases by sex hormones. Proc Natl Acad Sci U S A. 1994;91:5212–521. 50. Chung TH, Wang SM, Liang JY, Yang SH, Wu JC. The interaction of estrogen receptor alpha and caveolin-3 regulates connexin43 phosphorylation in metabolic inhibition-treated rat cardiomyocytes. Int J Biochem Cell Biol. 2009;41(11):2323–33. 51. Lee TM, Lin MS, Chou TF, Tsai CH, Chang NC. Adjunctive 17beta-estradiol administration reduces infarct size by altered expression of canine myocardial connexin43 protein. Cardiovasc Res. 2004;63(1):109–17. 52. Radosinska J, Bacova B, Bernatova I, Navarova J, Zhukovska A, Shysh A, Okruhlicova L, Tribulova N. Myocardial NOS activity and connexin-43 expression in untreated and omega-3 fatty acidstreated spontaneously hypertensive and hereditary hypertriglyceridemic rats. Mol Cell Biochem. 2011;347(1–2):163–73. 53. Jackson PE, Feng QP, Jones DL. Nitric oxide depresses connexin 43 after myocardial infarction in mice. Acta Physiol (Oxf). 2008;194(1):23–33.
360 54. Chen CC, Lien HY, Hsu YJ, Lin CC, Shih CM, Lee TM. Effect of pravastatin on ventricular arrhythmias in infarcted rats: role of connexin43. J Appl Physiol. 2010;109(2):541–52. 55. Ye Y, Martinez JD, Perez-Polo RJ, Lin Y, Uretsky BF, Birnbaum Y. The role of eNOS, iNOS, and NF-kappaB in upregulation and activation of cyclooxygenase-2 and infarct size reduction by atorvastatin. Am J Physiol Heart Circ Physiol. 2008;295(1):H343–51. 56. Teunissen BE, Jongsma HJ, Bierhuizen MF. Regulation of myocardial connexins during hypertrophic remodelling. Eur Heart J. 2004;25(22):1979–89. 57. Iravanian S, Sovari AA, Lardin HA, Liu H, Xiao HD, Dolmatova E, Jiao Z, Harris BS, Witham EA, Gourdie RG, Duffy HS, Bernstein KE, Dudley Jr SC. Inhibition of renin-angiotensin system (RAS) reduces ventricular tachycardia risk by altering connexin43. J Mol Med (Berl). 2011;89(7):677–87. 58. Morawietz H, Rohrbach S, Rueckschloss U, Schellenberger E, Hakim K, Zerkowski HR, Kojda G, Darmer D, Holtz J. Increased cardiac endothelial nitric oxide synthase expression in patients taking angiotensin-converting enzyme inhibitor therapy. Eur J Clin Invest. 2006;36(10):705–12. 59. Chen VC, Gouw JW, Naus CC, Foster LJ. Connexin multi-site phosphorylation: mass spectrometry-based proteomics fills the gap. Biochim Biophys Acta. 2013;1828(1):23–34. 60. Palatinus JA, Rhett JM, Gourdie RG. Enhanced PKCε mediated phosphorylation of connexin43 at serine 368 by a carboxyl-terminal mimetic peptide is dependent on injury. Channels (Austin). 2011;5(3):236–40. 61. Warn-Cramer BJ, Cottrell GT, Burt JM, Lau AF. Regulation of connexin-43 gap junctional intercellular communication by mitogenactivated protein kinase. J Biol Chem. 1998;273(15):9188–96. 62. Lampe PD, Lau AF. Regulation of gap junctions by phosphorylation of connexins. Arch Biochem Biophys. 2000;384:205–15. 63. Remo BF, Qu J, Volpicelli FM, Giovannone S, Shin D, Lader J, Liu FY, Zhang J, Lent DS, Morley GE, Fishman GI. Phosphataseresistant gap junctions inhibit pathological remodeling and prevent arrhythmias. Circ Res. 2011;108(12):1459–66. 64. Axelsen LN, Stahlhut M, Mohammed S, et al. Identification of ischemia-regulated phosphorylation sites in connexin43: a possible target for the antiarrhythmic peptide analogue rotigaptide (ZP123). J Mol Cell Cardiol. 2006;40:790–8.
C.S. McLachlan et al. 65. Macia E, Dolmatova E, Cabo C, Sosinsky AZ, Dun W, Coromilas J, Ciaccio EJ, Boyden PA, Wit AL, Duffy HS. Characterization of gap junction remodeling in epicardial border zone of healing canine infarcts and electrophysiological effects of partial reversal by rotigaptide. Circ Arrhythm Electrophysiol. 2011;4(3):344–51. 66. Dhein S, Hagen A, Jozwiak J, Dietze A, Garbade J, Barten M, Kostelka M, Mohr FW. Improving cardiac gap junction communication as a new antiarrhythmic mechanism: the action of antiarrhythmic peptides. Naunyn Schmiedebergs Arch Pharmacol. 2010;381(3):221–34. 67. Haugan K, Olsen KB, Hartvig L, Petersen JS, Holstein-Rathlou NH, Hennan JK, Nielsen MS. The antiarrhythmic peptide analogue ZP123 prevents atrial conduction slowing during metabolic stress. J Cardiovasc Electrophysiol. 2005;16:537–45. 68. Eloff BC, Gilat E, Wan X, Rosenbaum DS. Pharmacological modulation of cardiac gap junctions to enhance cardiac conduction: evidence supporting a novel target for antiarrhythmic therapy. Circulation. 2003;108:3157–63. 69. Xing D, Kjølbye AL, Nielsen MS, Petersen JS, Harlow KW, Holstein-Rathlou N-H, Martins JB. ZP123 increases gap junctional conductance and prevents reentrant ventricular tachycardia during myocardial ischemia in open chest dogs. J Cardiovasc Electrophysiol. 2003;14:510–20. 70. Smyth JW, Vogan JM, Buch PJ, Zhang SS, Fong TS, Hong TT, Shaw RM. Actin cytoskeleton rest stops regulate anterograde traffic of connexin 43 vesicles to the plasma membrane. Circ Res. 2012;110(7):978–89. 71. Cangemi R, Loffredo L, Carnevale R, Perri L, Patrizi MP, Sanguigni V, Pignatelli P, Violi F. Early decrease of oxidative stress by atorvastatin in hypercholesterolaemic patients: effect on circulating vitamin E. Eur Heart J. 2008;29(1):54–62. 72. Salameh A, Krautblatter S, Karl S, Blanke K, Rojas Gomez D, Dhein S, et al. The signal transduction cascade regulating the expression of the gap junction protein connexin43 by ß-adrenoceptors. Br J Pharmacol. 2009;158:198–208. 73. Bacova B, Radosinska J, Knezl V, Kolenova L, Weismann P, Navarova J, Barancik M, Mitasikova M, Tribulova N. Omega-3 fatty acids and atorvastatin suppress ventricular fibrillation inducibility in hypertriglyceridemic rat hearts: implication of intracellular coupling protein, connexin-43. J Physiol Pharmacol. 2010;61(6):717–23.
Biophysics of Modern Ablation Techniques and Their Limitations
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Erik Wissner and Andreas Metzner
Abstract
Catheter ablation is now the mainstay of therapy for most cardiac arrhythmias. The interventional electrophysiologist will need a thorough understanding of the underlying biophysics of frequently used ablation tools. Most commonly utilized in the electrophysiology laboratory, radio frequency ablation follows certain principles influenced by parameters such as convective cooling and resistive or conductive heating. The catheter tip design, either nonirrigated or irrigated, will have a profound impact on lesion formation. In the quest of permanent lesion transmurality, alternative energy sources have been developed. Cryoenergy ablation is now commonly used during atrial fibrillation ablation, while laser energy ablation is being tested in the clinical arena and demonstrating encouraging results. The present chapter will discuss the biophysics of these aforementioned technologies as well as their limitations as they apply to clinical practice. Keywords
Radio frequency current • Cryothermal energy • Laser energy • Lesion formation
Introduction
Radio Frequency Energy
Catheter ablation is essential for the treatment of cardiac arrhythmias and has undergone significant advancements from the early use of radio frequency (RF) current to the development of alternative energy sources. While pointby-point RF ablation is the most common commodity, alternative technologies have emerged to simplify lesion deployment in complex procedures such as atrial fibrillation (AF) ablation. This chapter will provide an overview of the biophysics of RF ablation and its limitations and will discuss newer technologies such as cryo- and laser energy ablation.
Tissue Response to Hyperthermia Myocardial tissue demonstrates a reproducible response to hyperthermia. In an animal model, a temperature below 45 °C had no effect on resting membrane depolarization of the myocardial cell. Conduction was significantly altered at a temperature between 45 and 50 °C, while irreversible tissue injury was seen at a threshold temperature ≥50 °C [1]. Thermal energy emanates from the electrode tip in a radial fashion, while temperature decreases exponentially with increasing distance from the source [2].
Radio Frequency Current E. Wissner, MD (*) • A. Metzner, MD Department of Cardiology, Asklepios Klinik St. Georg, Hamburg, Germany e-mail:
[email protected] A.S. Kibos et al. (eds.), Cardiac Arrhythmias, DOI 10.1007/978-1-4471-5316-0_28, © Springer-Verlag London 2014
Any frequency above 10 kHz is considered high frequency current or, alternatively, RF current. The advantage of RF current is that it has no effect on the human electrolyte milieu, nor will it stimulate nerves or cardiac tissue. Commercial generators 361
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in use in the electrophysiology laboratory commonly utilize an RF frequency of 500 kHz. A typical electrical circuit for RF ablation includes an RF generator, an ablation electrode, an indifferent electrode positioned along the back of the patient, and the ablation catheter. Importantly, the current density and degree of impedance differ within parts of the electrical circuit. If current flows from a small to a large contact area, e.g., the catheter tip-to-tissue interface, impedance and current density are high. Low impedance and current density are measured at the indifferent electrode-to-body surface contact area. If contact between the indifferent electrode and the body surface is poor, the resultant smaller area for current to flow through may result in inadvertent skin burns due to a significant rise in impedance and current density.
Radio Frequency Ablation RF current passing through the catheter into the tissue causes an increase in local tissue temperature, while the catheter electrode is not heated directly but passively by heat transferred back from the tissue. The RF generator adjusts tissue heating by titration of power measured in watts. Power (W) equals voltage (V) × current (mA). Ohm’s law states that current equals voltage divided by resistance. In the electrophysiology laboratory, the more common term used for resistance is impedance measured in ohm. Approximately 10 % of applied power will eventually be delivered to the endocardial tissue [3]. Tissue heating is accompanied by a fall in impedance of approximately 10 %. A thermocouple or thermistor embedded within the distal catheter measures temperature changes. True tissue temperature is typically higher than measured by the electrode, since the thermocouple is positioned proximal of the electrode tip-to-tissue interface. Once tissue temperature reaches ≥50 °C, electrical conductance of the myocardial cell is irreversibly blocked [1].
Parameters Influencing Tissue Heating The degree of tissue heating is influenced by heat lost to circulating blood (convective cooling), direct heating at the tip-totissue interface (resistive heating), and indirect heating through energy transfer to deeper tissue layers (conductive heating). Convective cooling is the result of RF current lost to the surrounding blood pool. The lower impedance of blood and its greater contact area with the electrode tip compared to tissue facilitate transmission of RF current to the blood pool. If wall contact with the electrode tip is maximized, tip-to-tissue contact area increases and more RF current enters the tissue [3]. Resistive heating is due to power dissipation at the tip-to-tissue
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interface causing direct tissue heating. Power decreases with the forth power of distance, resulting in 90 % of power delivered to the tissue being absorbed within the first 1–1.5 mm from the electrode surface by means of resistive heating. While resistive heating occurs immediately upon RF current delivery, conductive heating of deeper tissue layers follows a delayed response time with its effect lasting beyond cessation of RF energy. It follows that sufficient lesion volume requires at least 30 s of RF ablation [2]. In vitro, under standardized conditions, lesion volume demonstrates a linear increase with increasing power [4]. However, in vivo, the amount of power delivery varies due to alternating electrode tip-to-tissue contact throughout the cardiac cycle, change in catheter tip-to-tissue orientation, or variable degrees of blood flow. Consequently, predicting the amount of power entering the cardiac tissue poses a challenge, resulting in variable lesion size and volume at identical power settings. Factors that influence lesion formation are as follows.
Blood Flow Using a nonirrigated-tip catheter in temperature-control mode, smaller lesions form with less surrounding blood flow. This is the result of limited convective cooling by the blood pool allowing for a rapid rise to target temperature at lower power levels with resultant smaller lesion size. By contrast, high blood flow will result in a greater degree of convective cooling with temperature rising only at higher power levels and subsequent bigger lesion size. It is important to understand that regional differences in temperature may result in significant temperature gradients across the electrode surface. Typically, local electrode temperatures are higher in areas in direct contact with tissue, while the portion of the electrode immersed in the bloodstream records lower temperatures. Since the thermocouple is insensitive to local temperature changes, it may record temperatures below the cutoff limit, while a portion of the electrode exceeds 80 °C, increasing the risk for coagulum formation [5]. Anatomy The specific anatomic characteristics of the tissue targeted during ablation will dictate the best settings chosen during RF application. Trabeculated muscle such as that of the cavotricuspid isthmus may cause the catheter tip to wedge deep within the tissue, decreasing surrounding blood flow and resulting in rapid temperature rise and possible overheating and steam pop formation Similarly, judicious use of power should be applied targeting low-flow, thin-walled structures such as the coronary sinus. Electrode Size Comparing a conventional 4 to an 8 mm tip electrode, lesion size will be significantly larger using the bigger electrode tip in temperature-control mode (Fig. 28.1).
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8 mm conventional 30 W
4 mm conventional 15 W
43 °C
Target temperature 55°c Heat lost to circulating blood Zone of resistive heating
Zone of resistive heating
irrigation
Zone of conductive heating
Zone of conductive heating Maximum diameter
4 mm irrigated target power 30 W
Maximum diameter
Maximum diameter
Fig. 28.1 The influence of electrode tip size, mode of energy delivery, and irrigation flow on RF lesion formation. Left: A nonirrigated 4 mm tip catheter using temperature-control mode will allow a maximum of 15 W to be delivered before the target temperature of 55 °C is reached. The lesion is small with maximum diameter at the tissue surface. Middle: A nonirrigated 8 mm tip catheter using temperature-control mode delivers up to 30 W of power before the target temperature of 55 °C is achieved. Note that in comparison to the 4 mm nonirrigated tip, the lesion volume is increased with the maximum lesion diameter measured at the tissue surface. Right: An irrigated 4 mm tip catheter delivers a target power of 30 W in power-control mode unless the cutoff
temperature of 43 °C is recorded by the thermocouple embedded within the distal electrode tip. The distance between the thermocouple and the tip-to-tissue interface and continuous irrigation of the area in contact with the electrode tip result in lower temperature measured by the thermocouple than actually present in the tissue. The lesion volume is similar to that achieved with an 8 mm nonirrigated-tip catheter. By contrast, the maximum lesion diameter is measured at a greater depth within the myocardial tissue. Active cooling of the tissue surface by the irrigated electrode tip facilitates higher power delivery and improved energy transfer to deeper tissue levels
The larger tip area exposed to the blood pool will result in greater cooling, preventing early temperature rise. This in turn will allow higher-power delivery resulting in larger lesion size [6]. In an experiment using temperature-control mode comparing electrode tip sizes ranging from 2 to 12 mm, energy delivery via the 2 or 4 mm tip electrode terminated prematurely because of high electrode tip temperature, resulting in thrombus and char formation [7]. In summary, in temperaturecontrol mode, larger electrode tip size will permit greater electrode cooling and higher-power delivery resulting in larger lesion size. Larger electrode size, however, comes at the cost of inferior recording resolution due to greater distance between the distal and proximal recording electrode (Table 28.1).
Temperature- Versus Power-Control Mode Temperature-control mode is commonly used with nonirrigated-tip catheters. The operator sets a target temperature and maximum power, and the generator increases power to reach the target temperature. Since irrigated-tip catheters actively cool the electrode tip, the temperature measured by the embedded thermocouple is less accurate in predicting true tissue temperatures. Therefore, power-control mode is commonly used. The operator chooses a target power and maximum temperature to be delivered, and the generator applies the target power unless the temperature cutoff limits further power delivery.
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Table 28.1 Comparison of nonirrigated- and irrigated-tip catheters using radio frequency energy with alternative energy sources and the impact of their use on lesion size, recording resolution and the incidence of thrombus and steam pop formation Large lesion Recording resolution Risk of thrombus formation Risk of steam pop
Conventional 4 mm tip No High
Conventional 8 mm tip Yes Low
Irrigated 4 mm tip Yes High
Laser balloon Yes N/A
Medium
Cryo (tip/balloon) Yes High (tip) N/A (balloon) Low
High
Low
High
Low
Medium
N/A
Low
Low
N/A not applicable
Irrigation Technology Several limitations need to be considered when using conventional nonirrigated-tip catheters. First, smaller lesions are created using a 4 mm electrode tip, while the use of an 8 mm tip will increase lesion size but negatively affects recording detail. Nonirrigated-tip catheters may promote the incidence of char or thrombus formation due to significant temperature rise at the electrode tip-to-tissue interface. These limitations led to the development of irrigated-tip catheters that provide continuous flushing of the distal electrode tip. The effect is similar to that of high blood flow on convective electrode cooling, resulting in active cooling of the electrode tip-to-tissue interface and permitting higher-energy delivery using smaller electrode tip sizes. Lesion formation is significantly improved comparing a 4 mm irrigated to a 4 mm nonirrigatedtip ablation catheter. First, lesion volume will be larger using irrigation technology. Second, the maximum lesion diameter is transferred to a deeper level within the myocardial tissue [8] (Fig. 28.1). Since the electrode tip is continuously flushed, temperature measurement by the embedded thermocouple is less accurate. Consequently, irrigated-tip RF catheters are commonly used in power-control mode targeting a specific power, while a temperature cutoff prevents overheating. Analyzing the impact of irrigation flow rate on lesion formation, at identical power delivery, greater lesion size was seen applying a lower flow rate [8]. By contrast, increasing the irrigation flow rate during RF ablation will result in greater cooling of the distal electrode tip, lowering the risk for thrombus formation. If power is increased without corresponding uptitration of flow rate, the risk rises for thrombus formation and steam pop. Hence, irrigation flow needs to be carefully adjusted to target power applied. While two different concepts for irrigation flow delivery, closed-loop and open irrigation, have been introduced, open irrigation tip catheters are more commonly used in daily practice. In a study by Yokoyama et al., the open irrigation electrode catheter demonstrated no thrombus or steam pop formation, in stark contrast to the closed-loop irrigation catheter [9]. Contrary to nonirrigated RF ablation, smaller electrode tip diameter will increase lesion size using irrigation technology (Table 28.1). Utilizing a larger electrode tip, a greater proportion of power is lost to the surrounding blood pool [10].
Limitations of Radio Frequency Ablation Tissue Charring, Thrombus Formation, and Embolic Events A sharp rise in impedance (>20 Ω) is seen if the electrode tip-to-tissue interface reaches a temperature of 100 °C [11]. At the boiling point of 100 °C, tissue adherent to the electrode tip will desiccate, and in combination with protein denaturation, an insulating layer (char) will form around the electrode tip with subsequent rise in impedance. Thrombus may develop at the site of char formation with the risk for embolization [11]. Using an irrigated-tip catheter, thrombus formation may occur without rise in impedance [5]. Embolization is particularly troublesome in high-risk areas such as the left atrium placing the patient at risk for stroke. If extensive ablation is anticipated in these locations, an irrigated-tip catheter should be selected. Steam Pop Formation and Cardiac Perforation Once tissue temperature reaches 100 °C, tissue boiling may result in steam formation with subsequent explosion (steam pop) within the myocardial layers. The extent of injury is directly related to the thickness of the underlying tissue and its proximity to the endo- or epicardial layer. Myocardial perforation will result if injury extends from the endo- to epicardium, while injury confined to the endocardium will cause crater formation. Clinically, the risk of perforation is lower in patients with ischemic heart disease undergoing catheter ablation for ventricular tachycardia. The thickness of the left ventricular myocardium combined with extensive intramyocardial fibrosis typically prevents perforation even at higher energy levels. By contrast, the risk of perforation is higher in thin-walled structures such as the atria or the coronary sinus.
Cryothermal Energy Tissue Response to Hypothermia Two factors contribute to tissue injury following cryoenergy application. First, freezing of myocardial cells causes rupture and cell necrosis eventually leading to apoptosis. The
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formation of extracellular ice crystals with cryoenergy application contributes to a hyperosmotic extracellular state. This in turn results in intracellular hyperosmotic stress, volume loss, and injury to cell constituents [12]. Extracellular ice crystal formation will contribute to mechanical cell damage causing injury to cell organelles and membranes culminating in cell death [13]. Freeze-induced cell injury leads to apoptosis or programmed cell death lasting for hours to days after application of cryoenergy [14]. Second, myocardial tissue exposure to cryoenergy results in microcirculatory failure leading to vascular stasis and ischemia. Freezing results in reflective vasoconstriction leading to a reduction in blood flow and ultimately microcirculatory collapse. Thawing, that is, rewarming of tissue, causes vasodilation and hyperemia. An increase in capillary permeability in combination with an intracellular hyperosmotic state will result in cellular swelling and further cell damage, platelet aggregation, and thrombosis. Hence, circulatory stasis will further contribute to cell death even after rewarming of the tissue [15]. The destructive effect of freezing on cardiac muscle cells depends on the duration of cryoenergy application [16]. Repetitive freeze-thaw cycles will result in larger lesions [16].
Lesion Formation There are inherent differences in lesion formation using RF- or cryoenergy. RF lesions are characterized by ragged edges, large surface area with endothelial destruction, and indistinct separation from normal myocardial tissue [17, 18]. By contrast, cryoenergy results in more distinct and homogeneous lesions with a clear demarcation from surrounding normal myocardium and an intact endothelial cell layer [17, 18]. Lesion depth is similar applying both technologies [17]. Using cryoablation, lower temperatures will result in deeper lesion diameter [17, 18]. An increase in peak temperature by −10 °C will result in greater lesion depth of approximately 0.4 mm [17].
Cryoablation The prerequisite for successful and effective ablation is optimal thermal conductivity from the catheter to the endocardial tissue. Due to convective heating by the surrounding blood flow, higher cooling power is required for endocardial ablation, whereas epicardial ablation necessitates less cooling due to the lack of pericardial blood flow. The lesion size is highly dependent on contact area, refrigerant flow rate, the orientation of the catheter in relation to the tissue surface, and the electrode tip size. Greater uptake of refrigerant by a larger tip with a bigger inner and outer surface area will result in higher cooling transfer and larger lesions. During cryothermal energy application the catheter tip will tightly freeze to the
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endocardial surface, contributing to greater catheter stability compared to RF ablation. Temperatures of −30 °C or warmer commonly result in reversible lesion formation. Reversible cooling of tissue (cryomapping), may be used at high-risk areas in order to identify successful target sites before applying an irreversible degree of cryoenergy. Alternatively, cryoenergy may be delivered through a balloon-based catheter system. Cryoballoon ablation is an established treatment option for pulmonary vein isolation in patients suffering from atrial fibrillation [19, 20]. The cryoballoon is a noncompliant balloon available in variable sizes of 23 and 28 mm. The system consists of an inner and an outer balloon. Nitrous oxide (N2O) is used as the refrigerant and delivered into the inner balloon. Direct and continuous contact between the outer balloon surface and the tissue is essential for complete circumferential lesion formation.
Limitations of Cryoablation Although inadvertent thrombus formation may occur, the incidence and volume of thrombus that may form is significantly less with cryoenergy compared to RF energy [17]. There has been concern over higher recurrence rates using cryoablation. In a study comparing cryo- and RF ablation for the treatment of atrioventricular nodal reentry tachycardia, the recurrence rate was more than double in the cryoablation group (9.4 versus 4.4; P = 0.029) [21]. A typical cryoenergy application is 4–5 min in duration, compared to a standard 30–40 s RF application. Hence, if a high number of lesions are required, procedure times may be longer using cryoablation.
Alternative Energy Sources Laser Energy Laser (light amplification by stimulated emission of radiation) energy has been evaluated in experimental studies for the treatment of cardiac arrhythmias but without widespread clinical use [22]. Electrons of a specific medium are brought into a higher energy state by an energy trigger. This results in emission of a monochromatic, focused beam of energy with a particular wavelength. Absorption of laser energy causes tissue heating and tissue injury. Diode lasers are able to deliver low-energy applications of prespecified length and power.
Laser Balloon Ablation and Lesion Formation Recently, a laser balloon (CardioFocus, Inc., Marlborough, MA, USA) was introduced demonstrating clinical feasibility
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and 1-year efficacy for ablation of atrial fibrillation in humans [23]. The catheter shaft houses a 980 nm laser diode. Optimal tissue contact is achieved by the use of a compliant balloon filled with deuterium (heavy water, D2O), which also facilitates cooling of the endocardial surface. Since D2O does not absorb 980 nm laser energy, the energy penetrates the first 1.5–2.0 mm of endocardial tissue before heating the deeper myocardial layers. Consequently superficial char formation is rare. Lesions are deployed in a point-bypoint fashion, while a single ablation lesion covers 30° of a circle. In an animal study targeting the pulmonary vein antra, lesion size extended to a maximal depth of 12.7 mm with an average acute and chronic lesion depth of 2.4 ± 2.0 and 5.0 ± 2.6 mm, respectively [24]. Hence, there is progressive lesion maturation resulting in further lesion extension over time.
Limitations of Laser Balloon Ablation Char formation or damage to the balloon surface resulting in perforation of the balloon may occur if laser energy is applied to areas in direct contact with blood. Complete sealing between the balloon and tissue surface is a prerequisite for safe laser ablation. If tissue-to-balloon contact is suboptimal, e.g., small pool of blood visible on endoscopic live view, a low-energy setting of 5.5 W for 30 s can safely be applied, while higher energy may increase the risk for clot formation.
Future Outlook Minimizing complications while achieving acute lesion transmurality combined with high chronic success rate is the fundamental objective of any energy source used for catheter ablation in humans. Due to inherent limitations of all currently available energy forms, further progress in catheter technology is imperative to facilitate significant advancement in this field. The addition of contact force measurement to currently used parameters that monitor successful lesion formation during RF ablation such as temperature, impedance, and time of energy application may promise better long-term outcome. True in-tissue temperature measurement using microwave technology may in the future guide the electrophysiologist during the ablation procedure confirming adequate target temperature at the core of the RF lesion. In order to allow lesion formation at deeper tissue level as commonly needed during ablation of ventricular tachycardia, an extendable RF needle delivery system using irrigation flow has demonstrated feasibility in an animal model [25]. Compared to a standard irrigated-tip catheter, lesion depth and lesion volume were significantly greater. Finally, there has been a trend in increasing the number of irrigation holes
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in commercially available RF catheters. Increasing irrigation flow would result in additional cooling of the tip-to-tissue interface allowing for higher-power delivery and improved lesion formation without increasing the risk for char or thrombus formation.
References 1. Nath S, Lynch 3rd C, Whayne JG, Haines DE. Cellular electrophysiological effects of hyperthermia on isolated guinea pig papillary muscle. Implications for catheter ablation. Circulation. 1993;88: 1826–31. 2. Haines DE, Watson DD. Tissue heating during radiofrequency catheter ablation: a thermodynamic model and observations in isolated perfused and superfused canine right ventricular free wall. Pacing Clin Electrophysiol. 1989;12:962–76. 3. Wittkampf FH, Nakagawa H. RF catheter ablation: lessons on lesions. Pacing Clin Electrophysiol. 2006;29:1285–97. 4. Hindricks G, Haverkamp W, Gulker H, Rissel U, Budde T, Richter KD, Borggrefe M, Breithardt G. Radiofrequency coagulation of ventricular myocardium: improved prediction of lesion size by monitoring catheter tip temperature. Eur Heart J. 1989;10:972–84. 5. Matsudaira K, Nakagawa H, Wittkampf FH, Yamanashi WS, Imai S, Pitha JV, Lazzara R, Jackman WM. High incidence of thrombus formation without impedance rise during radiofrequency ablation using electrode temperature control. Pacing Clin Electrophysiol. 2003;26:1227–37. 6. Otomo K, Yamanashi WS, Tondo C, Antz M, Bussey J, Pitha JV, Arruda M, Nakagawa H, Wittkampf FH, Lazzara R, Jackman WM. Why a large tip electrode makes a deeper radiofrequency lesion: effects of increase in electrode cooling and electrode-tissue interface area. J Cardiovasc Electrophysiol. 1998;9:47–54. 7. Hogh Petersen H, Chen X, Pietersen A, Svendsen JH, Haunso S. Lesion dimensions during temperature-controlled radiofrequency catheter ablation of left ventricular porcine myocardium: impact of ablation site, electrode size, and convective cooling. Circulation. 1999;99:319–25. 8. Weiss C, Antz M, Eick O, Eshagzaiy K, Meinertz T, Willems S. Radiofrequency catheter ablation using cooled electrodes: impact of irrigation flow rate and catheter contact pressure on lesion dimensions. Pacing Clin Electrophysiol. 2002;25:463–9. 9. Yokoyama K, Nakagawa H, Wittkampf FH, Pitha JV, Lazzara R, Jackman WM. Comparison of electrode cooling between internal and open irrigation in radiofrequency ablation lesion depth and incidence of thrombus and steam pop. Circulation. 2006;113: 11–9. 10. Nakagawa H, Wittkampf FH, Yamanashi WS, Pitha JV, Imai S, Campbell B, Arruda M, Lazzara R, Jackman WM. Inverse relationship between electrode size and lesion size during radiofrequency ablation with active electrode cooling. Circulation. 1998;98: 458–65. 11. Haines DE, Verow AF. Observations on electrode-tissue interface temperature and effect on electrical impedance during radiofrequency ablation of ventricular myocardium. Circulation. 1990;82: 1034–8. 12. Mazur P. Cryobiology: the freezing of biological systems. Science. 1970;168:939–49. 13. Taylor MJ, Pegg DE. The effect of ice formation on the function of smooth muscle tissue stored at −21 or −60 degrees c. Cryobiology. 1983;20:36–40. 14. Baust JM, Vogel MJ, Van Buskirk R, Baust JG. A molecular basis of cryopreservation failure and its modulation to improve cell survival. Cell Transplant. 2001;10:561–71.
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Biophysics of Modern Ablation Techniques and Their Limitations
15. Gage AA, Baust J. Mechanisms of tissue injury in cryosurgery. Cryobiology. 1998;37:171–86. 16. Tse HF, Ripley KL, Lee KL, Siu CW, Van Vleet JF, Pelkey WL, Lau CP. Effects of temporal application parameters on lesion dimensions during transvenous catheter cryoablation. J Cardiovasc Electrophysiol. 2005;16:201–4. 17. Khairy P, Chauvet P, Lehmann J, Lambert J, Macle L, Tanguay JF, Sirois MG, Santoianni D, Dubuc M. Lower incidence of thrombus formation with cryoenergy versus radiofrequency catheter ablation. Circulation. 2003;107:2045–50. 18. Rodriguez LM, Leunissen J, Hoekstra A, Korteling BJ, Smeets JL, Timmermans C, Vos M, Daemen M, Wellens HJ. Transvenous cold mapping and cryoablation of the av node in dogs: observations of chronic lesions and comparison to those obtained using radiofrequency ablation. J Cardiovasc Electrophysiol. 1998;9:1055–61. 19. Chun KR, Schmidt B, Metzner A, Tilz R, Zerm T, Koster I, Furnkranz A, Koektuerk B, Konstantinidou M, Antz M, Ouyang F, Kuck KH. The ‘single big cryoballoon’ technique for acute pulmonary vein isolation in patients with paroxysmal atrial fibrillation: a prospective observational single centre study. Eur Heart J. 2009;30: 699–709. 20. Neumann T, Vogt J, Schumacher B, Dorszewski A, Kuniss M, Neuser H, Kurzidim K, Berkowitsch A, Koller M, Heintze J, Scholz U, Wetzel U, Schneider MA, Horstkotte D, Hamm CW, Pitschner HF. Circumferential pulmonary vein isolation with the cryoballoon
367
21.
22.
23.
24.
25.
technique results from a prospective 3-center study. J Am Coll Cardiol. 2008;52:273–8. Deisenhofer I, Zrenner B, Yin YH, Pitschner HF, Kuniss M, Grossmann G, Stiller S, Luik A, Veltmann C, Frank J, Linner J, Estner HL, Pflaumer A, Wu J, von Bary C, Ucer E, Reents T, Tzeis S, Fichtner S, Kathan S, Karch MR, Jilek C, Ammar S, Kolb C, Liu ZC, Haller B, Schmitt C, Hessling G. Cryoablation versus radiofrequency energy for the ablation of atrioventricular nodal reentrant tachycardia (the cyrano study): results from a large multicenter prospective randomized trial. Circulation. 2010;122:2239–45. Saksena S, Gielchinsky I, Tullo NG. Argon laser ablation of malignant ventricular tachycardia associated with coronary artery disease. Am J Cardiol. 1989;64:1298–304. Metzner A, Schmidt B, Fuernkranz A, Wissner E, Tilz RR, Chun KR, Neven K, Konstantinidou M, Rillig A, Yoshiga Y, Mathew S, Koester I, Ouyang F, Kuck KH. One-year clinical outcome after pulmonary vein isolation using the novel endoscopic ablation system in patients with paroxysmal atrial fibrillation. Heart Rhythm. 2011;8:988–93. Dukkipati SR, Neuzil P, Skoda J, Petru J, d’Avila A, Doshi SK, Reddy VY. Visual balloon-guided point-by-point ablation: reliable, reproducible, and persistent pulmonary vein isolation. Circ Arrhythm Electrophysiol. 2010;3:266–73. Sapp JL, Cooper JM, Zei P, Stevenson WG. Large radiofrequency ablation lesions can be created with a retractable infusion-needle catheter. J Cardiovasc Electrophysiol. 2006;17:657–61.
Cardiac Imaging to Assist Complex Ablation Procedures
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Alejandro Jimenez Restrepo and Timm M. Dickfeld
Abstract
The introduction of three-dimensional (3D) electroanatomical mapping into the clinical electrophysiology realm has led to the ability to properly diagnose and treat a wide variety of complex arrhythmias such as ventricular tachycardia and atrial fibrillation. 3D mapping allows for reconstruction of heart models providing detailed anatomical information linked to voltage and activation data from local electrograms to help define regions of abnormal tissue, representing arrhythmic substrates which are amenable to ablation therapy. Unfortunately, the accuracy of these reconstructed images can be affected by intravascular volume changes, respiratory motion, patient movement, and electrical interference from surrounding equipment which can lead to inaccurate representation of the true cardiac anatomy and misguide adequate therapy. The use of linear image acquisition techniques such as computed tomography (CT), magnetic resonance imaging (MRI), and positron-emission tomography (PET) provides high-resolution cardiac image datasets which can be integrated with the 3D maps in a process called image integration or image fusion. Thus, the combination of pre-procedural linear imaging technology with intraprocedural imaging techniques such as 3D electroanatomical mapping and intracardiac ultrasound (ICE) allows real-time, accurate high-resolution anatomical reconstruction of cardiac structures. This chapter describes the process of image integration between pre-procedural imaging incorporated into 3D maps and intracardiac ultrasound and its clinical applicability to a wide variety of atrial and ventricular arrhythmias to safely and effectively guide complex ablation procedures. Keywords
Cardiac imaging • Computed tomography • Image fusion • Electroanatomical mapping
A.J. Restrepo, MD (*) Cardiology Department, Wellington Regional Hospital, Wellington, New Zealand International Arrhythmia Center, Fundacion Cardioinfantil, Bogota, Colombia e-mail:
[email protected] T.M. Dickfeld, MD, PhD Division of Cardiology, University of Maryland Medical Center, Baltimore, MD, USA e-mail:
[email protected] A.S. Kibos et al. (eds.), Cardiac Arrhythmias, DOI 10.1007/978-1-4471-5316-0_29, © Springer-Verlag London 2014
Introduction New techniques for cardiac imaging play an important role in the evaluation and treatment of different cardiac arrhythmias. Traditional imaging methods employed in the electrophysiology lab, such as X-ray fluoroscopy, lack the ability to evaluate tissue characteristics and visualize specific intracardiac structures to safely guide complex procedures such as atrial fibrillation (AF) and ventricular tachycardia (VT) ablations. Novel three-dimensional (3D) mapping techniques employ electromagnetic fields and/or electrical currents that 369
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allow for a detailed electroanatomical reconstruction of the heart and great vessels. These reconstructed images can guide real-time manipulation of catheters and provide important feedback on the electrical properties of the atrial and ventricular tissue. Nonetheless, these nonlinear 3D models can be affected by intravascular volume changes, respiratory motion, patient movement, and electrical interference from surrounding equipment which can lead to significant location errors and inaccurate representation of the cardiac anatomy. The aid of linear imaging techniques such as computed tomography (CT), magnetic resonance imaging (MRI), and positron-emission tomography (PET) results in very precise image acquisition [1]. The combination of pre-procedural imaging linear technology with intra-procedural imaging techniques such as 3D electroanatomical (EA) mapping and intracardiac ultrasound (ICE) imaging allows real-time highresolution anatomical visualization of cardiac structures to guide complex ablation procedures.
Computed Tomography Imaging Computed Tomography Imaging Fundamentals Computed tomography (CT) imaging employs X-ray beams which are projected in a fan-shaped configuration and are later funneled to a selected area of interest with the use of a collimator, which eliminates scattered X-rays, nonparallel to the specified direction defined by the collimator. These X-rays create an image in a biplane coordinate system, known as the imaging plane. By obtaining specific anatomical cross sections, CT achieves minimal image superimposition of tissue and allows for visualization of contrast differences within adjacent anatomical structures. Cardiac medical imaging is currently obtained with multislice helical CT systems, which allow for high-speed image acquisition reducing patients’ motion artifacts. 64-slice and higher resolution systems (currently up to 320 row detectors) have sub-second rotational speeds, allowing fast reconstruction of cardiac anatomy and assessment of functional parameters with the aid of electrocardiographic (ECG) gating. Digital data received from the detectors is transmitted to a computer using high-speed radio-frequency signals, which then synchronizes gantry and table motion to acquire data from known positions of the gantry rotation and the imaging table position, allowing for fast, accurate, high-speed image acquisition [2].
Image Data Acquisition, Reconstruction, and Display Raw image data is acquired as attenuated beams of radiation, processed using specific algorithms and, assigned a coefficient for each pixel in an image matrix, which is
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created as the gantry rotates and scans the patient volume to render anatomically accurate images. The reconstructed segments or voxels are isotropic and the pixel values assigned to the image are measured in Hounsfield units (HU) and represent the amount of X-ray attenuation. The Hounsfield clinical scale ranges from zero for water, −1,000 for air, 10–60 for cardiac tissue, and 500–1,000 for bone. Important variables during the image reconstruction process are the field of view (FOV) or reconstructed area and the matrix, which determines the pixel size for the different image planes. The kernel reconstruction defines the amount of smoothing required in the image reconstruction process. Different kernels are available depending on the body area and clinical application (higher kernel numbers provide sharper images). For cardiac CT imaging, ECG gating is required to avoid cardiac motion. To avoid respiratory motion artifacts, CT scanning is preferentially performed during the expiratory phase. The acquired data is synchronized with the QRS complex in order to define systole and diastole. The combination of consecutive multiple image slices which are gated to a specific phase of the cardiac cycle allows a reconstruction of the heart chambers, which can be done retrospectively (reconstructing images after all the data is acquired) or prospectively (image reconstruction simultaneous with data acquisition). CT images can be viewed as slices or volumetric image datasets. 3D reconstructed images are employed in the electrophysiology lab to provide accurate anatomical reconstruction of cardiac structures which can be integrated with EA mapping systems and used for real-time navigation of catheters and identification of arrhythmogenic areas.
Magnetic Resonance Imaging Magnetic Resonance Imaging Fundamentals Cardiac magnetic resonance (CMR) imaging is based on the principles of absorption and emission of energy in the radiofrequency (RF) range of the electromagnetic spectrum to image nuclei of atoms in the body. As the human body is composed primarily of water and fat, and both substances are composed of hydrogen ions, radio-frequency waves in the electromagnetic spectrum excite the hydrogen nuclei, creating tissue magnetization, which decays with time (relaxation), releasing energy as radio waves or echoes which are converted into images of radio signals (spatially resolved sinusoid waves) by Fourier transform (FT) [3]. Strong magnetic field gradients emitted by the MRI scanner cause nuclei at different locations to rotate at different speeds and 3D spatial information can be obtained by providing gradients in each direction. Important components of MRI scanners include superconducting magnets, a radio-frequency transmitter and receiver, and gradient coils or solenoids, which create magnetic fields when subjected to high
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electrical pulses. The magnetic field strength is reported in tesla (T) units. For CMR imaging, commonly used clinical magnet strengths are 1.5 or 3 T [4]. Protons in different tissues reach an equilibrium state at different rates and these variations which are unique to individual tissue properties can be measured (spin density, T1 and T2 relaxation times, and flow and spectral shifts) and are used to construct images. Tissue variations can be shown by the use of contrast agents and by modifying scanning parameters in order to enhance differences between the cardiac structures and surrounding tissue [5].
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malfunction, and device migration [5, 8, 9]. To this date, MRI studies are still considered contraindicated in patients with implanted defibrillators and most pacemakers [10, 11]. However, ongoing research in the field suggests that appropriate patient selection and specific pre- and post-procedural reprogramming allow for MRI scanning to be safely performed in this patient population [12–15, 17]. More recently, MRI conditional pacemaker systems have become available for clinical use [16].
Positron-Emission Tomography Cardiac Magnetic Resonance Imaging Modalities CMR employs different techniques for cardiac tissue imaging. Combining these different modalities results in a comprehensive evaluation of the heart’s anatomy and function. Scar tissue and epicardial fat can be visualized without the use of a contrast agent by acquiring image sequences known as spin-echo in which blood appears black in highresolution still images. However, contrast agents such as gadolinium are frequently employed in CMR imaging to improve the signal-to-noise ratio of myocardial scar tissue. Other imaging sequences such as inversion recovery (IR), allow for optimization of the inversion time to null the myocardium and better differentiate between scar and normal myocardium. During a delayed time period from contrast injection to scan acquisition, a larger percentage of the contrast medium is cleared from healthy myocardial tissue, but not from scar tissue due to slow washout of the gadolinium chelates [4, 6]; consequently, on the late gadolinium enhancement (LGE) images, normal heart muscle appears dark, while blood and areas of infarction appear bright white.
Comparison Between CMR and X-Ray-Based Imaging The lack of ionizing radiation is one of the main advantages of MRI technology compared to fluoroscopy-based systems, particularly in young patients and women in childbearing age. The MRI scanner bore diameter can be an issue for morbidly obese and claustrophobic patients. The use of gadolinium contrast should be avoided in patients with creatinine clearance <30 ml/min, as it can cause nephrogenic systemic fibrosis [7]. One of the main clinical limitations for CMR imaging has been the possible interaction with ferromagnetic material present in implanted cardiac rhythm devices (pacemakers and implantable cardioverter defibrillators), as the combined effects of pulsed radio-frequency (RF) and static and/or gradient magnetic field have the potential to cause thermal cardiac injury, arrhythmogenesis, rapid pacing, reed switch dysfunction, inappropriate detection of electromagnetic interference (EMI), device damage, software
Positron-emission tomography (PET) scanning has been used for noninvasive imaging of the heart since 1975. It was employed in basic science research to investigate myocardial blood flow regulation, metabolism, and autonomic innervation of the heart. Due to its quantitative nature, superior sensitivity, and better temporal and spatial resolution over other nuclear imaging techniques, PET is considered the “gold standard” for noninvasive assessment of myocardial perfusion and viability.
PET Imaging Fundamentals Beta (+) decay of a nucleus results in emission of a positron, which rapidly collides with an electron giving off two photons which travel in opposite directions. PET imaging is obtained by detecting these photons as they coincide in a ring scanner. Current clinical PET scanners have a spatial resolution in the range of 6–7 mm [18]. The high temporal resolution of PET scanners allow for creation of dynamic imaging sequences that describe tracer kinetics. Using specific radiotracers one can obtain information regarding myocardial perfusion and metabolic activity. In terms of image acquisition, multiple image reconstructions can be obtained from a single dataset, including static, gated, and dynamic images, thus allowing for advanced image processing. ECG gating allows for functional analysis [19] and respiratory gating reduces distortion from motion artifact [20]. The most common (FDA-approved) radiotracers are rubidium (82Rb) for perfusion studies and the glucose analogue fluorodeoxyglucose (18F-FDG) for assessment of myocardial viability.
Hybrid Cardiac PET/CT Imaging The main clinical application for PET imaging in electrophysiology is the evaluation of arrhythmic substrate in scarmediated ventricular tachycardia (VT). The combination of CT and PET imaging integrates detailed anatomical information of high spatial resolution with biological information about myocardial metabolic activity, which helps localize and characterize scar tissue responsible for reentrant ventricular arrhythmias [21–23].
372 Fig. 29.1 Triple image integration (pre-procedural cardiac MRI, electroanatomical map, and intracardiac ultrasound) using the Carto XP mapping system and CartoSOUND module in a patient with a large basal lateral LV scar (yellow mesh). The MRI-extracted scar was fused with a real-time EA map reconstructed with point-by-point voltage mapping (white mesh) and intracardiac ultrasound integration (green US fan) which allowed for real-time visualization of the thinned myocardium. Red tags represent the area of RF modulation in the lateral edge of the LV scar
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11.00 mV Bipolar 1-1-ReLVVT1 > 151 Points 12 contours
1.53 mV 1.63 mV 0.21 mV
P50scar
1.37cm
Intracardiac Ultrasound Imaging Technology Intracardiac ultrasound (ICE) imaging is the only available imaging modality that allows real-time imaging with detailed visualization of intracardiac structures in the electrophysiology laboratory. Three different ICE systems are clinically available. One system uses a single, radial 9 MHz transducer with a field of view of 115° and a rotational speed of 3,800 RPM, mounted on a 9 F no steerable catheter (ClearView Cardiovascular Imaging System, Freemont, CA and Boston Scientific, San Jose, California). Another system consists of a phased-array transducer with 64 piezoelectric crystals with frequencies ranging from 5 to 10 MHz, mounted on an 8 F or 10 F catheter with four degrees of motion (anterior, posterior, left, and right deflections) and a 90° field of view (Siemens Acuson, Mountain View, CA). The fixed catheter radial transducer type lacks depth resolution and adequate imaging of intracardiac structures requires substantial catheter manipulation. The phased-array ICE catheters provide a better far field resolution (up to a depth of 15 cm) and Doppler capabilities, making it the preferred ultrasound system in many centers [25]. In addition, the phased-array ICE catheter is also available with an integrated magnetic location sensor (SoundStar, Siemens Acuson), and has the ability to reference the 2D ICE images to the 3D matrix of the Carto XP or Carto 3 mapping system (CartoSOUND, Biosense Webster, Diamond Bar, CA). Sequential 2D ICE images are used to build an ECG-gated, 3D geometry of intracardiac structures and chambers, which can be fully registered with
pre-procedural CT, MRI, or PET image datasets (Fig. 29.1). Recently, another ICE system has been introduced (ViewFlex PLUS, St Jude Medical, Minneapolis, MN) which uses a phased-array 64 element, 9 F transducer, with a 90° field of view, steering capabilities (anterior, posterior, and lateral flexion), and multiple imaging modalities (M-Mode, 2D, TDI, CW, PW, and color Doppler) but currently lacks integration with any 3D mapping systems. The use of ICE imaging can potentially facilitate ablation procedures in a variety of atrial and ventricular arrhythmias [24, 26, 27]. Benefits include minimal use of fluoroscopy using ICE images fused with pre-procedural studies [28, 29]; real-time visualization of the ablation catheter tip to assess myocardial tissue contact, which may improve ablation success and safe energy delivery [30]; and early detection of potential complications such as acute ventricular dysfunction, valvular regurgitation, and cardiac tamponade, allowing for early intervention before hemodynamic instability ensues [31].
Three-Dimensional Mapping Systems Imaging Fundamentals The use of 3D mapping systems provides spatial location of one or several catheters within the different heart chambers and great vessels. The Carto mapping system (Biosense Webster, Diamond Bar, CA) uses ultralow electromagnetic
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a
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b
Fig. 29.2 Example of CFAE (complex fractionated atrial electrogram) mapping during a case of persistent atrial fibrillation ablation. The CFAE software analyzes the frequency and fractionation of local electrograms and creates a color map where regions with highly fractionated potentials are marked in red and areas with low fractionation are
coded blue. Panel (a). Shows a high density of CFAE at baseline in the anterior LA and LA appendage. Panel (b). Map after radio-frequency applications targeting tagged high-density CFAE areas, showing marked decrease in fractionated potentials
fields (5 × 10−5–5 × 10−6 T) emitted by an electromagnetic pad containing three coils located below the patient to assess the position of a catheter tip within the chamber of interest. The strength of each coil’s magnetic field decays as a function of distance from the coil, and by integrating each coil’s field strength and converting it into distance, the location sensor in the catheter tip can be triangulated in a threedimensional space (X, Y and, Z axis). When the mapping catheter is moved into the different cardiac chambers, mapping points are taken at sites of contact between the catheter tip and the tissue (point-by-point mapping). The combination of multiple mapping points generates an integrated 3D chamber reconstruction containing both anatomical and electrical information (Fig. 29.2), which can be used to identify scar areas (voltage maps by measurement of local electrogram amplitude) or define arrhythmia circuits (activation maps by timing of local electrograms in the roving catheter referenced to an electrogram obtained from a diagnostic catheter in a stable location or surface ECG). Activation and voltage electrogram information is then displayed in a color coded scale ranging from red (scar tissue in voltage maps or earliest activation in activation maps) to purple (healthy tissue on voltage maps or late activation in
activation maps). The system achieves superb spatial resolution of <1 mm but can be affected by electromagnetic interference from other equipment available in the electrophysiology suite [32]. The EnSite mapping system (St Jude Medical, Minneapolis, MN) is a non-contact mapping system that uses three low-amplitude, high frequency current fields which are generated in three axes (patches) over the patient’s chest to triangulate the position of an electrode in the thorax relative to a reference electrode located in a stable position inside the heart or in the patient’s chest [33, 34]. A catheter localization system is used to create the cardiac geometry by moving the catheter inside the heart chambers and the changes in current detected by the patches are translated into signals displaying the cardiac anatomy. The original system (NavX) and its newer version (EnSite Velocity) allow for simultaneous multielectrode mapping, collecting electroanatomical information from multiple electrodes at the same time. Activation mapping of arrhythmia circuits using point-by-point mapping is only feasible with stable arrhythmias over time. Unstable tachycardias or tachycardias with changing arrhythmia circuits can only be mapped with simultaneous multielectrode recordings. This can
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also be achieved by using a balloon catheter that contains 64 virtual electrodes inserted into the cardiac chamber of interest on the EnSite NavX system or by selecting the one map tool, which acquires simultaneous electrogram signals from all the catheters and electrodes positioned in the heart at one time on the EnSite Velocity System, thus creating a comprehensive activation sequence of multiple points. The newer version of the Carto system (Carto 3) has the ability to display multiple catheters such as circular multipolar and roving catheters simultaneously. This is known as advanced catheter location (ACL) technology, by combining magnetic localization and current-based visualization to provide an accurate display of catheter location and curvature. This new system also allows for fast anatomical mapping (FAM) which is a feature that provides detailed anatomical reconstruction by moving any of the NAV catheters inside the chamber of interest. The Carto 3 system has incorporated multielectrode FAM mapping, and more recently, a new version has been released, with the ability to perform multielectrode activation mapping as well.
Steps for Accurate 3D Electroanatomical Mapping The first step in the mapping process is to assure correct positioning of the patches and magnets so that they overlie the cardiac chamber of interest. This is particularly important in the Carto system for patients with dilated hearts where the mapping catheter may fall out of range and display an error message. The next step in the mapping process is to obtain mapping points during the same phase of the respiratory cycle (usually end expiration) to avoid respiratory motion artifact which can lead to mis-registration of the true cardiac anatomy, although both clinically available mapping systems currently have respiratory compensation algorithms which can help overcome this problem [35]. Another important consideration is to make sure a stable timing reference is used to reconstruct an activation map. Using the tachycardia cycle length (TCL) as a guide, one should use a window of interest (timing window where the mapping system “sees” electrograms during tachycardia) slightly shorter than the TCL. For reentrant arrhythmias, an activation map typically displays an “early meets late” pattern, whereas focal tachycardias will be seen as an earliest activation surrounded by a gradual change in the activation sequence or “early focal, late diffuse” pattern. For mapping supraventricular tachycardias, an atrial electrogram from the coronary sinus is usually chosen as this catheter positions tends to be fairly stable for the duration of the procedure. For ventricular tachycardias usually the surface ECG is chosen as it tends to be more stable than local electrograms recorded from the ventricular chambers. Higher mapping point density helps delineate
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reentry circuits or focal activation points with greater accuracy. An exercise of caution is to always be aware of sudden changes in the activation sequence and cycle length of the tachycardia, as spontaneous transitions from one tachycardia circuit to another can be seen. Failure to identify these tachycardia shifts will undoubtedly lead to inaccurate activation maps. Local electrogram interpretation is crucial for characterization of healthy myocardium and scar tissue. Local electrogram features of normal myocardium include sharp, biphasic, or triphasic spikes with bipolar voltage amplitudes of 3.7 ± 1.7 mV for the right ventricle and 4.8 ± 3.1 mV for the left ventricle, with >95 % of all normal electrograms having amplitudes greater than 1.5 mV [36]. This is the standard cutoff used in most laboratories to define healthy ventricular myocardium. Scar tissue and abnormal myocardium tend to display abnormal local electrogram signals characterized by lower amplitude, fractionation, and late and diastolic potentials [37].
Image Integration to Guide Complex Arrhythmia Ablation In recent years, integration of pre-procedural cardiac imaging studies with intra-procedural 3D mapping systems has become increasingly common in the catheter ablation of complex arrhythmias such as atrial fibrillation (AF), atrial tachycardias (AT), and ventricular tachycardia (VT) [38–40, 74]. The integration of linear images of the different cardiac and vascular structures provides great anatomical detail, and when integrated with a 3D mapping system, geometrical reconstruction has the potential to enhance the accuracy of intracardiac catheter manipulation during anatomically based ablation for AF and scar-mediated VT. Multiple trials have shown clinical benefits when image integration is incorporated into AF ablation procedures [41–44], and although some studies suggest a benefit in long-term outcomes (survival free of arrhythmias), the common denominator appears to be a marked reduction in fluoroscopy time when image integration is applied.
Fundamentals of Image Integration Commercially available 3D mapping systems are equipped with image integration software modules (Carto-MERGE, Biosense Webster Inc., and EnSite Verismo™, St Jude Medical Inc.). These software packages allow the registration of pre-procedural images obtained from cardiac CT, MRI, or modified PET imaging studies. New technology such as rotational 3D angiography (3DRA) can also be integrated with commercially available 3D mapping systems
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[45, 46]. Image integration (also known as image fusion) is composed of three main steps: Acquisition of Pre-procedural Images: It refers to obtaining CT, MR, PET, or 3DRA images of sufficient quality that guarantee depiction of images with anatomical accuracy. Most of these images are acquired during diastole, using electrocardiogram (ECG) gating and in a short duration of time (ideally during a single breath hold at end expiration or with respiratory gated sequences) in order to avoid motion artifact. Image Segmentation: It allows for separation of the different cardiac structures and chambers from the image datasets using a 3D volume rendered model obtained from the bidimensional (2D) image slices. Contrast agents are used to delineate intravascular and intracardiac volumes by enhancing signal intensities between the blood and adjacent tissue. The process of segmentation is facilitated by imaging software algorithms that use signal threshold, boundary detection, and regional identification parameters [47]. Image Registration: It represents the most critical step in the image integration or fusion process and consists of superimposition of the pre-procedural derived reconstructed 3D images into the real-time electroanatomical map. This allows for navigation of the intracardiac catheter(s) inside the registered 3D anatomy. Cardiac registration of radiographic-derived reconstructed images and 3D maps is intermodal, which means that both imaging datasets reside in different image spaces, thus requiring registration algorithms to transform one image space into another. Linear transformation uses six parameters or degrees of freedom (three translations and three rotations) while nonlinear transformation uses multiple degrees of freedom to avoid image distortion. Different registration methods are available for obtaining accurate image fusion. In geometry-based registration, for example, fiducial points (tagged points corresponding to a specific anatomical area) are used to align both imaging 3D sets (this is known as point-based registration). Alignment of fiducial points is done by either visually matching the point pairs or by automatically having the system align the point pair matches (landmark alignment). The net result is near synchronization of both image datasets by matching, aligning, and rotating the different fiducial points thus minimizing the distance between each point pair. The square root of the mean squared distance between point pairs is known as the fiducial registration error (FRE) [48]. For procedures involving the left atrium, the left atrial appendage, mitral ring, and pulmonary vein ostia are frequently used for landmark registration [49]. All registration methods are imperfect and a certain degree of misalignment between the fused images is observed. The misalignment of
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each registered point is referred to as fiducial localization error and is measured as the distance from the intended to the actual point obtained. Another method of image registration uses delineation of the cardiac contours of the different chambers in each image dataset to perform alignment and registration (this is known as surface-based registration). In routine practice, radiographic images are registered into the 3D environment of the electroanatomical mapping system by employing three translations and three rotations. Calibration of each device is used to determine appropriate image scaling [50]. Multiple studies have validated both point and surface registration methods with commercially available 3D mapping systems and pre-procedural imaging, with acceptable accuracies ranging from 2.9 ± 0.7 to 6.9 ± 2.2 mm for CT [39, 40, 51, 52], 3.8 ± 0.6–4.3 ± 3.2 mm for MRI [13, 53, 54], 3.7 ± 0.7–5.1 ± 2.1 mm for PET and PET/CT [21–23], and 2.2 ± 1.8–2.7 ± 2.3 mm for 3DRA [81]. The Carto XP and Carto 3 mapping systems use an image integration module (Carto-MERGE) where three different types of registration algorithms can be utilized: visual alignment, landmark registration, and surface registration (Fig. 29.3). The EnSite NavX and Velocity mapping systems use the Verismo™ module. The process consists of three main steps. First, a segmented surface rendering of a CT or MRI scan, known as the digital image fusion or DIF model, is imported into the 3D mapping system. Next, a field scaling algorithm is performed to measure inter-electrode spacing at collected geometry points in the chamber in order to compensate for discrepancies in the 3D mapping field, adjusting the volume of the 3D map to resemble the preprocedural image volume. As the last step, image fusion, which describes the integration of pre-procedural CT/MRI and 3D map, is accomplished. The Verismo fusion module uses paired locations (fiducial points) between the mapping and the CT/MRI 3D models to align the images for registration. A dynamic registration algorithm locally adjusts the 3D shell geometry and surface to the size and shape of the DIF model surface. Despite their differences in image fusion technique, clinical studies have shown comparable registration errors of these two commercially available 3D mapping systems [39, 55].
Factors Affecting Image Registration Error As the CT and MRI studies are obtained before the EP procedure, volumetric and motion-related discrepancies between the real-time EA map and the reconstructed 3D radiologic datasets are expected. Registration errors can be minimized by reducing the timing between the preprocedural radiologic study and the intracardiac mapping (ideally ≤24 h), limiting the effects of respiratory motion by obtaining end-expiratory phase image datasets using
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Fig. 29.3 Representation of landmark registration technique for image fusion prior to atrial fibrillation ablation (cardiac MRI in grey and Carto map in light purple). The dotted white circles represent fiducial points taken at the left and right carinal areas prior to image integration. After landmark registration, visual alignment was used to synchronize both
image datasets. The white tags and blue line correspond to the mitral annulus. LSPV left superior pulmonary vein, LIPV left inferior pulmonary vein, RSPV right superior pulmonary vein, RIPV right inferior pulmonary vein, LAA left atrial appendage, MA mitral annulus
respiratory gating and minimizing cardiac motion by ECG gating to obtain both imaging sets during the same phase of the cardiac cycle (usually end diastole) and avoiding wall stretching by excessive catheter force contact which can lead to deformation and false spacing of the rendered 3D cardiac anatomy created with the mapping system.
to integrate high-resolution pre-procedural images of the LA and PV and display the 3D data in the mapping systems enables a rapid identification of anatomical variants and adjacent structures (e.g., esophagus) to minimize procedurerelated risks (Fig. 29.4). Different techniques can be employed for registration of LA CT/MRI images with the 3D mapping systems, with acceptable registration errors ranging from 2.5 to 5 mm [52, 55, 62–69]. Clinically, a combination of visual alignment or landmark registration together with surface registration of the LA and related structures such as the pulmonary veins are used for registration. Most commonly, the pulmonary veins carina is used as landmark point to integrate 3D maps with pre-procedural CT/MRI [70]. Anatomical variants such as a roof or middle pulmonary veins can also be used as landmark pairs for registration. Another method of image registration employs pre-procedural CT or MRI images with real-time intracardiac ultrasound (ICE) of the left atrial 3D anatomy incorporated into the 3D mapping system (CartoSOUND) fused by visual alignment, landmark, and surface registration. The registration error between the ICE and CT/MRI datasets was 1.83 ± 0.32 (with the ICE probe advanced transeptally into the LA) and 2.52 ± 0.58 (when LA images were obtained from the RA) [65]. Once the images are fused, the electrophysiologist must confirm an accurate registration has been achieved. This is usually done by manipulating the roving catheter under guidance of a real-time imaging modality (fluoroscopy or ICE) and placing it in a specific structure (e.g., pulmonary vein), confirming overlapping contours of images between the CT/MRI/ PET and 3D map and positioning of the catheter in the right chamber [47].
Clinical Applications for Image Fusion Technology Atrial Fibrillation Pulmonary vein isolation (PVI) using different sources of energy (mostly radio frequency and more recently, cryoenergy, laser, and duty cycle multipolar energy) is the cornerstone of AF ablation; however, delivery of ablation lesions inside the pulmonary veins (PV) or its ostia can lead to PV stenosis, associated with significant morbidity, often requiring further interventional treatment [56, 57]. The close proximity of the esophagus to the posterior wall of the left atrium places this organ at risk of injury from ablation energy sources, and although few cases of atrio-esophageal fistula (AEF) formation post AF ablation have been reported over recent years, they tend to be catastrophic [58]. A variety of gross anatomy and imaging studies demonstrated a wide range of anatomical variability in the pulmonary veins, such as common left trunk PV, right middle PV, and right top PV, found in up to 38 % of the patients [59, 60]. Additionally, other anatomical variables, such as roof pouches, were reported in up to 15 % of patients with atrial fibrillation and may contribute to occasional complications [61]. The ability
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Fig. 29.4 Integration of cardiac computed tomography (CCT) with a 3D map of the left atrium (Carto 3) during RF ablation for persistent atrial fibrillation. Top panels. Left lateral and posterior views during RF application in the LA ridge after pulmonary vein isolation failed to
terminate AF. Bottom panel. Intracardiac electrograms of the ablation catheter and coronary sinus during RF delivery. Note the disappearance of local atrial EGM in the ablation catheter and conversion to sinus rhythm at the end of the strip (red circle)
Ventricular Tachycardia The creation of reliable 3D anatomical models with endo-epicardial voltage information and electrical activation patterns allow detailed mapping of complex arrhythmia circuits involving scar, border zone, and healthy tissue areas as well as differentiation and localization of reentrant versus focal arrhythmia mechanisms to guide ablation of suitable targets for arrhythmia termination. The incorporation of 3D reconstructed imaging datasets allows comprehensive pre-procedural substrate evaluation. MRI, CT, and PET imaging provide detailed information on the anatomical substrate (wall thinning, intramural calcifications, focal aneurysms), dynamic characterization of wall motion abnormalities (CT/MRI cine sequences), perfusion data (first-pass and delayed enhancement MRI), and metabolic evaluation of scar substrates (ischemia, necrosis and hibernating myocardium using rubidium and FDG PET sequences) (Fig. 29.5). The MRI-, CT-, and PET-derived
anatomic, dynamic, metabolic, and perfusion data can be used to create individual reconstruction that accurately describe the location and size of abnormal myocardial substrates [21–23, 71]. Pre-procedural planning can be performed based on the known localization of scar and/or metabolically abnormal and help define the best approach to target the pro-arrhythmic areas, by guiding the vascular access, energy delivery, and potential need for epicardial mapping [53]. Several studies have applied image fusion of preprocedural MRI, CT, and PET datasets with 3D mapping systems for treatment of ventricular arrhythmias [13, 21– 23, 53, 54, 71–73, 75, 76]. The technique for image integration and registration of ventricular chambers, outflow tract and aorta/pulmonary artery follows the same principles described for the left atrium and pulmonary veins. The non-symmetric shape of the RV normally enables an acceptable registration accuracy using the surface align-
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Fig. 29.5 Example of a PET/CT three-dimensional reconstruction of the left ventricle (olive green) and a large anterior myocardial scar (mesh) fused with a 3D voltage map obtained with the Carto XP mapping system in a patient with prior history of myocardial infarction undergoing VT ablation for recurrent ICD shocks. Note the correlation between the PET/CT extracted scar (mesh) and the scar by voltage mapping (<0.5 V bipolar, dotted circle). This pre-procedural image integration approach allows for localized intra-procedural voltage mapping, limiting high-density mapping to the region of interest (scar and borderzone), decreasing procedural time, and facilitating substrate modulation. Red tags represent RF applications
ment algorithm. Due to its cone shape, the left ventricle requires the acquisition of apical and mitral valve fiducial points together with right ventricular or aortic mapping points to obtain adequate registration images and minimize rotational errors. 3D substrate maps derived from contrastenhanced MRI, CT, or PET datasets can be fused with the 3D mapping system after complete or partial electroanatomical mapping or they can be registered with ICE 3D chamber reconstruction using the CartoSOUND system to define substrates for VT in ischemic and nonischemic heart disease (Fig. 29.6) [13]. • Positron-Emission Tomography (PET)/CT: PET/CT combination allows for simultaneous metabolic-anatomical characterization of the scar substrate by assessing myocardial viability using 18-F fluorodeoxyglucose (FDG) and perfusion with 82-Rubidium chloride (Rb). The three-dimensional contours of the ventricle and scar tissue can be incorporated into the 3D EA map geometry to create an accurate representation of the anatomical area of interest. In several studies, the combination of visual and surface alignment yielded the lowest amount of registration error (3.7 ± 0.7; 4.34 ± 0.6 mm) [21–23]. The main advantages of PET imaging are that it can be safely used in patients with renal dysfunction and ICDs (and no metal artifacts are produced during metabolic imaging). Its main limitations are an imperfect spatial resolution (about 6 mm) when compared to MRI or CT
imaging alone and the insufficient image quality in patients with uncontrolled diabetes. • Contrast-Enhanced Computed Tomography (CE-CT): Contrast-enhanced CT imaging enables detailed characterization of the left ventricular myocardium, including myocardial scar and border zone (BZ), due to differences in anatomic, dynamic, and perfusion characteristics when performing first-pass CT. Using this technology, registration accuracies of 3.31 ± 0.52 mm can be achieved, predicting 82 % of abnormal voltage segments seen intra-procedurally on 3D EA maps and accurately defining scar transmurality [58, 65]. In our experience, highquality delayed enhanced CT scar images are difficult to obtain consistently in chronic human infarcts. Therefore, published studies using this data for image integration are limited (Fig. 29.6). • Magnetic Resonance Imaging (MRI): Magnetic resonance imaging provides images of high spatial resolution with accurate reconstruction of anatomical details and can allow visualization of myocardial scar with the addition of late gadolinium enhancement (LGE) sequences [69, 70]. Contrary to PET and CT imaging, MRI avoids ionizing radiation exposure to patients. Prior studies have shown that integration of pre-procedural MRI datasets with 3D mapping systems for guiding VT ablation procedures in patients with ischemic and nonischemic cardiomyopathy is feasible and safe, with registration accuracies ranging from 3 to 5 mm [13, 53, 54, 72, 77]. In these studies, patients had more prevalence of abnormal EGM signals, lower voltage amplitude, and longer EGM duration in MRI identified scar areas compared to healthy myocardial tissue. The best correlation between MR and voltage scar was found using a bipolar threshold of 1–1.5 mV and abnormal EGM characteristics (isolated diastolic potentials and fractionated electrograms) were present in areas of abnormal DE were VT and PVCs originated. Mismatch between MRI and voltage-derived scar occurred in 18–20 % of bipolar voltage recordings [54]. In patients with LGE and nonischemic cardiomyopathy, the presence of midmyocardial scar on MRI was predictive of radiofrequency ablation failure to eliminate VT or PVCs, compared to endo- or epicardial LGE sites [72]. It is important to mention that most patients with structural heart disease who would be candidates for MRI imaging have already received ICDs. Although still considered a contraindication, a significant number of ICD recipients have undergone MR imaging worldwide, the majority of these studies have been conducted in highly experienced centers with strict inclusion/exclusion criteria. Limited data is available for the use of pre-procedural cardiac MRI to define scar in patients with ICDs. A recent study showed that despite pronounced metal artifacts in LGE imaging reconstruction, LGE scar was successfully registered (registration error 3.9 ± 1.8 mm) and the fusion of the
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Fig. 29.6 Integration of 3D activation map (Carto 3) of the left ventricle with a 3D shell of the right ventricle obtained with the CartoSOUND module during mapping and ablation of a septal ventricular tachycardia. Panel (a). Inferior view of an LV activation map with earliest activation in the mid septal area where multiple RF applications slowed down, but did not terminate VT. A real-time 3D map of the RV was quickly created with an intracardiac ultrasound probe (SoundStar) and the CartoSOUND module. Although pacing points at both RV and LV septal sites (blue tags) were less than ideal pace map
matches for the clinical VT (Panel (c), right insert), RF applications at the mid RV septum terminated the tachycardia, suggesting a midmyocardial arrhythmic substrate. Panel (b). RAO view of the RV during RF application at the mid septum (ablation catheter marked with red arrow). Right panel shows a monitor screen displaying temperature, impedance, and power output values. Panel (c). Intracardiac ultrasound view of the RV showing the ablation catheter tip (green) oriented towards the mid RV septum
MRI defined scar into the 3D mapping system was able to reliably identify excellent pace map sites, obviating the need for complete ventricular voltage mapping in 64 % of patients, and was able to identify VT exit sites successfully despite preserved bipolar voltages [13].
(involving a small gap in a lesion set or automatic foci) in nature and are often refractory to anti-arrhythmic medications. The use of CT or MRI images to reproduce accurate anatomy, with the addition of 3D voltage and activation maps, can identify the arrhythmic substrate (scar areas, gaps in prior ablation lines). Newer MRI technology is now able to detect atrial fibrosis and scar from prior ablation lines and this information can prove useful in planning and treating these recurrent arrhythmias [73]. • Arrhythmias Occurring After Corrective and Palliative Congenital Heart Surgery: Correction of congenital conditions, such as tetralogy of Fallot, atrial and ventricular septal defects, transposition of the great arteries, and Ebstein’s anomaly at a young age, can lead to the development of atrial and ventricular arrhythmias later in life. The mechanisms for these arrhythmias are often related to a macro-reentrant circuits occurring around a scar from prior surgical incision, patches, or shunts or as a consequence of chamber dilatation with subsequent tissue stretching. The use of CT/MRI images fused with 3D EA
Other Cardiac Arrhythmias Traditionally, advanced mapping techniques have not been routinely utilized in the diagnosis and treatment of arrhythmias such as AV nodal reentrant tachycardia, AV reentrant tachycardia and typical atrial flutter, as conventional methods are highly successful in these cases. The use of image integration techniques is usually reserved for selected complex arrhythmias where conventional mapping fails to indentify and adequately guide successful ablation sites. • Atrial Tachycardias Occurring After AF Ablation/Surgery: Atrial arrhythmias are common in patients who underwent surgical or percutaneous AF ablation (up to onethird of patients during follow up). These arrhythmias can be macro-reentrant (around a valvular structure or encircled pulmonary vein) or focal/micro-reentrant
380 Fig. 29.7 Integration between fast anatomical map (FAM) of the right ventricular outflow tract (RVOT) and cardiac computed tomography (CCT) reconstructed RVOT anatomy (Carto 3 mapping system) in a patient with symptomatic palpitations and ventricular bigeminy. Panel (a). Image fusion of the RVOT FAM map (grey) and CCT (blue) with activation map displaying the earliest activation in the anterior aspect of the RVOT below the pulmonic valve (red circle) with corresponding local electrograms (Panel c) showing QS unipolar signal and pre-QRS local activation. Panel (b). Pace mapping site in the RVOT (green tag in white circle) showing similar but not identical pace map match with the clinical ventricular premature beats
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maps can facilitate manipulation of intracardiac catheters through abnormal chamber connections, stenosed segments, and distorted anatomy. In addition, the correlation between the anatomical variants with activation maps helps in the diagnosis and ablation of the arrhythmia circuits [78]. • Ventricular Outflow Tract and Idiopathic Tachycardias: Ablation of idiopathic ventricular tachycardias or premature ventricular contractions arising from structures in the outflow and inflow tracts (RV infundibulum, aortic cusps, LV summit, papillary muscles) can be challenging due to the complex anatomy and close spatial relationship between these structures, coronary arteries, and the conduction tissue, posing potential risk for collateral damage during RF energy delivery. Conventional mapping techniques and fluoroscopy lack the spatial resolution and ability to properly display complex intracardiac anatomy. The integration of accurate 3D anatomical reconstruction with activation maps can localize the site of origin of these focal arrhythmias, allowing for safe energy delivery and minimizing the risk of potential damage to critical adjacent structures. Key points for a successful ablation in this region are obtaining adequate catheter to tissue contact and direct visualization of the coronary anatomy and its proximity to the potential ablation site. Although traditionally, intra-procedural coronary angiography has been
the gold standard for depicting the coronary anatomy, nowadays techniques such as integration of 3D CT/MRI models of the outflow tract and coronaries with the 3D EA map (Figs. 29.7 and 29.8) or the use of real-time ICE or ICE integrated with the 3D map (CartoSOUND) have been successfully employed for the ablation of these arrhythmias (Figs. 29.9 and 29.10) [24, 79].
Three-Dimensional Rotational Angiography Newer angiographic suites capable of creating volume rendered images after a single contrast bolus can be used in the treatment of complex arrhythmias. These three-dimensional rotational angiography (3DRA) systems can be used alone or in combination with current 3D EA mapping systems. The main advantage of this technology over preprocedural radiological images is the fact that they are used intra-procedurally to render an accurate volume of a given cardiac chamber thus eliminating any time gap between the study and the procedure, as opposed to pre-procedural data where volume changes can occur and lead to mis-registration errors during image integration. Available 3DRA systems (Xper FD 10 system, Philips Medical Systems, Best, The Netherlands and syngo DynaCT, Siemens, Malvern, PA) use an ECG gated, power injection of contrast dye to depict a
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Fig. 29.8 Integration of cardiac CT and 3D electroanatomical map (FAM) using the Carto 3 system during ablation of VT originating in the right coronary cusp (RCC). Panel (a). 3D reconstruction of the left and right outflow tract anatomy and origin of the coronary arteries. Panel (b). FAM reconstruction of the right and left outflow tract
anatomy with activation map showing earliest site at the RCC. Panel (c). Integration of the coronary anatomy allowed for successful ablation (red tags) at a site distant to the right coronary artery os. Box insert shows the ECG and local EGM of the earliest activation site during VT
chamber of interest. The contrast transit time (time from injection of dye to opacification of the chamber of interest) is timed with the camera rotation (120° RAO to 120° LAO in 5 s) and image acquisition (30 frames per second). Once the images are obtained, specific software is used for segmentation and creation of a 3D geometry which is registered in the live fluoroscopy screen using radio-opaque landmarks to be used for catheter navigation. The use of this technology has been validated during ventricular tachycardia and atrial fibrillation ablation procedures [80–82]. Although segmentation and registration times, X-ray exposure, and procedure duration are similar, the use of pre-procedural CT or MRI image integration protocols still provides images of higher anatomical resolution.
Future Imaging Applications: Real-Time MRI-Guided EP Procedures, Assessment of Atrial Fibrosis and Creation of Ablation Lesions Although great progress has been made with the incorporation of these imaging techniques for the understanding and management of complex arrhythmias, newer technology is under development to overcome the current limitations of the available imaging technology. These areas of improvement include accuracy of image registration, volumetric discrepancies between real-time and pre-procedural datasets, visualization and measurement of catheter to tissue contact, evaluation of the effectiveness of ablation lesions, and peri-procedural
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Fig. 29.9 3D map of the coronary cusps using the Carto XP mapping system and the CartoSOUND in a patient with frequent ventricular premature beats (VPBs). Panel (a). Using real-time ICE images, the contours of the right (R), left (L), and non (N) coronary cusps were drawn and projected into the 3D map (purple lines). Panel (b). 3D point-bypoint map of the aortic root with projected cusp anatomy. The earliest local activation during a VPB (red mesh) corresponds to a site
immediately superior to the left coronary cusp (purple mesh). Panel C. Electrocardiograms and local electrograms during VPB at earliest site (red tag) showing earliest activation 30 ms pre-QRS (bipolar EGM in blue) and QS morphology on the unipolar electrogram (red EGM). After coronary angiography was performed to confirm location away from the left coronary os, 3 s of RF ablation (irrigated catheter, 25 W) eliminated the VPBs
ionizing radiation exposure. All these limitations could be overcome by real-time magnetic resonance imaging. Experimental studies have demonstrated the ability of this technology to visualize catheter manipulation inside the heart chambers [83], monitoring RF energy delivery, and assessment of intra-procedural lesion formation [84–88]. Another potential application of real-time MRI is the use of MRI thermography. In an animal model, radio frequency-induced lesion extent seen on thermography images correlated well with the gross anatomy specimens [88]. Another area where MRI technology has shown promise is in the ability to visualize atrial fibrosis and ablation lesions, placing this technology at the brink of clinical feasibility. Several groups have evaluated the use of pre-procedural cardiac MRI assessment of atrial fibrosis before AF ablation to
predict procedural outcomes [89, 90] and post-procedural cardiac MRI for assessment of lesion formation after AF ablation [73, 90–92]. These studies have shown that in patients with mild LA fibrosis, circumferential PV scarring was predictive of successful ablation, while patients with more extensive pre-procedural LA fibrosis required more extensive post-ablation scarring to achieve procedural success. Most notably, post-procedural DE cardiac MRI integrated with 3D mapping data was able to indentify LA scar on MRI in 80 % of areas post-ablation and to visualize gaps in the intended ablation lines in up to 20 % of all ablated sections. The integration of DE cardiac MRI fibrosis and scar reconstructions into the 3D mapping systems may allow for a substrate-guided approach for redo AF and post AF atrial flutter ablations.
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Fig. 29.10 CartoSOUND electroanatomical map of the left ventricle and papillary muscles in a patient with idiopathic VT. Panel (a). Cross sectional views of the left ventricle obtained by sequential 10° rotations of the ICE probe. The green lines mark the LV contours, which are ECG gated with the QRS (box insert). The pink lines mark the contours
Conclusions
The use of radiologic imaging techniques before, during, or after electrophysiologic procedures, alone or in combination with 3D mapping systems, provides detailed and comprehensive assessment of the cardiac tissue. Cardiac anatomy, ventricular function, coronary perfusion, myocardial metabolism, and tissue characteristics can be used to facilitate complex arrhythmia ablations by improving catheter guidance and allowing for a more efficient targeting of arrhythmogenic tissue. Multiple studies have demonstrated safe and efficient ablative therapy employing this imaging approach. Obtaining a pre-procedural radiographic study of excellent quality and assuring correct image integration is crucial for accuracy and clinical applicability of image fusion techniques. Current intraprocedural imaging modalities such as ICE allow for evaluation of the complex intracardiac anatomy, monitoring of cardiac functional parameters, as well as visualization of
of the anterolateral papillary muscle (ALPM). Panel (b). 3D reconstruction of the papillary muscles (pink for the anterolateral (AL) and blue for the posteromedial (PM)). Activation map during ventricular tachycardia shows earliest activation and QS unipolar EGM morphology in the anterior portion of the ALPM (yellow tag)
catheter to tissue contact and safe energy delivery in specific anatomical areas. Newer imaging techniques under development such as real-time MRI guidance hold promise for monitoring of ablation therapies in the near future. Acknowledgments The authors acknowledge the assistance of Angela Uribe (Biosense Webster, Latin America) and Thomas Severino (Biosense Webster, USA) with the preparation of some of the images presented in this chapter.
References 1. Luenberger DG. Linear and nonlinear programming. 2nd ed. Reading: Addison-Wesley Publishing Company; 2005. 2. Christian PE, Waterstram-Rich KM, editors. Nuclear medicine and PET/CT: technologies and techniques. 6th ed. St Louis: Mosby/ Elsevier; 2007.
384 3. Sra JS. Cardiac magnetic resonance imaging and computed tomography: anatomic fundamentals. J Interv Card Electrophysiol. 2011;31(1):39–46. 4. Hendee WR, Morgan CJ. Magnetic resonance imaging part I— physical principles. West J Med. 1984;141(4):491–500. 5. Bogaert J, Taylor AM, Van Kerkhove F, Dymarkowski S. Use of inversion recovery contrast-enhanced MRI for cardiac imaging: spectrum of applications. AJR Am J Roentgenol. 2004;182(3):609–15. 6. Levine GN, Gomes AS, Arai AE, et al. Safety of magnetic resonance imaging in patients with cardiovascular devices: an American Heart Association scientific statement from the Committee on Diagnostic and Interventional Cardiac Catheterization, Council on Clinical Cardiology, and the Council on Cardiovascular Radiology and Intervention: endorsed by the American College of Cardiology Foundation, the North American Society for Cardiac Imaging, and the Society for Cardiovascular Magnetic Resonance. Circulation. 2007;116:2878–91. 7. Perazella MA. Current status of gadolinium toxicity in patients with kidney disease. Clin J Am Soc Nephrol. 2009;4:461–9. 8. Sommer T, Vahlhaus C, Lauck G, von Smekal A, Reinke M, Hofer U, et al. MRI and cardiac pacemakers: in-vitro evaluation and in vivo studies in 51 patients at 0.5T. Radiology. 2000;215:869–79. 9. Duru F, Luechinger R, Candinas R. MRI in patients with cardiac pacemakers. Radiology. 2001;219:856–8. 10. Faris OP, Shein M. Food and drug administration perspective: magnetic resonance imaging of pacemaker and implantable cardioverter-defibrillator patients. Circulation. 2006;114(12):1232–3. 11. Roguin A, Schwitter J, Vahlhaus C, Lombardi M, Brugada J, Vardas P, Auricchio A, Priori S, Sommer T. Magnetic resonance imaging in individuals with cardiovascular implantable electronic devices. Europace. 2008;10(3):336–46. 12. Zikria JF, Machnicki S, Rhim E, Bhatti T, Graham RE. MRI of patients with cardiac pacemakers: a review of the medical literature. Am J Roentgenol. 2011;196(2):390–401. 13. Dickfeld T, Tian J, Ahmad G, Jimenez A, Turgeman A, Kuk R, Peters M, Saliaris A, Saba M, Shorofsky S, Jeudy J. MRI-guided ventricular tachycardia ablation: integration of late gadolinium enhanced 3D scar in patients with ICD. Circ Arrhythm Electrophysiol. 2011;4(2):172–84. 14. Nazarian S, Roguin A, Zviman MM, Lardo AC, Dickfeld TL, Calkins H, Weiss RG, Berger RD, Bluemke DA, Halperin HR. Clinical utility and safety of a protocol for noncardiac and cardiac magnetic resonance imaging of patients with permanent pacemakers and implantable-cardioverter defibrillators at 1.5 Tesla. Circulation. 2006;114(12):1277–84. 15. Roguin A, Zviman MM, Meininger GR, Rodrigues ER, Dickfeld TM, Bluemke DA, Lardo A, Berger RD, Calkins H, Halperin HR. Modern pacemaker and implantable cardioverter/ defibrillator systems can be magnetic resonance imaging safe: in vitro and in vivo assessment of safety and function at 1.5 T. Circulation. 2004;110(5):475–82. 16. Wilkoff BL, Bello D, Taborsky M, et al. Magnetic resonance imaging in patients with a pacemaker system designed for the magnetic resonance environment. Heart Rhythm. 2011;8(1):65–73. 17. Nazarian S, Hansford R, Roguin A, Goldsher D, Zviman MM, Lardo AC, Caffo BS, Frick KD, Kraut MA, Kamel IR, Calkins H, Berger RD, Bluemke DA, Halperin HR. A prospective evaluation of a protocol for magnetic resonance imaging of patients with implanted cardiac devices. Ann Intern Med. 2011;155(7):415–24. 18. Pichler BJ, Wehrl HF, Judenhofer MS. Latest advances in molecular imaging instrumentation. J Nucl Med. 2008;49 Suppl 2:5S–23. 19. Chander A, Brenner M, Lautamaki R, Voicu C, Merrill J, Bengel FM. Comparison of measures of left ventricular function from electrocardiographically gated 82Rb PET with contrastenhanced CT ventriculography: a hybrid PET/CT analysis. J Nucl Med. 2008;49:1643–50.
A.J. Restrepo and T.M. Dickfeld 20. Schafers KP, Stegger L. Combined imaging of molecular function and morphology with PET/CT and SPECT/CT: image fusion and motion correction. Basic Res Cardiol. 2008;103:191–9. 21. Dickfeld T, Lei P, Dilsizian V, Jeudy J, Dong J, Voudouris A, Peters R, Saba M, Shekhar R, Shorofsky S. Integration of threedimensional scar maps for ventricular tachycardia ablation with positron emission tomography-computed tomography. JACC Cardiovasc Imaging. 2008;1(1):73–82. 22. Fahmy TS, Wazni OM, Jaber WA, Walimbe V, Di Biase L, Elayi CS, DiFilippo FP, Young RB, Patel D, Riedlbauchova L, Corrado A, Burkhardt JD, Schweikert RA, Arruda M, Natale A. Integration of positron emission tomography/computed tomography with electroanatomical mapping: a novel approach for ablation of scar-related ventricular tachycardia. Heart Rhythm. 2008;5(11):1538–45. 23. Tian J, Smith MF, Chinnadurai P, Dilsizian V, Turgeman A, Abbo A, Gajera K, Xu C, Plotnick D, Peters R, Saba M, Shorofsky S, Dickfeld T. Clinical application of PET/CT fusion imaging for three-dimensional myocardial scar and left ventricular anatomy during ventricular tachycardia ablation. J Cardiovasc Electrophysiol. 2008;20(6):597–604. 24. Lin D, Ilkhanoff L, Gerstenfeld E, Dixit S, Beldner S, Bala R, Garcia F, Callans D, Marchlinski FE. Twelve-lead electrocardiographic characteristics of the aortic cusp region guided by intracardiac echocardiography and electro-anatomic mapping. Heart Rhythm. 2008;5(5):663–9. 25. Robinson MR, Hutchinson MD. Use of imaging techniques to guide catheter ablation procedures. Curr Cardiol Rep. 2010;12:374–81. 26. Verma A, Marrouche NF, Natale A. Pulmonary vein antrum isolation: intracardiac echocardiography-guided technique. J Cardiovasc Electrophysiol. 2004;15:1335–40. 27. Seiler J, Lee JC, Roberts-Thomson KC, Stevenson WG. Intracardiac echocardiography guided catheter ablation of incessant ventricular tachycardia from the posterior papillary muscle causing tachycardia—mediated cardiomyopathy. Heart Rhythm. 2009;6:389–92. 28. Reddy VY, Morales G, Ahmed H, Neuzil P, Dukkipati S, Kim S, Clemens J, D’Avila A. Catheter ablation of atrial fibrillation without the use of fluoroscopy. Heart Rhythm. 2010;7(11):1644–53. 29. Bunch JT, Weiss P, Crandall BG, Day JD, DiMarco JP, Ferguson JD, Mason PK, McDaniel G, Osborn J, Wiggins D, Mahapatra S. Image integration using intracardiac ultrasound and 3D reconstruction for scar mapping and ablation of ventricular tachycardia. J Cardiovasc Electrophysiol. 2010;21:678–84. 30. Ren JF, Marchlinski FE. Utility of intracardiac echocardiography in left heart ablation for tachyarrhythmias. Echocardiography. 2007; 24:533–40. 31. Saad EB, Costa IP, Camanho LE. Use of intracardiac echocardiography in the electrophysiology laboratory. Arq Bras Cardiol. 2011;96(1):e11–7. 32. Gepstein L, Hayam G, Ben-Haim SA. A novel method for nonfluoroscopic catheter-based electroanatomical mapping of the heart in vitro and in vivo accuracy results. Circulation. 1997;95:1611–22. 33. Wittkampf F, Wever E, Derksen R, Wilde A, Ramanna H, Hauer R, et al. LocaLisa: new technique for real-time 3-dimensional localization of regular intracardiac electrodes. Circulation. 1999;99: 1312–7. 34. Schilling RJ, Peters NS, Davies DW. Simultaneous endocardial mapping in the human left ventricle using a noncontact catheter: comparison of contact and reconstructed electrograms during sinus rhythm. Circulation. 1998;98:887–98. 35. Noseworthy PA, Malchano ZJ, Ahmed J, et al. The impact of respiration on left atrial and pulmonary venous anatomy: implications for image-guided intervention. Heart Rhythm. 2005;2:1173–8. 36. Marchlinski FE, Callans DJ, Gottlieb CD, et al. Linear ablation lesions for control of unmappable ventricular tachycardia in patients with ischemic and nonischemic cardiomyopathy. Circulation. 2000;101:1288–96.
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Cardiac Imaging to Assist Complex Ablation Procedures
37. de Bakker JM, van Capelle FJ, Janse MJ, et al. Reentry as a cause of ventricular tachycardia in patients with chronic ischemic heart disease: electrophysiologic and anatomic correlation. Circulation. 1988;77:589–606. 38. Dickfeld T, Calkins H, Zviman M, et al. Anatomic stereotactic catheter ablation on three-dimensional magnetic resonance images in real time. Circulation. 2003;108:2407–13. 39. Richmond L, Rajappan K, Voth E, Rangavajhala V, Earley MJ, Thomas G, Harris S, Sporton SC, Schilling RJ. Validation of computed tomography image integration into the EnSite NavX mapping system to perform catheter ablation of atrial fibrillation. J Cardiovasc Electrophysiol. 2008;19(8):821–7. 40. Sra J, Krum D, Hare J, et al. Feasibility and validation of registration of three-dimensional left atrial models derived from computed tomography with a noncontact cardiac mapping system. Heart Rhythm. 2005;2:55–63. 41. Della Bella P, Fassini G, Cireddu M, Riva S, Carbucicchio C, Giraldi F, Maccabelli G, Trevisi N, Moltrasio M, Pepi M, Galli CA, Andreini D, Ballerini G, Pontone G. Image integration guided catheter ablation of atrial fibrillation: a prospective randomized study. J Cardiovasc Electrophysiol. 2009;20:258–65. 42. Caponi D, Corleto A, Scaglione M, Blandino A, Biasco L, Cristoforetti Y, Cerrato N, Toso E, Morello M, Gaita F. Ablation of atrial fibrillation: does the addition of three-dimensional magnetic resonance imaging of the left atrium to electro-anatomic mapping improve the clinical outcome?: a randomized comparison of CartoMerge vs Carto-XP three-dimensional mapping ablation in patients with paroxysmal and persistent atrial fibrillation. Europace. 2010;12:1098–104. 43. Bertaglia E, Bella PD, Tondo C, Proclemer A, Bottoni N, De Ponti R, Landolina M, Bongiorni MG, Corò L, Stabile G, Dello Russo A, Verlato R, Mantica M, Zoppo F. Image integration increases efficacy of paroxysmal atrial fibrillation catheter ablation: results from the CartoMerge Italian Registry. Europace. 2009;11:1004–10. 44. Kistler PM, Rajappan K, Harris S, Earley MJ, Richmond L, Sporton SC, Schilling RJ. The impact of image integration on catheter ablation of atrial fibrillation using electro-anatomic mapping: a prospective randomized study. Eur Heart J. 2008;29:3029–36. 45. Nölker G, Asbach S, Gutleben KJ, Rittger H, Ritscher G, Brachmann J, Sinha AM. Image-integration of intraprocedural rotational angiography-based 3D reconstructions of left atrium and pulmonary veins into electro-anatomical mapping: accuracy of a novel modality in atrial fibrillation ablation. J Cardiovasc Electrophysiol. 2010;21(3):278–83. 46. Ejima K, Shoda M, Yagishita D, Futagawa K, Yashiro B, Sato T, Manaka T, Nakajima T, Ohmori H, Hagiwara N. Image integration of three-dimensional cone-beam computed tomography angiogram into electro-anatomical mapping system to guide catheter ablation of atrial fibrillation. Europace. 2010;12(1):45–51. 47. Dong J, Dickfeld T, Dalal D, Cheema A, Vasamreddy CR, Henrikson CA, Marine JE, Halperin HR, Berger RD, Lima JA, Bluemke DA, Calkins H. Initial experience in the use of integrated electro-anatomic mapping with three-dimensional MR/CT images to guide catheter ablation of atrial fibrillation. J Cardiovasc Electrophysiol. 2006;17(5):459–66. 48. Sonka M, Fitzpatrick JM, editors. Handbook of medical imaging, vol. 2. Bellingham: SPIE Press; 2000. 49. Dong J, Dickfeld T. Image integration in electro-anatomic mapping. Herzschrittmacherther Elektrophysiol. 2007;18(3):122–30. 50. Sra J, Ratnakumar S. Cardiac image registration of the left atrium and pulmonary veins. Heart Rhythm. 2008;5(4):609–17. 51. Solomon SB, Dickfeld T, Calkins H. Real-time cardiac catheter navigation on three-dimensional CT images. J Interv Card Electrophysiol. 2003;8:27–36. 52. Kistler PM, Earley MJ, Harris S, Abrams D, Ellis S, Sporton SC, Schilling RJ. Validation of three-dimensional cardiac image
385
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
integration: use of integrated CT image into electroanatomic mapping system to perform catheter ablation of atrial fibrillation. J Cardiovasc Electrophysiol. 2006;17(4):341–8. Wijnmaalen AP, van der Geest RJ, van Huls van Taxis CF, Siebelink HM, Kroft LJ, Bax JJ, Reiber JH, Schalij MJ, Zeppenfeld K. Head-to-head comparison of contrast-enhanced magnetic resonance imaging and electro-anatomical voltage mapping to assess post-infarct scar characteristics in patients with ventricular tachycardias: real-time image integration and reversed registration. Eur Heart J. 2011;32(1):104–14. Desjardins B, Crawford T, Good E, Oral H, Chugh A, Pelosi F, Morady F, Bogun F. Infarct architecture and characteristics on delayed enhanced magnetic resonance imaging and electroanatomic mapping in patients with post infarction ventricular arrhythmia. Heart Rhythm. 2009;6(5):644–51. Brooks AG, Wilson L, Kuklik P, Stiles MK, John B, Shashidhar, Dimitri H, Lau DH, Roberts-Thomson RL, Wong CX, Young GD, Sanders P. Image integration using NavX fusion: initial experience and validation. Heart Rhythm. 2008;5(4):526–35. Saad EB, Marrouche NF, Saad CP, Ha E, Bash D, White RD, Rhodes J, Prieto L, Martin DO, Saliba WI, Schweikert RA, Natale A. Pulmonary vein stenosis after catheter ablation of atrial fibrillation: emergence of a new clinical syndrome. Ann Intern Med. 2003;138(8):634–8. Barrett CD, Di Biase L, Natale A. How to identify and treat patient with pulmonary vein stenosis post atrial fibrillation ablation. Curr Opin Cardiol. 2009;24(1):42–9. Ghia KK, Chugh A, Good E, Pelosi F, Jongnarangsin K, Bogun F, Morady F, Oral H. A nationwide survey on the prevalence of atrioesophageal fistula after left atrial radiofrequency catheter ablation. J Interv Card Electrophysiol. 2009;24(1):33–6. Ho SY, Sanchez-Quintana D, Cabrera JA, Anderson RH. Anatomy of the left atrium: implications for radiofrequency ablation of atrial fibrillation. J Cardiovasc Electrophysiol. 1999;10(11):1525–33. Kato R, Lickfett L, Meininger G, Dickfeld T, Wu R, Juang G, Angkeow P, LaCorte J, Bluemke D, Berger R, Halperin HR, Calkins H. Pulmonary vein anatomy in patients undergoing catheter ablation of atrial fibrillation: lessons learned by use of magnetic resonance imaging. Circulation. 2003;107(15):2004–10. Wongcharoen W, Tsao HM, Wu MH, Tai CT, Chang SL, Lin YJ, Lo LW, Chen YJ, Sheu MH, Chang CY, Chen SA. Morphologic characteristics of the left atrial appendage, roof, and septum: implications for the ablation of atrial fibrillation. J Cardiovasc Electrophysiol. 2006;17(9):951–6. Pratola C, Baldo E, Artale P, Marcantoni L, Toselli T, Percoco G, Sassone B, Ferrari R. Different image integration modalities to guide AF ablation: impact on procedural and fluoroscopy times. Pacing Clin Electrophysiol. 2011;34(4):422–30. Wagner M, Butler C, Rief M, Beling M, Durmus T, Huppertz A, Voigt A, Baumann G, Hamm B, Lembcke A, Vogtmann T. Comparison of non-gated vs. electrocardiogram-gated 64-detectorrow computed tomography for integrated electro-anatomic mapping in patients undergoing pulmonary vein isolation. Europace. 2010;12(8):1090–7. Tops LF, Schalij MJ, Bax JJ. Imaging and atrial fibrillation: the role of multimodality imaging in patient evaluation and management of atrial fibrillation. Eur Heart J. 2010;31(5):542–51. Singh SM, Heist EK, Donaldson DM, Collins RM, Chevalier J, Mela T, Ruskin JN, Mansour MC. Image integration using intracardiac ultrasound to guide catheter ablation of atrial fibrillation. Heart Rhythm. 2008;5(11):1548–55. Heist EK, Chevalier J, Holmvang G, Singh JP, Ellinor PT, Milan DJ, D’Avila A, Mela T, Ruskin JN, Mansour M. Factors affecting error in integration of electro-anatomic mapping with CT and MR imaging during catheter ablation of atrial fibrillation. J Interv Card Electrophysiol. 2006;17(1):21–7.
386 67. Malchano ZJ, Neuzil P, Cury RC, Holmvang G, Weichet J, Schmidt EJ, Ruskin JN, Reddy VY. Integration of cardiac CT/MR imaging with three-dimensional electro-anatomical mapping to guide catheter manipulation in the left atrium: implications for catheter ablation of atrial fibrillation. J Cardiovasc Electrophysiol. 2006;17(11):1221–9. 68. Tops LF, Bax JJ, Zeppenfeld K, Jongbloed MR, Lamb HJ, van der Wall EE, Schalij MJ. Fusion of multislice computed tomography imaging with three-dimensional electro-anatomic mapping to guide radiofrequency catheter ablation procedures. Heart Rhythm. 2005;2(10):1076–81. 69. Fahmy TS, Mlcochova H, Wazni OM, Patel D, Cihak R, Kanj M, Beheiry S, Burkhardt JD, Dresing T, Hao S, Tchou P, Kautzner J, Schweikert RA, Arruda M, Saliba W, Natale A. Intracardiac echo-guided image integration: optimizing strategies for registration. J Cardiovasc Electrophysiol. 2007;18(3):276–82. 70. Tops LF, Schalij MJ, den Uijl DW, Abraham TP, Calkins H, Bax JJ. Image integration in catheter ablation of atrial fibrillation. Europace. 2008;10(3):iii48–56. 71. Tian J, Jeudy J, Smith MF, Jimenez A, Yin X, Bruce PA, Lei P, Turgeman A, Abbo A, Shekhar R, Saba M, Shorofsky S, Dickfeld T. Three-dimensional contrast-enhanced multidetector CT for anatomic, dynamic, and perfusion characterization of abnormal myocardium to guide ventricular tachycardia ablations. Circ Arrhythm Electrophysiol. 2010;3(5):496–504. 72. Bogun FM, Desjardins B, Good E, Gupta S, Crawford T, Oral H, Ebinger M, Pelosi F, Chugh A, Jongnarangsin K, Morady F. Delayed-enhanced magnetic resonance imaging in nonischemic cardiomyopathy: utility for identifying the ventricular arrhythmia substrate. J Am Coll Cardiol. 2009;53:1138–45. 73. Badger TJ, Daccarett M, Akoum NW, Adjei-Poku YA, Burgon NS, Haslam TS, Kalvaitis S, Kuppahally S, Vergara G, McMullen L, Anderson PA, Kholmovski E, MacLeod RS, Marrouche NF. Evaluation of left atrial lesions after initial and repeat atrial fibrillation ablation: lessons learned from delayed-enhancement MRI in repeat ablation procedures. Circ Arrhythm Electrophysiol. 2010; 3(3):249–59. 74. Dong J, Calkins H, Solomon SB, Lai S, Dalal D, Lardo AC, Brem E, Preiss A, Berger RD, Halperin H, Dickfeld T. Integrated electro-anatomic mapping with three-dimensional computed tomographic images for real-time guided ablations. Circulation. 2006;113(2):186–94. 75. Kim RJ, Fieno DS, Parrish TB, Harris K, Chen EL, Simonetti O, Bundy J, Finn JP, Klocke FJ, Judd RM. Relationship of MRI delayed contrast enhancement to irreversible injury, infarct age, and contractile function. Circulation. 1999;100:1992–2002. 76. Ashikaga H, Sasano T, Dong J, Zviman MM, Evers R, Hopenfeld B, Castro V, Helm RH, Dickfeld T, Nazarian S, Donahue JK, Berger RD, Calkins H, Abraham MR, Marban E, Lardo AC, McVeigh ER, Halperin HR. Magnetic resonance-based anatomical analysis of scar-related ventricular tachycardia: implications for catheter ablation. Circ Res. 2007;101:939–47. 77. Codreanu A, Odille F, Aliot E, Marie PY, Magnin-Poull I, Andronache M, Mandry D, Djaballah W, Régent D, Felblinger J, de Chillou C. Electroanatomic characterization of post-infarct scars comparison with 3-dimensional myocardial scar reconstruction based on magnetic resonance imaging. J Am Coll Cardiol. 2008;52(10):839–42. 78. Tops LF, de Groot NM, Bax JJ, Schalij MJ. Fusion of electroanatomical activation maps and multislice computed tomography to guide ablation of a focal atrial tachycardia in a fontan patient. J Cardiovasc Electrophysiol. 2006;17(4):431–4.
A.J. Restrepo and T.M. Dickfeld 79. Callans DJ. Catheter ablation of idiopathic ventricular tachycardia arising from the aortic root. J Cardiovasc Electrophysiol. 2009; 20(8):969–72. 80. Orlov MV, Hoffmeister P, Chaudhry GM, Almasry I, Gijsbers GH, Swack T, Haffajee C. Three-dimensional rotational angiography of the left atrium and esophagus—a virtual computed tomography scan in the electrophysiology lab? Heart Rhythm. 2007;4:37–43. 81. Thiagalingam A, Manzke R, D’Avila A, et al. Intraprocedural volume imaging of the left atrium and pulmonary veins with rotational X-ray angiography: implications for catheter ablation of atrial fibrillation. J Cardiovasc Electrophysiol. 2008;19:293–300. 82. Orlov MV, Ansari MM, Akrivakis ST, Jadidi A, Nijhof N, Natan SR, Wylie JV, Hicks A, Amstrong J, Jaïs P. First experience with rotational angiography of the right ventricle to guide ventricular tachycardia ablation. Heart Rhythm. 2011;8:207–11. 83. Lardo AC, McVeigh ER, Jumrussirikul P, Berger RD, Calkins H, Lima J, Halperin HR. Visualization and temporal/spatial characterization of cardiac radiofrequency ablation lesions using magnetic resonance imaging. Circulation. 2000;102(6):698–705. 84. Dickfeld T, Kato R, Zviman M, Nazarian S, Dong J, Ashikaga H, Lardo AC, Berger RD, Calkins H, Halperin H. Characterization of acute and subacute radiofrequency ablation lesions with non enhanced magnetic resonance imaging. Heart Rhythm. 2007;4(2): 208–14. 85. Kolandaivelu A, Lardo AC, Halperin HR. Cardiovascular magnetic resonance guided electrophysiology studies. J Cardiovasc Magn Reson. 2009;11:21. 86. Hoffmann BA, Koops A, Rostock T, Müllerleile K, Steven D, Karst R, Steinke MU, Drewitz I, Lund G, Koops S, Adam G, Willems S. Interactive real-time mapping and catheter ablation of the cavotricuspid isthmus guided by magnetic resonance imaging in a porcine model. Eur Heart J. 2010;31(4):450–6. 87. Nordbeck P, Bauer WR, Fidler F, Warmuth M, Hiller KH, Nahrendorf M, Maxfield M, Wurtz S, Geistert W, Broscheit J, Jakob PM, Ritter O. Feasibility of real-time MRI with a novel carbon catheter for interventional electrophysiology. Circ Arrhythm Electrophysiol. 2009;2(3):258–67. 88. Kolandaivelu A, Zviman MM, Castro V, Lardo AC, Berger RD, Halperin HR. Noninvasive assessment of tissue heating during cardiac radiofrequency ablation using MRI thermography. Circ Arrhythm Electrophysiol. 2010;3(5):521–9. 89. Vergara GR, Marrouche NF. Tailored management of atrial fibrillation using a LGE-MRI based model: from the clinic to the electrophysiology laboratory. J Cardiovasc Electrophysiol. 2011;22(4): 481–7. 90. Akoum N, Daccarett M, McGann C, Segerson N, Vergara G, Kuppahally S, Badger T, Burgon N, Haslam T, Kholmovski E, Macleod R, Marrouche N. Atrial fibrosis helps select the appropriate patient and strategy in catheter ablation of atrial fibrillation: a DE-MRI guided approach. J Cardiovasc Electrophysiol. 2011;22(1): 16–22. 91. Mahnkopf C, Badger TJ, Burgon NS, Daccarett M, Haslam TS, Badger CT, McGann CJ, Akoum N, Kholmovski E, Macleod RS, Marrouche NF. Evaluation of the left atrial substrate in patients with lone atrial fibrillation using delayed-enhanced MRI: implications for disease progression and response to catheter ablation. Heart Rhythm. 2010;7(10):1475–81. 92. Taclas JE, Nezafat R, Wylie JV, Josephson ME, Hsing J, Manning WJ, Peters DC. Relationship between intended sites of RF ablation and post-procedural scar in AF patients, using late gadolinium enhancement cardiovascular magnetic resonance. Heart Rhythm. 2010;7(4):489–96.
AVNRT Ablation: Significance of Anatomic Findings and Nodal Physiology
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Félix Ayala-Paredes, Jean-Francois Roux, and Mariano Badra Verdu
Abstract
The AV node is a fascinating region, with particular and complex anatomy and physiology. It well illustrates the evolution of the rhythm disorders and their treatments; it was the first target when invasive electrophysiology started; from His recordings to DC ablation and from selective radiofrequency “slow pathway” modification to cryoablation, we have followed a long road of learning while burning; as our knowledge broadens, we can now very precisely target this region to invasive treatments. This chapter reviews the literature and discusses an approach regarding anatomic findings and physiology and its relationship to AVNRT ablation. Keywords
AV node • AVNRT • Slow pathway ablation
Introduction
General Concepts
In the previous chapters, the anatomy and the relationship between the right atrium and its involvement in atrioventricular nodal reentrant tachycardia (AVNRT) were discussed extensively. However, even today, ablation of an AVNRT is a poorly exact science, with – in most of cases – a “burn and see” approach, either anatomic or signal guided, aiming to modify or eliminate the slow pathway, in order to prevent the recurrence of the arrhythmia, meaning that ablation starts as far as possible from the His and progresses closer and closer expecting to have the arrhythmia non-inducible or to be too close to be safe.
The AV node is a complex structure, where in normal AV nodal physiology, each electrical impulse coming from the sinus node is conducted with decremental properties (as it is necessary to allow the blood – traversing the valves much slower than electrical signals – fill in the ventricles), using the anterior (or superior) aspect of the AV node, the so-called fast pathway (FP) which translates in a surface normal PR interval between 120 and 200 ms, whereas during typical AVNRT another arm is necessary to complete the circuit, the so-called slow pathway (SP), located in the posterior (inferior) aspect of the AV node, near the ostium of the coronary sinus. The normal sequence is then inverted; downward conduction proceeds by the SP (long PR) as the FP is usually blocked by an atrial premature beat (more premature than the FP’s effective refractory period (ERP)), and if the SP conducts slowly enough to allow the recovery of the FP, the impulse can at the same continue to the ventricle and return to the atrium by the recovered FP to start the reentry (Fig. 30.1a, b). In order to prevent the AVNRT initiation, it is necessary to eliminate or at least modify one of the reentry arms, usually the SP.
F. Ayala-Paredes, MD, PhD (*) • J.-F. Roux, MD M.B. Verdu, MD Cardiology Service, CHUS, Sherbrooke University Hospitals, Sherbrooke, QC, Canada e-mail:
[email protected] A.S. Kibos et al. (eds.), Cardiac Arrhythmias, DOI 10.1007/978-1-4471-5316-0_30, © Springer-Verlag London 2014
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Following the previous concepts, the FP is associated with the His recording, and usually a catheter placed in that region is used as a marker to prevent the damage of the His
bundle. However, the first retrograde activation during typical AVNRT does not occur at the His level but a halfway between the His and the roof of the coronary sinus: in the right anterior oblique (RAO) view, posterior to the tendon of Todaro (electrical barrier), and in left anterior oblique (LAO) view, more in the left side of the septum. The SP shows rarely a signal as clear as the His signal (which is almost always easy to find), the reason why an anatomic-only approach is very frequently used to ablate the SP. Unlike the FP, the SP region is less well defined and can be targeted for ablation in different locations. The normal AV node conducts with decremental properties, and these properties as a reaction to atrial programmed stimulation were studied by Moe Preston and Burlington in the 1950s. Usually, the answer to earlier and earlier atrial extra stimuli is to prolong further and further the His signal until the impulse blocks in the AV node (AV node ERP); the AH prolongation is progressive, adding 10–30 ms to the previous AH values at each 10 ms decrease in the extra stimulus. Using canine models, they demonstrated in some cases the so-called dual nodal physiology which consists of an abrupt AH prolongation (more than 50 ms), also named as a “jump.” This “jump” reflects the FP ERP, and if the impulse is still conducted downward, the only way to arrive to the His is by the SP, named “slow” as it takes at least 50 ms more than the previous impulse to arrive to the His [1]. At normal heart rates, conduction occurs via the FP, situated just posterior and inferior to where the His bundle lies, so the normal PR lasts between 120 and 200 ms. But when a train of fixed impulses is delivered in the atrium (S1, to homogenize refractory periods), followed by 10 ms shorter extra stimuli (S2), and suddenly the His appears delayed at least 50 ms further than the previous AH, it means that the impluse has blocked at the anterior His (FP) level, and it has taken another pathway (SP) to arrive to the ventricle (Fig. 30.2a, b). This type of dual physiology is common in as much as half the population. Two other conditions are necessary to start an AVNRT: first, refractory periods of both pathways should be different enough to allow reentry (at the AV node level, refractory periods vary also a lot depending on autonomic influences); second, a premature beat is needed, as premature as able to block in the FP to start reentry using downward conduction over the SP and coming back to the atrium by the recovered FP, which, as it conducts faster than the SP, makes the upward conduction so fast that ventricles and atria are activated almost at the same time (this first beat
Fig. 30.2 (a) Atrial programmed stimulation, S1 at 500 ms and an extra stimulus (S2) at 310 ms, with an AH interval (in red) obtained of 170 ms: conduction by the “fast pathway”. (b) A further earlier extra stimulus at 300 ms (10 ms shorter than panel a) prolongs the AH from 170 to 260 ms: it depicts the “jump” where the FP has reached its ERP and the
impulse is conducted downward by the SP. (c) The premature beat (S2) provokes not only the “jump” (sudden increase of AH interval – ERP of the FP – downward conduction by the SP), but almost at the same time the ventricle is activated (usually not more than 80 ms later); the same impulse is retro-conducted by the recovered FP, origin of the “echo”
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Fig. 30.1 (a) Schema depicting both arms during the reentry and almost simultaneous activation of the atria and ventricles. (b) Schema depicting the reentry with the anatomic boundaries: the “downward” SP activation proceeds first in the left aspect of the circuit (as the tendon of Todaro prevents the reentry back to the triangle of Koch but activates the right atrium) with leftward direction, activating the left atrium and then enters at different levels into the floor of the coronary sinus (CS) and heads back to the ostium of the CS – first 180° turn, responsible of the slowness of the pathway. When the impulsion arrives to the ostium of the CS, it makes another 180° turn and heads now superiorly “upward” much faster (FP) to arrive then somewhere lower than the His recording (and always in the left aspect of the septum) conducting via the His to the ventricles and downward again to the right and left atria at the same time, and the circuit starts over with new reentry into the floor of the CS
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of reentry, when a retrograde P wave is visualized very close to the QRS, is called echo beat (Fig. 30.2c)); after this first upward beat, the impulse arrives at the SP going downward again at the posterior (inferior) aspect of the AV node; the reentry is established and the AVNRT starts (Fig. 30.3). Anatomic and physiologic relationships mentioned above are related to the typical slow-fast AVNRT (FP ERP reached, downward conduction using the SP and upward reentry using the already recovered FP), which accounts for 90 % of all AVNRTs encountered in clinical practice; but in some cases this circuit could be inverted: “fast-slow” AVNRT, with the first upward activation arriving at different levels in the coronary sinus before reaching back the atrium, and also some even more rare forms with similar ERPs between both arms (type “slow-slow”) and very similar times turning up and down. The dissociation between a “fast” pathway with a longer refractory period and a “slow” pathway with a shorter refractory period is necessary to start reentry; a dual pathway physiology is required for the initiation and maintenance of
AV nodal reentry. In Figs. 30.4 and 30.5, we depicted the initiation of the AVNRT either in a surface rhythm strip or in the EP lab with different mechanisms. In some patients the induction is only found with a progressive increment of AV conduction times without a clear “jump” (either during progressively shorter S1 train – to test the Wenckebach point – or with mini “jumps” not reaching the 50 ms cutoff); but even in these cases, the ablation in the “slow” pathway region eliminates the AVNRT, confirming that sometimes smaller differences in refractory periods of both arms are enough to sustain the arrhythmia. Another manifestation of a dual physiology is the presence of two different PR intervals during sinus rhythm in the same patient (sometimes visible following termination of an AVNRT with drugs affecting the AV node). Even more difficult to see is the presence of two QRS for only one P wave or a “double ventricular response” (one A followed by two AH intervals and H1-V1 and H2-V2), which proves the orthodromic conduction at the same time by the FP and the SP (Fig. 30.5).
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reentry using the FP), and the AVNRT starts. The left atrium is activated passively as we see the proximal to distal signals in the CS
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which conducts to the following QRS with a long PR (300 ms) – conduction by the SP – and after that long PR, the QRS shows a “notch” on its terminal part, a retrograde P wave coming up by the FP, and the AVNRT starts
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Fig. 30.5 At end of an S1 train at 400 ms with an S2 at 300 ms, there is a first A-H-V sequence followed by a second HV coming from the same S2; almost simultaneously with the second HV, there is a retrograde A wave (turning up by the FP) and the AVNRT starts
The same dual physiology could be found with a ventricular programmed stimulation and with the same criteria to define a retrograde “jump.” In another chapter, the relationship between the atrial tissue and the nodal tissue to sustain the AVNRT is discussed, but even with the controversy still debated, sometimes we can observe in clinical practice a sustained AVNRT with 2:1 relationship either to the ventricles or to the atrium, which may indicate that in order to sustain the AVNRT, only the AV node is necessary or that a minimal tissue other than the AV node is needed with intermittent block to the rest of upper or lower chambers. In most of cases, the first atrial activity is detected after the FP upward conduction near the His catheter recording (concentric activation), but sometimes the first retrograde A wave appears in the coronary sinus recordings, complicating the diagnosis.
Clinical Presentation and Variants of the AVNRT The clinical presentation depends on heart rate, but almost all patients mention palpitations as the first symptom. The frequency and duration of episodes are highly variable. In most of cases either palpitations are coming closer and closer (so the
patient seeks help) or – with aging – palpitations are poorly tolerated and other hypoperfusion symptoms appear (dizziness, dyspnea, and sometimes angina). A detailed anamnesis would bring sudden onset and also sudden termination of palpitations, and due to the atria and ventricles contracting at the same time during AVNRT, in most of cases palpitations are felt more in the neck (and “cannon” A waves can be seen, as atria contract with closed AV valves). The faster the heart rates, the higher the chances to have a lower cardiac output status and cerebral hypoperfusion leading sometimes to syncope. In some cases and especially when palpitations are short lived to be confirmed with an EKG, recurrent palpitations could be taken as panic attacks – in young females – and an arrhythmia should always be in the differential diagnosis. A troponin elevation is sometimes seen in AVNRT patients, not related to the presence of underlying coronary artery disease, but just to the heart rate of the arrhythmia; heart rates higher than 190 bpm during AVNRT are highly associated with troponin elevation, but no other investigation is needed in almost all patients [2]. Palpitations felt at the neck (due to simultaneous AV mechanical contraction), first episode after 30 years old, and being a woman are variables more related with the presence of an AVNRT when palpitations are encountered in clinical practice (in contrast to another supraventricular arrhythmias as AVRT) [3].
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Fig. 30.6 EKG of a typical AVNRT: at the end of the QRS (V1 and V2), a notch or pseudo R is seen, corresponding to the retrograde P wave going up by the FP, inscribed simultaneous to the QRS (short RP), and responsible for the next QRS (using the SP or long PR)
“Slow-Fast” or Typical AVNRT This is the most commonly encountered AVNRT (90 %) with the SP conducting downward and the FP turning upward to complete the circuit. Electrophysiological manifestation is a tachycardia with a long AH interval (long PR) and a short HA (short RP) with a VA interval (or RP) in most of the cases shorter than 70 ms, so at the same time the QRS is seen in surface EKG, the FP produces a retrograde P wave, sometimes partially hidden in the terminal segment of the QRS, and even – if left and right branches conduct slow enough – a P wave seen preceding the QRS or completely hidden into the QRS, with negative or very short VA intervals. Retrograde P waves may be seen at the end of lead II or V1, usually less than 80 ms from the peak of the QRS, seen as a notching or R’ (in other words with RP < PR) (Fig. 30.6).
Atypical Variants: “Fast-Slow” and “Slow-Slow” The “fast-slow” form uses the circuit in the opposite way: with downward conduction by the FP and retrograde conduction by one of the SP; the retrograde P wave is inscribed far from the QRS (short PR and long RP). Differential diagnosis is an AVRT using an accessory pathway, and an atrial tachycardia. In most of cases this type of AVNRT is obtained
with ventricular stimulation or PVCs, while the typical form starts after programmed atrial stimulation or PACs. The less frequent variants of “slow-slow” AVNRT will show similar AH and HA intervals, with intermediate values between typical and atypical AVNRT. Most of patients will show only one form of AVNRT, but some of these atypical variants could be seen in the same patient, especially during the EP study.
Treatment of the AVNRT Acute termination is obtained when we can slow enough the conduction velocity of one of the reentry arms (SP or FP). To stop the AVNRT, we can use non-pharmacological maneuvers, varying autonomic tone, or drugs that act at the AV node level. Valsalva maneuver or carotid sinus massage is effective in at least one third of patients [4, 5]. If these simple interventions do not stop the arrhythmia, any AV-blocking agent could be used: adenosine starting with 6 mg and going up in increasing dose boluses, verapamil 10 mg, or diltiazem 5 to 25 mg all in IV bolus [6–9]. The only curative treatment is AVNRT ablation, targeting usually the SP, with over 95 % acute success rate, less than 10 % recurrence rate, and a low complication rate – complete AV block – ranging from 0 to 1 % depending on the type of
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I AVF V1 V6 HRA HRA d HIS p HIS m 86 msec
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Fig. 30.7 Ventricular fixed stimulation, with a vertical line showing the first atrial activation proceeding through the His catheter recording and in the CS catheter proceeding from proximal (CS 9, 10) to distal (CS 1)
energy used for ablation. Nowadays, this easy technique has evolved in very few years from surgical ablation [10–12] to DC shocks destroying SP and FP at the same time [13–17] and to radiofrequency ablation [18], selective SP ablation [19–22], and cryoablation [23].
EP Study in Patients with AVNRT Even with very low complication rate, a good preparation includes discussion of all the options available and at least 2 or 3 days of all AV-blocking agent discontinuation before the procedure (or 5 half-lives whichever longer). Surface EKG helps to decide how many catheters are needed, as sometimes the diagnosis is so clear that less information is necessary to obtain at the EP study. In the most complete setting, four diagnostic catheters are used: one for the right high atrium, one for the His, one for the ventricle, and one for the coronary sinus; all catheters can be inserted using both femoral accesses, but if the coronary sinus is hard to find, a superior (jugular, subclavian, or brachial) access could be used. Usually a CS catheter inserted from below allows mapping the roof of the CS, while a catheter inserted from above is useful to map the floor of the CS.
Mild sedation is widely used, but for AVNRT the rule is as less as possible, as too much would render the arrhythmia non-inducible.
Induction Once the catheters are placed and basal measurements are done, decremental atrial and then ventricular stimulation is initiated (to find the AV and VA Wenckebach point). This simple maneuver sometimes shows a dual pathway physiology when the AH (PR) prolongs enough to see the P waves coming from the S1 train inscribed before the previous QRS; this phenomenon tends to occur just prior to find the Wenckebach point, and in some cases the arrhythmia starts only in this way. The same protocol but with ventricular stimulation would exclude an accessory pathway if a VA dissociation is observed or at least the presence of a left-sided accessory pathway when the retro conduction is concentric (first atrial activity seen in the His catheter by opposition to the distal coronary sinus recordings) (Fig. 30.7). Accessory pathways seldom have decremental properties, so decremental retrograde conduction (with P waves seen later and later) makes an accessory pathway less likely in the differential diagnosis.
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Atrial (or ventricular) programmed stimulation (fixed S1 and progressive 10 ms decrement in S2) is highly effective to prove the dual AV node physiology, when a “jump” of at least 50 ms is found. Conventional S1 trains are used at 600 and 400 ms, but different options could be used, slower if the Wenckebach point is found before 400 ms or faster if isoproterenol is utilized (Figs. 30.2a–c and 30.3). If the arrhythmia has not been found yet, options include: • Revert sedation. • Increase the number of extra stimuli (S1-S2-S3, etc.) if the atrial refractory period was reached before the AV nodal refractory period. • Infuse isoproterenol (to increase at least 10 % in the heart rate) and redo all the atrial and ventricular programmed stimulation protocol. • Stop isoproterenol and continue induction maneuvers during the “washout” of the drug. • Change stimulation site (coronary sinus, low atrium). • Use short-lived beta-blockers (to vary refractory periods and conduction properties in one arm more than in the other). • If a premenopausal female, try to repeat the EP study 2 weeks later in another phase of the hormonal cycle. Ideally the AVNRT should be inducible in a reproducible manner, as to abolish an easily induced arrhythmia is the best success target.
Differential Diagnosis Very rarely an arrhythmia mechanism is confirmed only with one maneuver; in most of cases different pieces of information add to a puzzle to confirm or exclude a putative mechanism; even when clear, it is important not to rely on only one piece of evidence. The dual AV nodal physiology and a “jump” seen during programmed stimulation are highly related to the AVNRT, but sometimes, for example, an accessory pathway is also needed to conduct upward and have the arrhythmia sustained. The diagnosis of AVNRT is the sum of exclusion of other possible mechanisms of arrhythmia There are simple maneuvers to exclude other mechanisms [24]: • If during arrhythmia there is no one-to-one relationship between the atria and ventricles (more P waves than QRS or vice versa), an accessory pathway (AVRT) is excluded, as all parts including the atria, AV node, ventricles, and accessory pathway are needed to sustain the arrhythmia. • Typical AVNRT conducts with a concentric fashion, with a short HA (VA less than 70 ms), while other forms have a VA superior to 100 ms. • If we can dissociate (without entrainment) the arrhythmia with brief faster atrial or ventricular trains, we can also eliminate an accessory pathway as a mechanism.
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• Ventricular stimulation and a short train faster than the arrhythmia with entrainment would help at the end of the train as two different patterns could be seen: AAV or AV type, the former in atrial tachycardia cases and the latter in reentrant arrhythmias (AVNRT and AVRT). • Finally if during arrhythmia we apply ventricular extra stimuli during refractory His, with advancement of the A signal, it proves that an accessory pathway is present as there is no way to arrive to the atrium while the His is refractory, and more than that, if the arrhythmia stops without an A, it proves that the accessory pathway participates in the arrhythmia. Once other mechanisms, have been excluded, ablation of AVNRT can be started. When a limited number of catheters are used, the position of catheters during the arrhythmia should be moved to confirm that the activation sequence is always septal first (e.g., if only a His and a coronary sinus recording are used, we can miss a right atrial tachycardia if the coronary sinus catheter is not moved to the right atrium during the arrhythmia, to find finally that the right atrium was activated before the His catheter).
Radio Frequency Ablation of the AVNRT In RAO, the ablation catheter is advanced into the ventricle to have more V than A, near the coronary ostium region. Even if the His catheter showing the FP region (that we should avoid), it is important, before starting RF, to carefully look for His signals in the ablation catheter, to prevent FP damage and AV block. As the RF catheter tends to move with heartbeats and respiration, RF application starts as far as possible from the His (FP) region as heat tends to travel wider than the catheter contact (Fig. 30.8a, b). Once the area is targeted, a small clockwise torque to put it as close as possible to the septal area (confirmed with LAO), and ablation is started as inferior as possible in the radiologic view (and posterior or caudal/dorsal in the anatomic plane), looking for a big ventricular EGM and a small (and if possible fractionated) atrial EGM (if the atrial signal is too big, we could have entered in the coronary sinus); again LAO confirms this impression. We can then start ablation with 40–50 W and 15–20 s in each application waiting for a junctional rhythm to appear, which suggests irritation of the SP. If so ablation can continue for another 30–60 s; if not, advance or retract by small movements the catheter, looking for better EGMs, and if there is no junctional rhythm, start moving upward, toward the His catheter (FP), until we consider we are too close (usually less than 1 cm is too close) to the His to safely apply RF. Once a junctional rhythm is obtained, we can follow in that region until complete abolition of that automatic rhythm, usually 1–2 min;
396 Fig. 30.8 (a) Right anterior oblique (RAO) projection at 30°. The most superior catheter is the CS catheter, the middle one the His catheter, and the lower curved one the RF ablation catheter in the successful site. (b) Left anterior oblique (LAO) incidence at 45°. Simultaneous image (biplane) as the previous image; the catheter going to the right is the CS catheter, superior one the His catheter, and inferior catheter the RF ablation catheter at the successful SP ablation site
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in each position and before each application, it is important to confirm that the catheter has not displaced to the coronary sinus (Fig. 30.9). With time less and less fluoroscopy is needed, but usually with the first cases, we want to control the stability of the catheter during continuous fluoroscopy. It is even more important to confirm that during applications there is a stable AV relationship (one P followed by one QRS); any single P or QRS should prompt RF immediate cessation. It can be useful (once the junctional rhythm has appeared) to start pacing the atrium, to monitor 1:1 conduction over the ventricles, especially if approaching the His (FP) region. Once a lesion with good junctional rhythm is obtained, we test the result trying to restart the arrhythmia. Once the arrhythmia is no longer inducible, we stop the procedure; minimal end point is to prevent the arrhythmia to start; a better result is obtained if the SP physiology (“jump”) persist, but with no or single “echoes”; the best result is achieved if
the SP is completely abolished and no more “jump” is found. Focal lesions are preferred, but with time and experience, minimal movements are allowed without stopping RF in order to find the junctional rhythm. Once an effective lesion is achieved, it is used to (without any evidence found) wait for a variable time frame (30–60 min) in order to see if the SP “recovers.” Some patients have a giant coronary sinus ostium, with the catheter displacing always into the coronary sinus; this characteristic, as in older patients the “shrinking” of the AV node (His closer to the coronary sinus ostium), diminishes the area available for ablation, and in these cases some applications can be done in the first 2 cm of the coronary sinus (with lower-energy 20–30 W settings) in order to find the SP region. Unfortunately how close to apply RF near the His is not an exact science either; it depends on the age at the time of ablation, severity of symptoms, and energy used, and all these could be summarized as that it comes with experience. In order
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Fig. 30.9 Three-catheter study, simultaneous RAO (to the right) and LAO (to the left); the most superior catheter is CS catheter, in RAO, the most to the right catheter, is the catheter placed in the apex (in LAO it
seems coming at us), and the ablation catheter is placed in both cases in the middle of both
to prevent a complete AV block, we should always try first to target the other putative slow pathways, located always far into the coronary sinus, instead of approaching further and further close to the compact AV node and the His. Very rarely, a complete AV block is obtained with RF when we ablate into or very near the posterior aspect of coronary sinus ostium (far from the His region and with no His potentials); the mechanism invoked is the mechanical damage of the AV node artery, with an ischemic AV block, as wherever the origin of this artery, there is no dual irrigation of the AV node and if this terminal artery is occluded, an AV block could follow. The other possibility is the downward displacement of the compact AV node, as it occurs in aging patients. Following some Spanish experience with the NaV-X system [25], we did a small study using the Biosense Carto-3 in 39 patients where we tagged all His potentials found in the virtual anatomy. We found that in all patients, His signals were recorded in more than a single area, with a mean His area of 1.44 cm2 (±0.95 cm2, range 0.9–4.2 cm2), and mean distances from the closer effective RF ablation lesion to caudal and cephalic His recordings were 15.9 and 25.5 mm (range for caudal to RF of 4.7–31.5 mm and for cephalic to RF 10.9–39.9 mm) (Fig. 30.10); we had one complete intraprocedural AV block; the closest RF lesion was delivered at
6 mm from the most caudal His but at 26.9 mm from the upper His recording (the usual position of a single quadripolar catheter). This case depicted sometimes how close FP can be found to the places judged “safe” for fluoroscopy. No transient or complete AV block was found in lesions applied at least 10 mm far (caudal) from the lowest His recording, so we can say that 10 mm far from the lowest His recorded is probably a safe window to apply RF but that lower or caudal His is impossible to be marked in the fluoroscopy system. So one possible solution could be to start with the ablation catheter placed side by side from the His catheter position and then start to carefully map for His potentials while bending down to the SP region near the coronary sinus and to keep in mind the lowest His recorded, not to apply in the 10 mm vicinity. We should keep in mind, that usually going upward (approaching the His catheter) even if it is the most tempting idea (especially when we obtain good junctional rhythms all the way up – which is easy to understand as there is slow pathway all the way up), once a good junctional rhythm is obtained in a lower position, SP is already eliminated and if there is still AVRNT induced and it uses another SP, then it is rewarding to try to go into the coronary sinus to try to safely ablate the SP responsible of the tachycardia. Yes we can destroy those other SP also burning up in the septum, as
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Fig. 30.10 Left lateral view; in yellow are all His potentials found and tagged in the virtual anatomy; in red are all ablation sites (in pink successful site); note how close one ablation site – with low power – was tempted
near the lowest His found, in this case with transient AV block. However, if a single His catheter were used to monitor the His position (upper His potentials), the lower area were unfairly accepted as safe to apply full RF
they should to close the circuit, to arrive to the compact AV node, but the price to pay is sometimes an AV block; going leftward is time consuming but safe. Finally when a too close position is no longer safe to test RF, we can either try other sources of energy or accept some possible effects of non-successful RF lesions to modify at long term SP physiology. In cases of documented arrhythmia but no induction at the procedure, the SP can be targeted for ablation if no other mechanisms are found, with the same previous considerations.
some of them, the cryo-adhesion (the catheter sticks to the tissue once the cooling starts), allowing smaller lesions, more superficial and with sharper borders. We describe the principal concepts related to cryoablation: • Safer technique does not mean that a complete AV bloc is not possible (actually the first human cases were tested for AV node cryoablation); however, we can apply closer to the FP, as all the surroundings have a higher temperature and the freezing is applied only to the contact surface between the catheter and the tissue. Even more, we can use the cryo-mapping (to test safety at −30 °C), and even a complete AV block at −30° will be reverted if the cryomap is stopped or continued to freeze at −70 to −80° to obtain a permanent lesion. • Each full application for cryo-energy takes between 4 and 5 min, allowing to monitor inducibility during applications; we can also monitor the AH times, as prolongation will preclude AV node damage (Fig. 30.11). • In contrast to RF ablation, a junctional rhythm is rarely or never seen during cryoablation. • As small lesion volume allows to be closer to the His region applications, it also means that more recurrences are possible, as RF will burn a wider area than the catheter area, helped with the movements of the heart.
Cryoablation of the AVNRT If in most cases RF ablation is a safe and successful source of energy, in some patients even the far low risk of 1 % to damage permanently the AV conduction is too high, or once RF is attempted, the arrhythmia is still inducible, and close to the FP applications are judged too risky; cryoablation can be used. All the anatomic and physiologic considerations are the same at the time to search for the right spot to find the SP; however, we can lower to 0 % the risk of inadvertent complete AV node damage. This is due to multiple factors, to cite
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Fig. 30.11 Start of cryoablation, showing the typical “noise” associated in the map catheter tracings. AH is monitored, in this case 73 ms
There are no available guidelines to decide when to mandatorily use cryoablation, but depending on resources, it should be used at least when an RF procedure was complicated by a transient AV block and the arrhythmia is still inducible or, a more flexible indication, when 1 % of risk is deemed too high, as newer cryo-catheters showed a similar efficacy profile, with a lesser risk [26]. Conclusion
Anatomy and physiology are needed when an AVNRT is targeted to ablation. Usually both fast and slow pathways are well differentiated to let the RF catheter safely eliminate the slow pathway, but the AV node and its surroundings are a complex structure to navigate, and a good sense of this 3-D space and a good dose of respect are needed to cure AVNRT.
References 1. Moe GK, Preston JB, Burlington H. Physiologic evidence for dual A-V transmission system. Circ Res. 1956;4:357–75. 2. Ben Yedder N, Roux JF, Paredes FA. Troponin elevation in supraventricular tachycardia: primary dependence on heart rate. Can J Cardiol. 2011;27:105–9.
3. González-Torrecilla E, Almendral J, Arenal A, Atienza F, Altea LF, del Castillo S, Fernández-Avilés F. Combined evaluation of bedside clinical variables and the electrocardiogram for the differential diagnosis of paroxysmal atrioventricular reciprocating tachycardias in patients without pre-excitation. J Am Coll Cardiol. 2009;53:2353–8. 4. Lim SH, Anantharaman V, Teo WS, Goh PP, Tan AT. Comparison of treatment of supraventricular tachycardia by Valsalva maneuver and carotid sinus massage. Ann Emerg Med. 1998;31:30–5. 5. Walker S, Cutting P. Impact of a modified Valsalva manoeuvre in the termination of paroxysmal supraventricular tachycardia. Emerg Med J. 2010;27:287–91. 6. DiMarco JP, Sellers TD, Berne RM, West GA, Belardinelli L. Adenosine: electrophysiologic effects and therapeutic use for terminating paroxysmal supraventricular tachycardia. Circulation. 1983;68:1254–63. 7. Wu D, Denes P, Dhingra R, Khan A, Rosen KM. The effects of propranolol on induction of AV nodal reentrant paroxysmal tachycardia. Circulation. 1974;50:665–77. 8. Reddy CP, McAllister Jr RF. Effect of verapamil on retrograde conduction in atrioventricular nodal reentrant tachycardia. Am J Cardiol. 1984;54:535–43. 9. Shenasa M, Denker S, Mahmud R, Lehmann MH, Murthy VS, Akhtar M. Effect of verapamil on retrograde atrioventricular nodal conduction in the human heart. J Am Coll Cardiol. 1983;2:545–50. 10. Pritchett LC, Anderson RR, Benditt DG, Kasell J, Harrison L, Wallace AG, Sealy WC, Gallagher JJ. Reentry within the atrioventricular node: surgical cure with preservation of atrioventricular conduction. Circulation. 1979;60:440–6. 11. Ross DL, Johnson DC, Denniss AR, Cooper MJ, Richards DA, Uther JB. Curative surgery for atrioventricular junctional (“AV nodal”) reentrant tachycardia. J Am Coll Cardiol. 1985;6:1383–92.
400 12. Cox JL, Holman WL, Cain ME. Cryosurgical treatment of atrioventricular node reentrant tachycardia. Circulation. 1987;76:1329–36. 13. Scheinman M, Morady F, Hess DS, Gonzalez R. Catheter-induced ablation of the atrioventricular junction to control refractory supraventricular arrhythmias. JAMA. 1982;248:851–5. 14. Gallagher JJ, Svenson RH, Kasell JH, et al. Catheter technique for closed-chest ablation of the atrioventricular conduction system: a therapeutic alternative for the treatment of refractory supraventricular tachycardia. N Engl J Med. 1982;306:194–200. 15. Haissaguerre M, Warin JF, Lemetayer P, Saoudi N, Guillem JP, Blanchot P. Closed-chest ablation of retrograde conduction in patients with atrioventricular nodal reentrant tachycardia. N Engl J Med. 1989; 320:426–33. 16. Epstein L, Scheinman M, Langberg J, Chilson D, Goldberg HR, Griffin JC. Percutaneous catheter modification of the atrioventricular node. Circulation. 1989;80:757–68. 17. Goy JJ, Fromer M, Schlaepfer J, et al. Clinical efficacy of radiofrequency current in the treatment of patients with atrioventricular node reentrant tachycardia. J Am Coll Cardiol. 1990;6:418–23. 18. Lee MA, Morady F, Kadish A, Schamp DJ, Chin MC, Scheinman MM, Griffin JC, Lesh MD, Pederson D, Goldberfer J, Calkins H, deBuitleir M, Kou WH, Rosenheck S, Sousa J, Langberg JJ. Catheter modification of the atrioventricular junction with radiofrequency energy for control of atrioventricular nodal reentry tachycardia. Circulation. 1991;83:827–35. 19. Haissaguerre M, Gaita F, Fischer B, Commenges D, Montserrat P, d’Ivernois C, Le Metayer P, Warin JF. Elimination of atrioventricular nodal reentrant tachycardia using discrete slow potentials to guide application of radiofrequency energy. Circulation. 1992;85: 2162–75.
F. Ayala-Paredes et al. 20. Jackman WM, Beckman KJ, McClelland JH, Wang X, Friday KJ, Roman CA, Moulton KP, Twidale N, Hazlitt A, Prior MI, Oren J, Overholt ED, Lazzara R. Treatment of supraventricular tachycardia due to atrioventricular nodal reentry by radiofrequency catheter ablation of slow-pathway conduction. N Engl J Med. 1992;327:313–8. 21. Jazayeri MR, Hempe SL, Sra JS, Hempe SL, Dhala AA, Blanck Z, Deshpande SS, Avitall B, Krum DP, Gilbert CI, Akhtar M. Selective transcatheter ablation of the fast and slow pathways using radiofrequency energy in patients with atrioventricular nodal re-entrant tachycardia. Circulation. 1992;85:1318–28. 22. Akhtar M, Jazayeri MR, Sra J, Blanck Z, Desphande S, Dhala A. Atrioventricular nodal re-entry: clinical, electrophysiological, and therapeutic considerations. Circulation. 1993;88:282–95. 23. Friedman PL, Dubuc M, Green MS, Jackman WM, Keane DT, Marinchak RA, Nazari J, Packer DL, Skanes A, Steiberg JS, Stevenson WG, Tchou PJ, Wilber DJ, Worley SJ. Catheter cryoablation of supraventricular tachycardia: results of the multicenter prospective “frosty” trial. Heart Rhythm. 2004;1:129–38. 24. Knight BP, Ebinger M, Oral H, Kim MH, Sticherling C, Pelosi F, Michaud GF, Strickberger SA, Morady F. Diagnostic value of tachycardia features and pacing maneuvers during paroxysmal supraventricular tachycardia. J Am Coll Cardiol. 2000;36:574–82. 25. Alvarez M, Tercedor L, Almansa I, Ros N, Galdeano RS, Burillo F, Santiago P, Penas R. Safety and feasibility of catheter ablation of atrioventricular nodal re-entrant tachycardia without fluoroscopic guidance. Heart Rhythm. 2009;6(12):1714–20. 26. Rivard L, Dubuc M, Guerra P, Novak P, Roy D, Macle L, Thibault B, Talajic M, Khairy P. Cryoablation outcomes for AV nodal reentrant tachycardia comparing 4-mm versus 6-mm electrode-tip catheters. Heart Rhythm. 2008;5(2):230–4.
Mechanisms of Atrial Fibrillation
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Rishi Arora and Hemantha K. Koduri
Abstract
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. The prevalence of AF is increasing as the median age of the population is on rise. Incidence of AF increases with age, as one in five individuals over age 85 has AF. Several clinical conditions are associated with AF, most importantly ischemic heart disease, diabetes, hypertension, cardiomyopathy, valvular heart disease, and heart failure. AF is a complex disease and its pathogenesis is multifactorial. The relatively recent discovery of the importance of the pulmonary veins (PV) in the origin of triggers and generation of AF has helped us better understand the pathophysiology of AF. The region of the PVs and the adjoining posterior left atrium (PLA) possesses a unique, heterogeneous pattern of myocyte orientation; the abrupt changes in electrical conduction patterns that result in these regions make the atria more susceptible to AF (by setting up substrate for reentry). Another important factor that contributes to atrial arrhythmogenesis is the unique expression of key ion channels in the atrium. Compared to the ventricles, some ion channels, e.g., IKAch and IKur, are predominantly expressed in atrial myocytes; these channels, by contributing to shortening of refractoriness, make the atria more vulnerable to fibrillation. In addition, the PVs and PLA have a unique pattern of ion channel and gap junction expression that makes the atria susceptible to AF. Ca2+ dysregulation has also been noted to play an important role in generation and maintenance of AF, with excitation-contraction coupling being significantly altered in fibrillating myocytes (as compared to normal atrial myocytes). In addition to ion channel, gap junction, and Ca2+ remodeling, structural remodeling – specifically fibrosis – has been implicated in AF initiation and maintenance, especially in the setting of structural heart disease, e.g., heart failure. Key signaling pathways that are thought to create fibrosis in the atrium including TGF-β signaling, oxidative stress, and angiotensin II signaling. The autonomic nervous system is also thought to play an important role in generation of AF, with both the sympathetic and parasympathetic thought to play an important role in AF initiation and maintenance. Recently, Genome-wide association studies have also provided us with new insights into genetic predisposition in AF generation. In this chapter, we have reviewed in detail the role of these pathophysiological mechanisms in the generation and maintenance of AF. Keywords
Atrial fibrillation • Mechanisms of atrial fibrillation
R. Arora, MD (*) • H.K. Koduri, MD Division of Cardiology, Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL, USA e-mail:
[email protected];
[email protected] A.S. Kibos et al. (eds.), Cardiac Arrhythmias, DOI 10.1007/978-1-4471-5316-0_31, © Springer-Verlag London 2014
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Introduction Atrial fibrillation (AF) is the most sustained cardiac arrhythmia in humans. Its incidence increases with age, with up to 20 % of population of the population above the age of 85 having AF [1]. As the population ages, the prevalence of AF is expected to increase two- or threefold in the next two to three decades [2]. AF increases both mortality and morbidity in the effected populations. One in four strokes is caused by AF [3]. Heart failure (HF) and AF frequently coexist in patients, with each condition predisposing towards the other [4]. Indeed, at least one-third of HF patients have concomitant AF [5]. In addition to heart failure, several other clinical conditions like hypertension, diabetes, valvular disease, cardiomyopathy, coronary artery disease, myocarditis, atrial myxomas, hyperthyroidism, and probably sleep apnea are associated with AF. These clinical conditions cause changes in the atria leading to its remodeling. These changes create conditions favorable for AF initiation and maintenance. Pathophysiological processes involved in both the initiation and perpetuation of AF are complex and include peculiarities of pulmonary vein anatomy, aging, neuronal activation, chronic stretch, and unique genetic mutations (to name a few). These processes lead to electrophysiological and histological changes in the atrium that cause “atrial remodeling.”
Electrophysiology of Atria Of the ion channels expressed in cardiomyocytes, some ion channels are present predominantly in the atrial myocytes (as compared to ventricular myocytes), while others have relatively lower expression in the atrium. The peculiarities of ion channel expression in atrial myocytes contribute to the vulnerability of the atria to AF. For example, IKur (the ultrarapid delayed rectifier current) is expressed mostly in the atrial myocytes [6, 7]. It contributes to repolarization during phase 2 of the action potential. Drugs blocking IKur prolonged the atrial effective refractory period (ERP) and decrease stability of AF as observed in goats [8, 9]. Another ion channel that is highly expressed in the atria is Ikach, which causes vagal-activated inward rectifier current during phase 3 and 4 of the action potential. Ikach [10] shortens action potential duration (APD) and ERP during vagal stimulation making AF more stable. Ik1 channels responsible for the inward rectifier current have significantly lower expression in atrial myocytes than in ventricular myocytes [11], thereby causing higher membrane resistance in atrial myocytes [12]. Thus atrial myocytes need less depolarizing current, hence making atrial myocytes more excitable than ventricular myocytes. In addition to differences between the atrium and ventricle, there are also differences in ion channel expression and properties within the atrium itself (see next section).
R. Arora and H.K. Koduri
Atrial Anatomy and Variations in Atrial Electrophysiology In 1998 Haïssaguerre et al. [13] showed that rapid activation with short cycle lengths can occur in pulmonary veins (PVs) and can cause paroxysms of AF. Similar activity has also been demonstrated in the superior vena cava (SVC) and vein of Marshall (VOM) that can trigger AF [14, 15]. As observed in canine studies, atrial myocytes have higher ICaL and Ito than PV myocytes along with less Ikr and Iks [16, 17]. These differences cause shorter APD in PV myocytes as compared to the rest of the atrium. In animal studies it has been shown that PVs are not usually spontaneously active under normal conditions, but under sympathetic stimulation they can generate triggered and spontaneous activity [18]. Similarly, at the coronary sinus (CS) junction and in myocardial tissue in atrioventricular valves, catecholamines can cause triggered activity and delayed after depolarizations (DADs) [19–21]. Nguyen et al. [22] reported the presence of periodic acidSchiff (PAS) positive myocytes having HCN4 channel protein (typically present in the sinus node in pacemaker cells) at the PV and left atrial (LA) junction in patients with chronic AF. The structure and electrophysiology of the intact PV also differs from the rest of the left atrium. Canine PV histology sections showed sudden changes in myocardial fiber orientation from the proximal to the distal PV [23]. Patients with AF have been found to have areas of thickened PV walls and more fibrosis than patients with no AF [24, 25]. The peculiar histology of the PV-LA junction is reflected in the electrophysiology of this region, with the PV-LA junction demonstrating delayed and heterogeneous conduction patterns [26, 27]. These conduction patterns set up substrate for conduction block [28] and reentry [29] (with resulting AF) in response to rapid pacing and extrastimulus testing.
Basic Arrhythmia Mechanisms Both ectopy and reentry mechanisms can trigger AF. Ectopy can be secondary to automaticity or triggered activity. The reentry can be single-circuit reentry or multiple wavelet reentry.
Atrial Ectopy 1. Automaticity: The resting membrane potential is at least partially maintained by Ik1. The presence of either decreased Ik1 current or increased If creates conditions for increased automaticity in the cell [30], as can be seen in acute ischemia. 2. Triggered activity: Under certain conditions like in the presence of abnormal intracellular Ca2+ handling, cardiac myocytes can generate afterdepolarizations that can lead
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to triggered activity. Depending on their timing during the action potential, triggered beats are classified as delayed after depolarizations (DAD) (Fig. 31.1a) or early afterdepolarizations (EAD) (Fig. 31.1b).
Reentry Mechanisms Initiation of reentry needs suitable tissue conditions and an ectopic impulse that can act as a trigger. Substrate for reentry is produced either by remodeling of ion channels and/or tissue remodeling. Slowed conduction, shorter APD, and decreased ERP create ideal conditions for reentry to occur. Atrial enlargement and increased fibrosis, by causing conduction slowing and resulting conduction block, create conditions for the formation of reentrant circuits. Several reentry mechanisms have been proposed which can initiate and maintain AF. 1. Circus movement reentry: This type of reentry needs unidirectional block, occurring when part of tissue is not completely recovered after prior excitation. Circus movement reentry travels via a predefined anatomical pathway [31]. After depolarization
Normal AP
DAD
EAD
Fig. 31.1 Timing of early versus delayed after depolarizations
a
Wavelength (WL) is the distanced traveled by electrical impulse in one refractory period (RP). So WL = RP × CV (conduction velocity) [32]. The shorter the refractory period and lower the CV, the higher the propensity for the reentry to occur (Fig. 31.2a). 2. Leading circle reentry: Allessie et al. [33] first showed that reentry does not need an anatomical blockade. Reentry circuit takes the smallest loop around the central tissue that is not fully excitable. Reentry impulse moves in tangentially, centripetally, and centrifugally. Centripetal propagation encounters tissue that is not excitable as it is still in refractory phase. The tangential impulse that can form the shortest loop is propagated. The excitable gap is very short in leading circle reentry making it less stable (Fig. 31.2b). 3. Spiral wave reentry: To better understand spiral wave theory, it is important to know what is the “source” and “sink” of depolarizing current. The source of a wave front is the diffusion current produced by excited tissue that is attempting to depolarize the downstream myocytes. If the source is bigger than the downstream cells (sink) then the wave is propagated. If the sink is larger than the source, source current is not sufficient to activate downstream tissue and wave propagation fails. Spiral wave reentry is generated when a depolarizing wave front collides perpendicularly with another depolarizing wave’s tail [34]. At the point of collision, the wave front bends towards recovered tissue beyond the second wave tail. In this type of reentry, the central core tissue is excitable but is not excited as the source is very small compared to the sink (Fig. 31.2c). 4. Moe’s multiple wavelet theory: In 1959 Moe proposed that fibrillation occurs secondary to multiple wavelets colliding with each other and creating reentry circuits [35]. Conditions that favor formation of multiple reentry circuits are (1) increased size of the substrate, i.e., increase in the size of the atrium can accommodate more reentry circuits and (2) decreased refractory period and decreased conduction velocity, thus decreasing wavelength (product of refractory period and conduction velocity). Wavelength is
b
c Front
Fig. 31.2 Mechanisms of reentry. (a) Circus movement reentry. (b) Leading circle concept. (c) Rotor theory reentry (Modified from Schotten et al. [31])
Anatomical obstacle Excitable gap
Core
Tail
404 Fig. 31.3 Atrial signal transduction pathways regulating gene expression in atrial tissue. AT-1 angiotensin II type 1 receptors, TGF-? transforming growth factor ? PDGF platelet-derived growth factor, JNK c-jun terminal kinase, ERK extracellular signal regulated kinases, STAT signal tranducer and activators of transcription, CaMK II Ca2+/ calmodulin-dependent protein kinase II, PAI plasminogen activator inhibitor, VCAM vascular cell adhesion molecule (Modified from Schotten et al. [31])
R. Arora and H.K. Koduri PDGF ↑ MMP Angiotensin II TGF-β1 PDGF-R
TGF-β1 ↑
Angiotensin II ↑ VCAM ↑
L-type Ca2+ TGF-R
PAI-1 ↑
Channel AT1-R
Cell membrane
Calpain ↑ JAK/STAT
Smad2 ↑
PP2A ↑
p38 ↑ JNK ERK1/2 ↑
CAMK Calmodulin/ Calcineurin ↑ NFAT ↑
Cell hypertrophy, fibroblast proliferation and collagen synthesis
NADPH ↑
Rac ↑ (JAK) STAT3
ROS ↑ NF-kB ↑
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distance traveled by a wave in one refractory period. Thus wavelength represents the shortest path length needed by a reentry circuit to be sustainable. So the shorter the wavelength the smaller is the reentry circuit size, thereby increasing the propensity for a larger number of reentrant circuits. Until the late 1990s, this theory was considered to be most important theory for AF formation. Subsequent studies by Haïssaguerre et al. and several other animal studies have showed that single-circuit reentry or ectopic foci are also important in generation of AF.
(SR). This Ca2+ leak is secondary to either RyR2 dysfunction or overload of SR with Ca2+. RyR2 dysfunction (and leakiness) occurs at least in part due to hyperphosphorylation of RyR2 [37]. Abnormal calsequestrin (CSQ) or loss of CSQ, the main Ca2+-binding protein in the SR, makes more free Ca2+ available in the SR causing Ca2+ overload in the SR [37]. EADs are produced after an abnormally prolonged AP, during which ICaL recovers and allows Ca2+ to move inwards triggering EADs. Myocytes that generate EADs cause the adjacent repolarizing myocytes to trigger an action potential [38].
Calcium Dysregulation
Molecular Mechanisms of AF
Under normal physiological conditions, Ca2+ enters myocytes during phase 2 of the action potential through L-type calcium channels. This inward Ca2+ stimulates Ca2+ release from sarcoplasmic reticulum (SR) through RyR2 channels. This increase in intracellular Ca2+ during systole causes contraction. During diastole, the Ca2+ from the cytoplasm is taken up by the SR through SR Ca2+ ATPase (SERCA) and also pumped out of the cell through the Na+, Ca2+ exchanger (NCX). DADs are generated when there is increased Ca2+ in the cytosol during diastole [36]. This excess Ca2+ is extruded by Na+, Ca2+ exchanger (NCX); for each Ca2+ ion, there are three Na+ ions that are transported into the cell causing a net positive gain in the cell that causes depolarization of the cell leading to a DAD. When DADs are large, they can generate an ectopic beat. Continuous DADs can cause atrial tachycardia. The diastolic increase of Ca2+ is secondary to its leak through ryanodine receptor 2 (RyR2) on the sarcoplasmic reticulum
Several signaling pathways are involved in initiation and maintenance of AF. Numerous factors upon interaction with cell membrane receptors induce intracellular events that include activation and expression of genes that promote apoptosis, hypertrophy and fibroblast proliferation. 1. Angiotensin II (Fig. 31.3): Angiotensin II (AGII) plays an important role in the development of fibrosis [39]. Both atrial stretch and left ventricular failure increase production of AGII in atria. AGII through Rac1/STAT3 (signal transducer and activation of transcription) [40] and ERK1/2 (extracellular signal-regulated kinases) [39] promotes hypertrophy, fibroblast proliferation, and collagen synthesis. Studies have shown that AGII can increase levels of TGF-β (transforming growth factor-β) [41]. AGII through ROS (reactive oxygen species)/NF-κB and p38/JNK pathways promotes cellular apoptosis [31]. AGII also causes CaMKII oxidation, which can increase
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phosphorylation of RyR2 receptors on SR causing diastolic Ca2+ leak into the cytoplasm triggering DADs [42]. 2. TGF-β (Fig. 31.3): Although the underlying molecular mechanisms that lead to the development of atrial fibrosis are complex, recent work suggests that the TGF-β pathway may be an important contributor to the development of fibrosis (especially in the setting of increasing atrial stretch/dilatation resulting from CHF). Transforming growth factor-β1 (TGF-β1) is an inflammatory, profibrotic cytokine that stimulates the production of extracellular matrix proteins in a number of different organ systems. However, overexpression of TGF-β1 results in tissue fibrosis and organ dysfunction. TGF-β1 has been implicated in the development of diabetic nephropathy, ulcerative colitis, hepatic, pulmonary, and skin fibrosis. Similarly, in the heart, TGF-β1 appears to be one of major factors that cause disease by inducing cardiac fibrosis, as evidenced by overexpression and knockout models [43–45]. TGF-β stimulates fibroblast production of collagen, fibronectin, and proteoglycans and promotes apoptosis, which can indirectly lead to replacement fibrosis. TGF-β-dependent stimulation results in activation and phosphorylation of the Smad transcription factors [45]. Smad proteins alter gene transcription and are key regulators of cell growth and death through their effects on the cell cycle. TGF-β receptor activation also turns on TGF-β-activated kinase-1 (TAK-1), a MAPKKK, which can activate p38 MAPK. p38 MAPK can, in turn, increase expression of collagen and fibronectin. Serum levels of TGF-β have been shown to be increased in patients with AF undergoing defibrillation [45]. Moreover, transgenic overexpression of TGF-β in the mouse causes selective fibrosis of atrial but not ventricular myocardium [46]. Later studies in this murine model showed that TGF-β overexpression elicited marked atrial fibrosis, decreased conduction velocity, and increased AF inducibility [43]. Recently, Lamirault and coworkers, using microarray analysis, illustrated that gene expression of TGF-β is upregulated in patients with AF secondary to valvular heart disease in right atrial preparations [47]. Lee et al recently demonstrated that pirfenidone – a nonspecific blocker of TGF-β, TNF-α, and multiple other cytokines – prevents the development of fibrosis (and resulting AF) in a canine model of CHF [48]. 3. PDGF (Fig. 31.3): Elevated PDGF levels in atria have been noted in pacing-induced ventricular failure. PDFG stimulates differentiation and proliferation of fibroblasts [49]. PDGF activates Ras/MEK1/2 and MAPK, JAK/ STAT, and PLC signaling pathways. PDGF promotes cellular hypertrophy and collagen synthesis [31, 50]. PDGF is found to produce more fibrosis in the atria than in the ventricles [43]. This increased fibrosis causes tissue remodeling and conduction abnormalities creating conditions favorable for AF inducibility.
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4. Oxidative Stress: Oxygen derivatives with instabilities and an increased reactivity, including superoxide (O2−), hydrogen peroxide (H2O2), and hydroxyl radical (OH−), are generically termed reactive oxygen species (ROS) [51]. Excess ROS production damages DNA, protein, and lipids and causes cell death in the heart and cardiomyocytes. A wealth of research data points to increased oxidative stress as a key driver of the cardiac remodeling caused by chronic pressure overload, loss of functional myocardial tissue, or AF. In addition, ROS are also involved in specific redoxregulated modulation of key signaling pathways and gene expression, which in turn are involved in the creation of cardiomyocyte hypertrophy, interstitial fibrosis, and chamber remodeling in the failing heart. Chronic ROS elevation also activates a variety of signaling pathways such as the transforming growth factor-β1 (TGF-β1) and mitogen-activated protein kinase subfamilies including extracellular signal-regulated kinase (ERK), c-Jun N terminal kinase (JNK), and p38 kinase; these pathways are important in the creation of structural changes in the atrium, e.g., fibrosis and also contribute to the perpetuation of the ion channel and Ca2+ changes mentioned above. Recent evidence indicates that oxidative stress also contributes to both the structural and electrical remodeling that occur in AF. Histological studies have demonstrated oxidative damage in both AF patients as well as in animal models of AF [52] and demonstrated significant oxidative damage in right atrial appendages of AF patients undergoing the Maze procedure. In an experimental model of AF, Carnes et al. showed that dogs with sustained AF had an increase in protein nitration, suggesting enhanced oxidative stress [53]. Kim et al. examined the gene transcriptional profiles in atrial tissue from patients with permanent AF and found a significant increase in the transcription of several genes associated with the production of ROS and a decrease in two antioxidant genes [54]. Recent clinical studies have shown that markers of oxidative stress are increased in AF. Neuman et al. showed that oxidative stress markers were significantly elevated in patients with persistent AF [55]. Ramlawi et al. found that patients with postoperative AF had significantly greater elevation in serum peroxide levels as compared to patients in sinus rhythm [56]. Importantly, drugs that have antioxidant properties appear to have beneficial effects on the development of AF. Carnes et al. showed that ascorbate administration attenuated pacing-induced atrial ERP shortening in a canine model of AF. The authors also demonstrated that patients undergoing coronary bypass surgery receiving perioperative treatment with ascorbate had a significant decrease in postoperative AF [53]. In another study, Korantzopoulos et al. found that patients receiving treatment with vitamin C had reduced early recurrence rates of AF after electrical cardioversion of persistent AF [57].
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5. Matrix Metalloproteinases (MMPs): Fig. 31.3. In persistent AF, low levels and decreased function of MMP-1 and also enhanced levels of tissue inhibitor of metalloproteinases (TIMPs) have been noted [58, 59]. MMPs are very important in the breakdown of extracellular matrix. Decreased functionality of MMPs causes increased fibrosis and changes in extracellular matrix that likely contribute to atrial dilatation [60]. These changes can also lead to conduction heterogeneity and formation of multiple reentry circuits. 6. A Disintegrin and Metalloproteinases (ADAMs): ADAMs are important for cell-to-cell interactions and as well as cellto-matrix interactions. Increased levels of ADAMs are noted in patients with AF, especially ADAM15 and ADAM10 [31]. ADAMs are known to be important in extracellular matrix composition. Increased ADAMs causes changes in the interstitial tissue that lead to dilatation of atria [47]. 7. Calcineurin and Calpain (Fig. 31.3): Increase in intracellular calcium activates calcineurin [61] and calpain [62]. Calcineurin in turn dephosphorylates NFAT (nuclear factor of activated T cells) leading to activation of hypertrophic signals [63]. Activated calpains play an important role in contractile dysfunction in AF by promoting lysis of L-type calcium channel [49] and contractile proteins [31]. 8. CaMKII (Fig. 31.3): Normally CaMKII is autoinhibited. Increased intracellular Ca2+ causes Ca2+ to bind to calmodulin leading to disinhibition of CaMKII [64]. Angiotensin II through oxidation can also activate CaMKII [42]. Activated CaMKII phosphorylates RyR2. RyR2 phosphorylation by CaMKII is increased during AF. RyR2 phosphorylation causes diastolic leak of Ca2+ into cytoplasm from SR causing DADs [42].
Ion Channels and Atrial Electrical Remodeling “AF begets AF,” in part by AF itself leading to remodeling of ion channels that help stabilize the AF. Paroxysmal AF with time becomes persistent and later permanent AF. Atrial tachyarrhythmias [65] including AF [32] cause atrial tachycardia remodeling (ATR). ATR leads to initiation as well maintenance of AF. Important components of this remodeling are shortening of ERP and APD. In canine and goat studies, a decrease in ERP by more than 50 % from baseline has been shown to contribute to increased stability of AF [32, 66]. Indeed, in patients with AF, both shortening of ERP and APD has been demonstrated [67]. In humans, in addition to decreased ERP, there is also increased dispersion of refractoriness [68]. Large dispersions of refractoriness promote reentry and contribute to the maintenance of AF. There is also increased propensity for AF when there is poor or loss of rate adaptation of ERP [69]. In patients with AF, ICaL currents are decreased compared to sinus rhythm patients [70–72]. Decreased ICaL is secondary to
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decreased production of Cav1.2 (α-subunit of L-type calcium channels) [71, 73]. Increase in intracellular Ca2+ load during AF causes activation of Ca2+/calmodulin/calcineurin/NFAT system that causes inhibition of Cav1.2 production [74, 75]. Increased calpain activity was also noted in patients with AF. Calpain mediates proteolysis of L-type channel proteins leading to decreased calcium currents in AF patients [62, 76]. With respect to potassium currents, Ito is decreased in patients with AF [70, 77, 78]. Decrease in Ito causes slowing of phase 1 of action potential. Ik1, an inward rectifier potassium current, is increased in AF [70, 78, 79]. Increase in Ik1 current causes APD shortening [80]. Alpha subunit of Ik1, Kir2.1 levels, and its mRNA expression are increased in AF patients [81]. Activation of Ik1 with dephosphorylation by increased activity of protein phosphatases (PP1 and PP2a) [82–84] may also cause reduction in APD and stabilization of AF. In AF patients, IKACH response to acetylcholine is reduced [85–87]. But agonist-independent IKACHC (IKACH constitutive) activity is increased due to abnormal phosphorylation [85, 86, 88]. Increased IKACHC activity causes APD shortening and promotion of AF. No clear changes have been noted in INa [70] and Na+/K+ pump [89] in AF. There was no change [70, 77] or a decrease [78, 90] noted for IKur. However, upregulation of NCX (Na+/ Ca+ exchanger) has been seen in AF patients. This increase in NCX in AF decreases intracellular Ca2+ leading to contractile dysfunction in AF [91].
Role of Gap Junctions in AF The dominant connexins in the atria are Cx40 and Cx43. Animal and human studies have shown varying results in gap junction protein expression levels and distribution in the setting of AF [92]. These changes may be important in the creation of microreentry circuits. Wilhelm et al. showed decreased Cx40 levels in chronic AF [93]. Polontchouk et al. showed an increase expression of Cx40 [94]. Kostin et al. showed a reduction in Cx43 and heterogeneity of Cx40 [95]. Takeuchi et al. showed that in patients with AF or atrial dilatation, the expression of Cx43 is similar to sinus rhythm patients. This study further showed that in the dilated atria, the distribution of Cx43 is disorganized at intercalated discs with a paucity of Cx43 expression at the center of the intercalated discs, suggesting that the altered distribution is probably due to atrial dilatation rather than AF itself [96].
Atrial Tissue Remodeling Atrial tissue changes like structural heart disease, ischemia, inflammation, hypertrophy, fibrosis, and aging create an ideal substrate that can favor the initiation and maintenance of AF. Fibrosis is considered especially important in the
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creation of AF substrate [97]. An increase in fibrous tissue buildup between atrial myocytes alters intercellular conduction; these conduction abnormalities predispose to the formation of reentrant circuits. In patients undergoing CABG (coronary artery bypass grafting), the degree of fibrosis correlated with incidence of postoperative AF [98]. Indeed, pharmacological agents that decrease fibrosis have shown to decrease AF as well [99, 100]. In addition to fibrosis, myocyte hypertrophy is also seen in animal models of heart failure [101], atrial dilatation [102, 103], and rapid pacing [104]. Assessing the effect of myocyte hypertrophy alone on conduction is difficult under these settings. Spach et al. [105] showed that increased cell size causes anisotropy in transverse conduction of the electrical impulses; they also showed that cell size is more important than the heterogeneity of gap junctions in creating anisotropy of electrical impulse conduction. These results can explain that even in the absence of fibrosis, hypertrophy of myocytes can cause conduction abnormalities in the atrium, as demonstrated in a goat model by Neuberger et al. [103]. Also see section “Molecular mechanisms of AF”.
Role of Autonomic Nervous System The autonomic nervous system is also thought to play an important role in the initiation and perpetuation of AF. Both the sympathetic and the parasympathetic nervous system have been shown to play an important role in the generation of AF. The parasympathetic nervous system, through IKACHmediated shortening of APD and ERP, can induce AF in normal individuals [106]. Vagal stimulation also stabilizes reentry circuits [107]. In canine myocytes, sympatheticmediated β-receptor stimulation causes a decrease in APD [108] and also causes an increase in SR calcium load, which can result in triggered activity. Studies by Patterson et al. [109–111] showed that sympathetic stimulation is an important modulator in the presence of increased vagal tone to generate focal drivers in the atrium and pulmonary veins. Another study by Sharifov et al. [112] showed that a lower concentration of acetylcholine is required to induce AF in the presence of isoproterenol (while a higher concentration of acetylcholine is needed to induce AF in the absence of sympathetic stimulation by isoproterenol). Pulmonary vein ectopic foci also appear to be at least partially affected by autonomic nervous system, as isoproterenol is frequently used to bring out these triggers in patients during AF ablation [113]. Bezold-Jarisch-like “vagal” reflexes have been noted during radiofrequency ablation of PVs. Pappone et al. [114] suggested that elimination of these vagal reflexes during ablation can improve success rates of AF ablation. In other studies, combining ganglionated plexi (GP) ablation with standard PV isolation appears to increase the success of AF ablation [115]. In recent data, ablation of
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atrial regions demonstrating complex fractionated atrial electrograms (CFAEs) appears to improve the efficacy of PV isolation procedures [116, 117]; this improvement in ablation success rate is likely because several CFAEs are have been shown to overlie autonomic GP [118, 119]. Arora et al. [120] showed in a canine study that the posterior left atrium (PLA) had more sympathetic and parasympathetic nerve fibers and M2 receptors compared to other areas of the left atrium, i.e., the pulmonary veins (PV) and left atrial appendage (LAA), and that sympathetic and parasympathetic fibers are co-localized in the atrium. Human studies have also showed coexistence of both parasympathetic and sympathetic nerve fibers in the atrium [121]. The increased concentration of nerve trunks in the PLA is paralleled by increased autonomic responsiveness of the PVs and PLA to autonomic stimulation as compared to the rest of the left atrium. These differences in autonomic responsiveness between the PLA and the rest of the left atrium also appear to be correlated with the amount and spatial distribution of Ikach in the left atrium [122]. The autonomic nervous system has also been shown to play an important role in the genesis of AF in the setting of structural heart disease, e.g., congestive heart failure. Ng et al. [123] demonstrated enhanced nerve growth in the canine heart failure left atrium, predominantly in the PVs and PLA. This study also showed increased responsiveness to sympathetic stimulation in heart failure in the PVs and PLA (as compared to normal PVs/PLA). This study also showed that despite a decrease in responsiveness to vagal stimulation that occurs in the heart failure atrium (due to a compensatory increase in acetylcholinesterase activity in the atrium), parasympathetic remodeling is still an important contributor to AF; indeed, atropine administration resulted in a significant decrease in AF duration in this model of heart failure.
Genetic Disorders and AF In the last decade, large-scale, genome-wide association studies (GWASs) have provided insights into genetic predisposition of AF. Two broad categories of genetic abnormalities have been found to predispose to AF: (1) single gene mutations and (2) single nucleotide polymorphisms (SNPs) (Table 31.1). One likely genetic cause of AF resulting from EADs is linked to a SNP causing loss of function in KCNE1, which encodes the β-subunit of Iks, a slow delayed rectifier K+ channel involved in long QT syndrome 5 (LQT5) [124]. SNP of KCNN3 gene on chromosome 1q21 affects Ca2+-activated K+ channels [125]. This KCNN3 gene mutation causes shortening of APD, thereby promoting reentry [126] or initiates EADs [127] that causes AF. A loss-of-function SNP in the gene encoding sarcolipin is also linked to causation of AF [128]. A single gene mutation of ANKB (LQT4) affects Ca2+ handling and causes DADs [129]. Single gene mutation of
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R. Arora and H.K. Koduri
Table 31.1 Genetic abnormalities associated with AF Single nucleotide polymorphisms KCNE 1 – affects slow delayed rectifier K+ channel KCNN3 – affects Ca2+ activated K+ channels
Single gene mutations ANKB – affects Caa+ handling KCNA5 – affects gene encoding Kv1.5 α-subunit of Ikur SCN5A – affects Na+ channels KCNQ1 – affects α-subunits of Iks KCNH2 – affects subunits of IKr KCNJ2 – affects subunits IK1 CACNA1C & CACNB2 – affects IcaL α and β subunits
KCNA5 gene encoding Kv1.5 α-subunit of Ikur causes EADs that result in AF during adrenergic stimulation [130]. Gainof-function single gene mutations in SCN5A gene that encodes Na+ channels are found to be associated with AF, probably through ectopic activity [131]. A gain-of-function single gene mutation in KCNQ1, gene that encodes α-subunit of Iks, causes APD shortening and promotes reentry [132]. Other similar gain-of-function single gene mutations in genes KCNH2 [133] and KCNJ2 [134] encoding ion channel subunits of IKr and IK1 cause AF. Single gene mutations of CACNA1C and CACNB2 genes that encode ICaL α and β subunits are also associated with AF [135]. AF is seen in 10–20 % of Brugada syndrome patients with loss-of-function SCN5A mutation [136]. Some patients with catecholaminergic ventricular tachycardia were found to have ryanodine receptor loss-of-function mutations that were associated with AF [137]. Five to fifteen percent of patients with hypertrophic cardiomyopathy have AF secondary to mutations in sarcomeric proteins [138, 139].
Postoperative AF AF is seen in approximately one third of patients undergoing open heart surgery [140, 141]. The single most important factor that determines postoperative AF is the type of surgery being performed, with AF occurring most commonly in patients undergoing mitral valve surgery [142, 143]. The greatest risk of AF in the postoperative period is on days 2 and 3. Indeed, nonuniformity of atrial conduction is found to be greatest on postoperative days 2 and 3. Moreover, longest atrial conduction times are also found on postoperative day three [144]. In canine studies, the degree of inflammation that occurs in the perioperative setting has been shown to be directly related to conduction abnormalities in the atrium [145]. Indeed, inflammatory processes are thought to be the predominant mechanism underlying this type of AF. Usage of anti-inflammatory agents has been shown to decrease the incidence of postoperative AF [146, 147],
stressing the role of inflammatory processes in AF generation. Autonomic activation is also thought to contribute to postoperative AF. The use of preoperative and postoperative β-adrenergic blockers has been shown to decrease the occurrence of postoperative AF in some series [148, 149]. A higher amount of interstitial fibrosis has also been shown to be correlated with the incidence of postoperative AF [84]. Age is another risk factor for postoperative AF, probably due to increased fibrosis with age and atrial dilatation. Recent study by Carnes et al. [53] showed that oxidative stress also contributes to postoperative AF. In the majority of the patients with postoperative AF, the AF is self-limited and antiarrhythmic therapy, if needed, is usually given only for a few weeks.
References 1. Heeringa J, van der Kuip DA, Hofman A, Kors JA, van Herpen G, Stricker BH, et al. Prevalence, incidence and lifetime risk of atrial fibrillation: the Rotterdam study. Eur Heart J. 2006;27:949–53. 2. Hobbs FD, Fitzmaurice DA, Mant J, Murray E, Jowett S, Bryan S, et al. A randomised controlled trial and cost-effectiveness study of systematic screening (targeted and total population screening) versus routine practice for the detection of atrial fibrillation in people aged 65 and over. The SAFE study. Health Technol Assess. 2005;9:iii–iv, ix–x, 1–74. 3. Miyasaka Y, Barnes ME, Gersh BJ, Cha SS, Seward JB, Bailey KR, et al. Time trends of ischemic stroke incidence and mortality in patients diagnosed with first atrial fibrillation in 1980 to 2000: report of a community-based study. Stroke. 2005;36: 2362–6. 4. Lloyd-Jones DM, Wang TJ, Leip EP, et al. Lifetime risk for development of atrial fibrillation: the Framingham Heart Study. Circulation. 2004;110:1042–6. 5. Stevenson WG, Stevenson LW, Middlekauff HR, et al. Improving survival for patients with atrial fibrillation and advanced heart failure. J Am Coll Cardiol. 1996;28:1458–63. 6. Mays DJ, Foose JM, Philipson LH, Tamkun MM. Localization of the Kv1.5 K_ channel protein in explanted cardiac tissue. J Clin Invest. 1995;96:282–92. 7. Wang Z, Fermini B, Nattel S. Sustained depolarization-induced outward current in human atrial myocytes. Evidence for a novel delayed rectifier K_ current similar to Kv1.5 cloned channel currents. Circ Res. 1993;73:1061–76. 8. Blaauw Y, Schotten U, van Hunnik A, Neuberger HR, Allessie MA. Cardioversion of persistent atrial fibrillation by a combination of atrial specific and non-specific class III drugs in the goat. Cardiovasc Res. 2007;75:89–98. 9. De Haan S, Greiser M, Harks E, Blaauw Y, van Hunnik A, Verheule S, et al. AVE0118, blocker of the transient outward current [I(to)] and ultrarapid delayed rectifier current [I(Kur)], fully restores atrial contractility after cardioversion of atrial fibrillation in the goat. Circulation. 2006;114:1234–42. 10. Dobrzynski H, Marples DD, Musa H, Yamanushi TT, Henderson Z, Takagishi Y, et al. Distribution of the muscarinic K_ channel proteins Kir3.1 and Kir3 4 in the ventricle, atrium, and sinoatrial node of heart. J Histochem Cytochem. 2001;49:1221–34. 11. Giles WR, Imaizumi Y. Comparison of potassium currents in rabbit atrial and ventricular cells. J Physiol. 1988;405:123–45. 12. Golod DA, Kumar R, Joyner RW. Determinants of action potential initiation in isolated rabbit atrial and ventricular myocytes. Am J Physiol Heart Circ Physiol. 1998;274:H1902–13.
31
Mechanisms of Atrial Fibrillation
13. Haïssaguerre M, Jais P, Shah DC, Takahashi A, Hocini M, Quiniou G, et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med. 1998; 339:659–66. 14. Hwang C, Wu TJ, Doshi RN, Peter CT, Chen PS. Vein of Marshall cannulation for the analysis of electrical activity in patients with focal atrial fibrillation. Circulation. 2000;101:1503–5. 15. Tsai CF, Tai CT, Hsieh MH, Lin WS, Yu WC, Ueng KC, et al. Initiation of atrial fibrillation by ectopic beats originating from the superior vena cava: electrophysiological characteristics and results of radiofrequency ablation. Circulation. 2000;102:67–74. 16. Ehrlich JR, Cha TJ, Zhang L, Chartier D, Melnyk P, Hohnloser SH, Nattel S. Cellular electrophysiology of canine pulmonary vein cardiomyocytes: action potential and ionic current properties. J Physiol. 2003;551:801–13. 17. Melnyk P, Ehrlich JR, Pourrier M, Villeneuve L, Cha TJ, Nattel S. Comparison of ion channel distribution and expression in cardiomyocytes of canine pulmonary veins versus left atrium. Cardiovasc Res. 2005;65:104–16. 18. Maupoil V, Bronquard C, Freslon JL, Cosnay P, Findlay I. Ectopic activity in the rat pulmonary vein can arise from simultaneous activation of alpha1- and beta1-adrenoceptors. Br J Pharmacol. 2007;150:899–905. 19. Henning B, Wit AL. The time course of action potential repolarization affects delayed afterdepolarization amplitude in atrial fibers of the canine coronary sinus. Circ Res. 1984;55:110–5. 20. Tseng GN, Wit AL. Effects of reducing [Na_]o on catecholamineinduced delayed afterdepolarizations in atrial cells. Am J Physiol Heart Circ Physiol. 1987;253:H115–25. 21. Wit AL, Cranefield PF. Triggered and automatic activity in the canine coronary sinus. Circ Res. 1977;41:434–45. 22. Nguyen BL, Fishbein MC, Chen LS, Chen PS, Masroor S. Histopathological substrate for chronic atrial fibrillation in humans. Heart Rhythm. 2006;6:454–60. 23. Verheule S, Wilson E, Arora R, Engle SK, Scott L, Olgin J. Tissue structure and connexin expression of canine pulmonary veins. Cardiovasc Res. 2002;55:727–38. 24. Kholova I, Kautzner J. Morphology of atrial myocardial extensions into human caval veins: a postmortem study in patients with and without atrial fibrillation. Circulation. 2004;110:483–8. 25. Hassink RJ, Aretz HT, Ruskin J, Keane D. Morphology of atrial myocardium in human pulmonary veins: a postmortem analysis in patients with and without atrial fibrillation. J Am Coll Cardiol. 2003;42:1108–14. 26. Hocini M, Ho SY, Kawara T, Linnenbank AC, Potse M, Shah D, et al. Electrical conduction in canine pulmonary veins: electrophysiological and anatomic correlation. Circulation. 2002;105: 2442–8. 27. Chou CC, Nihei M, Zhou S, Tan A, Kawase A, Macias ES, et al. Intracellular calcium dynamics and anisotropic reentry in isolated canine pulmonary veins and left atrium. Circulation. 2005;111: 2889–97. 28. Arora R, Verheule S, Scott L, Navarrete A, Katari V, Wilson E, et al. Arrhythmogenic substrate of the pulmonary veins assessed by high-resolution optical mapping. Circulation. 2003;107: 1816–21. 29. Kumagai K, Ogawa M, Noguchi H, Yasuda T, Nakashima H, Saku K. Electrophysiologic properties of pulmonary veins assessed using a multielectrode basket catheter. J Am Coll Cardiol. 2004;43: 2281–9. 30. Iwasaki YK, Nishida K, Kato T, Nattel S. Atrial fibrillation pathophysiology: implications for management. Circulation. 2011;124(20): 2264–74. 31. Schotten U, Verheule S, Kirchhof P, Goette A. Pathophysiological mechanisms of atrial fibrillation: a translational appraisal. Physiol Rev. 2011;91:265–325.
409 32. Wijffels M, Kirchhof C, Dorland R, Allessie M. Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats. Circulation. 1995;92:1954–68. 33. Allessie MA, Bonke FI, Schopman FJ. Circus movement in rabbit atrial muscle as a mechanism of tachycardia. Circ Res. 1973;33: 54–62. 34. Comtois P, Kneller J, Nattel S. Of circles and spirals: bridging the gap between the leading circle and spiral wave concepts of cardiac reentry. Europace. 2005;7 Suppl 2:10–20. 35. Moe GK, Abildskov JA. Atrial fibrillation as a self-sustaining arrhythmia independent of focal discharge. Am Heart J. 1959;58: 59–70. 36. Dobrev D, Voigt N, Wehrens XH. The ryanodine receptor channel as a molecular motif in atrial fibrillation: pathophysiological and therapeutic implications. Cardiovasc Res. 2011;89(4):734–43. 37. MacLennan DH, Chen SR. Store overload-induced Ca2+ release as a triggering mechanism for CPVT and MH episodes caused by mutations in RYR and CASQ genes. J Physiol. 2009;587(pt 13): 3113–5. 38. Nattel S. New ideas about atrial fibrillation 50 years on. Nature. 2002;415(6868):219–26. 39. Li D, Shinagawa K, Pang L, Leung TK, Cardin S, Wang Z, Nattel S. Effects of angiotensin-converting enzyme inhibition on the development of the atrial fibrillation substrate in dogs with ventricular tachypacing-induced congestive heart failure. Circulation. 2001;104:2608–14. 40. Tsai CTLL, Kuo KT, Hwang JJ, Hsieh CS, Hsu KL, Tseng CD, et al. Angiotensin II activates signal transducer and activators of transcription 3 via Rac1 in atrial myocytes and fibroblasts: implication for the therapeutic effect of statin in atrial structural remodeling. Circulation. 2008;117:344–55. 41. He X, Gao X, Peng L, Wang S, Zhu Y, Ma H, et al. Atrial fibrillation induces myocardial fibrosis through angiotensin II type 1 receptor-specific arkadia-mediated downregulation of Smad7. Circ Res. 2011;108(2):164–75. 42. Gassanov N, Brandt MC, Michels G, Lindner M, Er F, Hoppe UC. Angiotensin II–induced changes of calcium sparks and ionic currents in human atrial myocytes: potential role for early remodeling in atrial fibrillation. Cell Calcium. 2006;39(2):175–86. 43. Verheule S, Sato T, Everett 4th T, Engle SK, Otten D, Rubart-von der Lohe M, et al. Increased vulnerability to atrial fibrillation in transgenic mice with selective atrial fibrosis caused by overexpression of TGF-beta 1. Circ Res. 2004;94(11):1458–65. 44. Everett 4th T, Olgin JE. Atrial fibrosis and mechanism of atrial fibrillation. Heart Rhythm. 2007;4(3 Suppl):S24–7. 45. Khan R, Sheppard R. Fibrosis in heart disease: understanding the role of transforming growth factor-beta in cardiomyopathy, valvular disease and arrhythmia. Immunology. 2006;118(1):10–24. 46. Nakajima H, Nakajima HO, Salchar O, Dittie AS, Dembowsky K, Jing S, Field LJ. Atrial but not ventricular fibrosis in mice expressing a mutant transforming growth factor-beta(1) transgene in the heart. Circ Res. 2000;86(5):571–9. 47. Lamirault G, Gaborit N, Le Meur N, Chevalier C, Lande G, Demolombe S, et al. Gene expression profile associated with chronic atrial fibrillation and underlying valvular heart disease in man. J Mol Cell Cardiol. 2006;40(1):173–84. 48. Lee KW, Everett 4th TH, Rahmutula D, Guerra JM, Wilson E, Ding C, Olgin JE. Pirfenidone prevents the development of a vulnerable substrate for atrial fibrillation in a canine model of heart failure. Circulation. 2006;114(16):1703–12. 49. Burstein B, Nattel S. Atrial fibrosis: mechanisms and clinical relevance in atrial fibrillation. J Am Coll Cardiol. 2008;51(8):802–9. 50. Ponten A, Folestad EB, Pietras K, Eriksson U. Platelet-derived growth factor D induces cardiac fibrosis and proliferation of vascular smooth muscle cells in heart-specific transgenic mice. Circ Res. 2005;97(10):1036–45.
410 51. Maejima Y, Kuroda J, Matsushima S, Ago T, Sadoshima J. Regulation of myocardial growth and death by NADPH oxidase. J Mol Cell Cardiol. 2011;50(3):408–16. 52. Mihm MJ, Yu F, Carnes CA, Reiser PJ, McCarthy PM, Van Wagoner DR, Bauer JA. Impaired myofibrillar energetics and oxidative injury during human atrial fibrillation. Circulation. 2001; 104(2):174–80. 53. Carnes CA, Chung MK, Nakayama T, Nakayama H, Baliga RS, et al. Ascorbate attenuates atrial pacing-induced peroxynitrite formation and electrical remodeling and decreases the incidence of postoperative atrial fibrillation. Circ Res. 2001;89(6):E32–8. 54. Kim YH, Lim DS, Lee JH, Shim WJ, Ro YM, Park GH, et al. Gene expression profiling of oxidative stress on atrial fibrillation in humans. Exp Mol Med. 2003;35(5):336–49. 55. Neuman RB, Bloom HL, Shukrullah I, Darrow LA, Kleinbaum D, Jones DP, Dudley Jr SC. Oxidative stress markers are associated with persistent atrial fibrillation. Clin Chem. 2007;53(9):1652–7. 56. Ramlawi B, Otu H, Mieno S, Boodhwani M, Sodha NR, Clements RT, et al. Oxidative stress and atrial fibrillation after cardiac surgery: a case–control study. Ann Thorac Surg. 2007;84(4):1166–72. 57. Korantzopoulos P, Kolettis TM, Kountouris E, Dimitroula V, Karanikis P, Pappa E, et al. Oral vitamin C administration reduces early recurrence rates after electrical cardioversion of persistent atrial fibrillation and attenuates associated inflammation. Int J Cardiol. 2005;102(2):321–6. 58. Marin FRV, Climent V, Garcia A, Marco P, Lip GYH. Is thrombogenesis in atrial fibrillation related to matrix metalloproteinase-1 and its inhibitor, TIMP-1? Stroke. 2003;34:1181–6. 59. Goette ARC, Nepple K, Lendeckel U. Proteases and arrhythmias. In: Lendeckel U, editor. Proteases in tissue remodelling of lung and heart. New York: Plenum; 2003. p. 191–390. 60. Hunt MJ, Aru GM, Hayden MR, Moore CK, Hoit BD, Tyagi SC. Induction of oxidative stress and disintegrin metalloproteinase in human heart end-stage failure. Am J Physiol Lung Cell Mol Physiol. 2002;283:L239–45. 61. Crabtree GROE. NFAT signalling: choreographing the social lives of cells. Cell Mol Life Sci. 2002;109(Suppl):S67–79. 62. Brundel BJ, Ausma J, van Gelder IC, Van der Want JJ, van Gilst WH, Crijns HJ, Henning RH. Activation of proteolysis by calpains and structural changes in human paroxysmal and persistent atrial fibrillation. Cardiovasc Res. 2002;54:380–9. 63. Bukowska A, Hirte D, Wolke C, Striggow F, Röhnert P, Huth C, Klein HU, Goette A. Activation of the calcineurin signaling pathway induces atrial hypertrophy during atrial fibrillation. Cell Mol Life Sci. 2006;63:333–42. 64. Neef S, Dybkova N, Sossalla S, Ort KR, Fluschnik N, Neumann K, et al. CaMKII-dependent diastolic SR Ca2+ leak and elevated diastolic Ca2+ levels in right atrial myocardium of patients with atrial fibrillation. Circ Res. 2010;106(6):1134–44. 65. Shiroshita-Takeshita A, Mitamura H, Ogawa S, Nattel S. Ratedependence of atrial tachycardia effects on atrial refractoriness and atrial fibrillation maintenance. Cardiovasc Res. 2009;81(1):90–7. 66. Yue L, Feng J, Gaspo R, Li GR, Wang Z, Nattel S. Ionic remodeling underlying action potential changes in a canine model of atrial fibrillation. Circ Res. 1997;81:512–25. 67. Attuel P, Childers R, Cauchemez B, Poveda J, Mugica J, Coumel P. Failure in the rate adaptation of the atrial refractory period: its relationship to vulnerability. Int J Cardiol. 1982;2:179–97. 68. Boutjdir M, Le Heuzey JY, Lavergne T, Chauvaud S, Guize L, Carpentier A, Peronneau P. Inhomogeneity of cellular refractoriness in human atrium: factor of arrhythmia? Pacing Clin Electrophysiol. 1986;9:1095–100. 69. Misier AR, Opthof T, van Hemel NM, Defauw JJ, de Bakker JM, Janse MJ, van Capelle FJ. Increased dispersion of “refractoriness” in patients with idiopathic paroxysmal atrial fibrillation. J Am Coll Cardiol. 1992;19:1531–5.
R. Arora and H.K. Koduri 70. Bosch RF, Zeng X, Grammer JB, Popovic K, Mewis C, Kuhlkamp V. Ionic mechanisms of electrical remodeling in human atrial fibrillation. Cardiovasc Res. 1999;44:121–31. 71. Brundel BJ, Van Gelder IC, Henning RH, Tieleman R, Tuinenburg AE, Wietses M, et al. Ion channel remodeling is related to intraoperative atrial effective refractory periods in patients with paroxysmal and persistent atrial fibrillation. Circulation. 2001;103:684–90. 72. Skasa M, Jungling E, Picht E, Schondube F, Luckhoff A. L-type calcium currents in atrial myocytes from patients with persistent and non-persistent atrial fibrillation. Basic Res Cardiol. 2001;96: 151–9. 73. Brundel BJ, Van Gelder IC, Henning RH, Tuinenburg AE, Wietses M, Grandjean JG, et al. Alterations in potassium channel gene expression in atria of patients with persistent and paroxysmal atrial fibrillation: differential regulation of protein and mRNA levels for K_ channels. J Am Coll Cardiol. 2001;37:926–32. 74. Yue L, Melnyk P, Gaspo R, Wang Z, Nattel S. Molecular mechanisms underlying ionic remodeling in a dog model of atrial fibrillation. Circ Res. 1999;84(7):776–84. 75. Qi XY, Yeh YH, Xiao L, Burstein B, Maguy A, Chartier D, et al. Cellular signaling underlying atrial tachycardia remodeling of L-type calcium current. Circ Res. 2008;103(8):845–54. 76. Goette A, Arndt M, Rocken C, Staack T, Bechtloff R, Reinhold D, et al. Calpains and cytokines in fibrillating human atria. Am J Physiol Heart Circ Physiol. 2002;283:H264–72. 77. Grammer JB, Bosch RF, Kuhlkamp V, Seipel L. Molecular remodeling of Kv4.3 potassium channels in human atrial fibrillation. J Cardiovasc Electrophysiol. 2000;11:626–33. 78. Van Wagoner DR, Pond AL, McCarthy PM, Trimmer JS, Nerbonne JM. Outward K_ current densities and Kv1.5 expression are reduced in chronic human atrial fibrillation. Circ Res. 1997;80: 772–81. 79. Dobrev D, Wettwer E, Kortner A, Knaut M, Schuler S, Ravens U. Human inward rectifier potassium channels in chronic and postoperative atrial fibrillation. Cardiovasc Res. 2002;54:397–404. 80. Zhang H, Garratt CJ, Zhu J, Holden AV. Role of up-regulation of IK1 in action potential shortening associated with atrial fibrillation in humans. Cardiovasc Res. 2005;66:493–502. 81. Gaborit N, Steenman M, Lamirault G, Le Meur N, Le Bouter S, Lande G, et al. Human atrial ion channel and transporter subunit gene-expression remodeling associated with valvular heart disease and atrial fibrillation. Circulation. 2005;112:471–81. 82. El-Armouche A, Boknik P, Eschenhagen T, Carrier L, Knaut M, Ravens U, Dobrev D. Molecular determinants of altered Ca2+ handling in human chronic atrial fibrillation. Circulation. 2006;114(7): 670–80. 83. Christ T, Boknik P, Wöhrl S, Wettwer E, Graf EM, Bosch RF, et al. L-type Ca2+ current downregulation in chronic human atrial fibrillation is associated with increased activity of protein phosphatases. Circulation. 2004;110(17):2651–7. 84. Luo X, et al. Critical role of microRNAs miR-26 and miR-101 in atrial electrical remodeling in experimental atrial fibrillation. Circulation. 2010;122, A19435. 85. Dobrev D, Friedrich A, Voigt N, Jost N, Wettwer E, Christ T, et al. The G protein-gated potassium current I(K, ACh) is constitutively active in patients with chronic atrial fibrillation. Circulation. 2005;112(24):3697–706. 86. Cha TJ, Ehrlich JR, Chartier D, Qi XY, Xiao L, Nattel S. Kir3based inward rectifier potassium current: potential role in atrial tachycardia remodeling effects on atrial repolarization and arrhythmias. Circulation. 2006;113(14):1730–7. 87. Karle CA, Zitron E, Zhang W, Wendt-Nordahl G, Kathöfer S, Thomas D, et al. Human cardiac inwardly-rectifying K+ channel Kir(2.1b) is inhibited by direct protein kinase C-dependent regulation in human isolated cardiomyocytes and in an expression system. Circulation. 2002;106(12):1493–9.
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88. Voigt N, Friedrich A, Bock M, Wettwer E, Christ T, Knaut M, et al. Differential phosphorylation dependent regulation of constitutively active and muscarinic receptor-activated IK, ACh channels in patients with chronic atrial fibrillation. Cardiovasc Res. 2007;74: 426–37. 89. Workman AJ, Kane KA, Rankin AC. Characterisation of the Na, K pump current in atrial cells from patients with and without chronic atrial fibrillation. Cardiovasc Res. 2003;59:593–602. 90. Brandt MC, Priebe L, Bohle T, Sudkamp M, Beuckelmann DJ. The ultrarapid and the transient outward K_ current in human atrial fibrillation. Their possible role in postoperative atrial fibrillation. J Mol Cell Cardiol. 2000;32:1885–96. 91. Schotten U, Duytschaever M, Ausma J, Eijsbouts S, Neuberger HR, Allessie M. Electrical and contractile remodeling during the first days of atrial fibrillation go hand in hand. Circulation. 2003; 107:1433–9. 92. Duffy HS, Wit AL. Is there a role for remodeled connexins in AF? No simple answers. J Mol Cell Cardiol. 2008;44:4–13. 93. Wilhelm M, Kirste W, Kuly S, Amann K, Neuhuber W, Weyand M, et al. Atrial distribution of connexin 40 and 43 in patients with intermittent, persistent, and postoperative atrial fibrillation. Heart Lung Circ. 2006;15:30–7. 94. Polontchouk L, Haefliger JA, Ebelt B, Schaefer T, Stuhlmann D, Mehlhorn U, et al. Effects of chronic atrial fibrillation on gap junction distribution in human and rat atria. J Am Coll Cardiol. 2001;38: 883–91. 95. Kostin S, Klein G, Szalay Z, Hein S, Bauer EP, Schaper J. Structural correlate of atrial fibrillation in human patients. Cardiovasc Res. 2002;54:361–79. 96. Takeuchi S, Akita T, Takagishi Y, Watanabe E, Sasano C, Honjo H, Kodama I. Disorganization of gap junction distribution in dilated atria of patients with chronic atrial fibrillation. Circ J. 2006;70: 575–82. 97. Nattel S. Defining “culprit mechanisms” in arrhythmogenic cardiac remodeling. Circ Res. 2004;94:1403–5. 98. Goette A, Juenemann G, Peters B, Klein H, Roessner A, Huth C, Rocken C. Determinants and consequences of atrial fibrosis in patients undergoing open heart surgery. Cardiovasc Res. 2002;54: 390–6. 99. Pedersen OD, Bagger H, Kober L, Torp-Pedersen C. Trandolapril reduces the incidence of atrial fibrillation after acute myocardial infarction in patients with left ventricular dysfunction. Circulation. 1999;100:376–80. 100. Vermes ETJ, Bourassa MG, Racine N, Levesque S, White M, Guerra PG, Ducharme A. Enalapril decreases the incidence of atrial fibrillation in patients with left ventricular dysfunction: insight from the Studies Of Left Ventricular Dysfunction (SOLVD) trials. Circulation. 2003;107:2926–31. 101. Li D, Fareh S, Leung TK, Nattel S. Promotion of atrial fibrillation by heart failure in dogs: atrial remodeling of a different sort. Circulation. 1999;100:87–95. 102. Boyden PA, Hoffman BF. The effects on atrial electrophysiology and structure of surgically induced right atrial enlargement in dogs. Circ Res. 1981;49:1319–31. 103. Neuberger HR, Schotten U, Verheule S, Eijsbouts S, Blaauw Y, van Hunnik A, Allessie M. Development of a substrate of atrial fibrillation during chronic atrioventricular block in the goat. Circulation. 2005;111:30–7. 104. Ausma J, Wijffels M, Thone F, Wouters L, Allessie M, Borgers M. Structural changes of atrial myocardium due to sustained atrial fibrillation in the goat. Circulation. 1997;96:3157–63. 105. Spach MS, Heidlage JF, Barr RC, Dolber PC. Cell size and communication: role in structural and electrical development and remodeling of the heart. Heart Rhythm. 2004;1:500–15. 106. Chen PS, Tan AY. Autonomic nerve activity and atrial fibrillation. Heart Rhythm. 2007;4:S61–4.
411 107. Kneller J, Zou R, Vigmond EJ, Wang Z, Leon LJ, Nattel S. Cholinergic atrial fibrillation in a computer model of a twodimensional sheet of canine atrial cells with realistic ionic properties. Circ Res. 2002;90:E73–87. 108. Liang BT, Frame LH, Molinoff PB. Beta 2-adrenergic receptors contribute to catecholamine-stimulated shortening of action potential duration in dog atrial muscle. Proc Natl Acad Sci. 1985; 82:4521–5. 109. Patterson E, Lazzara R, Szabo B, Liu H, Tang D, Li YH, et al. Sodium-calcium exchange initiated by the Ca2+ transient: an arrhythmia trigger within pulmonary veins. J Am Coll Cardiol. 2006;47(6):1196–206. 110. Patterson E, Po SS, Scherlag BJ, Lazzara R. Triggered firing in pulmonary veins initiated by in vitro autonomic nerve stimulation. Heart Rhythm. 2005;2(6):624–31. 111. Patterson E, Yu X, Huang S, Garrett M, Kem DC. Suppression of autonomic-mediated triggered firing in pulmonary vein preparations, 24 hours postcoronary artery ligation in dogs. J Cardiovasc Electrophysiol. 2006;17(7):763–70. 112. Sharifov OF, Fedorov VV, Beloshapko GG, Glukhov AV, Yushmanova AV, Rosenshtraukh LV. Roles of adrenergic and cholinergic stimulation in spontaneous atrial fibrillation in dogs. J Am Coll Cardiol. 2004;43(3):483–90. 113. Crawford T, Chugh A, Good E, et al. Clinical value of noninducibility by high-dose isoproterenol versus rapid atrial pacing after catheter ablation of paroxysmal atrial fibrillation. J Cardiovasc Electrophysiol. 2010;21:13–20. 114. Pappone C, Santinelli V, Manguso F, et al. Pulmonary vein denervation enhances long-term benefit after circumferential ablation for paroxysmal atrial fibrillation. Circulation. 2004;109:327–34. 115. Kalifa J, Jalife J, Zaitsev AV, et al. Intra-atrial pressure increases rate and organization of waves emanating from the superior pulmonary veins during atrial fibrillation. Circulation. 2003;108:668–71. 116. Arruda M, Natale A. Ablation of permanent AF: adjunctive strategies to pulmonary veins isolation: targeting AF NEST in sinus rhythm and CFAE in AF. J Interv Card Electrophysiol. 2008;23:51–7. 117. Porter M, Spear W, Akar JG, et al. Prospective study of atrial fibrillation termination during ablation guided by automated detection of fractionated electrograms. J Cardiovasc Electrophysiol. 2008; 19:613–20. 118. Aimé-Sempé C, Folliguet T, Rücker-Martin C, et al. Myocardial cell death in fibrillating and dilated human right atria. J Am Coll Cardiol. 1999;34:1577–86. 119. Katritsis D, Giazitzoglou E, Sougiannis D, et al. Complex fractionated atrial electrograms at anatomic sites of ganglionated plexi in atrial fibrillation. Europace. 2009;11:308–15. 120. Arora R, Ulphani JS, Villuendas R, Ng J, Harvey L, Thordson S, et al. Neural substrate for atrial fibrillation: implications for targeted parasympathetic blockade in the posterior left atrium. Am J Physiol Heart Circ Physiol. 2008;294:H134–44. 121. Tan AY, Li H, Wachsmann-Hogiu S, Chen LS, Chen PS, Fishbein MC. Autonomic innervation and segmental muscular disconnections at the human pulmonary vein-atrial junction: implications for catheter ablation of atrial-pulmonary vein junction. J Am Coll Cardiol. 2006;48(1):132–43. 122. Arora R, Ng J, Ulphani J, Mylonas I, Subacius H, Shade G, et al. Unique autonomic profile of the pulmonary veins and posterior left atrium. J Am Coll Cardiol. 2007;49:1340–8. 123. Ng J, Villuendas R, Cokic I, Schliamser JE, Gordon D, Koduri H, et al. Autonomic remodeling in the left atrium and pulmonary veins in heart failure: creation of a dynamic substrate for atrial fibrillation. Circ Arrhythm Electrophysiol. 2011;4:388–96. 124. Ehrlich JR, Zicha S, Coutu P, Hebert TE, Nattel S. Atrial fibrillation-associated minK38G/S polymorphism modulates delayed rectifier current and membrane localization. Cardiovasc Res. 2005;67(3):520–8.
412 125. Ellinor PT, Lunetta KL, Glazer NL, Pfeufer A, Alonso A, Chung MK, et al. Common variants in KCNN3 are associated with lone atrial fibrillation. Nat Genet. 2010;42(3):240–4. 126. Ozgen N, Dun W, Sosunov EA, Anyukhovsky EP, Hirose M, Duffy HS, et al. Early electrical remodeling in rabbit pulmonary vein results from trafficking of intracellular SK2 channels to membrane sites. Cardiovasc Res. 2007;75(4):758–69. 127. Li N, Timofeyev V, Tuteja D, Xu D, Lu L, Zhang Q, et al. Ablation of a Ca2+ − activated K+ channel (SK2 channel) results in action potential prolongation in atrial myocytes and atrial fibrillation. J Physiol. 2009;587(pt 5):1087–100. 128. Nyberg MT, Stoevring B, Behr ER, Ravn LS, McKenna WJ, Christiansen M. The variation of the sarcolipin gene (SLN) in atrial fibrillation, long QT syndrome and sudden arrhythmic death syndrome. Clin Chim Acta. 2007;375(1–2):87–91. 129. Mohler PJ, Schott JJ, Gramolini AO, Dilly KW, Guatimosim S, duBell WH, et al. Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death. Nature. 2003;421(6923):634–9. 130. Olson TM, Alekseev AE, Liu XK, Park S, Zingman LV, Bienengraeber M, et al. Kv1.5 channelopathy due to KCNA5 lossof-function mutation causes human atrial fibrillation. Hum Mol Genet. 2006;15(14):2185–91. 131. Li Q, Huang H, Liu G, Lam K, Rutberg J, Green MS, et al. Gainof-function mutation of Nav1.5 in atrial fibrillation enhances cellular excitability and lowers the threshold for action potential firing. Biochem Biophys Res Commun. 2009;380(1):132–7. 132. Chen YH, Xu SJ, Bendahhou S, Wang XL, Wang Y, Xu WY, et al. KCNQ1 gain-of-function mutation in familial atrial fibrillation. Science. 2003;299(5604):251–4. 133. Hong K, Bjerregaard P, Gussak I, Brugada R. Short QT syndrome and atrial fibrillation caused by mutation in KCNH2. J Cardiovasc Electrophysiol. 2005;16(4):394–6. 134. Xia M, Jin Q, Bendahhou S, He Y, Larroque MM, Chen Y, et al. A Kir2.1 gain-of-function mutation underlies familial atrial fibrillation. Biochem Biophys Res Commun. 2005;332(4): 1012–9. 135. Antzelevitch C, Pollevick GD, Cordeiro JM, Casis O, Sanguinetti MC, Aizawa Y, et al. Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death. Circulation. 2007;115(4):442–9. 136. Eckardt L, Kirchhof P, Loh P, Schulze-Bahr E, Johna R, Wichter T, et al. Brugada syndrome and supraventricular tachyarrhythmias: a novel association? J Cardiovasc Electrophysiol. 2001;12:680–5.
R. Arora and H.K. Koduri 137. Bhuiyan ZA, van den Berg MP, van Tintelen JP, Bink-Boelkens MT, Wiesfeld AC, Alders M, et al. Expanding spectrum of human RYR2-related disease: new electrocardiographic, structural, and genetic features. Circulation. 2007;116:1569–76. 138. Lee CH, Liu PY, Lin LJ, Chen JH, Tsai LM. Clinical characteristics and outcomes of hypertrophic cardiomyopathy in Taiwan: a tertiary center experience. Clin Cardiol. 2007;30:177–82. 139. Losi MA, Betocchi S, Aversa M, Lombardi R, Miranda M, et al. Determinants of atrial fibrillation development in patients with hypertrophic cardiomyopathy. Am J Cardiol. 2004;94:895–900. 140. Spitzer SG, Richter P, Knaut M, Schuler S. Treatment of atrial fibrillation in open heart surgery: the potential role of microwave energy. Thorac Cardiovasc Surg. 1999;47 Suppl 3:374–8. 141. White CM, Giri S, Tsikouris JP, Dunn A, Felton K, Reddy P, Kluger J. A comparison of two individual amiodarone regimens to placebo in open heart surgery patients. Ann Thorac Surg. 2002;74:69–74. 142. Almassi GH, Schowalter T, Nicolosi AC, Aggarwal A, Moritz TE, Henderson WG, et al. Atrial fibrillation after cardiac surgery: a major morbid event? Ann Surg. 1997;226:501–11. 143. Auer J, Weber T, Berent R, Ng CK, Lamm G, Eber B. Risk factors of postoperative atrial fibrillation after cardiac surgery. J Card Surg. 2005;20:425–31. 144. Tsikouris JP, Kluger J, Song J, White CM. Changes in P-wave dispersion and P-wave duration after open heart surgery are associated with the peak incidence of atrial fibrillation. Heart Lung. 2001;30:466–71. 145. Ishii Y, Schuessler RB, Gaynor SL, et al. Inflammation of atrium after cardiac surgery is associated with inhomogeneity of atrial conduction and atrial fibrillation. Circulation. 2005;111:2881–8. 146. Baker WL, White CM, Kluger J, Denowitz A, Konecny CP, Coleman CI. Effect of perioperative corticosteroid use on the incidence of postcardiothoracic surgery atrial fibrillation and length of stay. Heart Rhythm. 2007;4:461–8. 147. Halonen J, Halonen P, Jarvinen O, Taskinen P, Auvinen T, Tarkka M, et al. Corticosteroids for the prevention of atrial fibrillation after cardiac surgery: a randomized controlled trial. JAMA. 2007;297:1562–7. 148. Kalman JM, Munawar M, Howes LG, Louis WJ, Buxton BF, Gutteridge G, Tonkin AM. Atrial fibrillation after coronary artery bypass grafting is associated with sympathetic activation. Ann Thorac Surg. 1995;60:1709–15. 149. White HD, Antman EM, Glynn MA, Collins JJ, Cohn LH, Shemin RJ, Friedman PL. Efficacy and safety of timolol for prevention of supraventricular tachyarrhythmias after coronary artery bypass surgery. Circulation. 1984;70:479–84.
Importance of Left Atrial Imaging in Catheter Ablation of Atrial Fibrillation
32
Seil Oh, Youngjin Cho, and Eue-Keun Choi
Abstract
Isolation of pulmonary veins (PV) has become a major part of catheter ablation for patients with atrial fibrillation (AF). Pre-procedural information on the variable anatomy of the left atrium (LA) is important in proper planning of AF ablation. Multi-detector computed tomography (MDCT) or magnetic resonance imaging (MRI) can visualize anatomy of PV–LA junction, as well as impeditive endocardial structures such as ridge, cord-like structure, and diverticulum. Also, MDCT can disclose the anatomic relationship between the LA and neighboring vessels which not only cause incomplete ablation block by reducing conductive heating but also can be injured during the procedure. In this manner, MDCT/MRI contributes to successful ablation procedure, reduction of fluoroscopic and procedural time, and prevention of unexpected complications. Several adjuvant ablation procedures to improve outcomes of PV isolation require detailed information on the anatomic variations of the entire LA, and the importance of pre-procedural MDCT/MR is more emphasized. Recently, MDCT/MR images are integrated with electroanatomic mapping systems to improve the outcomes of AF ablation. Keywords
Atrial fibrillation • Left atrium • MDCT • MRI • Catheter ablation
Abbreviations AF CFAE CS EAM LA LAA LCx LIPV LSPV MDCT
Atrial fibrillation Complex fragmented atrial electrogram Coronary sinus Electroanatomic mapping Left atrium Left atrial appendage Left circumflex coronary artery Left inferior pulmonary vein Left superior pulmonary vein Multi-detector computed tomography
S. Oh, MD, PhD, FHRS (*) • Y. Cho, MD E.-K. Choi, MD, PhD Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea e-mail:
[email protected] A.S. Kibos et al. (eds.), Cardiac Arrhythmias, DOI 10.1007/978-1-4471-5316-0_32, © Springer-Verlag London 2014
MRI PV SNA
Magnetic resonance imaging Pulmonary vein Sinus nodal artery
Introduction Atrial fibrillation (AF) is the most common arrhythmia in clinical practice with an estimated prevalence of 0.4–1 % in the general population. AF is a costly public health problem and it increases the long-term risk of ischemic stroke, heart failure, and all-cause death [1]. Restoring sinus rhythm was considered to have potential to improve quality of life and reduce the risk of stroke and mortality, and thus restoring and maintaining sinus rhythm is a desirable therapeutic goal in treating AF. However, the use of antiarrhythmic drug often failed to do so in the long term and was even associated with increased mortality in a few studies [2, 3]. The establishment of the dominance in the region of PVs in triggering AF promoted the development 413
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of nonpharmacologic, ablation-based approaches [4]. In 2003, Pappone et al. [5] reported that circumferential pulmonary vein (PV) ablation, or PV isolation, significantly reduced the morbidity and mortality of AF patients compared to antiarrhythmic drug treatment, and therefore catheter ablation has now become a reasonable treatment for patients with symptomatic paroxysmal AF [1]. Nevertheless, PV isolation alone was not sufficient for the treatment of AF and also raised the issue of macroreentrant left atrial flutter [6]. Complications such as PV stenosis and esophageal injury are also a matter of concern [7, 8]. A comprehensive understanding of the left atrial (LA) anatomy can help improve the efficacy of ablation therapy and reduce complications. Furthermore, by adopting several adjuvant procedures such as mitral isthmus or complex fragmented atrial electrogram (CFAE) ablation [9, 10], catheter ablation of AF has become more complex and information on individualized anatomic characteristics may play an important role in successful ablation therapy. In this chapter, various anatomic characteristics of the LA and its neighboring structures which can influence ablation procedure along with the role of imaging modalities in catheter ablation of AF will be reviewed.
Visualization of the Left Atrial Structures Pulmonary Vein: Left Atrium Junction Since isolation of arrhythmogenic PV is the cornerstone of ablation therapy in patients with AF, visualization of the PV anatomy is the main goal of preoperative imaging, directly related to the ablation procedure. The number of main PVs, branching patterns, length of preostial portions of the PVs, and diameters of PV ostia may influence ablation therapy; thus preoperative information on the exact anatomy of the PVs using imaging modalities is essential in the proper planning of AF ablation. In general, pulmonary circulation drains into the LA through four separate pulmonary veins: two right-sided and two left-sided PVs. However, variant PV anatomy is not uncommon, with the prevalence reported to be up to 30 % [11]. Several studies using multi-detector computed tomography (MDCT) or magnetic resonance (MR) scanning have demonstrated variability in the number of main PVs [12–14]. The variant PV anatomy results from the under- or overincorporation of the common PV into the left dorsal atrium during gestation, and supernumerary PV is common on the right side (18–29 %), whereas a common PV ostium is frequently observed on the left side (6–35 %). The morphology of PV–LA junction is associated with the risk of developing PV stenosis, a well-recognized complication of AF ablation, and accessory PV requires extra caution due to the relatively small diameter. Small accessory vein from an independent atriovenous junction is at high risk of occlusion at the time of catheter ablation [15].
S. Oh et al.
Ostial diameter of the PVs can be measured on crosssectional images of MDCT or MRI. Ostial diameter of the superior PVs is larger than that of the inferior PVs, and the ostium is usually ellipsoid with a longer superio-inferior dimension. In patients with AF, the PV ostium is often funnelshaped, making it difficult to determine precise PV–LA border, and tends to be larger than in patients without AF [16]. The ostial diameter is as important as the number of the main PVs in terms of the risk of PV stenosis, and measuring the accurate diameter using pre-ablation MDCT or MR scanning is mandatory when utilizing circular or novel balloon catheters [17].
Impeditive Endocardial Structures Ridge and Cord-Like Structure With the assistance of the 3D reconstruction technique, MDCT or MR images acquired prior to ablation is able to provide detailed information on variant endocardial structures of the LA which hinder complete ablation block by disturbing stable catheter positioning. A ridge, protruded band-like structure on the endocardial surface, is a wellrecognized obstacle during AF ablation. Occasionally, underlying muscular bundle is additionally targeted after circumferential PV ablation as the isthmus of the reentry barrier [18]. Therefore, anatomical knowledge of these structures may assist physicians planning ablation therapy. Left Lateral Ridge The left lateral ridge, first described as the left terminal band by Artheur Keith [19], is actually a fold of left lateral atrial wall interposed between the left atrial appendage (LAA) and the left PV orifices. Morphologic studies in the postmortem hearts showed considerable anatomic variations of this structure, and the width of the ridge was reported to be 5.6 ± 0.4 mm at the superior level and 10.2 ± 0.5 mm at the inferior level [20]. The anatomy of the left lateral ridge can be well delineated by MDCT or MR imaging, and Mansour et al. [21] analyzed 30 MR angiography of AF patients to report the narrowest width between the left superior pulmonary vein (LSPV) and LAA as 3.7 ± 1.1 mm. Wongcharoen et al. [22] classified the morphology of the left lateral ridge using MDCT data from 96 individuals into two types. According to this study, the majority of the ridge extends from the superior portion of the LSPV orifice to the inferior portion of the left inferior PV (LIPV) (77 %), but there is a variation of the ridge extending from the superior portion of the LSPV orifice to the left intervenous saddle (23 %), causing great differences in the length of the ridge. This site is in itself critical in AF ablation, because it is often considered as the most challenging structure during ablation around left PVs. Recent data indicate that wide-area ablation, 1–2 cm away from the PV ostia, is more effective than ostial ablation [23]. However, complete block
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Importance of Left Atrial Imaging in Catheter Ablation of Atrial Fibrillation
around the left PV in wide-area ablation may be hindered by the variable morphology of the left lateral ridge, emphasizing better understanding of this structure. Anteroseptal Ridge The anteroseptal ridge arises from the septal raphe in front of the fossa ovalis and passes upward to the anterior wall of the LA and backward into the superior and posterior walls between the right and left PVs [24]. In addition to the previous pathological studies, recent studies have provided description of this structure using MDCT technique. The anteroseptal ridge is not always identifiable, and Chang et al. [25] reported that 12 (28 %) of the 43 MDCT data from AF patients who underwent ablation therapy showed prominent ridges at this site. The mean thickness of the ridges was 4.2 ± 2.2 mm, the length 44.3 ± 14.1 mm, and the width 3.0 ± 1.1 mm on the MDCT images. In another study, the ridge was observed on the anteromedial wall of the LA in 8.6 % of the MDCT images from 140 subjects, with 2.1 ± 0.6 mm of thickness [26]. Although the anteroseptal ridge is not encountered in the usual circumferential ablation procedure around PVs, it may afflict additional linear ablation creation on the LA roof, septum, or anterior wall. Since the muscular bundle at this site has been highlighted as the functional barrier in a zone of double potentials during LA flutter after PV isolation [18, 25], the increasing frequency of additional ablation across this site after PV isolation is expected. Cord-Like Structure Cord-like structures may be encountered in the LA during AF ablation. They are more frequently identified on the medial side of the LA anterior wall on MDCT images, with the incidence of about 3 % [26]. This structure is considered as a part of the anteroseptal muscular bundle or a remnant structure of fossa ovalis. Although the electrophysiologic characteristics and the exact histologic composition of this structure are not clear, it deserves extra attention due to its potential to act as a mechanical obstacle.
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lence was not associated with other congenital cardiac abnormalities, presence of AF, or the LA chamber size. Although diverticula and accessory appendages can be found at any location within the LA, it seems that diverticula are more commonly identified in the superior anterior wall and accessory appendages in the left lateral inferior wall of the LA [27]. These site preferences are noteworthy in that additional linear ablation after PV isolation is frequently created at the left lateral inferior wall to terminate a macro-reentrant atrial flutter. Besides, many of the LA diverticula are located near the PVs and LA appendage, and Peng et al. [28] reported the mean distance from the orifice of antero–superior LA diverticulum to the right superior PV orifice as 9.0 ± 4.1 mm. Occasionally the roof of the LA forms drastic concavity without discernible opening orifice. These pouches are observed in about 15 % of MDCT scans [22].
Left Atrial Appendage Since catheter ablation is contraindicated in patients with thrombi within the LA appendage (LAA), preoperative visualization of the LAA is of critical importance, particularly in patients with persistent AF or patients who are in AF at the time of procedure. MDCT or MRI can be utilized for this purpose, but transesophageal echocardiography is considered the gold standard to date [30]. The variable location and morphology of the LAA has other meanings in AF ablation. The spatial relationship between the LAA and the LSPV determines the morphology of the left lateral ridge, which considerably affects the procedural difficulty of PV isolation. Recent investigations demonstrated extra-PV foci of AF originating from the LAA, which required elimination of these intra-LAA foci and highlighted the importance of preoperative visualization of the LAA [31].
Neighboring Structures of the Left Atrium Vascular Structures
Diverticulum and Accessory Appendage Atrial diverticula and accessory appendages are saclike anatomic variants outpouching from the endocardial lining of the atrium. These structures may entrap ablation catheters during AF ablation, contributing to incomplete block or complications such as cardiac tamponade. MDCT is an effective imaging modality for visualizing these structures. The shape of an atrial diverticulum is comparable to an accessory appendage on MDCT or MR images, but accessory appendages can be distinguished by irregular contours suggestive of the presence of pectinate muscles, in contrast to smooth contours of atrial diverticula. A diverticulum is a very common anatomic variant, and 19–36 % of patients with or without AF showed at least one LA diverticulum on cardiac MDCT images of recent studies [27–29]. This preva-
Disclosing the anatomic relationship between the LA and neighboring vascular structures using MDCT angiography is recommended for the AF patients planning ablation therapy, because adjacent vessels not only cause incomplete ablation block by reducing conductive heating, but also can be injured during the procedure.
Coronary Sinus and Left Circumflex Coronary Artery The coronary sinus (CS) is often used as an epicardial access for ablation catheter, and anatomic variations of the CS need to be addressed before ablation at the left lateral mitral isthmus [9]. The left circumflex coronary artery (LCx) has been noticed as a major heat sink in AF ablation, with its large diameter and
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a
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b
Fig. 32.1 (a) Visualization of the sinus nodal arteries (green arrow heads) from the right coronary artery (open arrow) and (b) from the left circumflex artery (arrow) in reconstructed MDCT images. Note the
proximity of the sinus nodal arteries to the LA in both cases. LA indicates left atrium, Ao aorta, LV left ventricle
rapid blood flow. The LCx has received particular attention in lateral mitral isthmus ablation because of its proximity to the site, and the mean depth from the endocardium of the lateral mitral isthmus was 4.6 ± 3.5 mm in a study analyzing MDCT data [26]. When interposed between the CS and the mitral isthmus, the LCx prevents successful mitral isthmus ablation, both from the CS and endocardial approaches [32].
Esophagus
Sinus Nodal Artery The sinus nodal artery (SNA) is important to maintain sinus rhythm, and thus delivering radio-frequency energy over the SNA requires extra caution. The route of the SNA is particularly of interest in ablation frequently targeting anterior wall of the LA, such as CFAE or low voltage area ablation [10, 33]. The previous studies in postmortem hearts demonstrated considerable variability in origins and routes of the SNA [34, 35]. In a recent study by Cho et al. [26], MDCT angiography effectively visualized various origins and routes of the SNA, and the results corresponded well with the previous pathological studies. In this study, about half of the SNA originated from the LCx and the SNA was easily encountered at the anterior wall of the LA. Even when the SNA arose from the right coronary artery (RCA), the SNA was identifiable at the medial side of the LA anterior wall, because it runs to the medial side of the right atrial appendage first and then supplies the sinus node region (Fig. 32.1). The average depth of the SNA at medial anterior section was 2.5 ± 1.1 mm. About 10 % of the SNA originates from mid- or distal LCx and crosses the entire anterior wall to supply the sinus nodal region.
The esophagus is located behind the LA in various positions between the left and right PVs and is surrounded by the esophageal arteries and the nerve plexus. Thus, delivering ablation heat near this site may result in esophageal wall damage or affect its innervation or blood supply. Atrioesophageal fistula is well-recognized as a rare (less than 0.25 %), but lifethreatening complication of AF ablation. Although the risk of atrioesophageal fistula is known to be associated with procedural factors, such as maximal energy delivered at the posterior wall and additional LA linear lesion creation, a recent investigation demonstrated a significant association between the LA–esophageal distance on CT image and the development of the esophageal ulceration, potential precursor lesions of the fistula [36]. Nevertheless, the common application of MDCT or MR imaging regarding this issue is diagnosing the fistula in suspected patients.
MDCT/MR and Clinical Outcomes of Ablation Therapy The experts of Heart Rhythm Society task force agreed on that CT/MR may facilitate AF ablation by the following manners: (1) identifying anatomic features of the PVs and LA pre-procedurally; (2) disclosing the anatomic relationship between the LA, esophagus, and adjacent vascular structures; (3) providing an understanding of the degree of
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Importance of Left Atrial Imaging in Catheter Ablation of Atrial Fibrillation
morphological remodeling of the PVs and LA; and (4) assisting in the detection of post-procedure complications [16]. As expected, several studies demonstrated reduction not only in the fluoroscopic and procedural time but also in the risk of unexpected complications with the use of pre-procedural MDCT evaluation of the LA and the PVs [15, 37]. Although intracardiac echocardiography is commonly used to assist the transseptal approach during AF ablation, MDCT can also help guide the transseptal puncture, especially in cases of abnormal positioning or angulation of the interatrial septum [15]. Currently, electroanatomic mapping (EAM) systems which provide online electrophysiologic data and allow tracking of mapping/ablation catheters are widely available, and MDCT/MR images improve outcomes of AF ablation, being integrated into an EAM system [38, 39]. MDCT/MR images may predict clinical outcomes after AF ablation. LA dimensions, PV dimensions, and PV anatomy evaluated in pre-procedural MDCT images are the parameters associated with the clinical outcome of catheter ablation treatment of AF [40]. Lastly, MDCT is a very useful imaging modality in performing post-procedural assessment, especially in evaluating the development of PV stenosis [41].
Summary Treatment for patients with AF has evolved and catheter ablation is now a commonly performed, reasonable treatment. Isolation of arrhythmogenic PV is the cornerstone of AF ablation, and thus pre-procedural knowledge on the variable anatomy of the PVs and its neighboring structures with the assistance of MDCT/MRI image is important in the proper planning of AF ablation. This can contribute to successful ablation procedure, reduction of fluoroscopic and procedural time, and prevention of unexpected complications. Several adjuvant ablation procedures to improve outcomes of PV isolation requires detailed information on the anatomic variations of the entire LA as well as those around the PVs, and the importance of pre-procedural MDCT/MR is more emphasized. Recently, MDCT/MR images are integrated with EAM systems to improve the outcomes of AF ablation.
References 1. Fuster V, Ryden LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation. 2006;114(7):e257–354. Epub 2006/08/16.
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2. Corley SD, Epstein AE, DiMarco JP, Domanski MJ, Geller N, Greene HL, et al. Relationships between sinus rhythm, treatment, and survival in the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Study. Circulation. 2004;109(12):1509–13. Epub 2004/03/10. 3. Flaker GC, Blackshear JL, McBride R, Kronmal RA, Halperin JL, Hart RG. Antiarrhythmic drug therapy and cardiac mortality in atrial fibrillation. The Stroke Prevention in Atrial Fibrillation Investigators. J Am Coll Cardiol. 1992;20(3):527–32. Epub 1992/09/01. 4. Haissaguerre M, Jais P, Shah DC, Takahashi A, Hocini M, Quiniou G, et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med. 1998;339(10): 659–66. Epub 1998/09/03. 5. Pappone C, Rosanio S, Augello G, Gallus G, Vicedomini G, Mazzone P, et al. Mortality, morbidity, and quality of life after circumferential pulmonary vein ablation for atrial fibrillation: outcomes from a controlled nonrandomized long-term study. J Am Coll Cardiol. 2003;42(2):185–97. Epub 2003/07/24. 6. Gerstenfeld EP, Callans DJ, Dixit S, Russo AM, Nayak H, Lin D, et al. Mechanisms of organized left atrial tachycardias occurring after pulmonary vein isolation. Circulation. 2004;110(11):1351–7. Epub 2004/09/09. 7. Robbins IM, Colvin EV, Doyle TP, Kemp WE, Loyd JE, McMahon WS, et al. Pulmonary vein stenosis after catheter ablation of atrial fibrillation. Circulation. 1998;98(17):1769–75. Epub 1998/10/27. 8. Cappato R, Calkins H, Chen SA, Davies W, Iesaka Y, Kalman J, et al. Worldwide survey on the methods, efficacy, and safety of catheter ablation for human atrial fibrillation. Circulation. 2005;111(9):1100–5. Epub 2005/02/23. 9. Jais P, Hocini M, Hsu LF, Sanders P, Scavee C, Weerasooriya R, et al. Technique and results of linear ablation at the mitral isthmus. Circulation. 2004;110(19):2996–3002. Epub 2004/11/03. 10. Oral H, Chugh A, Yoshida K, Sarrazin JF, Kuhne M, Crawford T, et al. A randomized assessment of the incremental role of ablation of complex fractionated atrial electrograms after antral pulmonary vein isolation for long-lasting persistent atrial fibrillation. J Am Coll Cardiol. 2009;53(9):782–9. Epub 2009/02/28. 11. Tops LF, Schalij MJ, Bax JJ. Imaging and atrial fibrillation: the role of multimodality imaging in patient evaluation and management of atrial fibrillation. Eur Heart J. 2010;31(5):542–51. Epub 2010/02/04. 12. Marom EM, Herndon JE, Kim YH, McAdams HP. Variations in pulmonary venous drainage to the left atrium: implications for radiofrequency ablation. Radiology. 2004;230(3):824–9. Epub 2004/01/24. 13. Mansour M, Holmvang G, Sosnovik D, Migrino R, Abbara S, Ruskin J, et al. Assessment of pulmonary vein anatomic variability by magnetic resonance imaging: implications for catheter ablation techniques for atrial fibrillation. J Cardiovasc Electrophysiol. 2004;15(4):387–93. Epub 2004/04/20. 14. Kato R, Lickfett L, Meininger G, Dickfeld T, Wu R, Juang G, et al. Pulmonary vein anatomy in patients undergoing catheter ablation of atrial fibrillation: lessons learned by use of magnetic resonance imaging. Circulation. 2003;107(15):2004–10. Epub 2003/04/19. 15. Niinuma H, George RT, Arbab-Zadeh A, Lima JA, Henrikson CA. Imaging of pulmonary veins during catheter ablation for atrial fibrillation: the role of multi-slice computed tomography. Europace. 2008;10 Suppl 3:iii14–21. Epub 2008/11/05. 16. Calkins H, Brugada J, Packer DL, Cappato R, Chen SA, Crijns HJ, et al. HRS/EHRA/ECAS expert Consensus Statement on catheter and surgical ablation of atrial fibrillation: recommendations for personnel, policy, procedures and follow-up. A report of the Heart Rhythm Society (HRS) Task Force on catheter and surgical ablation of atrial fibrillation. Heart Rhythm. 2007;4(6):816–61. 17. Reddy VY, Neuzil P, Themistoclakis S, Danik SB, Bonso A, Rossillo A, et al. Visually-guided balloon catheter ablation of atrial fibrillation: experimental feasibility and first-in-human multicenter clinical outcome. Circulation. 2009;120(1):12–20. Epub 2009/06/24.
418 18. Marrouche NF, Natale A, Wazni OM, Cheng J, Yang Y, Pollack H, et al. Left septal atrial flutter: electrophysiology, anatomy, and results of ablation. Circulation. 2004;109(20):2440–7. Epub 2004/05/12. 19. Keith A. An account of the structures concerned in the production of the jugular pulse. J Anat. 1907;42(Pt 1):1–25. Epub 1907/10/01. 20. Cabrera JA, Ho SY, Climent V, Sanchez-Quintana D. The architecture of the left lateral atrial wall: a particular anatomic region with implications for ablation of atrial fibrillation. Eur Heart J. 2008;29(3): 356–62. Epub 2008/02/05. 21. Mansour M, Refaat M, Heist EK, Mela T, Cury R, Holmvang G, et al. Three-dimensional anatomy of the left atrium by magnetic resonance angiography: implications for catheter ablation for atrial fibrillation. J Cardiovasc Electrophysiol. 2006;17(7):719–23. Epub 2006/07/14. 22. Wongcharoen W, Tsao HM, Wu MH, Tai CT, Chang SL, Lin YJ, et al. Morphologic characteristics of the left atrial appendage, roof, and septum: implications for the ablation of atrial fibrillation. J Cardiovasc Electrophysiol. 2006;17(9):951–6. Epub 2006/09/05. 23. Arentz T, Weber R, Burkle G, Herrera C, Blum T, Stockinger J, et al. Small or large isolation areas around the pulmonary veins for the treatment of atrial fibrillation? results from a prospective randomized study. Circulation. 2007;115(24):3057–63. Epub 2007/06/15. 24. Papez JW. Heart musculature of the atria. Am J Anat. 1920;27(3): 255–85. 25. Chang SL, Tai CT, Lin YJ, Wongcharoen W, Lo LW, Lee KT, et al. The role of left atrial muscular bundles in catheter ablation of atrial fibrillation. J Am Coll Cardiol. 2007;50(10):964–73. Epub 2007/09/04. 26. Cho Y, Lee W, Park EA, Oh IY, Choi EK, Seo JW, et al. The anatomical characteristics of three different endocardial lines in the left atrium: evaluation by computed tomography prior to mitral isthmus block attempt. Europace. 2012;14(8):1104–11. Epub 2012/03/16. 27. Abbara S, Mundo-Sagardia JA, Hoffmann U, Cury RC. Cardiac CT assessment of left atrial accessory appendages and diverticula. AJR Am J Roentgenol. 2009;193(3):807–12. Epub 2009/08/22. 28. Peng LQ, Yu JQ, Yang ZG, Wu D, Xu JJ, Chu ZG, et al. Left atrial diverticula in patients referred for radiofrequency ablation of atrial fibrillation: assessment of prevalence and morphologic characteristics by dual-source computed tomography. Circ Arrhythm Electrophysiol. 2012;5(2):345–50. 29. Wan Y, He Z, Zhang L, Li B, Sun D, Fu F, et al. The anatomical study of left atrium diverticulum by multi-detector row CT. Surg Radiol Anat. 2009;31(3):191–8. Epub 2008/10/17. 30. Kim YY, Klein AL, Halliburton SS, Popovic ZB, Kuzmiak SA, Sola S, et al. Left atrial appendage filling defects identified by multidetector computed tomography in patients undergoing radiofrequency pulmonary vein antral isolation: a comparison with transesophageal
S. Oh et al.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
echocardiography. Am Heart J. 2007;154(6):1199–205. Epub 2007/11/24. Takahashi Y, Sanders P, Rotter M, Haissaguerre M. Disconnection of the left atrial appendage for elimination of foci maintaining atrial fibrillation. J Cardiovasc Electrophysiol. 2005;16(8):917–9. Epub 2005/08/17. Yokokawa M, Sundaram B, Garg A, Stojanovska J, Oral H, Morady F, et al. Impact of mitral isthmus anatomy on the likelihood of achieving linear block in patients undergoing catheter ablation of persistent atrial fibrillation. Heart Rhythm. 2011;8(9):1404–10. Pak H-N, Oh YS, Lim HE, Kim Y-H, Hwang C. Comparison of voltage map-guided left atrial anterior wall ablation versus left lateral mitral isthmus ablation in patients with persistent atrial fibrillation. Heart Rhythm. 2011;8(2):199–206. Pardo Meo J, Scanavacca M, Sosa E, Correia A, Hachul D, Darrieux F, et al. Atrial coronary arteries in areas involved in atrial fibrillation catheter ablation. Circ Arrhythm Electrophysiol. 2010;3(6):600–5. Epub 2010/09/21. Ortale JR, Paganoti Cde F, Marchiori GF. Anatomical variations in the human sinuatrial nodal artery. Clinics (Sao Paulo). 2006;61(6):551–8. Epub 2006/12/26. Martinek M, Meyer C, Hassanein S, Aichinger J, Bencsik G, Schoefl R, et al. Identification of a high-risk population for esophageal injury during radiofrequency catheter ablation of atrial fibrillation: procedural and anatomical considerations. Heart Rhythm. 2010;7(9):1224–30. Epub 2010/03/02. Sra J, Narayan G, Krum D, Malloy A, Cooley R, Bhatia A, et al. Computed tomography-fluoroscopy image integration-guided catheter ablation of atrial fibrillation. J Cardiovasc Electrophysiol. 2007;18(4):409–14. Epub 2007/02/08. Kistler PM, Rajappan K, Jahngir M, Earley MJ, Harris S, Abrams D, et al. The impact of CT image integration into an electroanatomic mapping system on clinical outcomes of catheter ablation of atrial fibrillation. J Cardiovasc Electrophysiol. 2006;17(10):1093– 101. Epub 2006/09/23. Della Bella P, Fassini G, Cireddu M, Riva S, Carbucicchio C, Giraldi F, et al. Image integration-guided catheter ablation of atrial fibrillation: a prospective randomized study. J Cardiovasc Electrophysiol. 2009;20(3):258–65. Epub 2009/03/06. den Uijl DW, Tops LF, Delgado V, Schuijf JD, Kroft LJ, de Roos A, et al. Effect of pulmonary vein anatomy and left atrial dimensions on outcome of circumferential radiofrequency catheter ablation for atrial fibrillation. Am J Cardiol. 2011;107(2):243–9. Epub 2011/01/08. Saad EB, Rossillo A, Saad CP, Martin DO, Bhargava M, Erciyes D, et al. Pulmonary vein stenosis after radiofrequency ablation of atrial fibrillation: functional characterization, evolution, and influence of the ablation strategy. Circulation. 2003;108(25):3102–7. Epub 2003/11/19.
Atrial Fibrillation Ablation: From Guidelines to Clinical Reality
33
Joseph M. Lee and Steven M. Markowitz
Abstract
Atrial fibrillation (AF) results in electrical and anatomical remodeling that leads to progression of the arrhythmia and deterioration in mechanical function. Catheter ablation has evolved as an effective treatment that can maintain sinus rhythm and alleviate symptoms in many patients. Randomized studies show that catheter ablation is superior to antiarrhythmic drug therapy in selected patients with AF, particularly those who have failed prior antiarrhythmic drug treatment. Guidelines currently support catheter ablation in patients who have recurrent AF despite treatment with an antiarrhythmic drug, and ablation is also considered reasonable in optimal candidates who have not been exposed to an antiarrhythmic drug. The cornerstone of ablation involves pulmonary vein isolation, because the proximal pulmonary veins harbor the most common triggers for paroxysmal AF. Adjunctive lesion sets may be required in patients with more advanced disease. Long-term studies of catheter ablation reveal a high recurrence rate of AF and atrial tachycardias, especially among those with persistent and longlasting persistent AF, and multiple procedures may be required to achieve long-term control. Further investigation is needed to optimize lesions sets and procedural endpoints in order to minimize recurrences, to develop technologies to deliver better transmural lesions, and to develop techniques that further minimize procedure-related complications. Keywords
Atrial fibrillation • Pulmonary vein isolation • Catheter ablation
Background Atrial fibrillation (AF) is the most common arrhythmia affecting 1–2 % of the general population, and its prevalence is expected to increase at least twofold by 2050 [1]. This projected increase in prevalence is due to the aging population and increasing incidence of hypertension, heart failure,
J.M. Lee, MD, MSc (*) • S.M. Markowitz, MD (*) Division of Cardiology, Department of Medicine, Weill Cornell Medical College, 525 East 68th Street, New York, NY 10065, USA Division of Cardiac Electrophysiology Laboratory, New York Presbyterian Hospital, New York, NY, USA e-mail:
[email protected];
[email protected] A.S. Kibos et al. (eds.), Cardiac Arrhythmias, DOI 10.1007/978-1-4471-5316-0_33, © Springer-Verlag London 2014
ischemic heart disease, obesity, diabetes mellitus, sleep apnea, and renal disease. AF is associated with a fivefold increased risk of stroke and excess mortality. Over one-third of hospital admissions for arrhythmias in developed countries are attributed to AF, largely because of exacerbations of heart failure and thromboembolic complications. AF is a progressive disease that manifests clinically as disorganized electrical activity and impaired mechanical function in the atria. Paroxysmal AF is defined by recurrent episodes that terminate spontaneously in less than 7 days. Persistent AF lasts more than 7 days or requires an intervention for cardioversion, whereas long-lasting persistent AF lasts greater than 1 year [2, 3]. Permanent AF is diagnosed once cardioversions have failed or rhythm control strategies are no longer considered. This classification scheme categorizes patients by their most frequent duration, but patients may transition between paroxysmal and persistent forms of 419
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AF. In a prospective sub-study of 1,219 paroxysmal AF patients, 15 % of patients progressed to persistent or permanent AF, which was driven by comorbidities validated by the HATCH score: hypertension, age (>75 years), TIA/stroke, COPD, and heart failure [4]. The management of AF consists of preventing thromboembolism, alleviating symptoms, and treating the underlying heart disease or precipitating conditions [3]. Rate control is often sufficient to alleviate symptoms, maintain adequate cardiac output, and prevent tachycardia-induced cardiomyopathy. Randomized clinical trials of rhythm control with antiarrhythmic drugs versus rate control have not demonstrated improved survival or reduced thromboembolic complications with rhythm control [5]. However, a sub-study of the AFFIRM (Atrial Fibrillation Follow-up Investigation of Rhythm Management) trial showed that normal sinus rhythm conferred a survival advantage (HR 0.53), which was offset by the adverse effects from antiarrhythmic medications (HR 1.49) [6]. This analysis suggested that maintenance of sinus rhythm might ultimately prevent complications of AF, but antiarrhythmic drugs might not be the best means to achieve this goal. In the AFFIRM trial, antiarrhythmic treatment produced freedom from AF at 1 year in 34–66 % of patients, depending on the antiarrhythmic drug used, with the amiodarone and dofetilide demonstrating higher rates of maintaining sinus rhythm compared to sotalol, propafenone, and flecainide. Furthermore, the use of these medications may be limited by the presence of underlying structural heart disease, such as congestive heart failure, left ventricular hypertrophy, and coronary artery disease. Given the progressive course of AF into a chronic disease and the suboptimal efficacy and toxicity associated with antiarrhythmic medications, catheter ablation has evolved into a realistic treatment option for many patients with AF. This chapter will present the rationale for the development of catheter ablation of AF, discuss techniques and outcomes of this procedure, and review recent practice guidelines and the translation of these guidelines in realistic clinical practice.
Pathophysiology of Atrial Fibrillation AF is dependent on both triggers for its initiation and a diseased atrial substrate for its perpetuation. Within days of AF, there is both a decline in intracellular calcium and sodium and an increase in intracellular potassium due to downregulation of L-type calcium channels and upregulation of rectifier potassium channels [7]. This results in shortening of the atrial effective refractory period, which causes the atria to be vulnerable to after-depolarizations. If AF remains persistent, high atrial rates result in intracellular calcium overload, which can give rise to inactivation of calcium channels and oxidative stress, and this can lead to compromised contractile function, loss of atrial systole, and further maintenance
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of AF [8]. During persistent AF, apoptosis, necrosis and myolysis cause the injured atrial myocardium to undergo compensatory hypertrophy, fetal dedifferentiation, left atrial dilatation, deposition of extracellular matrix, muscle fibrosis, and inflammation, all of which results in a diseased atrial substrate that is more prone to arrhythmogenesis [9]. Ectopy from the pulmonary veins (PVs) has become recognized as the dominant trigger of AF. These tubular structures arise from the embryologic sinus venosus and extend into the left atrial wall to form funnel-shaped PV antra [10], which are surrounded by myocardial sleeves. These sleeves are made up of muscle fibers that are arranged vertically, horizontally, and obliquely and are observed to be most thick in the inferior carina of the superior PVs and the superior carina of the inferior PVs [11]. Spontaneous firing of the PVs can result in transmission of electrical impulses into the left atrium (Fig. 33.1) [12, 13]. The clinical importance of the PVs in human AF was identified in case series by Haissaguerre et al. in the mid-1990s, in which the PVs were discovered to be the predominant trigger of AF in over 94 % of patients [14]. PV potentials are sharp, high-frequency electrograms that represent electrical activation of myocardial sleeves within the PVs. Histologic analysis of the proximal PVs reveals both complex fiber orientation and discontinuities that create nonuniform anisotropy and conduction delays that promote AF [15]. Functional electrophysiology studies on PVs from patients with AF revealed significantly shorter effective and functional refractory periods and longer conduction times [16]. Untreated, 15–30 % patients with paroxysmal AF will progress to persistent AF over the course of 1–3 years [4, 17]. The electroanatomical substrate in persistent AF is complex, and several mechanisms have been proposed to explain this arrhythmia. One proposed mechanism of persistent AF is the multiple wavelet hypothesis, in which the arrhythmia is sustained by multiple reentrant waves that conduct in a chaotic pattern in the atrial myocardium [9]. These wavelets are augmented by the generation of new daughter waves and attenuated by fusion, blocking, and interference with existing waves [18]. Another proposed mechanism involves dominant rotors that activate at rapid frequencies and spawn complex wave fronts, described as fibrillatory conduction, to other regions of the atria [19]. Spectral studies in patients with paroxysmal AF reveal dominant frequencies confined to the PVs, whereas in persistent AF, dominant frequencies are found predominantly in the body of the left atrium [20].
Evolution of Catheter Ablation for Atrial Fibrillation MAZE surgery evolved as a procedure to prevent multiple wavelets and thus avert sustained AF. The original MAZE “cut and sew” procedure created complex barriers to allow
33 Atrial Fibrillation Ablation: From Guidelines to Clinical Reality Fig. 33.1 Initiation of atrial fibrillation (AF)/atrial tachycardia (AT) with a trigger arising from the right superior pulmonary vein (RSPV). Shown are two surface leads (aVF and V1), five intracardiac electrograms from the high to low right atrium (HRA to LRA), five electrograms from the coronary sinus (pCS to dCS), and ten electrograms from a circular mapping catheter in the right superior pulmonary vein (pRSPV through dRSPV). After three sinus beats, a premature PV potential appears on the distal RSPV (dRSPV), which initiates an irregular AT (arrow) that later transforms to AF
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aVF V1 HRA LRA pCS dCS pRSPV
dRSPV
impulses from the sinus node to reach the atrioventricular node while preventing large macroreentrant wavelets [21– 23]. This procedure demonstrated long-term efficacy of up to 75–90 % freedom from AF during a 15-year follow-up. A contemporary iteration of the MAZE procedure, the Cox MAZE III, entailed electrically isolating all the PVs and posterior left atrium in addition to other lines (from the isolated PVs to the mitral annulus, to the atrial appendages, an intercaval line in the right atrium, and to the tricuspid annulus). More recent developments involve using energy sources such as radiofrequency or cryoablation to create these lesion sets. Small randomized trials using various surgical approaches and different energy sources identified success rates between 58 and 94 % [24]. The MAZE lesion set, followed by the subsequent discovery of PV triggers, laid the groundwork for the development of catheter ablation techniques for AF. Focal ablation or direct targeting of a PV rhythm at the earliest site of activation within the PV was the first evidence that AF could be terminated with catheter ablation [14, 25]. This approach was limited by the inability to reliably reinduce the same PV trigger site and the recognition that ectopy from more than one PV site can trigger AF [26]. Electrically isolating the PVs from the left atrium with segmental ablation became the next strategy for treating AF. Entrance block with complete elimination or dissociation of these PV potentials required ablation of 30–80 % of the PV circumference. This technique entails placement of a circular mapping catheter within the PV and performing catheter ablation at the PV ostium until there is disappearance of PV potentials on the mapping catheter [27]. In a study of 110 patients who underwent segmental catheter ablation, 65 % were free of recurrent AF in the absence of antiarrhythmic drug therapy [28]. Isolation of all PVs appears to be necessary, in that patients who do not
have electrical isolation of all PVs have a lower long-term success rate [29, 30]. The technique of ostial PV isolation is limited by PV stenosis, high recurrence rates due to PV reconnection, and the presence of new triggers proximal to the site of ablation. The development of electroanatomical mapping systems facilitated the ability to perform an anatomical guided approach to catheter ablation of AF (Fig. 33.2) [31], in which circumferential ablation of all the PVs could now be reliably performed [32]. Complete circumferential electrical isolation of all the veins has a significantly lower recurrence rate when compared with segmental catheter ablation. In a study of 100 AF patients, freedom from arrhythmia symptoms at 1 year for segmental and circumferential ablation was 31 and 57 %, respectively [33]. In another study with 80 symptomatic AF patients, segmental ostial ablation resulted in an arrhythmia-free rate of 67 % at 6 months, compared to 88 % with circumferential PV isolation [34]. Awareness of PV stenosis and triggers arising from the PV antrum led to the development of wider encirclement of the PVs. PV antral isolation (PVAI) entails performing a wide circumferential ablation of ipsilateral PV pairs that is usually spaced 1–2 cm outside the PV ostia (Fig. 33.2). This technique requires the ability to localize the PV ostia using electrogram analysis and imaging such as intracardiac echocardiography, selective PV angiography, and electroanatomical mapping [32, 35]. Wider encirclement electrically isolates the PVs, arrhythmogenic triggers, and ganglionated plexi arising from the left atrial roof, posterior wall, and the intra-atrial septum [36]. In addition, this approach decreases the risk of PV stenosis [37]. In a randomized clinical trial of 110 AF patients who underwent a large antral versus ostial ablation of the PVs, freedom from symptomatic AF was 67 and 49 %, respectively. This higher success rate was
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Fig. 33.2 Electroanatomical maps of the left atrium in posteroanterior (PA) projection show lesions sets for pulmonary vein isolation. The left panel demonstrates pulmonary vein antral isolation (PVAI) displayed in a Carto 3
map. The right panel shows pulmonary vein isolation (PVI) displayed in a NAVX Ensite electroanatomical mapping. Red and white dots show circumferential radiofrequency lesions around all four pulmonary veins
attributed to local denervation or isolation of triggers and rotors that are found between the PV antrum and the posterior left atrial wall [38, 39]. Complete encirclement of the PVs is the cornerstone for catheter ablation for AF [2, 3]. Although PV triggers constitute over 90 % of triggers of paroxysmal AF, catheter ablation of inducible non-PV triggers has also been shown to be required in some patients [40–42]. Similar to the PVs, other thoracic veins (the coronary sinus, superior vena cava, the ligament of Marshall) have the capability to initiate and conduct electrical activity into the surrounding myocardium. Other non-PV trigger sites include but are not limited to the posterior left atrial wall, crista terminalis, left atrial appendage, and interatrial septum [40, 42–44]. Ganglionated plexi (GP) include both sympathetic and parasympathetic inputs from the autonomic nervous system that modulate left atrial electrical properties and can trigger AF in some patients. Four major GP sites have been identi-
fied in the epicardial fat pads near the PV ostium: superior left GP, inferior left GP, anterior right GP, and the inferior right GP [45]. High-frequency stimulation or endocardial ablation at these sites can induce profound vagal responses, characterized by sinus suppression and/or atrioventricular block. Animal studies have demonstrated that electrical stimulation of GPs can initiate AF, which suggests that autonomic inputs can trigger PV firing to initiate AF [46]. Since the location of GPs can be localized during catheter ablation by high-frequency pacing protocols, investigators have proposed that the abolition of the parasympathetic response after ablation can be used as an endpoint for catheter ablation. One study of patients with drug-resistant paroxysmal AF compared PV isolation alone with ablation of the GPs combined with a standard PV isolation, and AF-free survival rates were 99 and 85 %, respectively [47, 48]. Given that wide circumferential catheter ablation usually contains the majority of GPs, it is possible that autonomic modulation
33 Atrial Fibrillation Ablation: From Guidelines to Clinical Reality
contributes to the effectiveness of wide area circumferential ablation. The lower efficacy of PV isolation in persistent and longlasting persistent AF has led to the development of other ablation strategies in attempts to target the substrate that is essential to the maintenance of AF. One approach involves targeting complex fractionated electrograms (CFAEs) during AF, which are low-amplitude signals (between 0.06 and 0.25 mV) with a very short cycle lengths (<120 ms). Such electrograms are commonly found in certain atrial locations, namely, at the antrum of the left atrial appendage, inferior left atrium, coronary sinus, intra-atrial septum, and PV ostia. Controversy exists about the genesis of CFAE signals, which could be generated by focal rotors or by passive fibrillatory conduction, and current technology is incapable of distinguishing sites that are critical for maintaining AF from areas of complex conduction [49]. Endpoints for catheter ablation of CFAEs include elimination of the CFAEs and acute termination of AF with ablation. A single-center study of patients with both paroxysmal and persistent AF showed that catheter ablation of CFAEs maintained sinus rhythm in 91 % of patients at 1 year [50]. For those patients with long-lasting persistent AF who underwent CFAE ablation, 71 % maintained sinus rhythm at 1 year [50]. Lower success rates have been reported from other centers. In one study involving CFAE ablation, only 33 % of patients remained in sinus rhythm during a 14-month follow-up period [51]. These non-reproducible results may be due to the diverse mechanisms that produce CFAEs and different definitions of CFAEs employed by various investigators. Linear lesions are another form of substrate modification that can further “debulk” the left atrium and sometimes convert AF into atrial tachycardias or sinus rhythm. These linear lesions are drawn from an isolated PV to an electrically inert
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structure, such as the mitral valve annulus. The left atrial roof line is the most common linear lesion performed and is created between the isolated left and right superior PVs and has been shown to improve maintenance of sinus rhythm [52–54]. The mitral isthmus line is typically created between the isolated left inferior PV ostium and the lateral mitral annulus. This mitral line often requires both endocardial and epicardial ablation (via the coronary sinus) due to the presence of epicardial muscular connections and thicker myocardium in this region [55]. Alternatively, an anterior line may be created from the isolated left or right superior PVs near the roof and the anterior mitral valve annulus. A major limitation of linear lesions is proarrhythmia due to gaps along the ablated lines [56]. These various lesion sets and ablative approaches can be combined in a “stepwise approach” to treat persistent AF. This strategy consists of PV isolation, followed by ablation of complex electrograms, identification of apparent focal drivers, and linear lesions, with the endpoint of restoring sinus rhythm. During the course of ablation, the AF cycle length, as measured in an atrial appendage, typically slows, and atrial tachycardias frequently occur as transitional rhythms. Structures with the greatest impact on the AF cycle length and conversion to the organized rhythms include the left atrial appendage, the coronary sinus, and PV-atrial junction. These sites are also common locations of focal atrial tachycardias that demonstrate characteristics of localized reentry. Using this stepwise approach in 60 patients, Haissaguerre et al. were able to terminate long-lasting persistent AF in 87 % [57]. With an average follow-up of 11 months, 95 % remained in sinus rhythm, although repeat procedures were required in 23 patients [58]. The different lesion sets employed for catheter ablation of AF are summarized in Table 33.1.
Table 33.1 Lesion sets for AF ablation Etiology PV trigger PV trigger PV trigger Non-PV trigger Rotors PV triggers and substrate PV triggers and Substrate Ganglionic plexi trigger Macroreentrant atrial tachycardias
Lesion set Segmental ablation Pulmonary vein ostial isolation Pulmonary vein antral isolation Targeted activation mapping of trigger CFAE substrate modification Posterior wall substrate modification Posterior box lesion set Pulmonary vein antral isolation or target GP Linear lesions
Endpoints PV entrance block Entrance and exit block Entrance and exit block No AT/AF on isoproterenol 20 μg/min Eliminate CFAE, termination of AF to NSR Reduction in posterior wall electrograms, non-inducibility Entrance and exit block Abolition of vagal response Bidirectional block
Limitations PV stenosis, ↑recurrence Untreated ostial triggers Gaps along lesion Nonspecific arrhythmias Extensive ablation, proarrhythmia Ablation near esophagus, gaps along lesions Incomplete isolation, gaps in linear lesions Mostly epicardial Proarrhythmia from gaps in linear lesions
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Technical Aspects of Catheter Ablation for Atrial Fibrillation Pulmonary vein isolation remains the cornerstone of catheter ablation of AF. Pre-procedure imaging is recommended to ensure absence of a left atrial thrombus, and the patient should be able to take anticoagulants. In low-risk patients (e.g., CHADS2 score of 0), the likelihood of detecting a thrombus is low, and some practitioners defer such imaging in their lowest-risk patients [59]. Using fluoroscopy and/or intracardiac echocardiography, transseptal puncture is performed with verification (via pressure monitoring, contrast, and/or echocardiography) prior to the advancement of the sheath(s) into the left atrium. A single transseptal puncture is performed when the ablation catheter alone is used to ablate the PVs [60], such as the “pace and ablate” approach. Double transseptal puncture allows the operator to advance both the ablation catheter and a circular mapping catheter into the left atrium, which offers the advantage of being able to identify gaps within the encircling lines [31] and to use pacing maneuvers to confirm lines of block. There are several energy sources that can be used to ablate the PVs. Standard radiofrequency ablation can be performed with nonirrigated or irrigated catheters. Externally irrigated radiofrequency catheters infuse saline directly to the ablation site to prevent proximal heating and allow adequate delivery of current to the tissue. In contrast, internally irrigated radiofrequency catheters also prevent overheating of the electrode-tissue interface but avoid volume infusion into the patient. As an alternative to point-by-point ablation, multielectrode catheters that deliver duty-cycled bipolar and unipolar radiofrequency energy are also able to create encircling or linear lesions. Cryoballoon catheters are now available that deliver cryo-energy directly to the PV ostium. Another type of balloon catheter uses visually guided laser energy delivered in an arc to perform isolation of the PVs.
Procedural Endpoints for Catheter Ablation In contrast to catheter ablation of other arrhythmias, the endpoints for AF remain less established. During application of radiofrequency energy, there is usually a reduction in local electrogram amplitude and a fall in impedance, which are signs of effective tissue ablation. In the process of PV isolation, there may be progressive delay in the atrial-PV interval and change in the PV activation sequence before elimination of the PV potentials [27] (Fig. 33.3a). Interpretation of entrance block can be confounded by the presence of farfield electrograms from nearby cardiac structures, which requires pacing maneuvers to determine their site of origin. For example, far-field electrograms from the left atrial appendage are commonly recorded from poles of a circular
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mapping catheter on the anterior segment of the vein (Fig. 33.3a). These far-field electrograms can be identified by the timing of activation coincident with the left atrial appendage. Pacing from the appendage will advance the farfield electrograms into the pacing artifact, whereas this maneuver will delay PV potentials relative to the pacing spike. A similar maneuver can be employed to distinguish PV potentials in the right superior PV from far-field signals from superior vena cava. Assessment of exit conduction is an important endpoint of PV isolation. In one study, after entrance block was achieved, only 58 % of PVs also demonstrated exit block, and outcomes improved when these sites with exit conduction were reablated [61]. PV potentials that are dissociated from the left atrium are strong evidence of both entrance and exit block. Exit block can also be confirmed by pacing each paired electrode of the circular mapping catheter and demonstrating local capture of the PV, which is dissociated from the atria. Exit pacing is sometimes confounded by capture of adjacent structures, but analysis of the electrograms can identify capture of far-field structures (e.g., left atrial appendage, neighboring left atrial signals, superior vena cava) as opposed to exit conduction. Achievement of both entrance and exit block is proof of bidirectional block, and there may be a dissociated PV rhythm (Fig. 33.4). Another approach to achieving bidirectional block is to test for pacing capture along the ablation line. This “pace and ablate” approach consists of (1) ablating around the PV ostium and observing for elimination of the local potentials and then (2) pacing at the ablated site to verify loss of capture. The technique is based on the principle that effective ablation renders the myocardial tissue unexcitable. This approach requires only a single transseptal puncture, and any reconnected site can be reablated at the same time and location. In a study of 30 patients who underwent PV antral isolation with this approach (pace capture at 10 mA at 20 sites with ablation at reconnected sites), persistent entrance block was achieved in 95 % of veins [62]. In a larger study of 147 patients with both paroxysmal and persistent AF undergoing a PV isolation with a posterior box set (roof and lower box line), the “pace and ablate” approach was used to identify gaps for reablation [63]. Medicated infusions are used after catheter ablation to test for durability of lesion formation. Isoproterenol is frequently employed after catheter ablation, where infusions up to 20–30 μg/min can be used to identify dormant conduction as well as triggers of AF. More recent investigations have focused on adenosine to uncover dormant PV conduction between the left atrium and the PVs. Adenosine is an endogenous purine that activates the A1 receptor, which hyperpolarizes atrial myocardium and shortens both the action potential duration and atrial refractory period. After achieving bidirectional block, the reappearance of PV potentials during adenosine infusion is considered evidence of stunned
33 Atrial Fibrillation Ablation: From Guidelines to Clinical Reality Fig. 33.3 Progressive organization of atrial rhythm during ablation of persistent AF. Panel (a) Pulmonary vein antral isolation (PVAI) of left-sided pulmonary veins is performed during AF. During ablation, the left superior pulmonary vein (LSPV) becomes isolated, as indicated by the disappearance of the sharp pulmonary vein potentials, consistent with entrance block (arrow). Far-field electrograms are seen in the circular mapping catheter in the LSPV, reflecting activation of the left atrial appendage. Panel (b) During PVAI of the left pulmonary veins, the AF had organized into clockwise peri-mitral flutter, characterized by distal to proximal activation of the coronary sinus catheter. During radio frequency ablation of the mitral isthmus between the mitral annulus and the inferior left inferior PV, peri-mitral flutter converts to typical counterclockwise cavotricuspid isthmus-dependent atrial flutter. Note the change in the coronary sinus activation sequence (arrow), which is consistent with conduction block across the mitral isthmus. Panel (c) Radio frequency catheter ablation in the cavotricuspid isthmus terminates atrial flutter (arrow) and results in normal sinus rhythm. Note different paper speed in panels (b and c). Abbreviations as per previous figures
a
425
Ablation
aVF VI HRA LRA pCS dCS pLSPV 170
dLSPV
b
Ablation
aVF VI 220
HRA
215
LRA pCS
dCS
c
Ablation
I aVF VI HRA
240
LRA pCS
dCS
myocardium that has the ability to become re-excited, and these sites can be retargeted for ablation (Fig. 33.5). The mechanism of adenosine in unmasking dormant conduction is related to hyperpolarization of injured cells, which causes reactivation of transmembrane sodium channels and thus permits action potentials to generate. When adenosine is cleared, the injured cells again become depolarized, sodium
channels become deactivated, and conduction is interrupted [64]. Whether adenosine challenge will result in improved long-term clinical outcomes is the subject on ongoing investigation. One study compared the outcomes of patients who underwent segmental catheter ablation before 2005 with those who had ablation after 2005. The latter cohort had elimination of adenosine-induced PV reconnection. Among
426 Fig. 33.4 After catheter ablation with bidirectional block in the right superior pulmonary vein, demonstration of a pulmonary vein rhythm (line) is seen on the circular mapping catheter. No evidence of exit conduction into the left or right atrium is seen on the high right atrium and coronary sinus catheters. Abbreviations as per previous figure
J.M. Lee and S.M. Markowitz aVF VI HRA LRA pCS dCS pRSPV
dRSPV
Fig. 33.5 Adenosine-mediated demonstration of dormant conduction. After PV antral isolation, both entrance and exit block were achieved in the right superior pulmonary vein (RSPV). A bolus administration of adenosine 12 mg revealed transient atrioventricular (AV) block that is due to the acute effect of adenosine, and there is simultaneous reappearance of PV potentials in the circular mapping catheter (arrows). Abbreviations as per previous figures
Adenosine 12 mg aVF VI HRA LRA pCS dCS pRSPV
dRSPV
those who had elimination of dormant conduction, 80 % were free of atrial arrhythmias at 20 months compared to 60 % who were ablated in the earlier era [65]. Improved outcomes after elimination of ATP-mediated PV reconnection were also demonstrated in another study of 252 patients (in which 82 received ATP and 170 did not) [66]. A challenge in AF ablation is achieving durable PV isolation. A waiting period is usually performed after ablation to identify early recovery of PV conduction. In a large study of 424 patients who underwent PV isolation, 50 % of PVs had reconnected after a 20–60-min waiting [67]. Multivariable analysis showed that the independent risk factors for acute reconnection were hypertension, LA size >4.5 cm, age, obstructive sleep apnea, and persistent AF. Another study randomized patients who underwent PV isolation to different waiting periods of 0, 30, and 60 min, after which early reconnections were ablated. AT/AF-free survivals after a mean of 7 months were 61, 84, and 87 %, respectively [68]. This study emphasized the importance of a waiting period to uncover acute reconnection and suggested
that electrical re-isolation at these reconnected sites can reduce improve success. By employing multiple endpoints including entrance block, exit block, 60-min waiting period, and adenosine challenge, AF-free survival up to 92 % at 1 year has been reported [69]. A less commonly used endpoint for catheter ablation is the attainment of non-inducibility with both programmed stimulation and burst pacing, particularly in patients with paroxysmal AF. Patients who become non-inducible for AF have been shown to have a lower risk of recurrent AF during follow-up. Studies that have evaluated this endpoint suggest that linear lesions (in the mitral isthmus or left atrial roof) may be required beyond PV isolation to render patients non-inducible. For example, in a study of 70 patients who were randomized to PV isolation without or with a mitral isthmus line, those who received the linear lesion were more likely to be noninducible (77 % vs. 57 %), and non-inducible patients have a lower recurrence rate after an average of 7 months (13 % vs. 38 %). In a study of 74 patients with paroxysmal AF who underwent a PV isolation, additional ablation was performed
33 Atrial Fibrillation Ablation: From Guidelines to Clinical Reality
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Table 33.2 Randomized studies of catheter ablation of AF versus antiarrhythmic medications at 1 year Trials CACAF [74] RAAFT [75] A4 [76] APAF [77] ThermaCool AF [78] Oral et al. [79] Krittayaphong et al. [80] STOP-AF [81]
N 137 70 112 198 167 146 30 245
Endpoint No AT/AF > 30 s Recurrent Sx AF No recurrent AF Freedom AT Freedom Sx AF Freedom AF Freedom AF Freedom AF
in the left atrial roof or mitral isthmus if AF was induced with programmed stimulation [70]. Additional lesions beyond the PV isolation were required in approximately half the patients, and with this stepwise approach, 91 % were rendered noninducible. After an average 18-month follow-up and repeat procedures in a substantial minority, 91 % were free from arrhythmia without antiarrhythmic drugs. In a larger study that investigated 100 patients with paroxysmal AF undergoing PV isolation and linear lesions in the posterior left atrium and mitral isthmus, 40 % were rendered non-inducible with burst pacing. The inducible group was then randomized between no further ablation versus additional ablation of fractionated electrograms. After a 6-month follow-up, those patients who received further ablation because of inducibility had better AF-free survival compared to those inducible patients who did not receive additional ablation (86 % vs. 67 %), and the former had comparable outcomes to the noninducible group [71]. For ablation of persistent and long-lasting persistent AF, termination of AF during ablation is associated with favorable outcomes (Fig. 33.3). To achieve this endpoint, extensive ablation of multiple regions beyond PV isolation is usually required. Using the “stepwise approach” described previously, termination of AF occurs approximately 85 % of the time, and the likelihood of termination depends on the duration of AF before ablation. In a study of 153 patients treated in this manner, repeat procedures were still common regardless of whether AF terminated during the index procedure. Nevertheless, there was a lower incidence of atrial arrhythmias among those with AF termination during the index procedure compared with those without (5 % vs. 52 % after a mean follow-up 32 months) [72]. If linear lesions are created, it is important to verify bidirectional block along the ablation line. Conduction block can be demonstrated by pacing on one side the line and demonstrating late activation on the opposite side along with wave front propagation consistent with block in the line. In the lateral mitral isthmus, pacing anterior to line should result in counterclockwise activation of the mitral annulus if block is present [53]. Conversely, pacing lateral to the line should result in clockwise activation. In assessing a left atrial roof line, pacing on one side of the line should
Arms PVI/CT/MI vs. AAD PVI vs. AAD PVI vs. AAD PVI/CT/MI vs. AAD PVI vs. AAD PVI vs. PVI/amiodarone PV/linear RA vs. amiodarone Cryoballoon vs. AAD
Results (%) 91 vs. 44.1 13 vs. 63 23 vs. 89 86 vs. 22 66 vs. 16 74 vs. 58 79 vs. 40 70 vs. 7
Follow-up 1 year 1 year 1 year 1 year 9 months 1 year 1 year 1 year
result in an ascending wave front on the other side. The technique of differential pacing can also be used to verify line of block [73]. This involves pacing at two sides relative to an ablation line (closer and further from the line). If block is present, moving the pacing site away from the line should shorten activation time to an electrogram on the opposite side. In the absence of block, moving the pacing site further away prolongs activation time to the opposite side. Widely spaced double electrograms along the line, particularly when pacing adjacent to the line, also support the presence of conduction block.
Clinical Results of Catheter Ablation Randomized trials comparing catheter ablation to antiarrhythmic medications demonstrate superior results in the former at 1 year (Table 33.2) [74–78]. By early 2012, eight prospective randomized trials of antiarrhythmic therapy versus catheter ablation were published. In these trials, the efficacy of catheter ablation varied from 66 to 89 %, compared to 16 to 58 % for antiarrhythmic drugs. Most of the randomized studies cited above enrolled patients with few comorbidities who previously failed antiarrhythmic drug therapy. To date, there is no prospective evidence of survival advantage or reduction in thromboembolism in patients having catheter ablation for AF. However, retrospective comparisons have shown longer survival, on average, for those treated with catheter ablation compared to medically treated cohorts [82, 83]. Despite complete electrical isolation of the PVs at experienced high-volume centers, there remains a high recurrence rate of post-procedural atrial arrhythmias. Although not all reports are in agreement, a number of studies found that persistent and long-lasting persistent AF are associated with higher recurrence rates compared to paroxysmal AF [84]. Structural factors that influence AF recurrence include increased left atrial size, decreased left ventricular systolic function, and hypertrophic cardiomyopathy [85–87]. Clinical features, such as hypertension, sleep apnea, and advanced age, have also been implicated in AF recurrences in some studies [86, 87, 88]. Clinical trials such as A4
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428 Table 33.3 Long-term outcomes of catheter ablation of atrial fibrillation Trial/study Sawhney [89] Tzou [90] Weerasooriya [91] Shah [92] Fichtner [93] Bertaglia [94] Ouyang [95] Bhargava [96]
N 71 239 100 264 356 229 161 1,404
Lesion set Segmental Segmental Segmental Segmental PVI PVI PVI PVI + SVC
Mean follow-up (months) 63 71 60 34 58 49.7 58 57
Wokhlu [97] Miyazaki [98]
774 574
PVI/PVAI PVI/PVAI
36 30
Long-term success 1st ablation 56 % 71 %/5 years 29 %/5 years 75 %/5 years 36 % 45 %/6 years 47 % PAF 78 % Persistent 67 % 53 % 70 %
Pappone [99] Medi [100]
198 100
PVAI PVAI
48 39
73 %/4 years 49 %
Hussein [101]
831
PVAI
55
79 %
Long-term success >1 ablation 81 % 81 %/5 years 63 %/5 years – 71 % – 80 %a PAF 92 % Persistent 84 % – PAF 85 % Persistent 80 % – W/o AAD 57 % W/AAD 82 % –
Success rates are given for the mean follow-up period of each study unless a time is indicated after the rate, which was calculated from survival analysis AAD refers to antiarrhythmic drug, PAF paroxysmal atrial fibrillation, PVAI pulmonary vein antral isolation, PVI pulmonary vein isolation, SVC superior vena cava. a Median follow-up 4.6 months
(Atrial Fibrillation vs. Antiarrhythmic Drugs), ThermoCool IDE, STOP-AF (Sustained Treatment of Paroxysmal Atrial Fibrillation), and CABANA (Catheter Ablation vs. Antiarrhythmic Drug Therapy for Atrial Fibrillation) pilot trial showed atrial tachyarrhythmia-free survival rates at 1 year of 61–89 %, as listed in Table 33.2. Data have become available regarding long-term recurrences of AF (>3 years) post ablation. Several studies reporting long-term outcomes are summarized in Table 33.3. A study of 100 patients from Bordeaux showed that atrial arrhythmia-free survival after a single segmental ostial ablation procedure was 40, 37, and 29 % at 1, 2, and 5 years of follow-up [91]. But with additional procedures, the 5-year arrhythmia-free survival rate was 63 %. In another study of 230 patients who also received segmental ostial catheter ablation and achieved bidirectional block, 85 and 71 % of patients were free from AF at 3 and 5 years, respectively [90]. Another long-term study of 177 patients who underwent both PV isolation and mitral isthmus ablation revealed recurrent AF in 65 % at 6 years, and 19 % of patients were maintained on antiarrhythmic medications [94]. In this study, it is unclear whether the empiric mitral isthmus line contributed to recurrent arrhythmias. Another long-term study from Germany evaluated 161 patients with paroxysmal AF who underwent PV isolation; 47 % of patients remained in sinus rhythm after an average 4.8-year follow-up [95]. One of the randomized studies of ablation versus antiarrhythmic drug therapy, APAF (Ablation for Paroxysmal Atrial Fibrillation), has reported extended outcomes to 4 years
[99]. Although most of the drug-treated patients crossed over to ablation, intention to treat analysis showed that 73 % of patients in the ablation arm were free of recurrent arrhythmias compared to 57 % of those in the initial drug arm. Contemporary trials are needed on patients who undergo PV isolation with rigorous demonstration of entrance and exit block to determine whether long-term outcomes are improved. Recurrent AF after PV isolation is attributed primarily to PV reconnection. One observational study performed a repeat electrophysiology study on all patients who had recently underwent PV antral isolation and followed three groups of patients: (1) no recurrence, (2) maintained sinus rhythm on antiarrhythmic medications, and (3) recurrent AF on antiarrhythmic medications [102]. Those who required antiarrhythmic drugs or had recurrent AF were found to have a higher incidence of PV reconnection, and re-isolation conferred a higher freedom from AF of 97 and 91 %. This study showed that PV reconnection was the predominant cause of recurrent AF and that non-PV triggers are uncommon. In the German study of 161 patients having long-term follow-up, patients who underwent repeat procedures had high rates of PV reconnection on the second and third procedures (94 and 67 %, respectively) [95]. The timing of the recurrent AF may shed light into the underlying mechanism of early, late, and very late recurrence, respectively (Table 33.4). Early recurrences of AF have been hypothesized to occur due to the inflammatory consequences of ablation or recovery of conduction due to
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33 Atrial Fibrillation Ablation: From Guidelines to Clinical Reality Table 33.4 Timing of AF recurrence post ablation Outcomes Acute reconnection Early recurrence of atrial fibrillation
Definition Reconnect during waiting period 0–3 months
Late recurrence Very late recurrence
3 months–1 year >1 year
Mechanism Gaps in PV isolation Inflammation PV reconnection PV reconnection Non-PV triggers Atrial remodeling Underdetection of PV reconnection
Management Ablate until entrance/exit block Antiarrhythmic drugs, cardioversion, anti-inflammatory drugs Reisolate PVs Ablate non-PV triggers, target atrial substrate, reisolate PVs
Table 33.5 Complications of AF ablation Complication Vascular injury Tamponade, cardiac perforation
Incidence 1.47 % 1.31 %
Stroke/TIA Phrenic nerve injury Pulmonary vein stenosis Air embolism Pneumothorax Atrio-esophageal fistula Radiation exposure
0.23 %/0.71 % 0.48 % 0.29 % – 0.09 % 0.04 % Cumulative
Strategy Ultrasound guidance, using smaller sheaths, radial arterial lines Keep ACT <400, ICE for transseptal, arterial line, stop ablation impedance rise, carefully define appendage relative to PVs Pre-procedure TEE, heparin for ACT >300, flush transseptal lines High output pacing, palpation, or imaging of diaphragmatic excursion Wider ablation, reduce power, define ostia, ICE imaging of PVs Bubble trap, remove air from transseptal lines, slowly withdraw lines Avoid IJ access, ultrasound guidance ICE, limit power, temperature probe, move esophagus New fluoroscopy systems, remote navigation system, lower frame rate, coning
Adapted from Cappato et al. [108] ACT refers to activated clotting time, ICE intracardiac echocardiography, IJ internal jugular, TEE transesophageal echocardiogram, TIA transient ischemic attack
incomplete lesions. Early recurrences of AF appear to predict late arrhythmias. When patients with and without early recurrences were followed for an average of 7 months, 31 and 85 % patients remained free of AF, respectively [28]. Late recurrences (between 3 months and 1 year) have been shown to occur predominantly due to PV reconnection. Several studies showed that patients who developed recurrences in this time frame had PV reconnection rates of 75–82 % [103–105]. Repeat targeted ablation at the sites of PV reconnection resulted in more freedom from AF outcomes [106]. Very late recurrences (more than 1 year after index procedure) are due to multiple etiologies. Patients with very late recurrences exhibit a lower incidence of pulmonary vein triggers, fewer left atrial triggers, but more RA triggers compared to patients who recur within 1 year [107]. A long-term study of 831 patients treated with PV isolation revealed that approximately 9 % had very late recurrences. During repeat studies in these patients, PV reconnection was documented in at least one vein in all patients, but right-sided triggers are also frequently inducible with isoproterenol [101]. Targeted substrate modification via complex fractionated electrograms and linear lesions as well as targeting PV reconnection has been shown to improve long-term efficacy in patients with late recurrences [93].
Risks of Catheter Ablation Some complications of AF ablation have been associated with significant morbidity and mortality (Table 33.5). A worldwide survey of procedure performed between 1995 and 2002 reported a 6 % major complication rate [109]. A more recent survey of procedures performed between 2003 and 2006 reported a decline in major complication rates to 4.5 %, and periprocedural deaths were 0.15 % [108]. Cardiac tamponade is one of the most common complications, seen in approximately 1 % of procedures. It can occur as a result of transseptal puncture if the needle punctures the posterior wall of the left atrium or if the needle is aimed anterior to the fossa ovale and accesses the aortic root. Excessive mechanical force and thermal heating can result in cardiac perforation especially during linear ablations and delivery of high power. The administration of anticoagulation in patients who are already fully anticoagulated further increase their risk of bleeding. The diagnosis of significant effusions can be readily made by using echocardiography or visualizing diminished excursion of the cardiac silhouette under fluoroscopy. Management includes reversal of anticoagulation with protamine and timely percutaneous or surgical drainage. Given the required use of anticoagulation and the need for many venous access sites, venous vascular complications
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may occur. These include groin hematomas, retroperitoneal bleeds, pseudo-aneurysms, and femoral arteriovenous fistulas, the latter two of which were found to occur 0.93 and 0.54 %, respectively [108]. Preventive measures include using smaller sheaths, radial instead of femoral arterial lines, and ultrasound guidance for access. Both thromboembolism and air embolism are preventable complications that can lead to significant morbidity and mortality. Precautions to prevent thromboembolism include adequate screening for left atrial thrombus pre-procedure [110], administration of aggressive heparin dosed for an activated clotting time (ACT) >300–400 s [111], and flushing of transseptal sheaths to prevent thrombus formation and embolization [112, 113]. Air embolism occurs when air is directly introduced into transseptal lines or catheters are rapidly removed from the left atrium. Preventive measures include purging bubbles from the transseptal lines, attaching bubble traps to the lines, adequately aspirating sheaths, and slowly removing these catheters from the left atrium. Pulmonary vein stenosis may present as cough, dyspnea, chest pain, hemoptysis, or recurrent pneumonia. Severe PV stenosis is diagnosed when there is a 70 % reduction of the original PV diameter and either clinical symptoms or demonstration of reduced perfusion on cardiac imaging [114]. The incidence of PV stenosis is declining with wider antral ablations, increased operator experience, use of intracardiac echocardiography and other imaging modalities to define the PV ostia, and the reduction of power delivered inside the vein. Treatment entails either balloon angioplasty or stenting, and the latter is complicated by in-stent restenosis that occurred in over 60 % of stented patients [115]. Radiofrequency-induced injuries to the phrenic nerve, vagus nerve, and esophagus have been reported. The right phrenic nerve may follow a course between the superior vena cava and the anterior aspect of the right superior PV, while the left phrenic nerve lies near the left atrial appendage and descends into the pericardium overlying the left ventricle. Patients with phrenic nerve injury may present with dyspnea, cough, and hiccup, and the diagnosis is made using fluoroscopy to show an elevated hemidiaphragm and reduced diaphragm excursion. The majority of patients tend to recover by a mean of 7 months [116]. Preventive measures include monitoring diaphragmatic excursion during ablation and identifying the course of the phrenic nerve with high output pacing before delivering power anterior to the right PVs. The vagus nerve and plexus is another important structure that is located near the esophagus. Direct thermal injury to these structures has been reported to cause acute pyloric spasm and gastric hypomotility [54]. Patients may present with dyspepsia or early satiety, and the diagnosis is made by upper endoscopy. If necessary, therapeutic interventions include either botulinum toxin injection or dilatation of the pylorus. Atrio-esophageal fistula is another complication that is rare
J.M. Lee and S.M. Markowitz
but carries a mortality rate as high as 50 [117, 118]. Patients present with hematemesis, change in mental status, and fevers. Diagnosis can be made by CT and MRI; both transesophageal echocardiography and esophagogastroduodenoscopy should not be performed. Treatment requires urgent surgical intervention. Preventive measures include preprocedural imaging of the esophagus, localization of the esophagus using intracardiac echocardiography or swallowing contrast, use of esophageal temperature monitoring, and lowering power when ablating near the esophagus [119]. Esophageal ulcerations may occur with both radiofrequency and cryoablation. Given the complexity of AF ablation, the need for repeat procedures, and the need for pre-procedure imaging (i.e., CT scan), radiation exposure is now recognized as an important risk to the patient and operator. Through use of newer fluoroscopy equipment that can lower frame rates, minimize scatter, and avoid unnecessary magnification, it is possible to significantly lower radiation exposure. Remote navigation systems and intracardiac echocardiography can be utilized to diminish radiation exposure to the patient and operator.
Guidelines for Catheter Ablation of Atrial Fibrillation Consensus guidelines for catheter ablation of AF were issued by the Heart Rhythm Society (HRS), the European Heart Rhythm Association (EHRA), and the European Cardiac Arrhythmia Society (ECAS) in 2007 [120] and were updated in 2012 [121]. These guidelines stress that catheter ablation is indicated in patients with symptomatic AF who have failed at least one antiarrhythmic drug. The strength of the indication is highest (class I) for patients with paroxysmal AF and lower for patients with persistent AF (IIa) and long-lasting persistent AF (IIb). Catheter ablation may also be considered prior to treatment with an antiarrhythmic drug, but these indications are lower strength because of less extensive evidence of benefit (class IIa recommendation for persistent AF and IIb for persistent and long-lasting persistent AF). In 2011, the American College of Cardiology (ACC), American Heart Association (AHA), and HRS issued a focused update of AF management guidelines [122]. Similar to the HRS/EHRA/ECAS guidelines, catheter ablation is considered a class I indication in selected patients with symptomatic, paroxysmal AF who have failed at least one antiarrhythmic drug. The guidelines further stipulate that this class I recommendation pertains to patients who have normal or mildly dilated left atria, normal or mildly reduced left ventricular function, and no severe pulmonary disease. Catheter ablation is also considered reasonable to treat symptomatic persistent AF (class IIa). In recognition of data demonstrating improved outcomes in patients with heart failure, the guidelines also
33 Atrial Fibrillation Ablation: From Guidelines to Clinical Reality
consider catheter ablation may be reasonable to treat symptomatic paroxysmal AF in patients with significant left atrial dilatation or with significant LV dysfunction (class IIb). In 2010, the European Society of Cardiology (ESC) addressed catheter ablation of AF in the context of their broad guideline document on the management of AF [3]. The guidelines make clear that the decision to perform a catheter ablation for AF should take into account (1) the stage of atrial disease (AF type, left atrial size, AF history), (2) the presence and severity of underlying cardiovascular disease, (3) potential treatment alternatives, and (4) patient preference. The ESC guidelines state that catheter ablation for paroxysmal AF should be considered in symptomatic patients who have previously failed a trial of antiarrhythmic medication (class IIa), and ablation is also a treatment option for patients with persistent symptomatic AF that is refractory to antiarrhythmic medication (class IIa) [3]. As first-line therapy to maintain sinus rhythm, catheter ablation may be considered prior to antiarrhythmic drug therapy in symptomatic patients (despite adequate rate control) who are likely to have favorable outcomes, specifically patients with paroxysmal AF and no significant underlying heart disease (class IIb) [3, 121]. Finally, ablation of AF may be considered in patients with symptomatic long-standing persistent AF refractory to antiarrhythmic drugs (class IIb) [3]. All the consensus guidelines stress the need to continue longterm anticoagulation in patients with risk factors for thromboembolism (e. g., CHADS2 score ≥ 2 or CHA2DS2-VASc ≥ 2). This recommendation is based on the recognition that AF recurrences are common after ablation and may increase with longer followup. In fact, asymptomatic recurrences are known to occur in the post-ablation setting [123]. The frequency and intensity of monitoring will impact the yield of detecting AF [124]. Therefore, if discontinuation of anticoagulation is considered, patients should have continuous ECG monitoring to screen for asymptomatic AF or flutter. After ablation, routine follow-up should be performed at a minimum of 3 months following the procedure and then every 6 months for at least 2 years.
Realities of Catheter Ablation in Clinical Practice While the consensus documents provide guidelines for selecting candidates for AF ablation and for post-procedure care, realistic situations arise in clinical practice, which require interpretation beyond the formal guidelines.
AF Ablation in the Elderly The randomized clinical trials of AF ablation enrolled patients with mean ages of 51–62 years. However, the incidence of AF increases markedly with age, and in clinical practice, the
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majority of patients who need treatment for AF are elderly. A number of studies have reported ablation outcomes in elderly patients. These moderately sized studies included between 45 and 217 elderly patients, defined as age over 60 or 65, and some studies have specifically included subgroups of patients over age 75. The complications of ablation in the older patients were generally comparable to procedures in younger subjects [125], but one study reported a higher rate of periprocedural stroke among older patients [126]. There is some inconsistency in the literature with regard to efficacy of ablation in maintaining sinus rhythm in older patients. Some studies show that success rates in the elderly are similar to younger patients [126], and most studies have not identified age (between 40 and 70 years) as a predictor of ablation success [84]. Nevertheless, other reports have found that older patients more often use antiarrhythmic drugs after ablation [125, 127]. Most practitioners consider ablation to be reasonable in elderly patients who have good functional status and do not have extensive comorbidities. In addition, the elderly patient who undergoes ablation should be able to tolerate anticoagulation during and after the procedure.
AF Ablation in Patients with Advanced Structural Heart Disease The highest success rates for AF ablation are generally obtained in patients with normal left ventricular function and without significant left atrial dilatation. Nevertheless, small series have reported the outcomes of ablation in patients with congestive heart failure and hypertrophic cardiomyopathy. The first observation that catheter ablation of AF could improve heart failure status was reported in 2004 and included a study of 58 heart failure patients with left ventricular ejection fractions (LVEF) <45 % compared with 58 controls [128]. After an average follow-up of 12 months, the LVEF improved by 21 %, and there were improvements in quality of life and exercise capacity. Similarly, a later study of 36 subjects and 36 controls also found that LVEF improved on average by 8 % after AF ablation in patients with LV systolic dysfunction [129]. AF ablation has also been compared with atrioventricular nodal ablation in patients with heart failure, and the AF ablation cohort demonstrated better improvement in symptoms, walking distance, and higher LVEF [130]. Based on these studies, there is a rationale for performing AF ablation in patients with systolic left ventricular dysfunction, but multiple procedures may be required to achieve effective rhythm control. Several series have examined the effects of AF ablation in patients with hypertrophic cardiomyopathy, with sample sizes of 26–68 patients [88, 131–133]. In general, these studies show that ablation can be successful in restoring sinus rhythm and improving symptoms, but repeat procedures are
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commonly required. Left atrial size and AF type (paroxysmal vs. persistent) influence the success of the procedures. These studies support the role of catheter ablation in selected patients with hypertrophic cardiomyopathy.
Discontinuation of Anticoagulation After AF Ablation Patients who undergo catheter ablation for AF have been reported to have a stroke risk of 0.5–0.7 % [108]. The evidence behind the post-procedural practice of discontinuing anticoagulation data is limited. In one observational cohort study of 755 patients (55 % had CHADS2 score > 1), patients received only 3 months of oral anticoagulation after ablation followed by aspirin therapy at the discretion of the cardiologist if they did not have a history of stroke and had no AF recurrence [134]. After a 2-year follow-up, 0.9 % had a stroke within the first 2 weeks and 0.3 % had a late embolic event within 10 months, all of whom were on anticoagulation. Meanwhile, 383 patients (51 %) who remained in sinus rhythm were taken off warfarin and none of them sustained a stroke independent of stroke risk factors for up to 2 years. Another single-center retrospective study of 352 patients reported a strategy of discontinuing oral anticoagulation after 3 months (or longer in selected patients) followed by antiplatelet therapy regardless of their CHADS2 score [135]. This study found no ischemic strokes using this approach, and 3 patients sustained hemorrhagic stroke while on anticoagulation. The largest study to date was a multicenter retrospective series of 2,692 patients who were taken off oral anticoagulation at a mean of 5 months after AF catheter ablation and compared these to 663 who remained on anticoagulation: 2 patients (0.07 %) and 3 patients (0.45 %) experienced an ischemic stroke off and on anticoagulation, respectively. However, 2 % of patients on oral anticoagulation sustained major hemorrhage, which suggests that discontinuation of anticoagulation may be safe in select patients without AF recurrence [136]. The 2012 HRS/EHRA/ ECAS Task Force AF guidelines recommends oral anticoagulation for a minimum of 2 months following AF ablation and that the determination whether to discontinue anticoagulation should be based on the CHADS2 or CHA2DS2-VASc score with continuous follow-up monitoring to screen for asymptomatic atrial arrhythmias [121].
Catheter Ablation as First-Line Rhythm Control Therapy Despite guidelines that support catheter ablation prior to antiarrhythmic drug therapy in selected patients, the evidence for ablation as first-line therapy is limited. The RAAFT trial (Randomized Trial of Radiofrequency Ablation vs. Antiarrhythmic Drugs as
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First-Line Treatment of Symptomatic Atrial Fibrillation) was a multicenter randomized clinical trial that followed 70 symptomatic AF patients after PV isolation versus antiarrhythmic therapy as first-line rhythm control strategies [75]. The AF recurrence rates were substantially higher (63 % at 1 year) among patients randomized to antiarrhythmic drugs compared to those who received ablations (13 %). Hospitalization rates were similarly low among those randomized to ablation. The CABANA Trial (Catheter Ablation vs. Antiarrhythmic Drug Therapy for Atrial Fibrillation) is currently enrolling up to 3,000 AF patients older than 65 years or with at least one stroke risk factor and randomizing them to either antiarrhythmic or catheter ablation therapies. Endpoints for this trial are mortality, maintenance for sinus rhythm, hospitalization, quality of life, costs, and left atrial size. Preliminary results of the CABANA pilot study included 60 patients who were randomized to catheter ablation versus antiarrhythmic medications. Many patients in this pilot trial had persistent or long-lasting persistent AF. While ablative therapy was more effective than drug therapy in preventing recurrent symptomatic AF, there was no significant difference between the groups in overall atrial tachyarrhythmia recurrences. These limited data point toward the need for large long-term studies of catheter ablation as an alternative to antiarrhythmic drug therapy as a first-line strategy. Conclusions
AF is a highly prevalent arrhythmia that often progresses to a chronic disease and is associated with significant cardiovascular and neurologic morbidity and mortality. Catheter ablation has evolved as an effective treatment that can alleviate symptoms, halt the progression to chronic state, and achieve sinus rhythm in a majority of patients. Long-term studies of ablation show a high recurrence of AF that is due primarily to PV reconnection, incomplete ablation lesions, and non-PV triggers. The development of optimal lesions sets, refinement of valid endpoints, and utilization of technology to deliver better lesions will likely improve short-term outcomes; however, more research is needed to improve the long-term success of this procedure. Despite the complexity of the procedure, there is a worldwide decline in complications likely due to operator experience and awareness.
References 1. Lloyd-Jones D, Adams RJ, Brown TM, Carnethon M, Dai S, De Simone G, Ferguson TB, Ford E, Furie K, Gillespie C, Go A, Greenlund K, Haase N, Hailpern S, Ho PM, Howard V, Kissela B, Kittner S, Lackland D, Lisabeth L, Marelli A, McDermott MM, Meigs J, Mozaffarian D, Mussolino M, Nichol G, Roger VL, Rosamond W, Sacco R, Sorlie P, Roger VL, Thom T, WasserthielSmoller S, Wong ND, Wylie-Rosett J. Heart disease and stroke statistics – 2010 update: a report from the American Heart Association. Circulation. 2010;121(7):e46–215. doi:10.1161/ CIRCULATIONAHA.109.192667.
33 Atrial Fibrillation Ablation: From Guidelines to Clinical Reality 2. Calkins H, Brugada J, Packer DL, Cappato R, Chen SA, Crijns HJ, Damiano Jr RJ, Davies DW, Haines DE, Haissaguerre M, Iesaka Y, Jackman W, Jais P, Kottkamp H, Kuck KH, Lindsay BD, Marchlinski FE, McCarthy PM, Mont JL, Morady F, Nademanee K, Natale A, Pappone C, Prystowsky E, Raviele A, Ruskin JN, Shemin RJ. HRS/ EHRA/ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for personnel, policy, procedures and follow-up. A report of the Heart Rhythm Society (HRS) Task Force on Catheter and Surgical Ablation of Atrial Fibrillation developed in partnership with the European Heart Rhythm Association (EHRA) and the European Cardiac Arrhythmia Society (ECAS); in collaboration with the American College of Cardiology (ACC), American Heart Association (AHA), and the Society of Thoracic Surgeons (STS). Endorsed and approved by the governing bodies of the American College of Cardiology, the American Heart Association, the European Cardiac Arrhythmia Society, the European Heart Rhythm Association, the Society of Thoracic Surgeons, and the Heart Rhythm Society. Europace. 2007;9(6):335–79. doi:10.1093/europace/eum120. 3. Camm AJ, Kirchhof P, Lip GY, Schotten U, Savelieva I, Ernst S, Van Gelder IC, Al-Attar N, Hindricks G, Prendergast B, Heidbuchel H, Alfieri O, Angelini A, Atar D, Colonna P, De Caterina R, De Sutter J, Goette A, Gorenek B, Heldal M, Hohloser SH, Kolh P, Le Heuzey JY, Ponikowski P, Rutten FH, Vahanian A, Auricchio A, Bax J, Ceconi C, Dean V, Filippatos G, FunckBrentano C, Hobbs R, Kearney P, McDonagh T, Popescu BA, Reiner Z, Sechtem U, Sirnes PA, Tendera M, Vardas PE, Widimsky P, Vardas PE, Agladze V, Aliot E, Balabanski T, BlomstromLundqvist C, Capucci A, Crijns H, Dahlof B, Folliguet T, Glikson M, Goethals M, Gulba DC, Ho SY, Klautz RJ, Kose S, McMurray J, Perrone Filardi P, Raatikainen P, Salvador MJ, Schalij MJ, Shpektor A, Sousa J, Stepinska J, Uuetoa H, Zamorano JL, Zupan I. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Europace. 2010;12(10):1360–420. doi:10.1093/europace/euq350. 4. de Vos CB, Pisters R, Nieuwlaat R, Prins MH, Tieleman RG, Coelen RJ, van den Heijkant AC, Allessie MA, Crijns HJ. Progression from paroxysmal to persistent atrial fibrillation clinical correlates and prognosis. J Am Coll Cardiol. 2010;55(8):725– 31. doi:10.1016/j.jacc.2009.11.040. 5. Wyse DG, Waldo AL, DiMarco JP, Domanski MJ, Rosenberg Y, Schron EB, Kellen JC, Greene HL, Mickel MC, Dalquist JE, Corley SD. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med. 2002;347(23):1825– 33. doi:10.1056/NEJMoa021328. 6. Corley SD, Epstein AE, DiMarco JP, Domanski MJ, Geller N, Greene HL, Josephson RA, Kellen JC, Klein RC, Krahn AD, Mickel M, Mitchell LB, Nelson JD, Rosenberg Y, Schron E, Shemanski L, Waldo AL, Wyse DG. Relationships between sinus rhythm, treatment, and survival in the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Study. Circulation. 2004;109(12):1509–13. doi:10.1161/01.CIR.0000121736.16643.11. 7. Daoud EG, Bogun F, Goyal R, Harvey M, Man KC, Strickberger SA, Morady F. Effect of atrial fibrillation on atrial refractoriness in humans. Circulation. 1996;94(7):1600–6. 8. Nattel S. New ideas about atrial fibrillation 50 years on. Nature. 2002;415(6868):219–26. doi:10.1038/415219a. 9. Allessie M, Ausma J, Schotten U. Electrical, contractile and structural remodeling during atrial fibrillation. Cardiovasc Res. 2002;54(2): 230–46. 10. Kanj M, Wazni O, Natale A. Pulmonary vein antrum isolation. Heart Rhythm. 2007;4(3 Suppl):S73–9. doi:10.1016/j.hrthm.2006.12.036. 11. Nathan H, Eliakim M. The junction between the left atrium and the pulmonary veins. An anatomic study of human hearts. Circulation. 1966;34(3):412–22.
433 12. Spach MS, Barr RC, Jewett PH. Spread of excitation from the atrium into thoracic veins in human beings and dogs. Am J Cardiol. 1972;30(8):844–54. 13. Zipes DP, Knope RF. Electrical properties of the thoracic veins. Am J Cardiol. 1972;29(3):372–6. 14. Haissaguerre M, Jais P, Shah DC, Takahashi A, Hocini M, Quiniou G, Garrigue S, Le Mouroux A, Le Metayer P, Clementy J. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med. 1998;339(10):659–66. doi:10.1056/NEJM199809033391003. 15. Hocini M, Ho SY, Kawara T, Linnenbank AC, Potse M, Shah D, Jais P, Janse MJ, Haissaguerre M, De Bakker JM. Electrical conduction in canine pulmonary veins: electrophysiological and anatomic correlation. Circulation. 2002;105(20):2442–8. 16. Jais P, Hocini M, Macle L, Choi KJ, Deisenhofer I, Weerasooriya R, Shah DC, Garrigue S, Raybaud F, Scavee C, Le Metayer P, Clementy J, Haissaguerre M. Distinctive electrophysiological properties of pulmonary veins in patients with atrial fibrillation. Circulation. 2002;106(19):2479–85. 17. Abe Y, Fukunami M, Yamada T, Ohmori M, Shimonagata T, Kumagai K, Kim J, Sanada S, Hori M, Hoki N. Prediction of transition to chronic atrial fibrillation in patients with paroxysmal atrial fibrillation by signal-averaged electrocardiography: a prospective study. Circulation. 1997;96(8):2612–6. 18. Moe GK, Rheinboldt WC, Abildskov JA. A computer model of atrial fibrillation. Am Heart J. 1964;67:200–20. 19. Jalife J, Berenfeld O, Mansour M. Mother rotors and fibrillatory conduction: a mechanism of atrial fibrillation. Cardiovasc Res. 2002;54(2):204–16. 20. Sanders P, Berenfeld O, Hocini M, Jais P, Vaidyanathan R, Hsu LF, Garrigue S, Takahashi Y, Rotter M, Sacher F, Scavee C, Ploutz-Snyder R, Jalife J, Haissaguerre M. Spectral analysis identifies sites of high-frequency activity maintaining atrial fibrillation in humans. Circulation. 2005;112(6):789–97. doi:10.1161/ CIRCULATIONAHA.104.517011. 21. Cox JL, Canavan TE, Schuessler RB, Cain ME, Lindsay BD, Stone C, Smith PK, Corr PB, Boineau JP. The surgical treatment of atrial fibrillation. II. Intraoperative electrophysiologic mapping and description of the electrophysiologic basis of atrial flutter and atrial fibrillation. J Thorac Cardiovasc Surg. 1991;101(3):406–26. 22. Cox JL. The surgical treatment of atrial fibrillation. IV. Surgical technique. J Thorac Cardiovasc Surg. 1991;101(4):584–92. 23. Cox JL, Schuessler RB, D’Agostino Jr HJ, Stone CM, Chang BC, Cain ME, Corr PB, Boineau JP. The surgical treatment of atrial fibrillation. III. Development of a definitive surgical procedure. J Thorac Cardiovasc Surg. 1991;101(4):569–83. 24. Lee R, Kruse J, McCarthy PM. Surgery for atrial fibrillation. Nat Rev Cardiol. 2009;6(8):505–13. doi:10.1038/nrcardio.2009.106. 25. Jais P, Haissaguerre M, Shah DC, Chouairi S, Gencel L, Hocini M, Clementy J. A focal source of atrial fibrillation treated by discrete radiofrequency ablation. Circulation. 1997;95(3):572–6. 26. Hocini M, Haissaguerre M, Shah D, Jais P, Peng JT, Yamane T, Deisenhofer I, Garrigue S, Fuimaono K, Pike R, Clementy J. Multiple sources initiating atrial fibrillation from a single pulmonary vein identified by a circumferential catheter. Pacing Clin Electrophysiol. 2000;23(11 Pt 2):1828–31. 27. Haissaguerre M, Jais P, Shah DC, Garrigue S, Takahashi A, Lavergne T, Hocini M, Peng JT, Roudaut R, Clementy J. Electrophysiological end point for catheter ablation of atrial fibrillation initiated from multiple pulmonary venous foci. Circulation. 2000;101(12):1409–17. 28. Oral H, Knight BP, Ozaydin M, Tada H, Chugh A, Hassan S, Scharf C, Lai SW, Greenstein R, Pelosi Jr F, Strickberger SA, Morady F. Clinical significance of early recurrences of atrial fibrillation after pulmonary vein isolation. J Am Coll Cardiol. 2002;40(1):100–4.
434 29. Katritsis DG, Ellenbogen KA, Panagiotakos DB, Giazitzoglou E, Karabinos I, Papadopoulos A, Zambartas C, Anagnostopoulos CE. Ablation of superior pulmonary veins compared to ablation of all four pulmonary veins. J Cardiovasc Electrophysiol. 2004;15(6):641–5. doi:10.1046/j.1540-8167.2004.03620.x. 30. Gerstenfeld EP, Callans DJ, Dixit S, Zado E, Marchlinski FE. Incidence and location of focal atrial fibrillation triggers in patients undergoing repeat pulmonary vein isolation: implications for ablation strategies. J Cardiovasc Electrophysiol. 2003;14(7):685–90. 31. Ouyang F, Bansch D, Ernst S, Schaumann A, Hachiya H, Chen M, Chun J, Falk P, Khanedani A, Antz M, Kuck KH. Complete isolation of left atrium surrounding the pulmonary veins: new insights from the double-lasso technique in paroxysmal atrial fibrillation. Circulation. 2004;110(15):2090–6. doi:10.1161/01. CIR.0000144459.37455.EE. 32. Pappone C, Rosanio S, Oreto G, Tocchi M, Gugliotta F, Vicedomini G, Salvati A, Dicandia C, Mazzone P, Santinelli V, Gulletta S, Chierchia S. Circumferential radiofrequency ablation of pulmonary vein Ostia: a new anatomic approach for curing atrial fibrillation. Circulation. 2000;102(21):2619–28. 33. Nilsson B, Chen X, Pehrson S, Kober L, Hilden J, Svendsen JH. Recurrence of pulmonary vein conduction and atrial fibrillation after pulmonary vein isolation for atrial fibrillation: a randomized trial of the ostial versus the extraostial ablation strategy. Am Heart J. 2006;152(3):537.e531–8. doi:10.1016/j.ahj.2006.05.029. 34. Oral H, Scharf C, Chugh A, Hall B, Cheung P, Good E, Veerareddy S, Pelosi Jr F, Morady F. Catheter ablation for paroxysmal atrial fibrillation: segmental pulmonary vein ostial ablation versus left atrial ablation. Circulation. 2003;108(19):2355–60. doi:10.1161/01. CIR.0000095796.45180.88. 35. Pappone C, Oreto G, Rosanio S, Vicedomini G, Tocchi M, Gugliotta F, Salvati A, Dicandia C, Calabro MP, Mazzone P, Ficarra E, Di Gioia C, Gulletta S, Nardi S, Santinelli V, Benussi S, Alfieri O. Atrial electroanatomic remodeling after circumferential radiofrequency pulmonary vein ablation: efficacy of an anatomic approach in a large cohort of patients with atrial fibrillation. Circulation. 2001;104(21):2539–44. 36. Marrouche NF, Martin DO, Wazni O, Gillinov AM, Klein A, Bhargava M, Saad E, Bash D, Yamada H, Jaber W, Schweikert R, Tchou P, Abdul-Karim A, Saliba W, Natale A. Phased-array intracardiac echocardiography monitoring during pulmonary vein isolation in patients with atrial fibrillation: impact on outcome and complications. Circulation. 2003;107(21):2710–6. doi:10.1161/01. CIR.0000070541.83326.15. 37. Robbins IM, Colvin EV, Doyle TP, Kemp WE, Loyd JE, McMahon WS, Kay GN. Pulmonary vein stenosis after catheter ablation of atrial fibrillation. Circulation. 1998;98(17):1769–75. 38. Arentz T, Weber R, Burkle G, Herrera C, Blum T, Stockinger J, Minners J, Neumann FJ, Kalusche D. Small or large isolation areas around the pulmonary veins for the treatment of atrial fibrillation? results from a prospective randomized study. Circulation. 2007;115(24):3057–63. doi:10.1161/CIRCULATIONAHA.107.690578. 39. Jalife J. Rotors and spiral waves in atrial fibrillation. J Cardiovasc Electrophysiol. 2003;14(7):776–80. 40. Chen SA, Tai CT. Catheter ablation of atrial fibrillation originating from the non-pulmonary vein foci. J Cardiovasc Electrophysiol. 2005;16(2):229–32. doi:10.1046/j.1540-8167.2005.40665.x. 41. Sauer WH, Alonso C, Zado E, Cooper JM, Lin D, Dixit S, Russo A, Verdino R, Ji S, Gerstenfeld EP, Callans DJ, Marchlinski FE. Atrioventricular nodal reentrant tachycardia in patients referred for atrial fibrillation ablation: response to ablation that incorporates slow-pathway modification. Circulation. 2006;114(3):191– 5. doi:10.1161/CIRCULATIONAHA.106.621896. 42. Lin WS, Tai CT, Hsieh MH, Tsai CF, Lin YK, Tsao HM, Huang JL, Yu WC, Yang SP, Ding YA, Chang MS, Chen SA. Catheter ablation of paroxysmal atrial fibrillation initiated by non-pulmonary
J.M. Lee and S.M. Markowitz
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
vein ectopy. Circulation. 2003;107(25):3176–83. doi:10.1161/01. CIR.0000074206.52056.2D. Lee SH, Tai CT, Hsieh MH, Tsao HM, Lin YJ, Chang SL, Huang JL, Lee KT, Chen YJ, Cheng JJ, Chen SA. Predictors of nonpulmonary vein ectopic beats initiating paroxysmal atrial fibrillation: implication for catheter ablation. J Am Coll Cardiol. 2005;46(6):1054–9. doi:10.1016/j.jacc.2005.06.016. Shah D, Haissaguerre M, Jais P, Hocini M. Nonpulmonary vein foci: do they exist? Pacing Clin Electrophysiol. 2003;26(7 Pt 2): 1631–5. Tan AY, Li H, Wachsmann-Hogiu S, Chen LS, Chen PS, Fishbein MC. Autonomic innervation and segmental muscular disconnections at the human pulmonary vein-atrial junction: implications for catheter ablation of atrial-pulmonary vein junction. J Am Coll Cardiol. 2006;48(1):132–43. doi:10.1016/j.jacc.2006.02.054. Zhou J, Scherlag BJ, Edwards J, Jackman WM, Lazzara R, Po SS. Gradients of atrial refractoriness and inducibility of atrial fibrillation due to stimulation of ganglionated plexi. J Cardiovasc Electrophysiol. 2007;18(1):83–90. doi:10.1111/j.1540-8167.2006.00679.x. Pappone C, Santinelli V, Manguso F, Vicedomini G, Gugliotta F, Augello G, Mazzone P, Tortoriello V, Landoni G, Zangrillo A, Lang C, Tomita T, Mesas C, Mastella E, Alfieri O. Pulmonary vein denervation enhances long-term benefit after circumferential ablation for paroxysmal atrial fibrillation. Circulation. 2004;109(3):327– 34. doi:10.1161/01.CIR.0000112641.16340.C7. Scherlag BJ, Nakagawa H, Jackman WM, Yamanashi WS, Patterson E, Po S, Lazzara R. Electrical stimulation to identify neural elements on the heart: their role in atrial fibrillation. J Interv Card Electrophysiol. 2005;13 Suppl 1:37–42. doi:10.1007/ s10840-005-2492-2. Narayan SM, Wright M, Derval N, Jadidi A, Forclaz A, Nault I, Miyazaki S, Sacher F, Bordachar P, Clementy J, Jais P, Haissaguerre M, Hocini M. Classifying fractionated electrograms in human atrial fibrillation using monophasic action potentials and activation mapping: evidence for localized drivers, rate acceleration, and nonlocal signal etiologies. Heart Rhythm. 2011;8(2):244– 53. doi:10.1016/j.hrthm.2010.10.020. Nademanee K, McKenzie J, Kosar E, Schwab M, Sunsaneewitayakul B, Vasavakul T, Khunnawat C, Ngarmukos T. A new approach for catheter ablation of atrial fibrillation: mapping of the electrophysiologic substrate. J Am Coll Cardiol. 2004;43(11):2044–53. doi:10.1016/j.jacc.2003.12.054. Oral H, Chugh A, Good E, Wimmer A, Dey S, Gadeela N, Sankaran S, Crawford T, Sarrazin JF, Kuhne M, Chalfoun N, Wells D, Frederick M, Fortino J, Benloucif-Moore S, Jongnarangsin K, Pelosi Jr F, Bogun F, Morady F. Radiofrequency catheter ablation of chronic atrial fibrillation guided by complex electrograms. Circulation. 2007;115(20):2606–12. doi:10.1161/ CIRCULATIONAHA.107.691386. Kottkamp H, Tanner H, Kobza R, Schirdewahn P, Dorszewski A, Gerds-Li JH, Carbucicchio C, Piorkowski C, Hindricks G. Time courses and quantitative analysis of atrial fibrillation episode number and duration after circular plus linear left atrial lesions: trigger elimination or substrate modification: early or delayed cure? J Am Coll Cardiol. 2004;44(4):869–77. doi:10.1016/j.jacc.2004.04.049. Jais P, Hocini M, Hsu LF, Sanders P, Scavee C, Weerasooriya R, Macle L, Raybaud F, Garrigue S, Shah DC, Le Metayer P, Clementy J, Haissaguerre M. Technique and results of linear ablation at the mitral isthmus. Circulation. 2004;110(19):2996–3002. doi:10.1161/01.CIR.0000146917.75041.58. Willems S, Klemm H, Rostock T, Brandstrup B, Ventura R, Steven D, Risius T, Lutomsky B, Meinertz T. Substrate modification combined with pulmonary vein isolation improves outcome of catheter ablation in patients with persistent atrial fibrillation: a prospective randomized comparison. Eur Heart J. 2006;27(23):2871–8. doi:10.1093/eurheartj/ehl093.
33 Atrial Fibrillation Ablation: From Guidelines to Clinical Reality 55. Hocini M, Jais P, Sanders P, Takahashi Y, Rotter M, Rostock T, Hsu LF, Sacher F, Reuter S, Clementy J, Haissaguerre M. Techniques, evaluation, and consequences of linear block at the left atrial roof in paroxysmal atrial fibrillation: a prospective randomized study. Circulation. 2005;112(24):3688–96. doi:10.1161/ CIRCULATIONAHA.105.541052. 56. Haissaguerre M, Jais P, Shah DC, Gencel L, Pradeau V, Garrigues S, Chouairi S, Hocini M, Le Metayer P, Roudaut R, Clementy J. Right and left atrial radiofrequency catheter therapy of paroxysmal atrial fibrillation. J Cardiovasc Electrophysiol. 1996;7(12): 1132–44. 57. Haissaguerre M, Sanders P, Hocini M, Takahashi Y, Rotter M, Sacher F, Rostock T, Hsu LF, Bordachar P, Reuter S, Roudaut R, Clementy J, Jais P. Catheter ablation of long-lasting persistent atrial fibrillation: critical structures for termination. J Cardiovasc Electrophysiol. 2005;16(11):1125–37. doi:10.1111/j.1540-8167.2005.00307.x. 58. Haissaguerre M, Hocini M, Sanders P, Sacher F, Rotter M, Takahashi Y, Rostock T, Hsu LF, Bordachar P, Reuter S, Roudaut R, Clementy J, Jais P. Catheter ablation of long-lasting persistent atrial fibrillation: clinical outcome and mechanisms of subsequent arrhythmias. J Cardiovasc Electrophysiol. 2005;16(11):1138–47. doi:10.1111/j.1540-8167.2005.00308.x. 59. Puwanant S, Varr BC, Shrestha K, Hussain SK, Tang WH, Gabriel RS, Wazni OM, Bhargava M, Saliba WI, Thomas JD, Lindsay BD, Klein AL. Role of the CHADS2 score in the evaluation of thromboembolic risk in patients with atrial fibrillation undergoing transesophageal echocardiography before pulmonary vein isolation. J Am Coll Cardiol. 2009;54(22):2032–9. doi:10.1016/j. jacc.2009.07.037. 60. Dong J, Liu X, Long D, Yu R, Tang R, Lu F, Ma C. Single-catheter technique for pulmonary vein antrum isolation: is it sufficient to identify and close the residual gaps without a circular mapping catheter? J Cardiovasc Electrophysiol. 2009;20(3):273–9. doi:10.1111/j.1540-8167.2008.01324.x. 61. Gerstenfeld EP, Dixit S, Callans D, Rho R, Rajawat Y, Zado E, Marchlinski FE. Utility of exit block for identifying electrical isolation of the pulmonary veins. J Cardiovasc Electrophysiol. 2002;13(10):971–9. 62. Steven D, Reddy VY, Inada K, Roberts-Thomson KC, Seiler J, Stevenson WG, Michaud GF. Loss of pace capture on the ablation line: a new marker for complete radiofrequency lesions to achieve pulmonary vein isolation. Heart Rhythm. 2010;7(3):323–30. doi:10.1016/j.hrthm.2009.11.011. 63. Eitel C, Hindricks G, Sommer P, Gaspar T, Kircher S, Wetzel U, Dagres N, Esato M, Bollmann A, Husser D, Hilbert S, ZakerShahrak R, Arya A, Piorkowski C. Circumferential pulmonary vein isolation and linear left atrial ablation as a single-catheter technique to achieve bidirectional conduction block: the paceand-ablate approach. Heart Rhythm. 2010;7(2):157–64. doi:10.1016/j.hrthm.2009.10.003. 64. Datino T, Macle L, Qi XY, Maguy A, Comtois P, Chartier D, Guerra PG, Arenal A, Fernandez-Aviles F, Nattel S. Mechanisms by which adenosine restores conduction in dormant canine pulmonary veins. Circulation. 2010;121(8):963–72. doi:10.1161/ CIRCULATIONAHA.109.893107. 65. Matsuo S, Yamane T, Date T, Inada K, Kanzaki Y, Tokuda M, Shibayama K, Miyanaga S, Miyazaki H, Sugimoto K, Mochizuki S. Reduction of AF recurrence after pulmonary vein isolation by eliminating ATPinduced transient venous re-conduction. J Cardiovasc Electrophysiol. 2007;18(7):704–8. doi:10.1111/j.1540-8167.2007.00842.x. 66. Hachiya H, Hirao K, Takahashi A, Nagata Y, Suzuki K, Maeda S, Sasaki T, Kawabata M, Isobe M, Iesaka Y. Clinical implications of reconnection between the left atrium and isolated pulmonary veins provoked by adenosine triphosphate after extensive encircling pulmonary vein isolation. J Cardiovasc Electrophysiol. 2007;18(4):392–8. doi:10.1111/j.1540-8167.2006.00753.x.
435 67. Sauer WH, McKernan ML, Lin D, Gerstenfeld EP, Callans DJ, Marchlinski FE. Clinical predictors and outcomes associated with acute return of pulmonary vein conduction during pulmonary vein isolation for treatment of atrial fibrillation. Heart Rhythm. 2006;3(9):1024–8. doi:10.1016/j.hrthm.2006.05.007. 68. Wang XH, Liu X, Sun YM, Gu JN, Shi HF, Zhou L, Hu W. Early identification and treatment of PV re-connections: role of observation time and impact on clinical results of atrial fibrillation ablation. Europace. 2007;9(7):481–6. doi:10.1093/europace/eum101. 69. Yamane T, Matsuo S, Date T, Lellouche N, Hioki M, Narui R, Ito K, Tanigawa S, Yamashita S, Tokuda M, Yoshida H, Inada K, Shibayama K, Miyanaga S, Miyazaki H, Abe K, Sugimoto K, Yoshimura M. Repeated provocation of time- and ATP-induced early pulmonary vein reconnections after pulmonary vein isolation: eliminating paroxysmal atrial fibrillation in a single procedure. Circ Arrhythm Electrophysiol. 2011;4(5):601–8. doi:10.1161/CIRCEP.110.960138. 70. Jais P, Hocini M, Sanders P, Hsu LF, Takahashi Y, Rotter M, Rostock T, Sacher F, Clementy J, Haissaguerre M. Long-term evaluation of atrial fibrillation ablation guided by noninducibility. Heart Rhythm. 2006;3(2):140–5. doi:10.1016/j.hrthm.2005.11.012. 71. Oral H, Chugh A, Lemola K, Cheung P, Hall B, Good E, Han J, Tamirisa K, Bogun F, Pelosi Jr F, Morady F. Noninducibility of atrial fibrillation as an end point of left atrial circumferential ablation for paroxysmal atrial fibrillation: a randomized study. Circulation. 2004;110(18):2797–801. doi:10.1161/01.CIR.0000146786.87037.26. 72. O’Neill MD, Wright M, Knecht S, Jais P, Hocini M, Takahashi Y, Jonsson A, Sacher F, Matsuo S, Lim KT, Arantes L, Derval N, Lellouche N, Nault I, Bordachar P, Clementy J, Haissaguerre M. Long-term follow-up of persistent atrial fibrillation ablation using termination as a procedural endpoint. Eur Heart J. 2009;30(9):1105–12. doi:10.1093/eurheartj/ehp063. 73. Shah D, Haissaguerre M, Takahashi A, Jais P, Hocini M, Clementy J. Differential pacing for distinguishing block from persistent conduction through an ablation line. Circulation. 2000;102(13):1517–22. 74. Stabile G, Bertaglia E, Senatore G, De Simone A, Zoppo F, Donnici G, Turco P, Pascotto P, Fazzari M, Vitale DF. Catheter ablation treatment in patients with drug-refractory atrial fibrillation: a prospective, multi-centre, randomized, controlled study (Catheter Ablation For The Cure Of Atrial Fibrillation Study). Eur Heart J. 2006;27(2):216–21. doi:10.1093/eurheartj/ehi583. 75. Wazni OM, Marrouche NF, Martin DO, Verma A, Bhargava M, Saliba W, Bash D, Schweikert R, Brachmann J, Gunther J, Gutleben K, Pisano E, Potenza D, Fanelli R, Raviele A, Themistoclakis S, Rossillo A, Bonso A, Natale A. Radiofrequency ablation vs antiarrhythmic drugs as first-line treatment of symptomatic atrial fibrillation: a randomized trial. JAMA. 2005;293(21):2634–40. doi:10.1001/jama.293.21.2634. 76. Jais P, Cauchemez B, Macle L, Daoud E, Khairy P, Subbiah R, Hocini M, Extramiana F, Sacher F, Bordachar P, Klein G, Weerasooriya R, Clementy J, Haissaguerre M. Catheter ablation versus antiarrhythmic drugs for atrial fibrillation: the A4 study. Circulation. 2008;118(24):2498– 505. doi:10.1161/CIRCULATIONAHA.108.772582. 77. Pappone C, Augello G, Sala S, Gugliotta F, Vicedomini G, Gulletta S, Paglino G, Mazzone P, Sora N, Greiss I, Santagostino A, LiVolsi L, Pappone N, Radinovic A, Manguso F, Santinelli V. A randomized trial of circumferential pulmonary vein ablation versus antiarrhythmic drug therapy in paroxysmal atrial fibrillation: the APAF Study. J Am Coll Cardiol. 2006;48(11):2340–7. doi:10.1016/j.jacc.2006.08.037. 78. Wilber DJ, Pappone C, Neuzil P, De Paola A, Marchlinski F, Natale A, Macle L, Daoud EG, Calkins H, Hall B, Reddy V, Augello G, Reynolds MR, Vinekar C, Liu CY, Berry SM, Berry DA. Comparison of antiarrhythmic drug therapy and radiofrequency catheter ablation in patients with paroxysmal atrial fibrillation: a randomized controlled trial. JAMA. 2010;303(4):333–40. doi:10.1001/jama.2009.2029.
436 79. Oral H, Pappone C, Chugh A, Good E, Bogun F, Pelosi Jr F, Bates ER, Lehmann MH, Vicedomini G, Augello G, Agricola E, Sala S, Santinelli V, Morady F. Circumferential pulmonary-vein ablation for chronic atrial fibrillation. N Engl J Med. 2006;354(9):934–41. doi:10.1056/NEJMoa050955. 80. Krittayaphong R, Raungrattanaamporn O, Bhuripanyo K, Sriratanasathavorn C, Pooranawattanakul S, Punlee K, Kangkagate C. A randomized clinical trial of the efficacy of radiofrequency catheter ablation and amiodarone in the treatment of symptomatic atrial fibrillation. J Med Assoc Thai. 2003;86 Suppl 1:S8–16. 81. Packer DLIJ, Champagne J, Guerra PG, Dubuc M, Wheelan KR, Kowal RC, Lehmann JW, Holcomb RG, Ruskin JN. Cryoballoon ablation of pulmonary veins for paroxysmal atrial fibrillation: first results of the North American Arctic Front Stop-AF pivotal trial. J Am Coll Cardiol. 2010;55:E3015–6. 82. Pappone C, Santinelli V, Rosanio S, Vicedomini G, Nardi S, Pappone A, Tortoriello V, Manguso F, Mazzone P, Gulletta S, Oreto G, Alfieri O. Usefulness of invasive electrophysiologic testing to stratify the risk of arrhythmic events in asymptomatic patients with WolffParkinson-White pattern: results from a large prospective long-term follow-up study. J Am Coll Cardiol. 2003;41(2):239–44. 83. Bunch TJ, Crandall BG, Weiss JP, May HT, Bair TL, Osborn JS, Anderson JL, Muhlestein JB, Horne BD, Lappe DL, Day JD. Patients treated with catheter ablation for atrial fibrillation have long-term rates of death, stroke, and dementia similar to patients without atrial fibrillation. J Cardiovasc Electrophysiol. 2011;22(8):839–45. doi:10.1111/j.1540-8167.2011.02035.x. 84. Balk EM, Garlitski AC, Alsheikh-Ali AA, Terasawa T, Chung M, Ip S. Predictors of atrial fibrillation recurrence after radiofrequency catheter ablation: a systematic review. J Cardiovasc Electrophysiol. 2010;21(11):1208–16. doi:10.1111/j.1540-8167.2010.01798.x. 85. McCready J, Smedley T, Lambiase P, Ahsan S, Segal O, Rowland E, Lowe M, Chow A. Predictors of Recurrence Following Radiofrequency Ablation for Persistent Atrial Fibrillation. Europace 2011;13:355–361. 86. Arya A, Hindricks G, Sommer P, Huo Y, Bollmann A, Gaspar T, Bode K, Husser D, Kottkamp H, Piorkowski C. Long-term Results and the Predictors of Outcome of Catheter Ablation of Atrial Fibrillation Using Steerable Sheath Catheter Navigation After Single Procedure in 674 Patients. Europace 2010;12: 173–180. 87. Berruezo A, Tamborero D, Mont L, Benito B, Tolosana J, Sitges M, Vidal B, Arriagada G, Mendez F, Matiello M, Molina I, Brugada J. Pre-procedural Predictors of Atrial Fibrillation Recurrence After Circumferential Pulmonary Vein Ablation. European Heart Journal 2007;28:836–841 88. Kilicaslan F, Verma A, Saad E, Themistoclakis S, Bonso A, Raviele A, Bozbas H, Andrews MW, Beheiry S, Hao S, Cummings JE, Marrouche NF, Lakkireddy D, Wazni O, Yamaji H, Saenz LC, Saliba W, Schweikert RA, Natale A. Efficacy of catheter ablation of atrial fibrillation in patients with hypertrophic obstructive cardiomyopathy. Heart Rhythm. 2006;3(3):275–80. doi:10.1016/j. hrthm.2005.11.013. 89. Sawhney N, Anousheh R, Chen WC, Narayan S, Feld GK. Fiveyear outcomes after segmental pulmonary vein isolation for paroxysmal atrial fibrillation. Am J Cardiol. 2009;104(3):366–72. doi:10.1016/j.amjcard.2009.03.044. 90. Tzou WS, Marchlinski FE, Zado ES, Lin D, Dixit S, Callans DJ, Cooper JM, Bala R, Garcia F, Hutchinson MD, Riley MP, Verdino R, Gerstenfeld EP. Long-term outcome after successful catheter ablation of atrial fibrillation. Circ Arrhythm Electrophysiol. 2010;3(3):237–42. doi:10.1161/CIRCEP.109.923771. 91. Weerasooriya R, Khairy P, Litalien J, Macle L, Hocini M, Sacher F, Lellouche N, Knecht S, Wright M, Nault I, Miyazaki S, Scavee C, Clementy J, Haissaguerre M, Jais P. Catheter ablation for atrial
J.M. Lee and S.M. Markowitz fibrillation: are results maintained at 5 years of follow-up? J Am Coll Cardiol. 2011;57(2):160–6. doi:10.1016/j.jacc.2010.05.061. 92. Shah AN, Mittal S, Sichrovsky TC, Cotiga D, Arshad A, Maleki K, Pierce WJ, Steinberg JS. Long-term outcome following successful pulmonary vein isolation: pattern and prediction of very late recurrence. J Cardiovasc Electrophysiol. 2008;19(7):661–7. doi:10.1111/j.1540-8167.2008.01101.x. 93. Fichtner S, Czudnochowsky U, Hessling G, Reents T, Estner H, Wu J, Jilek C, Ammar S, Karch MR, Deisenhofer I. Very late relapse of atrial fibrillation after pulmonary vein isolation: incidence and results of repeat ablation. Pacing Clin Electrophysiol. 2010;33(10):1258–63. doi:10.1111/j.1540-8159.2010.02808.x. 94. Bertaglia E, Tondo C, De Simone A, Zoppo F, Mantica M, Turco P, Iuliano A, Forleo G, La Rocca V, Stabile G. Does catheter ablation cure atrial fibrillation? Single-procedure outcome of drugrefractory atrial fibrillation ablation: a 6-year multicentre experience. Europace. 2010;12(2):181–7. doi:10.1093/europace/eup349. 95. Ouyang F, Tilz R, Chun J, Schmidt B, Wissner E, Zerm T, Neven K, Kokturk B, Konstantinidou M, Metzner A, Fuernkranz A, Kuck KH. Long-term results of catheter ablation in paroxysmal atrial fibrillation: lessons from a 5-year follow-up. Circulation. 2010;122(23):2368–77. doi:10.1161/CIRCULATIONAHA.110.946806. 96. Bhargava M, Di Biase L, Mohanty P, Prasad S, Martin DO, Williams-Andrews M, Wazni OM, Burkhardt JD, Cummings JE, Khaykin Y, Verma A, Hao S, Beheiry S, Hongo R, Rossillo A, Raviele A, Bonso A, Themistoclakis S, Stewart K, Saliba WI, Schweikert RA, Natale A. Impact of type of atrial fibrillation and repeat catheter ablation on long-term freedom from atrial fibrillation: results from a multicenter study. Heart Rhythm. 2009;6(10):1403–12. doi:10.1016/j.hrthm.2009.06.014. 97. Wokhlu A, Hodge DO, Monahan KH, Asirvatham SJ, Friedman PA, Munger TM, Cha YM, Shen WK, Brady PA, Bluhm CM, Haroldson JM, Hammill SC, Packer DL. Long-term outcome of atrial fibrillation ablation: impact and predictors of very late recurrence. J Cardiovasc Electrophysiol. 2010;21(10):1071–8. doi:10.1111/j.1540-8167.2010.01786.x. 98. Miyazaki S, Kuwahara T, Kobori A, Takahashi Y, Takei A, Sato A, Isobe M, Takahashi A. Long-term clinical outcome of extensive pulmonary vein isolation-based catheter ablation therapy in patients with paroxysmal and persistent atrial fibrillation. Heart. 2011;97(8):668–73. doi:10.1136/hrt.2009.186874. 99. Pappone C, Vicedomini G, Augello G, Manguso F, Saviano M, Baldi M, Petretta A, Giannelli L, Calovic Z, Guluta V, Tavazzi L, Santinelli V. Radiofrequency catheter ablation and antiarrhythmic drug therapy: a prospective, randomized, 4-year follow-up trial: the APAF study. Circ Arrhythm Electrophysiol. 2011;4(6):808– 14. doi:10.1161/CIRCEP.111.966408. 100. Medi C, Sparks PB, Morton JB, Kistler PM, Halloran K, Rosso R, Vohra JK, Kumar S, Kalman JM. Pulmonary vein antral isolation for paroxysmal atrial fibrillation: results from long-term follow-up. J Cardiovasc Electrophysiol.2011;22(2):137–41.doi:10.1111/j.1540-8167.2010.01885.x. 101. Hussein AA, Saliba WI, Martin DO, Bhargava M, Sherman M, Magnelli-Reyes C, Chamsi-Pasha M, John S, Williams-Adrews M, Baranowski B, Dresing T, Callahan T, Kanj M, Tchou P, Lindsay BD, Natale A, Wazni O. Natural history and long-term outcomes of ablated atrial fibrillation. Circ Arrhythm Electrophysiol. 2011;4(3):271–8. doi:10.1161/CIRCEP.111.962100. 102. Verma A, Kilicaslan F, Pisano E, Marrouche NF, Fanelli R, Brachmann J, Geunther J, Potenza D, Martin DO, Cummings J, Burkhardt JD, Saliba W, Schweikert RA, Natale A. Response of atrial fibrillation to pulmonary vein antrum isolation is directly related to resumption and delay of pulmonary vein conduction. Circulation. 2005;112(5):627–35. doi:10.1161/CIRCULATIONAHA.104.533190. 103. Mainigi SK, Sauer WH, Cooper JM, Dixit S, Gerstenfeld EP, Callans DJ, Russo AM, Verdino RJ, Lin D, Zado ES, Marchlinski FE. Incidence and predictors of very late recurrence
33 Atrial Fibrillation Ablation: From Guidelines to Clinical Reality
104.
105.
106.
107.
108.
109.
110.
111.
112.
113.
114.
115.
of atrial fibrillation after ablation. J Cardiovasc Electrophysiol. 2007;18(1):69– 74. doi:10.1111/j.1540-8167.2006.00646.x. Cappato R, Negroni S, Pecora D, Bentivegna S, Lupo PP, Carolei A, Esposito C, Furlanello F, De Ambroggi L. Prospective assessment of late conduction recurrence across radiofrequency lesions producing electrical disconnection at the pulmonary vein ostium in patients with atrial fibrillation. Circulation. 2003;108(13):1599–604. doi:10.1161/01.CIR.0000091081.19465.F1. Nanthakumar K, Plumb VJ, Epstein AE, Veenhuyzen GD, Link D, Kay GN. Resumption of electrical conduction in previously isolated pulmonary veins: rationale for a different strategy? Circulation. 2004;109(10):1226–9. doi:10.1161/01.CIR.0000121423.78120.49. Callans DJ, Gerstenfeld EP, Dixit S, Zado E, Vanderhoff M, Ren JF, Marchlinski FE. Efficacy of repeat pulmonary vein isolation procedures in patients with recurrent atrial fibrillation. J Cardiovasc Electrophysiol. 2004;15(9):1050–5. doi:10.1046/j.1540-8167.2004.04052.x. Hsieh MH, Tai CT, Lee SH, Lin YK, Tsao HM, Chang SL, Lin YJ, Wongchaoen W, Lee KT, Chen SA. The different mechanisms between late and very late recurrences of atrial fibrillation in patients undergoing a repeated catheter ablation. J Cardiovasc Electrophysiol. 2006;17(3):231–5. doi:10.1111/j.1540-8167.2005.00323.x. Cappato R, Calkins H, Chen SA, Davies W, Iesaka Y, Kalman J, Kim YH, Klein G, Natale A, Packer D, Skanes A, Ambrogi F, Biganzoli E. Updated worldwide survey on the methods, efficacy, and safety of catheter ablation for human atrial fibrillation. Circ Arrhythm Electrophysiol. 2010;3(1):32–8. doi:10.1161/CIRCEP.109.859116. Cappato R, Calkins H, Chen SA, Davies W, Iesaka Y, Kalman J, Kim YH, Klein G, Packer D, Skanes A. Worldwide survey on the methods, efficacy, and safety of catheter ablation for human atrial fibrillation. Circulation. 2005;111(9):1100–5. doi:10.1161/01. CIR.0000157153.30978.67. Wazni OM, Rossillo A, Marrouche NF, Saad EB, Martin DO, Bhargava M, Bash D, Beheiry S, Wexman M, Potenza D, Pisano E, Fanelli R, Bonso A, Themistoclakis S, Erciyes D, Saliba WI, Schweikert RA, Brachmann J, Raviele A, Natale A. Embolic events and char formation during pulmonary vein isolation in patients with atrial fibrillation: impact of different anticoagulation regimens and importance of intracardiac echo imaging. J Cardiovasc Electrophysiol. 2005;16(6):576–81. doi:10.1111/j.1540-8167.2005.40480.x. Ren JF, Marchlinski FE, Callans DJ, Gerstenfeld EP, Dixit S, Lin D, Nayak HM, Hsia HH. Increased intensity of anticoagulation may reduce risk of thrombus during atrial fibrillation ablation procedures in patients with spontaneous echo contrast. J Cardiovasc Electrophysiol. 2005;16(5):474–7. doi:10.1046/j.1540-8167.2005.40465.x. Cauchemez B, Extramiana F, Cauchemez S, Cosson S, Zouzou H, Meddane M, d’Allonnes LR, Lavergne T, Leenhardt A, Coumel P, Houdart E. High-flow perfusion of sheaths for prevention of thromboembolic complications during complex catheter ablation in the left atrium. J Cardiovasc Electrophysiol. 2004;15(3):276– 83. doi:10.1046/j.1540-8167.2004.03401.x. Maleki K, Mohammadi R, Hart D, Cotiga D, Farhat N, Steinberg JS. Intracardiac ultrasound detection of thrombus on transseptal sheath: incidence, treatment, and prevention. J Cardiovasc Electrophysiol. 2005;16(6):561–5. doi:10.1111/j.1540-8167.2005.40686.x. Neumann T, Sperzel J, Dill T, Kluge A, Erdogan A, Greis H, Hansel J, Berkowitsch A, Kurzidim K, Kuniss M, Hamm CW, Pitschner HF. Percutaneous pulmonary vein stenting for the treatment of severe stenosis after pulmonary vein isolation. J Cardiovasc Electrophysiol. 2005;16(11):1180–8. doi:10.1111/j.1540-8167.2005.50073.x. Packer DL, Keelan P, Munger TM, Breen JF, Asirvatham S, Peterson LA, Monahan KH, Hauser MF, Chandrasekaran K, Sinak LJ, Holmes Jr DR. Clinical presentation, investigation, and management of pulmonary vein stenosis complicating ablation for atrial fibrillation. Circulation. 2005;111(5):546–54. doi:10.1161/01.CIR.0000154541.58478.36.
437 116. Bai R, Patel D, Di Biase L, Fahmy TS, Kozeluhova M, Prasad S, Schweikert R, Cummings J, Saliba W, Andrews-Williams M, Themistoclakis S, Bonso A, Rossillo A, Raviele A, Schmitt C, Karch M, Uriarte JA, Tchou P, Arruda M, Natale A. Phrenic nerve injury after catheter ablation: should we worry about this complication? J Cardiovasc Electrophysiol.2006;17(9):944–8.doi:10.1111/j.1540-8167.2006.00536.x. 117. Pappone C, Oral H, Santinelli V, Vicedomini G, Lang CC, Manguso F, Torracca L, Benussi S, Alfieri O, Hong R, Lau W, Hirata K, Shikuma N, Hall B, Morady F. Atrio-esophageal fistula as a complication of percutaneous transcatheter ablation of atrial fibrillation. Circulation. 2004;109(22):2724–6. doi:10.1161/01. CIR.0000131866.44650.46. 118. Scanavacca MI, D’Avila A, Parga J, Sosa E. Left atrial-esophageal fistula following radiofrequency catheter ablation of atrial fibrillation. J Cardiovasc Electrophysiol. 2004;15(8):960–2. doi:10.1046/j.1540-8167.2004.04083.x. 119. Cummings JE, Schweikert RA, Saliba WI, Burkhardt JD, Brachmann J, Gunther J, Schibgilla V, Verma A, Dery M, Drago JL, Kilicaslan F, Natale A. Assessment of temperature, proximity, and course of the esophagus during radiofrequency ablation within the left atrium. Circulation. 2005;112(4):459–64. doi:10.1161/CIRCULATIONAHA.104.509612. 120. Calkins H, Brugada J, Packer DL, Cappato R, Chen SA, Crijns HJ, Damiano Jr RJ, Davies DW, Haines DE, Haissaguerre M, Iesaka Y, Jackman W, Jais P, Kottkamp H, Kuck KH, Lindsay BD, Marchlinski FE, McCarthy PM, Mont JL, Morady F, Nademanee K, Natale A, Pappone C, Prystowsky E, Raviele A, Ruskin JN, Shemin RJ. HRS/EHRA/ECAS expert Consensus Statement on catheter and surgical ablation of atrial fibrillation: recommendations for personnel, policy, procedures and follow-up. A report of the Heart Rhythm Society (HRS) Task Force on catheter and surgical ablation of atrial fibrillation. Heart Rhythm. 2007;4(6):816– 61. doi:10.1016/j.hrthm.2007.04.005. 121. Calkins H, Kuck KH, Cappato R, Brugada J, Camm AJ, Chen SA, Crijns HJ, Damiano RJ Jr, Davies DW, Dimarco J, Edgerton J, Ellenbogen K, Ezekowitz MD, Haines DE, Haissaguerre M, Hindricks G, Iesaka Y, Jackman W, Jalife J, Jais P, Kalman J, Keane D, Kim YH, Kirchhof P, Klein G, Kottkamp H, Kumagai K, Lindsay BD, Mansour M, Marchlinski FE, McCarthy PM, Mont JL, Morady F, Nademanee K, Nakagawa H, Natale A, Nattel S, Packer DL, Pappone C, Prystowsky E, Raviele A, Reddy V, Ruskin JN, Shemin RJ, Tsao HM, Wilber D, Calkins H, Kuck KH, Cappato R, Chen SA, Prystowsky EN, Kuck KH, Natale A, Haines DE, Marchlinski FE, Calkins H, Davies DW, Lindsay BD, Damiano Jr R, Packer DL, Brugada J, Camm AJ, Crijns HJ, Dimarco J, Edgerton J, Ellenbogen K, Ezekowitz MD, Haissaguerre M, Hindricks G, Iesaka Y, Jackman WM, Jais P, Jalife J, Kalman J, Keane D, Kim YH, Kirchhof P, Klein G, Kottkamp H, Kumagai K, Mansour M, Marchlinski F, McCarthy P, Mont JL, Morady F, Nademanee K, Nakagawa H, Nattel S, Pappone C, Raviele A, Reddy V, Ruskin JN, Shemin RJ, Tsao HM, Wilber D. 2012 HRS/ EHRA/ECAS Expert Consensus Statement on Catheter and Surgical Ablation of Atrial Fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design: a report of the Heart Rhythm Society (HRS) Task Force on Catheter and Surgical Ablation of Atrial Fibrillation. Developed in partnership with the European Heart Rhythm Association (EHRA), a registered branch of the European Society of Cardiology (ESC) and the European Cardiac Arrhythmia Society (ECAS); and in collaboration with the American College of Cardiology (ACC), American Heart Association (AHA), the Asia Pacific Heart Rhythm Society (APHRS), and the Society of Thoracic Surgeons (STS). Endorsed by the governing bodies of the American College of Cardiology Foundation, the American Heart Association, the European Cardiac Arrhythmia Society, the European Heart Rhythm
438
122.
123.
124.
125.
126.
127.
128.
129.
J.M. Lee and S.M. Markowitz Association, the Society of Thoracic Surgeons, the Asia Pacific Heart Rhythm Society, and the Heart Rhythm Society. Heart Rhythm. 2012;9(4):632–96. doi:10.1016/j.hrthm.2011.12.016 Fuster V, Ryden LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, Halperin JL, Kay GN, Le Huezey JY, Lowe JE, Olsson SB, Prystowsky EN, Tamargo JL, Wann LS, Smith Jr SC, Priori SG, Estes 3rd NA, Ezekowitz MD, Jackman WM, January CT, Lowe JE, Page RL, Slotwiner DJ, Stevenson WG, Tracy CM, Jacobs AK, Anderson JL, Albert N, Buller CE, Creager MA, Ettinger SM, Guyton RA, Halperin JL, Hochman JS, Kushner FG, Ohman EM, Stevenson WG, Tarkington LG, Yancy CW. 2011 ACCF/AHA/HRS focused updates incorporated into the ACC/ AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2011;123(10):e269–367. doi:10.1161/ CIR.0b013e318214876d. Oral H, Veerareddy S, Good E, Hall B, Cheung P, Tamirisa K, Han J, Fortino J, Chugh A, Bogun F, Pelosi Jr F, Morady F. Prevalence of asymptomatic recurrences of atrial fibrillation after successful radiofrequency catheter ablation. J Cardiovasc Electrophysiol. 2004;15(8):920–4. doi:10.1046/j.1540-8167.2004.04055.x. Ziegler PD, Koehler JL, Mehra R. Comparison of continuous versus intermittent monitoring of atrial arrhythmias. Heart Rhythm. 2006;3(12):1445–52. doi:10.1016/j.hrthm.2006.07.030. Zado E, Callans DJ, Riley M, Hutchinson M, Garcia F, Bala R, Lin D, Cooper J, Verdino R, Russo AM, Dixit S, Gerstenfeld E, Marchlinski FE. Long-term clinical efficacy and risk of catheter ablation for atrial fibrillation in the elderly. J Cardiovasc Electrophysiol. 2008;19(6):621–6. doi:10.1111/j.1540-8167.2008.01183.x. Bhargava M, Marrouche NF, Martin DO, Schweikert RA, Saliba W, Saad EB, Bash D, Williams-Andrews M, Rossillo A, Erciyes D, Khaykin Y, Burkhardt JD, Joseph G, Tchou PJ, Natale A. Impact of age on the outcome of pulmonary vein isolation for atrial fibrillation using circular mapping technique and cooled-tip ablation catheter. J Cardiovasc Electrophysiol. 2004;15(1):8–13. doi:10.1046/j.1540-8167.2004.03266.x. Kusumoto F, Prussak K, Wiesinger M, Pullen T, Lynady C. Radiofrequency catheter ablation of atrial fibrillation in older patients: outcomes and complications. J Interv Card Electrophysiol. 2009;25(1):31–5. doi:10.1007/s10840-008-9346-7. Hsu LF, Jais P, Sanders P, Garrigue S, Hocini M, Sacher F, Takahashi Y, Rotter M, Pasquie JL, Scavee C, Bordachar P, Clementy J, Haissaguerre M. Catheter ablation for atrial fibrillation in congestive heart failure. N Engl J Med. 2004;351(23): 2373–83. doi:10.1056/NEJMoa041018. De Potter T, Berruezo A, Mont L, Matiello M, Tamborero D, Santibanez C, Benito B, Zamorano N, Brugada J. Left ventricular
130.
131.
132.
133.
134.
135.
136.
systolic dysfunction by itself does not influence outcome of atrial fibrillation ablation. Europace. 2010;12(1):24–9. doi:10.1093/ europace/eup309. Khan MN, Jais P, Cummings J, Di Biase L, Sanders P, Martin DO, Kautzner J, Hao S, Themistoclakis S, Fanelli R, Potenza D, Massaro R, Wazni O, Schweikert R, Saliba W, Wang P, Al-Ahmad A, Beheiry S, Santarelli P, Starling RC, Dello Russo A, Pelargonio G, Brachmann J, Schibgilla V, Bonso A, Casella M, Raviele A, Haissaguerre M, Natale A. Pulmonary-vein isolation for atrial fibrillation in patients with heart failure. N Engl J Med. 2008;359(17):1778–85. doi:10.1056/NEJMoa0708234. Di Donna P, Olivotto I, Delcre SD, Caponi D, Scaglione M, Nault I, Montefusco A, Girolami F, Cecchi F, Haissaguerre M, Gaita F. Efficacy of catheter ablation for atrial fibrillation in hypertrophic cardiomyopathy: impact of age, atrial remodelling, and disease progression. Europace. 2010;12(3):347–55. doi:10.1093/ europace/euq013. Bunch TJ, Munger TM, Friedman PA, Asirvatham SJ, Brady PA, Cha YM, Rea RF, Shen WK, Powell BD, Ommen SR, Monahan KH, Haroldson JM, Packer DL. Substrate and procedural predictors of outcomes after catheter ablation for atrial fibrillation in patients with hypertrophic cardiomyopathy. J Cardiovasc Electrophysiol. 2008;19(10):1009–14. doi:10.1111/j.1540-8167. 2008.01192.x. Gaita F, Di Donna P, Olivotto I, Scaglione M, Ferrero I, Montefusco A, Caponi D, Conte MR, Nistri S, Cecchi F. Usefulness and safety of transcatheter ablation of atrial fibrillation in patients with hypertrophic cardiomyopathy. Am J Cardiol. 2007;99(11): 1575–81. doi:10.1016/j.amjcard.2006.12.087. Oral H, Chugh A, Ozaydin M, Good E, Fortino J, Sankaran S, Reich S, Igic P, Elmouchi D, Tschopp D, Wimmer A, Dey S, Crawford T, Pelosi Jr F, Jongnarangsin K, Bogun F, Morady F. Risk of thromboembolic events after percutaneous left atrial radiofrequency ablation of atrial fibrillation. Circulation. 2006;114(8):759–65. doi:10.1161/ CIRCULATIONAHA.106.641225. Saad E, d’Avila A, Costa I, Aryana A, Slater C, Costa R, Inacio L, Maldonado P, Neto D, Camiletti A, Camanho L, Polanczyk C. Very Low Risk of Thromboembolic Events in Patients Undergoing Successful Catheter Ablation of Atrial Fibrillation With a CHADS2 Score<=3: A Long-Term Outcome Study. Circ Arrhythm Electrophysiol 2011;4:615–21. Themistoclakis S, Corrado A, Marchlinski FE, Jais P, Zado E, Rossillo A, Di Biase L, Schweikert RA, Saliba WI, Horton R, Mohanty P, Patel D, Burkhardt DJ, Wazni OM, Bonso A, Callans DJ, Haissaguerre M, Raviele A, Natale A. The risk of thromboembolism and need for oral anticoagulation after successful atrial fibrillation ablation. J Am Coll Cardiol. 2010;55(8):735–43. doi:10.1016/j.jacc.2009.11.039.
Atrial Fibrillation: Should Cardiac Surgeons Be Consulted?
34
Max Baghai, Randolph H.L. Wong, Innes Y.P. Wan, and Malcolm John Underwood
Abstract
The role of surgery in the treatment of arrhythmias has evolved due to improvements in catheter-based ablation techniques. In most centers, atrial fibrillation is now the only condition that is referred to the cardiac surgeon. The increasing demand for minimally invasive therapy gives the cardiologist first pick, but with the growing body of evidence there has been a shift back towards the surgeon. This chapter compares various surgical and catheterbased techniques and analyzes the current available outcome data. Although minimally invasive surgical approaches are increasing in popularity and have been shown to be safe and non-inferior to catheter ablation, they lack adequate follow-up data. Future data from randomized studies will clarify the role for the various approaches and formation of a multidisciplinary approach to the treatment of atrial fibrillation. Keywords
Atrial fibrillation • Mechanisms • Surgery • Catheter • Hybrid
Introduction
Atrial Fibrillation
The treatment of cardiac arrhythmias has significantly evolved over the past 50 years due to the advent of catheter ablation. In the past, the mainstay treatment for tachyarrhythmias was either lifelong medication or open heart surgery. Patients are now offered catheter-guided radio-frequency ablation which is not only less invasive but also in the long run economically more viable. The only role surgery is currently playing is in the treatment of atrial fibrillation (AF). In this chapter we will focus on the non-pharmacological treatments of AF in the past, present, and where we might be heading to in the future.
AF is the most common dysrhythmia in the world, affecting 1–2 % of the population and rising to above 17 % in the over 84 year olds [1]. In the USA and China alone, there are approximately 2.2 and 10 million people diagnosed with AF, respectively [2, 3]. This has both a clinical and financial burden on the health service, particularly with the rising number of individuals over the age of 80 and the expectation that the prevalence of AF will double over the next 25 years [4]. AF has previously been referred to as innocuous; however, there is now clear evidence that it affects both morbidity and mortality [5]. Patients above the age of 55 with AF are 1.5–1.9 times more likely to die than those without [6]. Symptoms can range from none to debilitating congestive heart failure. As demonstrated by the Framingham Study, the risk of stroke in AF patients can be as much as five times higher than the normal population [7]. Although there are various classification systems for AF, there is a global consensus that the ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial
M. Baghai, MBBS PhD FRCS(CTh) R.H.L. Wong, MB ChB, FCSHK, FAMHK I.Y.P. Wan, MB ChB, FCSHK, FAMHK M.J. Underwood, MD, FRCS (*) Division of Cardiothoracic Surgery, Chinese University of Hong Kong, Prince of Wales Hospital, Sha Tin, Hong Kong e-mail:
[email protected] A.S. Kibos et al. (eds.), Cardiac Arrhythmias, DOI 10.1007/978-1-4471-5316-0_34, © Springer-Verlag London 2014
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440 Table 34.1 Definitions for atrial fibrillation Paroxysmal AF is defined as recurrent AF (≥2 episodes) that terminates spontaneously within 7 days Persistent AF is defined as AF which is sustained beyond 7 days or lasting less than 7 days but necessitating pharmacologic or electrical cardioversion Long-standing persistent AF is defined as continuous AF of greater than 1-year duration The term permanent AF is not appropriate in the context of patients undergoing catheter ablation of AF as it refers to a group of patients where a decision has been made not to pursue restoration of sinus rhythm by any means, including catheter or surgical ablation
Fibrillation should be the one used in all future studies (Table 34.1) [8].
Mechanism of AF There have been some recent advances in the understanding of exactly how AF is triggered and sustained over time. One of the earliest hypotheses was the multiple wavelet which was developed by Moe et al. in 1964 [9]. According to their hypothesis, AF results from the presence of multiple reentrant wavelets occurring simultaneously in the left and right atria. The number of wavelets at any point in time depends on the atrial conduction velocity, refractory period, and mass. Therefore the likelihood of AF increases with slowed conduction, shortened refractory periods, and increased atrial mass. It was not until 1994 when Haïssaguerre et al. noticed that AF appeared to originate more often than not from a specific focus within the atria [10]. They were also able to demonstrate that ablation of the “focal AF” would prevent its recurrence [10, 11]. While mapping these abnormal foci of electrical activity, it was noted that majority of them resided in the proximal segment of the pulmonary veins (PVs) within the well-documented myocardial cuffs [12, 13]. This was the beginning of our current understanding of how AF requires both a “trigger” to initiate it and a “substrate” to propagate and maintain the arrhythmia. Numerous animal-based models have been used to investigate the role of PVs in both triggering and maintaining AF. Specialized conduction tissue has been shown to be located within the myocardial sleeves of the PVs [14]. A recent human study demonstrated the presence of P cells, transitional cells, and Purkinje cells in the PVs [15]. This explains why there is continued electrical activity after the PVs are disconnected from the atrium [16]. Focal automaticity of the PVs has been identified in further studies to be arrhythmogenic, with abnormal ion channel activity identified as a possible mechanism [17, 18]. There is some evidence that variation in action potential duration (APD) and conduction velocity within the PVs and the surrounding atrial tissue could initiate reentrant
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arrhythmias [19, 20]. A study was able to show that a rise in the intra-atrial pressure increased the frequency of wavelets emanating from the PVs [21]. Studies have also demonstrated a possible role of the junction between the PV and atrium in the maintenance of AF due to reentrant activity [22]. Patients with long-standing persistent AF appear to behave differently to patients with paroxysmal AF. The evidence is suggesting that the trigger appears not only around the PVs but also elsewhere within the atria [23]. This atrial remodeling phenomenon involves both changes to size and ultrastructure which appear to increase the number of focal AF drivers as well as move them away from the origin of the PVs. As an adjunct to the various foci found within the atrial myocardium, the autonomic nervous system may also have a part to play. Bettoni et al. were able to show that in patients with PAF there is a preceding increase in adrenergic activity followed by an increase in vagal tone just prior to the initiation of the AF [24]. This has been demonstrated in various experimental models, and as the location of the intrinsic cardiac autonomic system is adjacent to the origin of the PVs, it is not inconceivable to think they may be involved in either initiating AF or reentry which can go on to trigger AF [25–27].
Current Treatment Strategy for AF The primary aims of AF treatment are to improve quality of life by relieving symptoms and preventing stroke and tachyarrhythmia-induced heart failure. First-line treatment has always been pharmacological, with or without DC cardioversion. The question of whether it is better to rate or rhythm control patients has now been passed around for several decades with numerous trials looking at which one is better. As one would expect, it is never black and white. The randomized trials such as PIAF, STAF, AFFIRM, and RACE all showed no significant difference in survival and rate of stroke in either the rate or rhythm group [28–31]. All these trials involved the use of drugs to control the rhythm, and in fact many of the patients remained in AF. Later analysis of the AFFIRM trial showed that patients in sinus rhythm had a lower mortality which may have been overshadowed by the adverse effects of the antiarrhythmic drugs [32]. Clear guidelines by all the major cardiologic societies (ACCF/AHA/HRS/CCS/ESC) have recently been published on how to assess patients with AF using the CHAD2 scoring system and initiate most appropriate therapy tailored to the patient’s thromboembolic versus bleeding risk [33–35]. For patients who are in either paroxysmal or persistent AF, it is essential to initiate either warfarin, dabigatran, or a combination of antiplatelet therapy for stroke prophylaxis. In majority of the units worldwide, the first-line therapy is medication. However, not all patients can tolerate the side effects of the medication or even respond to the
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Atrial Fibrillation: Should Cardiac Surgeons Be Consulted?
treatment [36]. This has triggered a great deal of interest in non-pharmacological treatment of AF, which we will discuss in the rest of the chapter.
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I lesion set using radio-frequency energy via a transvenous approach [44]. Even though it was less effective than surgery and associated with a significant complication rate, it inspired other cardiologist to further improve the technique.
History of AF Surgery Surgical Ablation The first non-pharmacological therapy for AF was “left atrial isolation” as described by Williams et al. and involved electrical isolation of the left atrium from the rest of the heart – so while the left atrium remained in AF, the rest of the heart would enjoy sinus rhythm [37]. Even though 72 % freedom from AF has been documented, it is unlikely to decrease the risk of stroke as the LA remains in AF [38]. Next came the “corridor” procedure described in 1985 by Guiraudon [39]. This involved isolation of a strip of right atrium connecting the sinoatrial (SA) and atrioventricular (AV) nodes, which was below a specific critical surface area, preventing the development of AF within the strip as described by Moe et al. [9]. The rest of the right and left atrium would continue to remain in AF, and there would be no improvement to atrial transport nor the risk of thromboembolic events. The original Maze procedure, which superseded the corridor, was described by Cox et al. in 1991. It involved the laborious task of “cutting and sewing” of both the right and left atrium such that specific areas such as the PVs and appendages were electrically isolated and the rest of the atrial tissue were in thin strips [40]. The impulse from the SA node would have to travel along a specific windy route across to the left atrium and then back round to the AV node – hence the name “Maze.” This not only maintained sinus rhythm within the majority of the atrial tissue but also atrial transport to some degree, with a subsequent decrease in thromboembolic risk. This procedure was subsequently modified several times into Cox-Maze II and III due to problems with generating a sinus tachycardia and synchronous atrioventricular contractions [41]. Cox et al. have reported a success rate of 93 % in curing AF at 8.5 years, and this has been verified by other groups [42, 43]. These results caught the eye of some interventional cardiologist in the early 1990s, and they began to develop a catheter-based technique to reproduce the Maze procedure. Swartz et al. attempted to copy the Cox-Maze
There is no doubt that the “cut and sew” Maze is an effective treatment for AF; however, it is technically difficult, particularly if it is done only a few times a year and requires cardiopulmonary bypass. Even if one limits its use in patients undergoing concomitant surgery, an additional Cox-Maze III adds another 40–50 min of ischemic time which can be deleterious in some patients. These limitations gave birth to alternative energy sources that could produce similar lesions as the “cut and sew” technique. The new technology uses thermal energy to produce transmural lesions that result in the desired electrical isolation. The different energy sources for ablation therapy include microwave, radio-frequency (RF), high-frequency ultrasound (HIFU), laser, and cryotherapy. See Table 34.2 for comparative analysis of various energy sources. The energy source can be delivered using either a unipolar or bipolar device. The unipolar energy sources (cryosurgery, RF, microwave, laser, HIFU) radiate either energy or cold from a single source. Unipolar devices do not provide the surgeon with an indication of when the ablation results in a transmural lesion. These devices also had difficulty creating transmural lesions when used from the epicardial surface as the circulating intracavitary blood pool makes transmural lesions difficult to achieve. This may improve with the newer energy sources such as HIFU and laser as they are more focused and have a fixed depth of penetration. Bipolar RF ablation consists of energy delivered between two closely approximated electrodes embedded in the jaw of a clamp device; the energy is focused and results in relatively discrete lesions. The energy is confined to within the jaws of the clamp, reducing the possibility of collateral cardiac or extracardiac damage, and is able to predict transmurality. Limitations of the bipolar device include the inability to produce adequate isthmus lesions and so requires the
Table 34.2 Comparison between ablative energy sources Modality RF Cryoablation Microwave HIFU Laser a
Transmurality ++ ++ + +++ +++
Circumflex artery damage Minimal collateral damage
b
Accuracy ++ ++ +++ +/− +/−
Advantages Fast/effective Isthmus lesion/MCDb MCD Fast/visual aid Fast/deep/uniform
Complication Thrombus/CxAa/Oesoph/PV stenosis CxA CxA Collateral/perforation Crater formation/perforation
References [45–47] [47–49] [45, 46, 50] [51, 52] [45, 53]
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addition of a unipolar device to complete the Cox-Maze III lesions (see Fig. 34.1). There have been numerous centers that have published compatible results with ablation therapy – which is technically less demanding and time consuming than the old “cut and sew.” [43, 54–56] The advent of these new devices has meant that surgeons are now less intimidated by AF therapy, and most centers offer it to patients who are having concomitant valve or coronary bypass surgery. Gradually small modifications were made to the Cox-Maze III to take into account the use of the bipolar
Fig. 34.1 Cox-Maze III lesion set as seen from the posterior aspect of the heart
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radio-frequency probe, which gave birth to the Cox-Maze IV (see Fig. 34.2) [57]. The results in both concomitant and stand-alone AF patients were as good as its predecessor, all the while taking less time to complete [54, 58]. There is no doubt that the Cox-Maze IV lesion set is very effective, especially in the cohort of patients with persistent AF, but it requires full cardiopulmonary bypass with bicaval cannulation, cardioplegic arrest, and a midline sternotomy. The meta-analysis performed by Kong et al. looked at nine randomized clinical trials comparing concomitant Cox-Maze III or IV procedure versus antiarrhythmic drug in patients undergoing mitral valve surgery [59]. They demonstrated that the Maze procedure was associated with significantly lower incidence of postoperative AF with no increase in the early mortality or morbidity. They stated that more trials are required to look at the long-term benefits of concomitant AF surgery. With the available technology the less invasive the procedure, the less complete are the ablation lines. The minimally invasive approaches for AF surgery include uni- or bilateral mini-thoracotomy, total thoracoscopic, and a hybrid trans-diaphragmatic. The former two provide similar exposure resulting in similar lesion set (see Fig. 34.3), amputation of the left atrial appendage with the addition of ganglion plexus stimulation and ablation. The patients are under general anesthesia, with double lumen intubation for single-lung ventilation in a supine position (see Fig. 34.3). The procedure takes around 1½–2 h to complete, systemic heparin is not required, and the patient is
Fig. 34.2 Cox-Maze IV ablation lesion set as seen from the posterior aspect of the heart. These lesions can only be performed while on cardiopulmonary bypass via a median sternotomy
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Fig. 34.3 Ablation lesions amenable via a bilateral thoracoscopic/mini-thoracotomy approach as seen from the posterior aspect of the heart
extubated prior to leaving the operating theater or within an hour of returning to recovery. Patients are usually back home within 2–3 days of surgery. The success rate using the minimally invasive approach is acceptable with PAF at around 80–90 % at 6 months yet not as effective in the persistent group which is between 25 and 39 % [60–64]. Another advantage of surgery is the ability to obliterate or amputate the left atrial appendage and subsequently decreasing the probability of future thromboembolic events [65–67].
Catheter Ablation In the 1980s catheter ablation gradually started to take over arrhythmia surgery. Today, procedures are performed in a specific electrophysiology laboratory where the patient is diagnosed and treated by using virtually the same setup (see Fig. 34.4). Its dominance was inevitable due both to human nature and the growing infatuation with minimally invasive procedures. Procedures can take up to 3–5 h, and patients are either sedated or administered general anesthetic depending on the circumstances. The cardiac electrophysiologist (EP) is able to insert all the electrode catheters via the femoral vein (the jugular and subclavian veins are also sometimes used). This left atrium can be accessed either through a transseptal approach or the aortic valve via the femoral artery. Radiofrequency ablation is currently the commonest form of energy source utilized in labs around the world. Other sources including cryoablation balloons, ultrasound, and laser ablation are currently being assessed in clinical trials [68–70]. Catheter ablation can be used in several ways to treat AF. Patients in whom ventricular rate control is difficult, the AV node can be ablated and a permanent pacemaker implanted [71]. However, rendering someone in complete heart block is not an attractive option in young patients.
The main role of CA in AF is to cure and free the patient from lifelong medication. As mentioned earlier, the initial approach was catheter-based linear ablation copying the Maze procedure but with little success and significant rate of complications [72, 73]. As interest moved towards the PVs as the source of the triggers that initiate AF, ablation strategies which target the PVs and PV antrum became the cornerstone for most AF ablation procedures. If a focal trigger is identified outside a PV at the time of an AF ablation procedure, it should also be targeted if possible. Addition of superior vena cava isolation has been shown to increase long-term freedom from AF [74]. As previously eluded to, patients with long-standing persistent AF are likely to require more extensive lesion set than just PV isolation. For this group, linear lesions can be applied, and completeness should be demonstrated by mapping or pacing maneuvers. In the presence of atrial flutter, ablation of the cavo-tricuspid isthmus is recommended. It is also not uncommon for patients to have to visit the EP laboratory on more than one occasion, especially with the persistent AF.
Catheter Versus Surgery in Lone AF The lack of any randomized clinical trials comparing catheter ablation versus surgery makes it very difficult to compare the two modalities. There are numerous studies reporting the efficacy of CA, and some of the more recent are summarized in Table 34.3. There appears to be large variation in the success rates published after CA, with differences in technique, follow-up, and most importantly the difference in what actually is the definition of success. For patients with PAF, there is a range of 40–80 % after the first procedure increasing to 50–90 % with a two ablation strategy. In patients with persistent AF,
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Fig. 34.4 A cardiac EP laboratory with specific equipment including fluoroscopy, multielectrode circumferential mapping catheters, and electroanatomic mapping systems
Table 34.3 Result of catheter ablation studies in atrial fibrillation Study Pappone et al. [75] Lee et al. [76] Cheema et al. [77] Oral et al. [78] Bhargava et al. [79] O’Neill et al. [80] Hunter et al. [81]
Year 2003 2004 2006 2006 2009 2009 2010
Patients(n) 589 207 200 755 1,404 153 285
FU (years) 2.5 2.5 2.1 2.1 4.7 2.8 2.7
PAF (%) 69 100 46 65 52 0 53
AF free (%) 79 72 41 71 88 89 70
the majority claim a success of above 60 % with O’Neill et al. reporting 89 % without the need for drugs [80]. There are a handful of randomized trials comparing CA to antiarrhythmic drugs in AF that have been completed and published [82–87]. The trials all show superiority to drug therapy and DC cardioversion alone. Success rates with regard to freedom from AF are similar to the nonrandomized
series, and they were able to demonstrate a greater improvement in quality of life with CA. The introduction of novel energy delivery systems and competition with the minimal invasive nature of CA has resulted in significant heterogeneity in the surgical literature with respect to treatment of lone AF. The various approaches have been summarized in Table 34.4. The results demonstrate that the surgical series are all relatively small compared to the catheter-based group. Taking this bias into account, we can still be encouraged by these early results with success rate ranging from 65 to 91 % up to 1 year in the minimally invasive group. All current guidelines (ACCF/AHA/HRS/ESC/CCS) for the first time consider CA as a possible first-line treatment in patients with symptomatic PAF and minimal structural heart disease [33, 34, 91]. Both the European and Canadian Societies have recommended surgical AF ablation with concomitant cardiac surgery and minimally invasive surgery for lone AF in symptomatic patients with failed catheter ablation
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Table 34.4 Result of surgical ablation for one AF Study Cox et al. [42] Weimar et al. [58] Wolf et al. [88] Edgerton et al. [64] Wudel et al. [62] Han et al. [89] Yilmaz et al. [63] Krul et al. [90]
Procedure Cut and Sew Sternotomy C-M IV Stern/Thora PVA + GP Mini-T PVA + GP Mini-T PVA + GP Mini-T PVA + GP Mini-T PVA + GP Three port VATS PVA + Box + GP Three port VATS
Modality N/A
Patient (n) 178
FU (years) 8.5
PAF N/A
AF free (%) 93
RF Cryotherapy RF Bipolar RF Bipolar RF Bipolar RF Bipolar RF Bipolar RF Bipolar
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(Class IIa, level of evidence A) [33, 91]. The main reason for why the various guidelines are unlikely to support surgery above CA in lone AF is that there is a lack of adequate consistent data and randomized trials. Minimally invasive surgery is still much more invasive than CA and so will have to significantly improve on its long-term results, especially in the persistent AF group to win over CA. Not even the higher complication rates and procedure time of CA appear to tip the balance in favor of surgery.
approach with both the interventional EP and cardiac surgeon simultaneously ablating the myocardium from both sides may be superior. This should provide real-time 3D mapping, faster more reliable ablation lines, and easy access to remove the left atrial appendage. The future success rate of such treatment strategies will enable clinicians to reduce the AF-related morbidities and mortalities. A multidisciplinary approach involving an EP and cardiac surgeon is likely to improve the overall outcome by ensuring appropriate patient selection, procedural completeness, and post-procedural follow-up.
Conclusion and Future Direction Arrhythmia surgery has come a long way since the early 1980s. Catheter ablation is currently in the lead due to obvious reasons, but, in the field of lone AF, surgery is not far behind. It is clearly an exciting time for the development of non-pharmacological therapy in the treatment of AF. With the ever-growing aging population, there is an epidemic of AF developing around the world, and this will bring with it a large economic burden if inadequately treated. What is clear from the evidence is that even minimally invasive surgery is significantly more invasive than CA, and unless there is more stringent and consistent long-term data, including randomized trials, it will continue to play second fiddle. There are many promising innovations that are currently being developed and evaluated which are likely to help improve the efficacy of surgical ablation. There are several trials currently underway (AMAZE and AFACT) which are evaluating the efficacy of concomitant surgical ablation and ganglionic plexus ablation in thoracoscopic ablation of lone AF. All future trials should adhere to the guidelines updated in 2012, so that all relevant information is gathered and published in peer-reviewed journals [92]. There is a growing consensus that a hybrid
References 1. Reardon M, Camm AJ. Atrial fibrillation in the elderly. Clinical cardiology. 1996;19:765–75. 2. Zhou ZQ, Hu DY, Chen J, Zhang RH, Li KB, Zhao XL. [An epidemiological survey of atrial fibrillation in china]. Zhonghua nei ke za zhi [Chinese journal of internal medicine]. 2004;43:491–4. 3. Thom T, Haase N, Rosamond W, Howard VJ, Rumsfeld J, Manolio T, Zheng ZJ, Flegal K, O'Donnell C, Kittner S, Lloyd-Jones D, Goff Jr DC, Hong Y, Adams R, Friday G, Furie K, Gorelick P, Kissela B, Marler J, Meigs J, Roger V, Sidney S, Sorlie P, Steinberger J, Wasserthiel-Smoller S, Wilson M, Wolf P, American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics–2006 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2006;113:e85–151. 4. Stewart S, Murphy NF, Walker A, McGuire A, McMurray JJ. Cost of an emerging epidemic: an economic analysis of atrial fibrillation in the uk. Heart. 2004;90:286–92. 5. Levitt H, Coplan NL. Mortality and atrial fibrillation: is there a causal relationship? Reviews in cardiovascular medicine. 2009;10: 25–8. 6. Benjamin EJ, Wolf PA, D’Agostino RB, Silbershatz H, Kannel WB, Levy D. Impact of atrial fibrillation on the risk of death: the framingham heart study. Circulation. 1998;98:946–52.
446 7. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the framingham study. Stroke; a journal of cerebral circulation. 1991;22:983–8. 8. Fuster V, Ryden LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, Halperin JL, Le Heuzey JY, Kay GN, Lowe JE, Olsson SB, Prystowsky EN, Tamargo JL, Wann S, Smith Jr SC, Jacobs AK, Adams CD, Anderson JL, Antman EM, Halperin JL, Hunt SA, Nishimura R, Ornato JP, Page RL, Riegel B, Priori SG, Blanc JJ, Budaj A, Camm AJ, Dean V, Deckers JW, Despres C, Dickstein K, Lekakis J, McGregor K, Metra M, Morais J, Osterspey A, Tamargo JL, Zamorano JL, American College of Cardiology/American Heart Association Task Force on Practice Guidelines; European Society of Cardiology Committee for Practice Guidelines; European Heart Rhythm Association; Heart Rhythm Society. ACC/ AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (writing committee to revise the 2001 guidelines for the management of patients with atrial fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation. 2006;114:e257–354. 9. Moe GK, Rheinboldt WC, Abildskov JA. A computer model of atrial fibrillation. American heart journal. 1964;67:200–20. 10. Haissaguerre M, Marcus FI, Fischer B, Clementy J. Radiofrequency catheter ablation in unusual mechanisms of atrial fibrillation: report of three cases. Journal of cardiovascular electrophysiology. 1994;5:743–51. 11. Jais P, Haissaguerre M, Shah DC, Chouairi S, Gencel L, Hocini M, Clementy J. A focal source of atrial fibrillation treated by discrete radiofrequency ablation. Circulation. 1997;95:572–6. 12. Nathan H, Eliakim M. The junction between the left atrium and the pulmonary veins. An anatomic study of human hearts. Circulation. 1966;34:412–22. 13. Haissaguerre M, Jais P, Shah DC, Takahashi A, Hocini M, Quiniou G, Garrigue S, Le Mouroux A, Le Metayer P, Clementy J. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. The New England journal of medicine. 1998;339:659–66. 14. Jongbloed MR, Schalij MJ, Poelmann RE, Blom NA, Fekkes ML, Wang Z, Fishman GI, Gittenberger-De Groot AC. Embryonic conduction tissue: a spatial correlation with adult arrhythmogenic areas. Journal of cardiovascular electrophysiology. 2004;15: 349–55. 15. Perez-Lugones A, McMahon JT, Ratliff NB, Saliba WI, Schweikert RA, Marrouche NF, Saad EB, Navia JL, McCarthy PM, Tchou P, Gillinov AM, Natale A. Evidence of specialized conduction cells in human pulmonary veins of patients with atrial fibrillation. Journal of cardiovascular electrophysiology. 2003;14:803–9. 16. Weerasooriya R, Jais P, Scavee C, Macle L, Shah DC, Arentz T, Salerno JA, Raybaud F, Choi KJ, Hocini M, Clementy J, Haissaguerre M. Dissociated pulmonary vein arrhythmia: incidence and characteristics. Journal of cardiovascular electrophysiology. 2003;14:1173–9. 17. Kim S, Chung DS. Characteristics of cancer blog users. Journal of the Medical Library Association: JMLA. 2007;95:445–50. 18. Wongcharoen W, Chen YC, Chen YJ, Chang CM, Yeh HI, Lin CI, Chen SA. Effects of a Na+/Ca2+ exchanger inhibitor on pulmonary vein electrical activity and ouabain-induced arrhythmogenicity. Cardiovascular research. 2006;70:497–508. 19. Arora R, Verheule S, Scott L, Navarrete A, Katari V, Wilson E, Vaz D, Olgin JE. Arrhythmogenic substrate of the pulmonary veins assessed by high-resolution optical mapping. Circulation. 2003; 107:1816–21. 20. Hocini M, Ho SY, Kawara T, Linnenbank AC, Potse M, Shah D, Jais P, Janse MJ, Haissaguerre M, De Bakker JM. Electrical
M. Baghai et al.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
conduction in canine pulmonary veins: electrophysiological and anatomic correlation. Circulation. 2002;105:2442–8. Kalifa J, Jalife J, Zaitsev AV, Bagwe S, Warren M, Moreno J, Berenfeld O, Nattel S. Intra-atrial pressure increases rate and organization of waves emanating from the superior pulmonary veins during atrial fibrillation. Circulation. 2003;108:668–71. Jais P, Hocini M, Macle L, Choi KJ, Deisenhofer I, Weerasooriya R, Shah DC, Garrigue S, Raybaud F, Scavee C, Le Metayer P, Clementy J, Haissaguerre M. Distinctive electrophysiological properties of pulmonary veins in patients with atrial fibrillation. Circulation. 2002;106:2479–85. Sanders P, Berenfeld O, Hocini M, Jais P, Vaidyanathan R, Hsu LF, Garrigue S, Takahashi Y, Rotter M, Sacher F, Scavee C, PloutzSnyder R, Jalife J, Haissaguerre M. Spectral analysis identifies sites of high-frequency activity maintaining atrial fibrillation in humans. Circulation. 2005;112:789–97. Bettoni M, Zimmermann M. Autonomic tone variations before the onset of paroxysmal atrial fibrillation. Circulation. 2002;105: 2753–9. Sharifov OF, Fedorov VV, Beloshapko GG, Glukhov AV, Yushmanova AV, Rosenshtraukh LV. Roles of adrenergic and cholinergic stimulation in spontaneous atrial fibrillation in dogs. Journal of the American College of Cardiology. 2004;43:483–90. Patterson E, Po SS, Scherlag BJ, Lazzara R. Triggered firing in pulmonary veins initiated by in vitro autonomic nerve stimulation. Heart rhythm: the official journal of the Heart Rhythm Society. 2005;2:624–31. Zhou J, Scherlag BJ, Edwards J, Jackman WM, Lazzara R, Po SS. Gradients of atrial refractoriness and inducibility of atrial fibrillation due to stimulation of ganglionated plexi. Journal of cardiovascular electrophysiology. 2007;18:83–90. Hohnloser SH, Kuck KH, Lilienthal J. Rhythm or rate control in atrial fibrillation–Pharmacological Intervention in Atrial Fibrillation (PIAF): a randomised trial. Lancet. 2000;356:1789–94. Van Gelder IC, Hagens VE, Bosker HA, Kingma JH, Kamp O, Kingma T, Said SA, Darmanata JI, Timmermans AJ, Tijssen JG, Crijns HJ, Rate Control Versus Electrical Cardioversion for Persistent Atrial Fibrillation Study Group. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. The New England journal of medicine. 2002;347:1834–40. Carlsson J, Miketic S, Windeler J, Cuneo A, Haun S, Micus S, Walter S, Tebbe U, STAF Investigators. Randomized trial of ratecontrol versus rhythm-control in persistent atrial fibrillation: the Strategies of Treatment of Atrial Fibrillation (STAF) study. Journal of the American College of Cardiology. 2003;41:1690–6. Wyse DG, Waldo AL, DiMarco JP, Domanski MJ, Rosenberg Y, Schron EB, Kellen JC, Greene HL, Mickel MC, Dalquist JE, Corley SD, Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation. The New England journal of medicine. 2002;347:1825–33. Corley SD, Epstein AE, DiMarco JP, Domanski MJ, Geller N, Greene HL, Josephson RA, Kellen JC, Klein RC, Krahn AD, Mickel M, Mitchell LB, Nelson JD, Rosenberg Y, Schron E, Shemanski L, Waldo AL, Wyse DG, Investigators A. Relationships between sinus rhythm, treatment, and survival in the atrial fibrillation follow-up investigation of rhythm management (affirm) study. Circulation. 2004;109:1509–13. European Heart Rhythm Association; European Association for Cardio-Thoracic Surgery, Camm AJ, Kirchhof P, Lip GY, Schotten U, Savelieva I, Ernst S, Van Gelder IC, Al-Attar N, Hindricks G, Prendergast B, Heidbuchel H, Alfieri O, Angelini A, Atar D, Colonna P, De Caterina R, De Sutter J, Goette A, Gorenek B, Heldal M, Hohloser SH, Kolh P, Le Heuzey JY, Ponikowski P, Rutten FH. Guidelines for the management of
34
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
Atrial Fibrillation: Should Cardiac Surgeons Be Consulted? atrial fibrillation: The task force for the management of atrial fibrillation of the european society of cardiology (esc). European heart journal. 2010;31:2369–429. Wann LS, Curtis AB, January CT, Ellenbogen KA, Lowe JE, Estes 3rd NA, Page RL, Ezekowitz MD, Slotwiner DJ, Jackman WM, Stevenson WG, Tracy CM, Writing Group M, Fuster V, Ryden LE, Cannom DS, Le Heuzey JY, Crijns HJ, Lowe JE, Curtis AB, Olsson SB, Ellenbogen KA, Prystowsky EN, Halperin JL, Tamargo JL, Kay GN, Wann LS, Writing Committee M, Jacobs AK, Anderson JL, Albert N, Hochman JS, Buller CE, Kushner FG, Creager MA, Ohman EM, Ettinger SM, Stevenson WG, Guyton RA, Tarkington LG, Halperin JL, Yancy CW, Members AATF. 2011 accf/aha/hrs focused update on the management of patients with atrial fibrillation (updating the 2006 guideline): A report of the american college of cardiology foundation/american heart association task force on practice guidelines. Circulation. 2011;123:104–23. Cairns JA, Connolly S, McMurtry S, Stephenson M, Talajic M, Committee CCSAFG. Canadian cardiovascular society atrial fibrillation guidelines 2010: Prevention of stroke and systemic thromboembolism in atrial fibrillation and flutter. The Canadian journal of cardiology. 2011;27:74–90. Fang MC, Stafford RS, Ruskin JN, Singer DE. National trends in antiarrhythmic and antithrombotic medication use in atrial fibrillation. Archives of internal medicine. 2004;164:55–60. Williams JM, Ungerleider RM, Lofland GK, Cox JL. Left atrial isolation: New technique for the treatment of supraventricular arrhythmias. The Journal of thoracic and cardiovascular surgery. 1980;80:373–80. Graffigna A, Pagani F, Minzioni G, Salerno J, Vigano M. Left atrial isolation associated with mitral valve operations. The Annals of thoracic surgery. 1992;54:1093–7. discussion 1098. Guiraudon GM, Campbell CS, Jones DL, McLellan JL, MacDonald JL. Combined sino-atrial node atrio-ventricular node isolation: A surgical alternative to his bundle ablation in patients with atrial fibrillation. Circulation. 1985;72:220. Cox JL, Schuessler RB, D’Agostino Jr HJ, Stone CM, Chang BC, Cain ME, Corr PB, Boineau JP. The surgical treatment of atrial fibrillation. Iii Development of a definitive surgical procedure The Journal of thoracic and cardiovascular surgery. 1991;101:569–83. Cox JL, Boineau JP, Schuessler RB, Jaquiss RD, Lappas DG. Modification of the maze procedure for atrial flutter and atrial fibrillation. I Rationale and surgical results The Journal of thoracic and cardiovascular surgery. 1995;110:473–84. Cox JL, Schuessler RB, Lappas DG, Boineau JP. An 8 1/2-year clinical experience with surgery for atrial fibrillation. Annals of surgery. 1996;224:267–73. discussion 273-265. Gaynor SL, Schuessler RB, Bailey MS, Ishii Y, Boineau JP, Gleva MJ, Cox JL, Damiano Jr RJ. Surgical treatment of atrial fibrillation: Predictors of late recurrence. The Journal of thoracic and cardiovascular surgery. 2005;129:104–11. Swartz JF, Pellerseis G, Silvers J, Patten L, Cervantez D. A catheter based curative approach to atrial fibrillation in humans. Circulation. 1994;90:1–335. Topkara VK, Williams MR, Cheema FH, Vigilance DW, Garrido MJ, Russo MJ, Oz MC, Argenziano M. Surgical ablation of atrial fibrillation: The columbia presbyterian experience. Journal of cardiac surgery. 2006;21:441–8. Wisser W, Khazen C, Deviatko E, Stix G, Binder T, Seitelberger R, Schmidinger H, Wolner E. Microwave and radiofrequency ablation yield similar success rates for treatment of chronic atrial fibrillation. European journal of cardio-thoracic surgery: official journal of the European Association for Cardio-thoracic Surgery. 2004; 25:1011–7. Chen MC, Chang JP, Guo GB, Chang HW. Atrial size reduction as a predictor of the success of radiofrequency maze procedure for chronic atrial fibrillation in patients undergoing concomitant
447
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
valvular surgery. Journal of cardiovascular electrophysiology. 2001;12:867–74. Baek MJ, Na CY, Oh SS, Lee CH, Kim JH, Seo HJ, Park SW, Kim WS. Surgical treatment of chronic atrial fibrillation combined with rheumatic mitral valve disease: Effects of the cryo-maze procedure and predictors for late recurrence. European journal of cardio-thoracic surgery: official journal of the European Association for Cardio-thoracic Surgery. 2006;30:728–36. Gillinov AM, Bakaeen F, McCarthy PM, Blackstone EH, Rajeswaran J, Pettersson G, Sabik 3rd JF, Najam F, Hill KM, Svensson LG, Cosgrove DM, Marrouche N, Natale A. Surgery for paroxysmal atrial fibrillation in the setting of mitral valve disease: A role for pulmonary vein isolation? The Annals of thoracic surgery. 2006;81:19–26. discussion 27-18. Knaut M, Tugtekin SM, Spitzer SG, Jung F, Matschke K. Intraoperative endocardial microwave ablation for treatment of permanent atrial fibrillation during coronary artery bypass surgery: 1-year follow-up. Europace: European pacing, arrhythmias, and cardiac electrophysiology: journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology. 2006;8:16–20. Mitnovetski S, Almeida AA, Goldstein J, Pick AW, Smith JA. Epicardial high-intensity focused ultrasound cardiac ablation for surgical treatment of atrial fibrillation. Heart, lung & circulation. 2009;18:28–31. Neven K, Schmidt B, Metzner A, Otomo K, Nuyens D, De Potter T, Chun KR, Ouyang F, Kuck KH. Fatal end of a safety algorithm for pulmonary vein isolation with use of high-intensity focused ultrasound. Circulation Arrhythmia and electrophysiology. 2010;3: 260–5. Comas GM, Imren Y, Williams MR. An overview of energy sources in clinical use for the ablation of atrial fibrillation. Seminars in thoracic and cardiovascular surgery. 2007;19:16–24. Lall SC, Melby SJ, Voeller RK, Zierer A, Bailey MS, Guthrie TJ, Moon MR, Moazami N, Lawton JS, Damiano Jr RJ. The effect of ablation technology on surgical outcomes after the cox-maze procedure: A propensity analysis. The Journal of thoracic and cardiovascular surgery. 2007;133:389–96. Gammie JS, Laschinger JC, Brown JM, Poston RS, Pierson 3rd RN, Romar LG, Schwartz KL, Santos MJ, Griffith BP. A multiinstitutional experience with the cryomaze procedure. The Annals of thoracic surgery. 2005;80:876–80. discussion 880. Ad N, Barnett S, Lefrak EA, Korach A, Pollak A, Gilon D, Elami A. Impact of follow-up on the success rate of the cryosurgical maze procedure in patients with rheumatic heart disease and enlarged atria. The Journal of thoracic and cardiovascular surgery. 2006; 131:1073–9. Gaynor SL, Diodato MD, Prasad SM, Ishii Y, Schuessler RB, Bailey MS, Damiano NR, Bloch JB, Moon MR, Damiano Jr RJ. A prospective, single-center clinical trial of a modified cox maze procedure with bipolar radiofrequency ablation. The Journal of thoracic and cardiovascular surgery. 2004;128:535–42. Weimar T, Bailey MS, Watanabe Y, Marin D, Maniar HS, Schuessler RB, Damiano Jr RJ. The cox-maze iv procedure for lone atrial fibrillation: A single center experience in 100 consecutive patients. Journal of interventional cardiac electrophysiology: an international journal of arrhythmias and pacing. 2011;31:47–54. Kong MH, Lopes RD, Piccini JP, Hasselblad V, Bahnson TD, Al-Khatib SM. Surgical maze procedure as a treatment for atrial fibrillation: A meta-analysis of randomized controlled trials. Cardiovascular therapeutics. 2010;28:311–26. Edgerton JR, Edgerton ZJ, Weaver T, Reed K, Prince S, Herbert MA, Mack MJ. Minimally invasive pulmonary vein isolation and partial autonomic denervation for surgical treatment of atrial fibrillation. The Annals of thoracic surgery. 2008;86:35–8. discussion 39.
448 61. McClelland JH, Duke D, Reddy R. Preliminary results of a limited thoracotomy: New approach to treat atrial fibrillation. Journal of cardiovascular electrophysiology. 2007;18:1289–95. 62. Wudel JH, Chaudhuri P, Hiller JJ. Video-assisted epicardial ablation and left atrial appendage exclusion for atrial fibrillation: Extended follow-up. The Annals of thoracic surgery. 2008;85: 34–8. 63. Yilmaz A, Geuzebroek GS, Van Putte BP, Boersma LV, Sonker U, De Bakker JM, Van Boven WJ. Completely thoracoscopic pulmonary vein isolation with ganglionic plexus ablation and left atrial appendage amputation for treatment of atrial fibrillation. European journal of cardio-thoracic surgery: official journal of the European Association for Cardio-thoracic Surgery. 2010;38:356–60. 64. Edgerton JR, Jackman WM, Mack MJ. Minimally invasive pulmonary vein isolation and partial autonomic denervation for surgical treatment of atrial fibrillation. Journal of interventional cardiac electrophysiology: an international journal of arrhythmias and pacing. 2007;20:89–93. 65. Johnson WD, Ganjoo AK, Stone CD, Srivyas RC, Howard M. The left atrial appendage: Our most lethal human attachment! Surgical implications. European journal of cardio-thoracic surgery: official journal of the European Association for Cardio-thoracic Surgery. 2000;17:718–22. 66. Mobius-Winkler S, Schuler GC, Sick PB. Interventional treatments for stroke prevention in atrial fibrillation with emphasis upon the watchman device. Current opinion in neurology. 2008;21:64–9. 67. Ohara K, Hirai T, Fukuda N, Sakurai K, Nakagawa K, Nozawa T, Inoue H. Relation of left atrial blood stasis to clinical risk factors in atrial fibrillation. International journal of cardiology. 2009;132: 210–5. 68. Kuck KH, Furnkranz A. Cryoballoon ablation of atrial fibrillation. Journal of cardiovascular electrophysiology. 2010;21:1427–31. 69. Nakagawa H, Antz M, Wong T, Schmidt B, Ernst S, Ouyang F, Vogtmann T, Wu R, Yokoyama K, Lockwood D, Po SS, Beckman KJ, Davies DW, Kuck KH, Jackman WM. Initial experience using a forward directed, high-intensity focused ultrasound balloon catheter for pulmonary vein antrum isolation in patients with atrial fibrillation. Journal of cardiovascular electrophysiology. 2007;18: 136–44. 70. Reddy VY, Houghtaling C, Fallon J, Fischer G, Farr N, Clarke J, McIntyre J, Sinofsky E, Ruskin JN, Keane D. Use of a diode laser balloon ablation catheter to generate circumferential pulmonary venous lesions in an open-thoracotomy caprine model. Pacing and clinical electrophysiology: PACE. 2004;27:52–7. 71. Rodriguez LM, Smeets JL, Xie B, de Chillou C, Cheriex E, Pieters F, Metzger J, den Dulk K, Wellens HJ. Improvement in left ventricular function by ablation of atrioventricular nodal conduction in selected patients with lone atrial fibrillation. The American journal of cardiology. 1993;72:1137–41. 72. Pappone C, Oreto G, Lamberti F, Vicedomini G, Loricchio ML, Shpun S, Rillo M, Calabro MP, Conversano A, Ben-Haim SA, Cappato R, Chierchia S. Catheter ablation of paroxysmal atrial fibrillation using a 3d mapping system. Circulation. 1999;100: 1203–8. 73. Jais P, Shah DC, Takahashi A, Hocini M, Haissaguerre M, Clementy J. Long-term follow-up after right atrial radiofrequency catheter treatment of paroxysmal atrial fibrillation. Pacing and clinical electrophysiology: PACE. 1998;21:2533–8. 74. Arruda M, Mlcochova H, Prasad SK, Kilicaslan F, Saliba W, Patel D, Fahmy T, Morales LS, Schweikert R, Martin D, Burkhardt D, Cummings J, Bhargava M, Dresing T, Wazni O, Kanj M, Natale A. Electrical isolation of the superior vena cava: An adjunctive strategy to pulmonary vein antrum isolation improving the outcome of af ablation. Journal of cardiovascular electrophysiology. 2007; 18:1261–6.
M. Baghai et al. 75. Pappone C, Rosanio S, Augello G, Gallus G, Vicedomini G, Mazzone P, Gulletta S, Gugliotta F, Pappone A, Santinelli V, Tortoriello V, Sala S, Zangrillo A, Crescenzi G, Benussi S, Alfieri O. Mortality, morbidity, and quality of life after circumferential pulmonary vein ablation for atrial fibrillation: Outcomes from a controlled nonrandomized long-term study. Journal of the American College of Cardiology. 2003;42:185–97. 76. Lee SH, Tai CT, Hsieh MH, Tsai CF, Lin YK, Tsao HM, Yu WC, Huang JL, Ueng KC, Cheng JJ, Ding YA, Chen SA. Predictors of early and late recurrence of atrial fibrillation after catheter ablation of paroxysmal atrial fibrillation. Journal of interventional cardiac electrophysiology: an international journal of arrhythmias and pacing. 2004;10:221–6. 77. Cheema A, Vasamreddy CR, Dalal D, Marine JE, Dong J, Henrikson CA, Spragg D, Cheng A, Nazarian S, Sinha S, Halperin H, Berger R, Calkins H. Long-term single procedure efficacy of catheter ablation of atrial fibrillation. Journal of interventional cardiac electrophysiology: an international journal of arrhythmias and pacing. 2006;15:145–55. 78. Oral H, Chugh A, Ozaydin M, Good E, Fortino J, Sankaran S, Reich S, Igic P, Elmouchi D, Tschopp D, Wimmer A, Dey S, Crawford T, Pelosi Jr F, Jongnarangsin K, Bogun F, Morady F. Risk of thromboembolic events after percutaneous left atrial radiofrequency ablation of atrial fibrillation. Circulation. 2006;114:759–65. 79. Bhargava M, Di Biase L, Mohanty P, Prasad S, Martin DO, Williams-Andrews M, Wazni OM, Burkhardt JD, Cummings JE, Khaykin Y, Verma A, Hao S, Beheiry S, Hongo R, Rossillo A, Raviele A, Bonso A, Themistoclakis S, Stewart K, Saliba WI, Schweikert RA, Natale A. Impact of type of atrial fibrillation and repeat catheter ablation on long-term freedom from atrial fibrillation: Results from a multicenter study. Heart rhythm: the official journal of the Heart Rhythm Society. 2009;6:1403–12. 80. O’Neill MD, Wright M, Knecht S, Jais P, Hocini M, Takahashi Y, Jonsson A, Sacher F, Matsuo S, Lim KT, Arantes L, Derval N, Lellouche N, Nault I, Bordachar P, Clementy J, Haissaguerre M. Long-term follow-up of persistent atrial fibrillation ablation using termination as a procedural endpoint. European heart journal. 2009;30:1105–12. 81. Hunter RJ, Berriman TJ, Diab I, Baker V, Finlay M, Richmond L, Duncan E, Kamdar R, Thomas G, Abrams D, Dhinoja M, Sporton S, Earley MJ, Schilling RJ. Long-term efficacy of catheter ablation for atrial fibrillation: Impact of additional targeting of fractionated electrograms. Heart. 2010;96:1372–8. 82. Wilber DJ, Pappone C, Neuzil P, De Paola A, Marchlinski F, Natale A, Macle L, Daoud EG, Calkins H, Hall B, Reddy V, Augello G, Reynolds MR, Vinekar C, Liu CY, Berry SM, Berry DA, ThermoCool AFTI. Comparison of antiarrhythmic drug therapy and radiofrequency catheter ablation in patients with paroxysmal atrial fibrillation: A randomized controlled trial. JAMA: the journal of the American Medical Association. 2010;303:333–40. 83. Jais P, Cauchemez B, Macle L, Daoud E, Khairy P, Subbiah R, Hocini M, Extramiana F, Sacher F, Bordachar P, Klein G, Weerasooriya R, Clementy J, Haissaguerre M. Catheter ablation versus antiarrhythmic drugs for atrial fibrillation: The a4 study. Circulation. 2008;118:2498–505. 84. Pappone C, Augello G, Sala S, Gugliotta F, Vicedomini G, Gulletta S, Paglino G, Mazzone P, Sora N, Greiss I, Santagostino A, LiVolsi L, Pappone N, Radinovic A, Manguso F, Santinelli V. A randomized trial of circumferential pulmonary vein ablation versus antiarrhythmic drug therapy in paroxysmal atrial fibrillation: The apaf study. Journal of the American College of Cardiology. 2006;48: 2340–7. 85. Stabile G, Bertaglia E, Senatore G, De Simone A, Zoppo F, Donnici G, Turco P, Pascotto P, Fazzari M, Vitale DF. Catheter ablation treatment in patients with drug-refractory atrial fibrillation:
34
86.
87.
88.
89.
Atrial Fibrillation: Should Cardiac Surgeons Be Consulted? A prospective, multi-centre, randomized, controlled study (catheter ablation for the cure of atrial fibrillation study). European heart journal. 2006;27:216–21. Oral H, Pappone C, Chugh A, Good E, Bogun F, Pelosi Jr F, Bates ER, Lehmann MH, Vicedomini G, Augello G, Agricola E, Sala S, Santinelli V, Morady F. Circumferential pulmonary-vein ablation for chronic atrial fibrillation. The New England journal of medicine. 2006;354:934–41. Wazni OM, Marrouche NF, Martin DO, Verma A, Bhargava M, Saliba W, Bash D, Schweikert R, Brachmann J, Gunther J, Gutleben K, Pisano E, Potenza D, Fanelli R, Raviele A, Themistoclakis S, Rossillo A, Bonso A, Natale A. Radiofrequency ablation vs antiarrhythmic drugs as first-line treatment of symptomatic atrial fibrillation: A randomized trial. JAMA: the journal of the American Medical Association. 2005;293:2634–40. Wolf RK, Schneeberger EW, Osterday R, Miller D, Merrill W, Flege Jr JB, Gillinov AM. Video-assisted bilateral pulmonary vein isolation and left atrial appendage exclusion for atrial fibrillation. The Journal of thoracic and cardiovascular surgery. 2005;130: 797–802. Han FT, Kasirajan V, Kowalski M, Kiser R, Wolfe L, Kalahasty G, Shepard RK, Wood MA, Ellenbogen KA. Results of a minimally invasive surgical pulmonary vein isolation and ganglionic plexi ablation for atrial fibrillation: Single-center experience with 12-month follow-up. Circulation Arrhythmia and electrophysiology. 2009;2:370–7.
449 90. Krul SP, Driessen AH, van Boven WJ, Linnenbank AC, Geuzebroek GS, Jackman WM, Wilde AA, de Bakker JM, de Groot JR. Thoracoscopic video-assisted pulmonary vein antrum isolation, ganglionated plexus ablation, and periprocedural confirmation of ablation lesions: First results of a hybrid surgicalelectrophysiological approach for atrial fibrillation. Circulation Arrhythmia and electrophysiology. 2011;4:262–70. 91. Gillis AM, Skanes AC, Committee CCSAFG. Canadian cardiovascular society atrial fibrillation guidelines 2010: Implementing grade and achieving consensus. The Canadian journal of cardiology. 2011;27:27–30. 92. European Heart Rhythm Association; European Cardiac Arrhythmia Surgery; American College of Cardiology; American Heart Association; Society of Thoracic Surgery, Calkins H, Brugada J, Packer DL, Cappato R, Chen SA, Crijns HJ, Damiano Jr RJ, Davies DW, Haines DE, Haissaguerre M, Iesaka Y, Jackman W, Jais P, Kottkamp H, Kuck KH, Lindsay BD, Marchlinski FE, McCarthy PM, Mont JL, Morady F, Nademanee K, Natale A, Pappone C, Prystowsky E, Raviele A, Ruskin JN, Shemin RJ. 2012 HRS/EHRA/ECAS Expert Consensus Statement on Catheter and Surgical Ablation of Atrial Fibrillation: Recommendations for Patient Selection, Procedural Techniques, Patient Management and Follow-up, Definitions, Endpoints, and Research Trial Design: A report of the Heart Rhythm Society (HRS) Task Force on Catheter and Surgical Ablation of Atrial Fibrillation. Heart rhythm: the official journal of the Heart Rhythm Society. 2012;9(4):632–96.
Atrial Arrhythmias After AF Ablation: Challenge for the Next Decade?
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Tamás Tahin and Gábor Széplaki
Abstract
The significance of atrial fibrillation is increasing, and also the impact of atrial fibrillation (AF) ablation procedures. After any ablation method, the chance to develop other atrial tachyarrhythmias is between 3 and 50 %. In this chapter the different AF ablation techniques, the pathophysiology of the atrial tachycardias, those diagnostic steps, and therapeutic possibilities are reviewed. Keywords
Atrial fibrillation • Atrial tachycardia • Ablation • Electroanatomical mapping
Introduction The rate of atrial fibrillation (AF) is increasing with age, and the impact of the disease on the healthcare system is well known. The effectiveness of the medical therapy – including antiarrhythmic and antithrombotic medication – has important limitations (efficacy, side effects). Therefore, the role of invasive treatment such as radio frequency and cryoablation is increasing. AF ablation has become one of the most common procedures in many electrophysiology laboratories around the world. During the pioneer era of AF ablation, two basic concepts have been introduced. The first was to use linear lesions in the right atrium, later in the left atrium as suggested by previous surgical data. This form of ablation had several drawbacks including complications and leaving possible scar substrates for secondary arrhythmias. The second approach is based on the finding that in some cases, especially when no other apparent reason behind the initiation of AF is present, a focal trigger starts the arrhythmia. The group of Haissaguerre found that in most cases, these foci are in the
T. Tahin, MD (*) • G. Széplaki, MD, PhD Department of Cardiology, Semmelweis University Heart Center, Budapest, Hungary e-mail:
[email protected],
[email protected] A.S. Kibos et al. (eds.), Cardiac Arrhythmias, DOI 10.1007/978-1-4471-5316-0_35, © Springer-Verlag London 2014
vicinity of the pulmonary vein (PV) ostia. The focal ablation of local pulmonary potentials and later the circumferential ablation of the antrum of the pulmonary veins became the most widely used method to treat paroxysmal AF [1].
Pathophysiology With the development of new catheters and the more frequent use of 3D mapping systems, the success rate and also the volume of AF ablation procedures have increased. Since ablation became a first choice for the treatment of AF, and more centers are introducing these methods in the daily practice, the number of patients who underwent ablation is increasing significantly. Although the tools are more effective for creating a continuous and transmural lesion, not every electrophysiology center reports the same success rate. Nowadays, the original concept to ablate triggers focally inside the PVs has been abandoned because of high recurrence rates and a high incidence of PV stenosis and was replaced with circumferential ablation around the PVs (antrum isolation). Even circumferential ablation can be done with different methods; the first is ostial ablation and the second is wide area circumferential ablation. Whereas the first option is easier to perform, the latter provides higher long-term success rate due to partial substrate modification of the atrial tissue and also debulking, reducing the atrial 451
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mass [1, 2]. Other techniques, such as CFAE ablation, are described later in this chapter. However, with the introduction of new interventional modalities, new forms of arrhythmias are seen secondary to all linear lesions performed in the left atrium. Since more procedures are done involving the left atrium, these “new” arrhythmias are seen more frequently. The incidence of ATs after PV isolation alone ranges from 2.9 to 10 %, whereas those after PV isolation and linear ablation had been reported in 10–30 % [3]. Possible etiologies include ineffective lesion formation, recurrent conduction over a previously ablated area, scar formation due to excessive intra-atrial ablation, or preexisting atrial scar from preexisting heart diseases. These arrhythmias can be classified into three main groups: focal tachycardias, micro-reentry tachycardias due to localized reentries, and macro-reentry tachycardias [4] and are related to the volume of ablation. Since paroxysmal AF ablation is usually treated by circumferential PV isolation alone and persistent AF requires the ablation of more atrial tissue including linear lesions on the roof of the left atrium and also on the mitral isthmus, these arrhythmias are seen more frequently after extensive ablation. Focal tachycardias originating in close vicinity to the PVs are more frequently seen after paroxysmal AF ablation, while macro-reentrant tachycardias are often observed after creating more linear lesions in persistent AF patients [3]. These tachycardias are often resistant to medical therapy and are more symptomatic due to a higher ventricular response rate [5]. Also, patients receiving antiarrhythmic drugs after ablation to avoid AF recurrence will also develop typical cavotricuspid isthmus (CTI) -dependent flutter.
Diagnosis Patients undergoing AF ablation are regularly monitored for recurrent arrhythmias and long-term success rate after the procedure. The follow-up period often exceeds for years. During this period, several methods have been used to assess the arrhythmia burden. These methods include transtelephonic monitoring, multiple-lead ECG Holter monitoring, 7-day Holter, or implantable device-based follow-up. Depending on the follow-up period and rate, the assessment of the arrhythmia burden may differ. Since these patients with ATs are often more symptomatic than during AF episodes, diagnosis of a new atrial tachycardia after AF ablation is frequent [6]. It should also be remembered that some patients would experience asymptomatic AF episodes post AF ablation. This might be a consequence of ablation-induced denervation or minimal symptoms at baseline. Patients with previously long-standing persistent AF more often turn to atrial tachycardia after successful AF ablation. Once the diagnosis is made, a therapeutic plan should be established. Highly symptomatic patients are to be treated rapidly with electric cardioversion. Due to the resilient nature of the arrhythmias, drug treatment is often
T. Tahin and G. Széplaki
ineffective, in a few cases drug therapy may even pose the risk of proarrhythmia; therefore, another ablation procedure might be essential. Additionally, rapid ventricular rates associated with these atrial arrhythmias can induce left ventricular dysfunction, the so-called tachycardiomyopathy.
Clinical Diagnosis Twelve-lead surface ECG in many cases is helpful in localizing the mechanism and the origin of ATs. Careful examination of the P wave axis and morphology may help planning the ablation procedure if needed. Generally speaking, if the P waves are more prominent in leads II, III, and aVF, the likely diagnosis is right-sided flutter, whereas prominent waves in the precordial leads (especially in V1) are more consistent with left-sided origin. Broad flutter waves favor atrial flutter rather than focal AT. Focal ATs classically exhibit alterations in cycle length with speeding (“warm up”) and slowing (“cool down”) at the onset and termination of tachycardia. Focal atrial tachycardias mostly present as a tachycardia with spontaneous onset and termination, although can be incessant, and may accelerate in response to sympathetic stimulus. Macro-reentrant ATs are more stable regarding cycle length [7]. Others believe that since the magnitude and direction of vector of atrial activation are tremendously influenced by the differential conduction velocity and low-voltage areas of extensively ablated atria, surface P waves do not provide consistent information on the mechanism of ATs and the location of focal ATs [3]. Although ECG signs can help in establishing the diagnosis, the accurate clinical diagnosis can only be obtained by an electrophysiological (EP) study. However, the timing of this study should be selected carefully, since many patients will become free of episodes under drug therapy after the first 3 months of “blanking period” after the initial ablation. If the patients are still symptomatic, the study should be scheduled after 3 months. If the patient has recurrent and symptomatic episodes within the blanking period, a redo study is recommended regardless of the elapsed time. Studies indicated that an arrhythmia burden higher than 4.5 % is a strong predictor of further recurrences for both ATs and AF [8, 9]. During the EP study a systematic approach is important. During the study one should answer numerous questions: what is the mechanism of the arrhythmia and what structure or structures play role in the initiation or maintenance of the arrhythmia. A stepwise approach is suggested, as described by a Greek group [10]. Their suggestion is to follow these steps: 1. Observe P wave morphology. P wave morphology may help to localize the origin of the tachycardia (Fig. 35.1). However, if macro-reentry is present, the various vectors and magnitude of atrial activation may prevent us from using P wave morphology as
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Atrial Arrhythmias After AF Ablation: Challenge for the Next Decade?
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Fig. 35.1 Regular atrial tachycardia with 2:1 AV conduction following atrial fibrillation ablation. The P wave morphology suggests left superior atrial origin (inferior axis, positive P waves in leads V1–V6)
a useful diagnostic tool. If P wave is not observed during ongoing tachycardia, carotid massage or intravenous adenosine should be administered to unmask the atrial activity. 2. Evaluate CS activation wave front. Distal to proximal activation strongly suggests a leftsided origin (Fig. 35.2). Proximal to distal activation may indicate right atrial tachycardia, tachycardias using the septal part of the left atrium or counterclockwise perimitral isthmus flutter. Simultaneous or nearly simultaneous activation of the CS suggests roof-dependent macroreentry or tachycardia arising near the superior veins. 3. Evaluate the regularity of the tachycardia cycle length. If the cycle length of the tachycardia varies more than 15 %, then it is consistent with a focal origin (Fig. 35.3). However, if it varies less than 15 %, then the mechanism can be either focal or macro-reentrant. 4. Exclude right-sided origin of the atrial tachycardia. The next step should be the confirmation or the exclusion of right-sided AT. If a right-sided origin is suspected, entrainment mapping of the CTI should be performed regardless of the surface 12-lead ECG, since post AF ablation ECGs do not always represent classical sawtooth pattern [11]. If entrainment at the CTI shows a long postpacing interval (PPI), then right-sided origin is practically
excluded (Fig. 35.4). If the PPI is close to the tachycardia cycle length, then CTI ablation should be performed first. 5. Entrainment from the proximal and distal coronary sinus. Good PPI after entrainment from both CS locations is consistent with perimitral isthmus flutter (Fig. 35.5). After transseptal puncture either 3D mapping system or further entraining maneuvers on the anterior mitral annulus should be used to establish the diagnosis. 6. Check PVs for potential reconnection. If none of the above procedures led to the diagnosis, then all of PVs should be assessed for reconnection (Fig. 35.6). This requires transseptal puncture, but since right-sided ATs are practically excluded, puncture would be necessary anyway to move toward the diagnosis. When the patient is in sinus rhythm at the beginning of the procedure, this should be the first step. Circular EP catheter is required to map the PVs, and every recovered potential should be targeted. If the cycle length of the tachycardia is shorter in the PVs than in the atria, the diagnosis of PV tachycardia is very likely (Fig. 35.6). 7. AT entrainment from the anterior and posterior left atrial wall. When perimitral isthmus flutter and PV tachycardia have been excluded, then entrainment should be performed on the anterior and posterior left atrial wall. Adequate PPI on
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Atrial Arrhythmias After AF Ablation: Challenge for the Next Decade? 100 ms
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both sites is consistent with roof-dependent flutter (Fig. 35.7). Also, activation of the anterior and the posterior wall in the opposite direction favors roof-dependent macro-reentry. On the other hand, performing reliable entrainment procedures is sometimes prohibited by the inability to capture even with high-pacing output at the site of interest. This may be a result of pacing in lowvoltage or scar areas. 8. 3D mapping system to further refine the diagnosis. Certainly, there are still a few cases, when these diagnostic steps would not lead to a definite diagnosis. In these cases, the use of 3D mapping systems, like CARTO or NavX, might be required (Fig. 35.8a). Then, by using a fixed intracardiac potential, like proximal or distal CS electrogram, a graphical activation map of the whole arrhythmia cycle could be addressed (Fig. 35.8b). Using a specific equation first introduced by de Ponti et al., the “head-meets-tail” region of the AT falls into the mid-diastolic slow conduction zone; therefore the ablation target is indicated [12]. Using this stepwise approach, a quick and safe diagnosis can be obtained in the majority of cases. However, when excessive scarring of the atrial tissue is present either due to extensive previous intracardiac ablation or due to the preexisting cardiac disease like cardiomyopathy or mitral valve disease, obtaining the exact definition of the reentrant circuit might be difficult, and mapping the consequent morphologies are time-consuming.
Therapy As indicated earlier, ablation is the first-line treatment for secondary ATs following AF ablation. The substrate for these arrhythmias is either inadequate PV isolation or scar formation from wide area circumferential ablation or substrate modification with partial recovery. Both conditions lead either focal or reentrant tachycardias. If the diagnosis is focal, or micro-reentrant AT due to insufficient circular lesion, then gaps should be targeted. This could be done with the conventional technique such as circular mapping catheters and irrigated tip ablation catheters compatible with a 3D mapping system. Macro-reentry however requires more attention, since current catheter design and technique renders continuous linear lesion hard to achieve (Fig. 35.9). In this situation the use of 3D mapping systems is very useful (Fig. 35.10).
Special Considerations If the diagnosis is made, there are still several different therapeutic methods to choose. Bai et al. published a paper on post AF ablation perimitral flutter (PMFL) [13]. In a randomized study two groups of patients with proven PMFL were formed. In the first group mitral isthmus ablation was performed between the left inferior PV and the
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Fig. 35.5 Entrainment from the distal and proximal coronary sinus (good PPI) supports the diagnosis of a left-sided perimitral isthmus flutter. S1S1 cycle-length is 240 ms (a) and 220 ms (b) post pacing interval is the same as the tachycardia cycle-lenght (262 ms and 271 ms respectively)
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Atrial Arrhythmias After AF Ablation: Challenge for the Next Decade?
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293 ms 205 BPM
Ls 4,5 Ls 5,6 Ls 6,7 Ls 7,8 Ls 8,9 Ls 9,10 Ls 10,1 REF 9,10 REF 7,8 REF 5,6 REF 3,4 REF 1,2 292 ms P1 ART
205 BPM 12:58:13 PM
Fig. 35.7 Entrainment mapping performed on the posterior wall on the left atrium is suggestive of roof-dependent left atrial flutter, which was confirmed by good PPI from the anterior wall
458 Fig. 35.8 (a) A regular atrial tachycardia after isolating the left pulmonary veins in persistent atrial fibrillation. Activation mapping with the use of a 3D mapping system identified a gap in the ablation line around the ostium of the left superior pulmonary vein, which was responsible for the arrhythmia. A single radio-frequency application immediately terminated the tachycardia. (b) Activation mapping during left atrial tachycardia revealed a roofdependent flutter propagating through the left atrial isthmus also. Radio-frequency applications on the roofline and the anterior mitral isthmus line successfully terminated the tachycardia and prevented re-induction
T. Tahin and G. Széplaki
a
b
lateral mitral valve annulus to achieve bidirectional conduction block. If necessary, additional ablations were performed in the adjacent coronary sinus segment. The procedural end point was defined as interruption and noninducibility of the target AFL as well as mitral valve annulus bidirectional conduction block, which was documented in sinus rhythm by pacing maneuvers and repeated CARTO mapping. The other group of patients was cardioverted to restore sinus rhythm immediately after the diagnosis of PMFL was established. All PVs were remapped to identify electrical reconnection of the PVs. Re-isolation of PV antra was achieved and confirmed by circular mapping catheter. After that, a challenge with isoproterenol infusion up to
30 μg/min was performed in all patients, and ectopic atrial beats or tachycardias (trigger activities) arising from extra-PV foci, such as the left or right atrial septum or free wall, CS, SVC, and atrial appendages, were abolished. The end point of procedure was complete PV antrum isolation as well as elimination of all potential trigger sites. After the blanking period, patients were monitored for recurrence of arrhythmias. ECG recordings were transmitted by a transtelephonic device every time the patient had symptoms compatible with arrhythmias and at least twice a week for the first 5 months. An office visit was scheduled at 3, 6, and 12 months post procedure and every 6 months thereafter. At each follow-up, an ECG and a 7-day Holter
35
Atrial Arrhythmias After AF Ablation: Challenge for the Next Decade?
459 200 ms
I II VI ABL d ABL
Ls 1,2 Ls 2,3 Ls 3,4 Ls 4,5 Ls 6,7 Ls 7,8 Ls 8,9 Ls 9,10 Ls 10,1 121 ms 492 BPM
CS 9,10
190 ms 315 BPM
CS 7,8 CS 5,6 CS 3,4 CS 1,2 50 mmHg P1 P1 10:20:14 AM
10:20:15 AM
Fig. 35.9 Block in the mitral isthmus during linear ablation. Note the prolongation of the conduction interval from the pacing site CS 1–2 (septal to the line) to Ls 10–1 (located in the left atrial appendage)
Fig. 35.10 The use of 3D electroanatomical mapping systems might be useful to generate linear lesions. A roofline termina ted the left atrial flutter that was initiated after isolation of all pulmonary veins in a case of persistent atrial fibrillation
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monitoring were obtained. The long-term outcome of the procedure was considered a “success” if patients were free of AF, PMFL, or other atrial tachyarrhythmia off AAD. They found that in 84 % of patients in the first group had recurrent atrial tachycardias compared to 85 % that were free of arrhythmia in the second group. They have concluded that in patients presenting with perimitral flutter after AF ablation for long-standing persistent AF, mitral isthmus block had limited impact on arrhythmia recurrence. On the other hand, elimination of all PV and non-PV triggers achieved higher freedom from atrial arrhythmias at follow-up. Complex fractionated atrial potentials (CFAEs) may also serve as a trigger to start AF. During atrial fibrillation these potentials may demonstrate continuous deflections from a prolonged activation complex or with a cycle length less than 150 ms. These potentials can exist almost everywhere in the left or even in the right atrium, but usually persist in the posterior left atrial wall, the septum, the coronary sinus area, and around the superior vena cava. Ablation of these potentials may not only increase the success rate of the AF ablation but also might be beneficial in preventing the development on new secondary arrhythmias. Therefore, ablating such potentials, especially in non-paroxysmal patients, is suggested [14].
T. Tahin and G. Széplaki
Conclusions
AF ablation occupies a significant role in modern EP. Newly trained physicians and EP centers are offering this treatment in the daily practice. However, not all aspects of AF initiation and maintenance are known; therefore, the success rate of ablation remains around 75–85 %. All AF ablation techniques are associated with a risk of focal or reentrant atrial tachycardia recurrence. In general, 3–50 % of all patients will later develop ATs after any AF ablation technique. Drug therapy is seldom effective and may even be pro-arrhythmic; therefore, other measures are required. Redo EP study seems to be the main solution in nearly all cases. However, as many as 30–50 % of patients with documented or symptomatic atrial arrhythmia recurrences during the first 3 months after an AF ablation will no longer have recurrence later on [5]. So, the timing of the redo procedure should include an observation period after the AF ablation procedure. To guide the redo procedure, many strategies should be considered such as P wave morphology and atrial cycle length and stability. In more complex cases, the use of 3D mapping systems is often required to achieve success. The introduction of MRI could be helpful, not only to register the atrial anatomy with the 3D mapping systems but for detection of preexisting and iatrogenic scar formation.
Future Directions References With the introduction of new technologies, physicians are trying to move toward safer and simpler procedures, while maintaining or even increasing short- and long-term success of these procedures. The use of balloon-based techniques, like cryoballoon ablation, is gaining popularity, while visually guided laser balloon ablation is under investigation. Cryoballoon ablation became a more widely used technique, with favorable results as compared to standard radiofrequency ablation. Laser balloon is still mainly experimental, although relevant clinical data is available already, with promising results [15]. However, these modalities are primarily focusing on PV isolation, and other complex atrial arrhythmias like macro-reentrant tachycardias are still targeted with conventional ablation catheters for now. Even after successful PV isolation, the risk of recurring atrial arrhythmias is still present. Better understanding of the atrial anatomy and the scar formation process in the left atrium may help us to tailor more effective lesion formation. Late enhancement MRI scan can reveal lesion formation after PV isolation and may correlate with short-time success rate [16]. MRI may help physicians to detect scar localization that may cause macro-reentry formation after AF ablation. The use of these imaging modalities in regular practice will require further studies.
1. Shah DC, Haissaguerre M, Jais P, Hocini M, Yamane T, Deisenhofer I, Garrigue S, Clementy J. Electrophysiologically guided ablation of the pulmonary veins for the curative treatment of atrial fibrillation. Ann Med. 2000;32(6):408–16. 2. Kanj MH, Wazni O, Natale A, et al. Pulmonary vein antral isolation using an open irrigation ablation catheter for the treatment of atrial fibrillation: a randomized pilot study. J Am Coll Cardiol. 2007;49(15):1634–41. 3. Shah AJ, Jadidi A, Liu X, Miyazaki S, Forclaz A, Nault I, Rivard L, Linton N, Xhaet O, Derval N, Sacher F, Bordachar P, Ritter P, Hocini M, Jais P, Haissaguerre M. Atrial tachycardias arising from ablation of atrial fibrillation: a proarrhythmic bump or an antiarrhythmic turn? Cardiol Res Pract. 2010;2010:950763. 4. Jais P, Matsuo S, Knecht S, Weerasooriya R, Hocini M, Sacher F, Wright M, Nault I, Lellouche N, Klein G, Clementy J, Haissaguerre M. A deductive mapping strategy for atrial tachycardia following atrial fibrillation ablation: importance of localized reentry. J Cardiovasc Electrophysiol. 2009;20(5):480–91. 5. Natale A, Raviele A, Arentz T, Calkins H, Chen SA, Haissaguerre M, Hindricks G, Ho Y, Kuck KH, Marchlinski F, Napolitano C, Packer D, Pappone C, Prystowsky EN, Schilling R, Shah D, Themistoclakis S, Verma A. Venice Chart international consensus document on atrial fibrillation ablation. J Cardiovasc Electrophysiol. 2007;18(5):560–80. 6. Dagres N, Kottkamp H, Piorkowski C, Weis S, Arya A, Sommer P, Bode K, Gerds-Li JH, Kremastinos DT, Hindricks G. Influence of the duration of Holter monitoring on the detection of arrhythmia recurrences after catheter ablation of atrial fibrillation: implications for patient follow-up. Int J Cardiol. 2010;139(3):305–6.
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7. Medi C, Kalman JM. Prediction of atrial flutter circuit location from the surface electrogram. Europace. 2008;10:786–96. 8. Pokushalov E, Romanov A, Corbucci G, Bairamova S, Losik D, Turov A, Shirokova N, Karaskov A, Mittal S, Steinberg JS. Does atrial fibrillation burden measured by continuous monitoring during the blanking period predict the response to ablation at 12-month follow-up? Heart Rhythm. 2012;9(9):1375–9. 9. Choi JI, Pak HN, Park JS, Kwak JJ, Nagamoto Y, Lim HE, Park SW, Hwang C, Kim YH. Clinical significance of early recurrences of atrial tachycardia after atrial fibrillation ablation. J Cardiovasc Electrophysiol. 2010;21(12):1331–7. 10. Tzeis S, Andrikopoulos G, Vardas P, Theodorakis G. Atrial tachycardia after ablation of atrial fibrillation: ten steps to diagnosis and treatment. Hellenic J Cardiol. 2011;52(4):345–51. 11. Chugh A, Latchamsetty R, Oral H, Elmouchi D, Tschopp D, Reich S, Igic P, Lemerand T, Good E, Bogun F, Pelosi Jr F, Morady F. Characteristics of cavotricuspid isthmus-dependent atrial flutter after left atrial ablation of atrial fibrillation. Circulation. 2006; 113(5):609–15. 12. De Ponti R, Verlato R, Bertaglia E, Del Greco M, Fusco A, Bottoni N, Drago F, Sciarra L, Ometto R, Mantovan R, Salerno-Uriarte JA. Treatment of macro-re-entrant atrial tachycardia based on electroanatomic mapping: identification and ablation of the mid-diastolic isthmus. Europace. 2007;9(7):449–57.
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13. Bai R, Biase LD, Mohanty P, Russo AD, Casella M, Pelargonio G, Themistoclakis S, Mohanty S, Elayi CS, Sanchez J, Burkhardt JD, Horton R, Gallinghouse GJ, Bailey SM, Bonso A, Beheiry S, Hongo RH, Raviele A, Tondo C, Natale A. Ablation of perimitral flutter following catheter ablation of atrial fibrillation: impact on outcomes from a Randomized Study (PROPOSE). J Cardiovasc Electrophysiol. 2012;23(2):137–44. 14. Verma A, Mantovan R, Macle L, De Martino G, Chen J, Morillo CA, Novak P, Calzolari V, Guerra PG, Nair G, Torrecilla EG, Khaykin Y. Substrate and Trigger Ablation for Reduction of Atrial Fibrillation (STAR AF): a randomized, multicentre, international trial. Eur Heart J. 2010;31(11):1344–56. 15. Reddy VY, Neuzil P, Themistoclakis S, Danik SB, Bonso A, Rossillo A, Raviele A, Schweikert R, Ernst S, Kuck KH, Natale A. Visually-guided balloon catheter ablation of atrial fibrillation: experimental feasibility and first-in-human multicenter clinical outcome. Circulation. 2009;120(1):12–20. 16. Peters DC, Wylie JV, Hauser TH, Nezafat R, Han Y, Woo JJ, Taclas J, Kissinger KV, Goddu B, Josephson ME, Manning WJ. Recurrence of atrial fibrillation correlates with the extent of post-procedural late gadolinium enhancement: a pilot study. JACC Cardiovasc Imaging. 2009;2(3):308–16.
Cavotricuspid Isthmus Anatomy Particularities in Atrial Flutter Ablation
36
Liviu Chiriac, Gabriel Cristian, Romi Bolohan, and Ion C. T¸intoiu
Abstract
Aims– The objective of this study was to identify clinical, electrocardiographic, and echocardiographic characteristics of atrial flutter catheter ablation in patients with aneurismal dilated atrium using EnSite System noncontact mapping. We perform reconstruction of the cavotricuspid isthmus in order to verify if the isthmus anatomy correlated with the isthmus ablation outcome. We tried to locate the sites of conduction gaps and to verify if sites of conduction gaps resistant to ablation correlated with specific anatomical particularities. Methods and Results – Isthmus was arbitrarily divided in an anterior—close to the tricuspid annulus—central, and inferior—close to the inferior vena cava orifice—portion. A gap of the resumed conduction through the IVC-TA isthmus was delineated as a mechanism of recurrence and ablated with one and three radio-frequency applications. In 45 of the 79 patients a total of 52 gaps were found. Seventy-three percent of gaps were in the central portion of the isthmus, 8 % was in an anterior portion close to the tricuspid annulus, and 19 % were in an inferior portion near the edge of the inferior vena cava orifice. No specific anatomical structures were identified as being correlated with these sites. In the 16 patients with a total of 18 gaps, all these gaps were located at the same site: the border between the central and inferior portion of the isthmus at the level of a prominent Eustachian ridge. Conclusion At patients with right aneurismal atrium the isthmus presents anatomical variants which may represent a site of conduction gaps “resistant” to ablation. Keywords
Atrial flutter • Radio-frequency ablation • Noncontact mapping • Isthmus anatomy
L. Chiriac, MD, PhD, FESC (*) • G. Cristian, MD, PhD, FESC Titu Maiorescu University of Medicine, Bucharest, Romania Department of Cardiology, Army’s Center for Cardiovascular Disease, Bucharest, Romania e-mail:
[email protected] R. Bolohan, PhD Department of Cardiology, Army’s Clinical Center for Cardiovascular Disease, Bucharest, Romania I.C. T¸intoiu, MD, PhD, FESC “Carol Davila” University of Medicine, Bucharest, Romania Interventional Cardiology Department, Army’s Center for Cardiovascular Diseases, Bucharest, Romania e-mail:
[email protected] A.S. Kibos et al. (eds.), Cardiac Arrhythmias, DOI 10.1007/978-1-4471-5316-0_36, © Springer-Verlag London 2014
Introduction Olshansky et al., using a mapping and pacing technique, demonstrated that a zone of slow conduction was present inferiorly and posteriorly in the right atrium [1] called cavotricuspid isthmus in the present time. The cavotricuspid isthmus (CTI) is crucial in the ablation of typical atrial flutter (AFL), and therefore the CTI anatomy and its relation to resistant ablation cases have been widely described. The purpose of this article is to review the anatomy and electrophysiology of the CTI and long-term outcome of radiofrequency ablation for the patients with atrial flutter. Cavotricuspid isthmus-dependent counterclockwise 463
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flutter is the anatomical circuit of which has now been well described with newer mapping modalities (Fig. 36.1). Flutter waves are atrial complexes of constant morphology, polarity, and cycle length in a rate range from 240 to 340/min. The morphology of flutter waves in the inferior limb leads and in V1 is specific for cavotricuspid isthmusdependent flutter: negative flutter waves in the inferior leads and a positive wave in V1 with transition of morphology across the anterior leads are consistent with a counterclockwise atrial circuit with lateral-to-medial activation of the cavotricuspid isthmus (CTI), while activation in the reverse direction (clockwise) is suggested by positive flutter waves in the inferior leads and a negative deflection in V1, which accounts for 5–10 % of all CTI-dependent flutter. There are rare forms of tachycardia with similar P wave morphology, for example, atrial tachycardia originating from the ostium of the coronary sinus. Endocardial mapping in this case will demonstrate caudo-cranial activation of both the RA septum and lateral wall, which is not in keeping with counterclockwise rotation around the previously described flutter circuit. The presence of negative flutter waves in the inferior leads is highly suggestive of CTI-dependent flutter, although their absence does not exclude the diagnosis, most notably in the context of structural heart disease or prior left atrial ablation.
Anatomy Particularities The area between the Eustachian valve or ridge posteriorly and the hinge of tricuspid valve anteriorly is described by an electrophysiologist as the posterior isthmus. The area is formed by Eustachian valve, thebesian valve, tricuspid valve,
Fig. 36.1 Three-dimensional map of the dilated right atrium using noncontact mapping (EnSite 3000, Endocardial Solutions, Inc., St. Paul, Minnesota, United States)
L. Chiriac et al.
and a line connecting the inferior vena cava and tricuspid valve [2]. In the majority of the patients (64 %), the wall of the posterior sector, immediately anterior to the orifice of the inferior vena cava, is composed mainly of fibrous and fatty tissue, with minimal muscular fibers coursing through it. The important implication is that this part of the isthmus needs the least radiofrequency energy. The middle part of CTI is, made up of muscular trabeculations separated by delicate membranes. The trabeculations originated either from the wall of the coronary sinus or else where the continuations of the muscular bundles of the crista terminalis. The anterior sector of CTI, adjacent to the tricuspide valve, is smooth, showing no evidence of trabeculation in this region, which formed a thick atrial wall. The muscular trabeculae radiated from the terminal crest are disposed parallel [2]. Ample crossover and connecting trabeculae are present particularly in the zone immediately inferior to the coronary sinus ostium (OCS) [3]. In this area, trabeculae of the ostium are interconnected along the inferior edge. On this basis, one can easily explain that nonuniform anisotropic conduction occurs and, thus, may indicate a conduction delay.
Imaging Studies Saremi et al. presented that the paraseptal isthmus (20 ± 3.5 mm) was significantly shorter than the central isthmus (24 ± 4.3 mm) and the central isthmus was shorter than the inferolateral isthmus (27 ± 4.8 mm) [4]. A subthebesian recess greater than 5-mm deep was identified in 45 % of patients. A compact Eustachian ridge greater than 4 mm was seen in 24 % of patients. Magnetic resonance imaging study showed that the mean CTI length was 38.6 ± 7.8 mm with a majority of concave profile CTI [5]. Sacks were seen in 41 % of patients, symmetrical in 22 % of patients and eccentric septally directed in 19 % of patients. They also noted that CTI demonstrating an eccentric septally directed sack required more radiofrequency energy to reach isthmus block. By using intracardiac three-dimensional echocardiography, Scaglione et al. demonstrated two different groups of CTI anatomy [6]. One group presented a flat isthmus with slight irregularities parallel to the tricuspid annulus with a small Eustachian ridge. The second group presented a different isthmus anatomy with a protuberant Eustachian ridge getting a different progression with a valley-shaped structure isthmus. In all the cases of unaffected atrial flutter ablation, the site of a conduction gap was correlated with a prominent Eustachian ridge crossing the isthmus. In our laboratory, we performed noncontact EnSite mapping (Endocardial Solutions, Inc.) of the CTI and found that the sack-type CTI had a longer length than the flat-type CTI and a greater profundity than the concave-type CTI [7]. The sack-type CTI needed a longer ablation time (Fig. 36.2).
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Cavotricuspid Isthmus Anatomy Particularities in Atrial Flutter Ablation
Fig. 36.2 Radiofrequency ablation lesions delivered at the “gap” site in a dilated cavotricuspid isthmus (EnSite 3000, Endocardial Solutions, Inc., St. Paul, Minnesota, United States)
Electrophysiology The incremental pacing from the low lateral right atrium and coronary sinus during sinus rhythm produced the ratedependent conduction delays in the low right atrial isthmus, especially the middle and septal isthmus [8]. Also, the gradual conduction delay with unidirectional block in the isthmus was associated to the progress of counterclockwise and clockwise atrial flutter. Patients with atrial flutter had much slower conduction in the low right atrial isthmus and shorter effective refractory periods in the right atrium than those without atrial flutter. This low conduction in the low right atrial isthmus played an important role in the development of atrial flutter. Feld et al. as well found that conduction velocity was slower in the CTI than in the right atrial free wall and interatrial septum [9]. Olgin et al. confirmed that pacing from the smooth right atrium induced counterclockwise atrial flutter, whereas pacing from the trabeculated right atrium induced clockwise atrial flutter [10]. The location of unidirectional block through beginning of both form of flutter is in the low right atrial isthmus. Poty et al. first elucidated the criteria of isthmus block after ablation [11]. If isthmus block happened, pacing at the proximal coronary sinus would display a complete descending activation of the low right atrium, and pacing at the low right atrium would display a complete descending activation of the septum. Tada et al. suggested double potentials along the ablation line as the criteria of isthmus block [12]. Isthmus block shifts direction of activation on the side of ablation line opposite from the pacing site, which changes in electrogram configuration. Unfiltered unipolar electrograms show an RS configuration when activation, in the presence of transcristal conduction, establishing the complete isthmus block
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is not easy [13]. This is for the reason that during proximal coronary sinus pacing, it will show a collision of clockwise and counterclockwise wave fronts in the anterior inferior right atrium. In spite of this, if we pace at the posterior lip of the ablation line and it shows a completely descending activation wave front in the anterior inferior right atrium, this finding confirms complete isthmus block. Ablation of the CTI with isthmus block was very effective in eliminating a typical atrial flutter and had a long-term recurrence rate from 5 to 12.9 % [14–21]. There were two studies showing that the 8-mm-tip catheter was more effective than the standard 4-mm-tip catheter for ablation of the CTI. A meta-analysis study confirmed that cooled-tip and 8-mm-large-tip catheters are equally efficient for CTI ablation with both similar primary success rates and procedure parameters [15, 20]. There was a high risk of atrial fibrillation (AF) incidence in patients who go through radiofrequency ablation for atrial flutter with a incidence is from 8 to 82 % [21, 22]. A probable mechanism for AF occurrence is the electrical remodeling in the atrium induced by atrial flutter that disposes to development of AF. Sparks et al. showed that in patients with paroxysmal atrial flutter, a 5- to 10-min period of induced atrial flutter is associated with a significant reduction in atrial refractoriness [23]. The supplementary mechanism for AF occurrence after ablation of atrial flutter is that AF is the primary arrhythmia that precedes the onset of atrial flutter because formation of a functional line of block between the vena cava during AF leads to the development of CTI-dependent atrial flutter. AF is exposed by the exclusion of atrial flutter substrate. The length, depth, and anatomical complexity of the cavotricuspid isthmus can vary considerably between patients with a resultant impact on the success of radiofrequency ablation [6, 23]. To facilitate effective ablation at the ventricular aspect of a “long” cavotricuspid isthmus, a long sheath can be used [24]. Similarly, where there is difficulty in completing the IVC end of the line because of a prominent Eustachian ridge preventing a smooth drag back across the isthmus, the catheter may be looped and apposed to the isthmus from the atrial side and advanced from the IVC towards the Eustachian ridge. In patients where conduction block across the isthmus cannot be achieved with a conventional catheter, the use of an irrigated tip catheter has been shown to facilitate achievement of bidirectional cavotricuspid isthmus conduction block [25]. Changes in activation sequence around the tricuspid annulus are used to confirm bidirectional block. However, it is difficult to demonstrate the bidirectional block in the presence of transverse conduction around the inferior vena cava. In such a case, bidirectional block should be confirmed by 3-dimensional mapping system. Cavotricuspid isthmus anatomy is highly variable. Patients with a short and straight cavotricuspid isthmus
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require fewer radiofrequency ablation applications and shorter x-ray exposure. Noncontact mapping knowledge about the anatomic details of this region can thus save time and improve the success rate and safety of the procedure by helping the electrophysiologist choose the appropriate region in which to perform the ablation. During atrial flutter ablation in patients with aneurismal dilated atrium, conduction gap sites are located in the inferior zone of the isthmus in most cases. It should be also noted that conduction gaps were present in the “nonresistant” atrial flutter as well. These gaps were eliminated by few RF deliveries and were located in the central portion of the isthmus in 73 % of cases. Noncontact mapping has been shown to be a safe method for demonstrating the complete circuit of typical atrial flutter, in dilated cavotricuspid isthmus. Noncontact mapping system provides a clear, accurate view of chamber anatomy and activation. The clinician can view and analyze arrhythmia conduction and precisely label anatomic and ablation sites. Confirmation of therapy is simplified with the dynamic isopotential maps and computed electrograms. The isthmus can be irregular and thick, and anatomical structures such as the Eustachian valve can make ablation both difficult and long. In experienced centers there are always attempts to improve success rates. Furthermore, the success rates in excess of 90 % with minimal radiation and short procedure times described by high volume units are presumably not always repeated by operators in less experienced centers, prompting attempts safely to improve these rates. Thus, there is a background which encourages operators to try new techniques not only to improve success rates but also to shorten procedure and radiation times. Numerous authors have compared different energy types, different catheter tip sizes, and different energy settings, as well as the use of advanced cardiac mapping systems, but the search for improved techniques continues. Whether this enhanced anatomical knowledge is best based on a pre-study, echocardiography will become clearer in the future. The ability to see lesions acutely and assess their placement and especially their adequacy, for example, by nonfluoroscopic computer-assisted advanced catheter mapping systems, helping us to place and form lesions, might also be a tool in increasing safety and efficacy in atrial flutter ablation.
References 1. Olshansky B, Okumura K, Hess PG, Waldo AL. Demonstration of an area of slow conduction in human atrial flutter. J Am Coll Cardiol. 1990;16:1639–48. 2. Cabrera JA, Sanchez-quintana D, Farre J, Rubio JM, Ho SY. The inferior right atrial isthmus: further architectural insights for cur-
L. Chiriac et al.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
rent and coming ablation technologies. J Cardiovasc Electrophysiol. 2005;16(4):402–8. Waki K, Saito T, Becker AE. Right atrial flutter isthmus revisited: normal anatomy favors nonuniform anisotropic conduction. J Cardiovasc Electrophysiol. 2000;11:90–4. Saremi F, Pourzand L, Krishnan S, Ashikyan O, Gurudevan SV, Narula J, Kaushal K, et al. Right atrial cavotricuspid isthmus: anatomic characterization with multi-detector row CT. Radiology. 2008;247:658–68. Lim KT, Murray C, Liu H, Weerasooriya R. Preablation magnetic resonance imaging of the cavotricuspid isthmus. Europace. 2007;9:149–53. Scaglione M, Caponi D, Di Donna P, Riccardi R, Bocchiardo M, Azzaro G, Leuzzi S, et al. Typical atrial flutter ablation outcome: correlation with isthmus anatomy using intracardiac echo 3D reconstruction. Europace. 2004;6(5):407–17. Chang SL, Tai CT, Lin YJ, Ong MG, Wongcharoen W, Lo LW, Chang SH, et al. The electroanatomic characteristics of the cavotricuspid isthmus: implications for the catheter ablation of atrial flutter. J Cardiovasc Electrophysiol. 2007;18:18–22. Tai CT, Chen SA, Chiang CE, Lee SH, Ueng KC, Wen ZC, Huang JL, et al. Characterization of low right atrial isthmus as the slow conduction zone and pharmacological target in typical atrial flutter. Circulation. 1997;96:2601–11. Feld GK, Mollerus M, Birgersdotter-Green U, Fujimura O, Bahnson TD, Boyce K, Rahme M. Conduction velocity in the tricuspid valve-inferior vena cava isthmus is slower in patients with type I atrial flutter compared to those without a history of atrial flutter. J Cardiovasc Electrophysiol. 1997;8:1338–48. Olgin JE, Kalman JM, Saxon LA, Lee RJ, Lesh MD. Mechanism of initiation of atrial flutter in humans: site of unidirectional block and direction of rotation. J Am Coll Cardiol. 1997;29:376–84. Poty H, Saoudi N, Abdel Aziz A, Nair M, Letac B. Radiofrequency catheter ablation of type I atrial flutter: prediction of late success by electrophysiological criteria. Circulation. 1995;92:1389–92. Tada H, Oral H, Sticherling C, Chough SP, Baker RL, Wasmer K, Pelosi Jr F, et al. Double potentials along the ablation line as a guide to radiofrequency ablation of typical atrial flutter. J Am Coll Cardiol. 2001;38:750–5. Saoudi N, Ricard P, Rinaldi JP, Yaïci K, Darmon JP, Anselme F. Methods to determine bi-directional block of the cavotricuspid isthmus in radiofrequency ablation of typical atrial flutter. J Cardiovasc Electrophysiol. 2005;16:801–3. Feld G, Wharton M, Plumb V, Daoud E, Friehling T, Epstein L, EPT-1000 XP Cardiac Ablation System Investigators. Radiofrequency catheter ablation of type 1 atrial flutter using largetip 8 or 10 mm electrode catheter and high-output radiofrequency energy generator: results of a multicenter safety and efficacy study. J Am Coll Cardiol. 2004;43:1466–72. Costa AD, Cucherat M, Pichon N, Messier M, Laporte S, RomeyerBouchard C, Mismetti P. Comparison of the efficacy of cooled tip and 8 mm-tip catheters for radiofrequency catheter ablation of the cavotricuspid isthmus: a metaanalysis. Pacing Clin Electrophysiol. 2005;28:1081–7. Direct Link. Gk F, Daubert JP, Weiss R, Miles WM, Pelkey W, Cryoablation Atrial Flutter Efficacy Trial Investigators. Acute and long-term efficacy and safety of catheter cryoablation of the cavotricuspid isthmus for treatment of type 1 atrial flutter. Heart Rhythm. 2008;5:1009–14. Tai CT, Chen SA, Chiang CE, Lee SH, Wen ZC, Huang JL, Chen YJ, et al. Long-term outcome of radiofrequency catheter ablation for typical atrial flutter: risk prediction of recurrent arrhythmias. J Cardiovasc Electrophysiol. 1998;9:115–21. Paydak H, Kall JG, Burke MC, Rubenstein D, Kopp DE, Verdino RJ, Wilber DJ. Atrial fibrillation after radiofrequency ablation of type I atrial flutter: time to onset, determinants, and clinical course. Circulation. 1998;98:315–22.
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19. Calkins H, Canby R, Weiss R, Taylor G, Wells P, Chinitz L, Milstein S, et al. Results of catheter ablation of typical atrial flutter. Am J Cardiol. 2004;94:437–42. 20. Ellis K, Wazni O, Marrouche N, Martin D, Gillinov M, McCarthy P, Saad EB, et al. Incidence of atrial fibrillation post-cavotricuspid isthmus ablation in patients with typical atrial flutter: left atrial size as an independent predictor of atrial fibrillation recurrence. J Cardiovasc Electrophysiol. 2007;18:799–802. Direct Link. 21. Chinitz JS, Gerstenfeld EP, Marchlinski FE, Callans DJ. Atrial fibrillation is common after ablation of isolated atrial flutter during long-term follow-up. Heart Rhythm. 2007;4:1029–33. 22. Morton JB, Byrne MJ, Power JM. Electrical remodeling of the atrium in an anatomic model of atrial flutter: relationship between
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substrate and triggers for conversion to atrial fibrillation. Circulation. 2002;105:258–64. 23. Sparks PB, Jayaprakash S, Vohra JK, Kalman JM. Electrical remodeling of the atria associated with paroxysmal and chronic atrial flutter. Circulation. 2000;102:1807–13. 24. Da Costa A, Faure E, Thevenin J, et al. Effect of isthmus anatomy and ablation catheter on radiofrequency catheter ablation of the cavotricuspid isthmus. Circulation. 2004;110(9):1030–5. 25. Jais P, Shah DC, Haissaguerre M, et al. Prospective randomized comparison of irrigated-tip versus conventional-tip catheters for ablation of common flutter. Circulation. 2000;101(7):772–6.
Location of Accessory Pathways in WPW: What and How Should We Ablate
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Bieito Campos, Xavier Viñolas, José M. Guerra, Concepción Alonso, and Enrique Rodríguez
Abstract
Treatment of accessory pathways has evolved substantially in the last decades, leading to radio-frequency catheter ablation as the therapeutic technique of choice in this setting. Some of the clues for its high rate of success and its low morbidity and mortality indices are a deeper knowledge of accessory pathways characteristics, the development of advanced technology for mapping and ablation, and the gained experience in the field. This chapter intends to be a guide that helps understand variability in accessory pathway characteristics along the atrioventricular junction in order to design the appropriate approach for mapping and correctly identify the site of most probable ablation success. The result combines the most relevant data available in literature, from renowned experts in the field, and our own experience. Important aspects as anatomy of accessory pathways or their electrocardiographic and electrophysiologic features are specifically discussed for the different regions along the atrioventricular junction. Moreover, the text summarizes the most important mapping criteria currently used to guide ablation of atrioventricular accessory pathways. Finally, we provide relevant clinical considerations that routinely guide our daily clinical practice when dealing with patients presenting with atrioventricular accessory connections. Keywords
Ablation • Tachycardia • Accessory pathway
Introduction Accessory atrioventricular pathways are aberrant muscle bundles that connect atrium and ventricle outside of the regular atrioventricular (AV) conduction system. The clinical expression of these pathways ranges from simply causing an abnormal electrocardiogram with ventricular preexcitation to forming an integral component of a macro-reentrant circuit involving atrial and ventricular myocardium or to functioning as an
B. Campos, MD • X. Viñolas, MD (*) • J.M. Guerra, MD, PhD C. Alonso, MD • E. Rodríguez, MD Electrophysiology and Arrhythmia Unit, Department of Cardiology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain e-mail:
[email protected] A.S. Kibos et al. (eds.), Cardiac Arrhythmias, DOI 10.1007/978-1-4471-5316-0_37, © Springer-Verlag London 2014
alternative pathway for transmission of rapid atrial tachyarrhythmias. Symptoms may range from none or occasional palpitations to severe palpitations, chest pain, dyspnea, and even lightheadedness, syncope, or cardiac arrest. During the last decades, catheter ablation of AV accessory pathways (APs) has become a relatively routine procedure in cardiac electrophysiology laboratories and reached high rates of success, based on deep knowledge and understanding of their anatomic, electrocardiographic, and electrophysiologic characteristics.
General Anatomic Considerations The AV junction represents the electric isolating plane between the atria and the ventricles. Atrioventricular APs are remnants of the AV connections usually composed of typical 469
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Fig. 37.1 Schematic representation of AV junctions in left anterior oblique view according to the new anatomically accurate nomenclature for accessory pathway location. Differences between old and new nomenclatures are showed in the table (From Cosio et al. [4], with permission of John Wiley and Sons)
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myocardial cells and caused by incomplete embryological development of the AV annulus, with failure of the fibrous separation between the atria and the ventricles. They breach the insulation provided by the fibrofatty tissues of the AV groove and the hinge lines of the valves. The anatomic variations along the AV junction provide specific features to APs from different locations that have important implications for the mapping and ablation approach. A wide knowledge of APs anatomy is key for the preparation and success of ablation procedures. Accessory pathway location along the right and left AV junction is assessed using fluoroscopy in the left anterior oblique projection. Approximately 60 % of APs insert along the mitral valve and are referred to as left free-wall pathways, 25 % insert along the septal aspect of the tricuspid or mitral valve and are classified as septal/paraseptal pathways, and the remaining 15 % are right free-wall pathways [1]. Multiple APs are present in approximately 5 % of patients [2, 3]. When multiple pathways are present, the most common locations are inferoparaseptal and right free wall. A detailed nomenclature to classify AV accessory pathway locations was initially developed to permit communication between electrophysiologists and surgeons. However, a recent reexamination of the AV junction anatomy has found that this widely used and ingrained nomenclature might be inaccurate and, in some cases, misleading [4]. In the new anatomically accurate terminology, right free-wall pathways are further classified as superior, superoanterior, anterior, inferoanterior, and inferior. In the same way, left free-wall APs are classified as superior, superoposterior, posterior, inferoposterior,
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and inferior. In the septal/paraseptal area, APs are further classified as superoparaseptal, septal, and inferoparaseptal. Old and new nomenclatures are shown in Fig. 37.1.
Left Free Wall The left free-wall area is limited superiorly by the aortic-mitral valve continuity, a region that rarely contains AP connections, and inferiorly by the anatomic continuation of the inferoparaseptal area. The mitral annulus is a structure formed by a distinct cord of fibrous tissue that separates the atrial and ventricular myocardium in the left side of the heart. As described in histopathological studies, accessory connections in this area usually skirt a wellformed annulus on its epicardial aspect, crossing the epicardial fat pad closely to the inner surface of the heart. Length of APs in this area is usually less than 10 mm and diameter ranges 0.1–7 mm [5, 6] (Fig. 37.2). While the atrial connection is usually discrete in size and near the annulus, the ventricular insertion tends to branch into multiple connections and may be displaced a small distance away from the annulus toward the ventricular apex [7, 8]. Their course through the AV groove can be oblique to the transverse plane of the AV groove, with the atrial insertion usually located inferiorly in relation to ventricular insertion [9]. The venous wall of the coronary sinus is surrounded by a continuous cuff of striated muscle that extends variably away from the ostium for 25–51 mm and usually connects to both
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Fig. 37.2 Histologic section (a) and detail (b) of the mitral annulus in a patient with a left lateral accessory pathway. The mitral annulus is formed by a distinct cord of fibrous tissue that creates a well-formed hinge between atrial and ventricular myocardium. A 140-μm-thick
accessory pathway (arrow) skirts the annulus crossing the epicardial fat pad closely to the endocardium (Heidenhain trichrome ×8 and ×24) (From Basso et al. [112], with permission of Wolters Kluwer Health)
right and left atria [10]. Sun et al. have described how musculature extensions of this cuff over the middle cardiac vein or the posterior coronary vein may serve as a connection to the epicardial surface of the left ventricle, forming an AP [11]. Some unusual forms of AV APs in the left free-wall area may exist, including the connection of the ventricle to the ligament of Marshall and the left atrial appendage. The ligament of Marshall is a fold of pericardium that contains the vein of Marshall, a remnant of the left superior vena cava and branch of the coronary sinus that ends near the left superior pulmonary vein. Connection between the ligament of Marshall, the atrium, and the coronary sinus has been described as part of the circuit for maintenance of circus movement tachycardia in some patients [12, 13]. An unusual form of accessory connection in the left free-wall area has been also described as an epicardial continuity between the left atrial appendage and the ventricle [14, 15]. Diffuse
adherence of left atrial appendage to the ventricle by epicardial fibrofatty connections and need of a surgical approach has been described in these cases if aggressive attempts at endocardial ablation have failed [15].
Right Free Wall The normal anatomy of the right AV fibrous annulus is quite different from the left side. In contrast to the mitral annulus, which is usually well formed and nearly always complete, the right annulus is poorly formed and frequently discontinuous at many sites [7, 8]. Moreover, the trend of right atrial and ventricular myocardia to overlap and fold over one another in their insertion on the annulus favors the existence of accessory connections, which pass through an area of incomplete development. However, right free-wall APs may
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Fig. 37.3 Histological section (a) and detail (b) of the tricuspid annulus in a patient with a right posterolateral accessory pathway. Along the tricuspid annulus, right atrial and ventricular myocardium are separated by a poorly defined fibrous component with frequent discontinuities. A 360-μm-thick accessory pathway fibers (arrow) connects atrial and ventricular myocardium (Heidenhain trichrome ×18 and ×36) (From Basso et al. [112], with permission of Wolters Kluwer Health)
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also skirt the epicardial aspect of the tricuspid annulus, as do left free-wall accessory connections [7, 8] (Fig. 37.3). The association of Ebstein anomaly with right-sided APs, which ranges between 10 and 23 %, and the challenge for catheter ablation approach in this setting, are noteworthy [16–18]. This disorder is characterized by the displacement into the right ventricle of the annular attachment of tricuspid valve leaflets. These patients usually present with multiple accessory connections because, although not anatomically displaced, the true tricuspid annulus is usually poorly developed and exhibits extensive discontinuities [8]. Catheter instability during tricuspid annulus mapping combined
with the fractionation and low amplitude exhibited by electrograms make ablation procedures even more challenging in this setting. As mentioned for the left free wall, and slightly more frequent, epicardial APs in otherwise normal hearts may also involve connections between the right atrial appendage and the anterior right ventricle. Milstein et al. first anatomically described such unusual AV connection as a broad band of myocardium which bridged the tricuspid ring epicardially, directly from the base of the atrial appendage to the right ventricle [19]. Subsequent reports have confirmed the existence of accessory connections in similar location and
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described different approaches for successful radio-frequency (RF) ablation [20–23].
The Septum and Paraseptum The boundary between the left and the right atria comprises the true septum and the paraseptal areas. Contrary to general conception of the atrial septum as a large muscular disk separating both atria, the true atrial septum, when defined as that part which can be removed without exiting from the cavities of the heart, is relatively small and consists in a thin rim of tissue surrounding the fossa ovalis [24]. Two specific features mark the anatomical configuration of AV junction in the septum: the apical displacement of the tricuspid annulus respect to the mitral annulus and the left displacement of the interatrial sulcus respect to the interventricular septum. Consequence of this characteristic configuration is the existence of the muscular AV septum, which separates the right atrium and the left ventricle [25]. The triangle of Koch is the right atrial surface of the muscular AV septum. It is limited posteriorly by the tendon of Todaro, a fibrous strand continuation of the valve of the inferior caval vein [26]. The anterior border is the line of attachment of the septal leaflet of the tricuspid valve. The base of the triangle is positioned inferiorly and is occupied by the coronary sinus. The compact AV node is located near the apex of the triangle, where the tendon of Todaro merges with the central fibrous body forming the AV component of the membranous septum. The His bundle perforates the central fibrous body in a location slightly superior and anterior to the AV node. Accessory pathways with atrial insertion in the floor of the triangle, below its apex and above the coronary sinus ostium level, were known as midseptal in the old nomenclature. As they are truly septal structures are now regarded as septal in the new anatomically accurate terminology [4]. The region comprising the apex of the triangle of Koch and the area immediately above was classically labeled as anteroseptal. This location is not truly septal, as atrial walls are separated here by the aortic root, and is now regarded as right superoparaseptal in the new anatomically accurate nomenclature [4]. In the same way, the region below the anterior portion of the coronary sinus ostium is inferior to the true AV septum and is not truly septal. Accessory pathways in this area were classically known as posteroseptal and are now regarded as inferoparaseptal in the new nomenclature [4]. This area exhibits an especially complex anatomy including the inferior portion of the pyramidal space [27]. From the right atrial perspective, the inferoparaseptal region includes the inferior portion of the triangle of Koch and the area surrounding the coronary sinus ostium. The left boundary of the inferoparaseptal region with the left free-wall area is usually between 2 and 3 cm far from the coronary
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sinus ostium [28]. From the surgical findings, most inferoparaseptal APs consist of fibers with a right atrial to left ventricular course and a ventricular insertion attaching onto the posterior superior process of the left ventricle, but some may also run from the left atrial paraseptum to left ventricle and from the right atrial paraseptum to right [29–31]. As previously mentioned, APs in the inferoparaseptal region might also be the result of connections of coronary sinus musculature between the atrium and the ventricle. The coronary sinus has a myocardial coat that is anatomically and electrically connected to both left and right atria. As described in extensive anatomic studies, the coronary sinus myocardial coat may cover the terminal portion of the middle cardiac vein and posterior cardiac vein in 2–3 % of hearts [32]. These sleeves extending over the middle and posterior cardiac veins may connect to the epicardial aspect of the ventricle and create an AP. Although 70 % of inferoparaseptal APs are associated with an anatomically normal coronary sinus, these connections are frequently associated with anomalies in the venous system. As described by Sun et al., in up to 21 % of patients with a coronary sinus AP and in 7.5 % of patients with any type of inferoparaseptal or left posterior AP, a coronary sinus diverticulum may be present [11]. These diverticula are muscular structures, exhibit a marked variability in size and shape, and usually arise from the proximal segment of the coronary sinus, within 1.5 cm from the ostium and before the middle cardiac vein, but may also originate from the middle or posterior cardiac veins [11]. Other venous anomalies may exist, as fusiform or bulbous enlargements of venous branches as the middle cardiac vein. When present, anatomical anomalies in the coronary sinus venous system are frequently related to the site of connection of the pathway [11, 33–35].
Electrocardiographic Location of Accessory Pathways The usefulness of the preexcitation pattern analysis on surface 12-lead surface ECG is key in establishing the initial diagnosis, directing mapping strategy, and anticipating procedural risk related to the approach needed to treat a particular AP.
Using the Delta Wave Pattern of Preexcitation The degree of preexcitation depends on (1) the difference in conduction time from the sinus node to the pathway atrial insertion and to the AV node, and (2) the difference in conduction time through the AP and the normal conduction system (AV node and His-Purkinje). Several algorithms that evaluate delta wave polarity and QRS configuration have been developed to help predict the AP ventricular insertion site [36–42]. Accuracy of these algorithms is high but may
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Fig. 37.4 Algorithm for localization of accessory pathways developed by Arruda et al. The algorithm analyzes the initial 20 ms of delta wave in leads I, II, aVF, and V1 (classified as positive, negative, or isoelectric) and the ratio of R and S wave amplitudes in leads III and V1 (classified as R ≥ S or R < S). LP left posterior, LPL left posterolateral,
LL left lateral, LAL left anterolateral, PSTA posteroseptal tricuspid annulus, PSMA posteroseptal mitral annulus, AS anteroseptal, MS midseptal, RA right anterior, RAL right anterolateral, RL right lateral, RP right posterior, RPL right posterolateral (From Arruda et al. [40], with permission of John Wiley and Sons)
be limited by the extent of preexcitation and fusion during sinus rhythm or the presence of more than one AP. Among the most known algorithms, the one developed by Arruda et al. analyzed the initial 20 ms of delta wave in leads I, II, aVF, and V1 (classified as positive, negative, or isoelectric) and the ratio of R and S wave amplitudes in leads III and V1 (classified as R ≥ S or R < S). This algorithm demonstrated prospectively an overall 90 % sensitivity and 99 % specificity to predict AP location in 135 patients and showed to be particularly useful in correctly localizing superoparaseptal and septal APs as well as pathways requiring ablation within ventricular venous branches or anomalies of the coronary sinus [40] (Fig. 37.4). Nevertheless, determining AP location may be frequently achieved by applying some basic rules easier to remember: • Right-sided APs usually exhibit a higher degree of preexcitation • Delta wave in V1.
– Right-sided pathways typically exhibit negative delta wave in V1. A delta wave precordial lead transition in V2 (the so called “septal pattern”) suggests a septal/ paraseptal location. A delta wave transition in V3 or later suggests a right free-wall location. – Left-sided pathways typically exhibit positive delta wave in V1. • A negative delta wave in limb leads helps locating APs more than when positive. – A negative delta wave in lead I/aVL suggests a left posterior (lateral) location. – A negative delta wave in all three inferior leads suggests an inferoparaseptal location. – A negative delta wave only in aVR while positive in all remaining limb leads suggests a superoparaseptal location. The ability of surface ECG to potentially distinguish between a right or left location in the inferoparaseptal region
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has particularly important implications in designing ablation strategy. As previously mentioned, a negative delta wave in V1 suggests a right-sided location, whereas a positive delta wave or R > S suggests a left-sided origin. Leads III and aVF are usually deeply negative at right-sided locations. However, aVF is less commonly negative if location is left-sided. Reevaluation of delta wave in a fully preexcited QRS, i.e., during atrial pacing maneuvers, may help improve accuracy in this setting. Moreover, a negative delta wave in lead II has been described as a helpful marker of an epicardial ventricular connection in the inferoparaseptal area related to coronary sinus venous system [11, 40]. Interestingly, even when APs may be located in the left inferoparaseptum according to these ECG criteria, some of them still can be successfully approached from the right side.
Using the Retrograde P Wave Polarity During Orthodromic AVRT Careful analysis of retrograde P wave polarity during orthodromic tachycardia may provide the location of the atrial insertion of the AP [43, 44]. While useful, this analysis may be found difficult, as P wave is usually inscribed within the ST segment during orthodromic tachycardia. The P wave morphology in V1, lead I, and inferior leads is generally the most useful. Some algorithms have been developed to locate pathway atrial insertion site, as the described by Tai et al. [44]. In the same way shown for delta wave analysis, some basic rules may be easily applied in this setting: • A negative retrograde P wave in V1 typically suggests a right free-wall pathway. • A negative retrograde P wave in lead I/aVL suggests a left free-wall pathway. • Septal and superoparaseptal pathways usually exhibit an isoelectric P wave in V1. • Inferoparaseptal pathways typically exhibit a narrow P wave, negative in inferior leads and positive in V1, aVR, and AVL.
Mapping and Ablation General Considerations The first RF catheter ablation of an AP was described in 1987 [45]. Since then, tools and techniques have evolved considerably. Today, catheter ablation has become the standard of care for elimination of APs, with excellent success and low complication rates [46–48]. Some authors have described simplified approaches with one or two catheters for ablation of APs [49–51]. However, as ablation procedures may be more complex than expected due to presence
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of multiple arrhythmias or multiple accessory connections, real advantage of these simplified approaches is still under debate. As complexity of the ablation procedure of an AP cannot be reliably predicted, we think the single-catheter approach should be discouraged. According to the standard protocol for ablation procedures of supraventricular arrhythmias in our center, three standard sheaths are normally introduced through the right (left if necessary) femoral vein. A quadripolar 6 F diagnostic catheter is typically used for His bundle recording and ventricular pacing. A steerable decapolar 6 F diagnostic catheter is typically positioned in the coronary sinus. In some electrophysiology laboratories a superior approach (via right jugular, left subclavian, or left basilic veins) is still used for coronary sinus cannulation, but it can be easily achieved using the femoral approach in most cases, increasing patient comfort and significantly reducing operator radiation exposure [52]. A standard electrophysiologic study protocol with programmed stimulation is routinely performed before mapping the AP. Arterial access with introduction of a standard sheath through the right (left if necessary) femoral artery is obtained only when need for a left approach has been confirmed after standard study protocol and presence of a patent foramen ovale has been ruled out. A steerable 7 F nonirrigated 4-mm-tip mapping/ablation catheter is typically used for mapping and ablating both right- and left-sided APs. Especially in the right side, long sheaths may be necessary to provide higher catheter stability and ensure adequate tissue contact. The mapping technique will depend on pathway conduction properties. The majority of AV APs (approximately 60–70 %) conduct both anterogradely and retrogradely, leading to manifest preexcitation on surface ECG. Pathways that conduct only retrogradely (termed concealed) are less frequent (20–30 %). Pathways that conduct only anterogradely are uncommon (<5 %), are usually right-sided and exhibit decremental properties [2, 53–55]. In our experience, the chance of an AP exhibiting only antegrade conduction is higher if the patient is asymptomatic. Some electrogram criteria have been developed to identify APs successful ablation sites, as explained below. As the predictive accuracy of any single electrogram criterion is limited, a combination of these criteria should be applied to correctly identify the site of highly probable successful ablation.
Mapping Antegrade Conduction of Accessory Pathway If manifest preexcitation is present on the surface ECG, mapping the earliest site of ventricular activation (preceding the onset of the delta wave) along the AV junction can identify the location of the AP ventricular insertion. As APs usually exhibit non-decremental properties, the use of atrial
476 Fig. 37.5 Mapping antegrade right septal pathway activation during preexcited sinus rhythm. The blue line marks the onset of the delta wave on the surface ECG. Red lines mark the onset of atrial and ventricular electrograms on the bipolar distal mapping electrodes. The onset of ventricular signal on the unipolar recording exhibits a QS deflection with an initial steep negative component. DVT delta-to-V time, AVT local atrioventricular time
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pacing may facilitate mapping by enhancing ventricular preexcitation and delta wave [56, 57]. The ECG lead with the earliest and sharpest delineation of its onset should be selected to serve as reference for mapping. Both bipolar and unipolar recordings provided by the mapping catheter are helpful and should be used. Bipolar signals from the distal pair of electrodes reflect timing, electrogram components, and AP potentials. Unipolar signals from the electrode tip (to the Wilson central terminal) provide local activation information through electrogram timing and morphology. Some general criteria are used to identify the ventricular insertion of the AP and thus the site of most probable successful ablation: earliest local ventricular activation, unipolar electrogram morphology pattern, shortest atrioventricular interval, and recording of a presumed AP potential (Fig. 37.5). The earliest local ventricular activation site is usually the most important criterion as it localizes, by definition, the pathway ventricular insertion. It is defined as the one with longest time from the onset of local activation to the onset of delta wave (delta-to-V time). The earliest activation time must be evaluated in both bipolar and unipolar recordings. In the bipolar recordings, the delta-to-V interval should be measured from the onset of delta wave to the peak of the first rapid deflection of local electrogram [58]. For unipolar electrograms, the maximal dV/dt can accurately reflect local ventricular activation [59]. As bipolar electrograms are recorded between the distal pair of electrodes of the mapping catheter, the earliest signal may indicate the proximity of the pathway insertion to either the distal or the proximal electrode. The unipolar recording is useful to check that distal tip, used for RF delivery, is truly registering the earliest activation in the bipolar electrogram [9, 59].
The analysis of unipolar electrogram morphology pattern is highly useful in identifying the successful ablation site. As mentioned, unipolar electrograms help determine local ventricular activation time and earliness respect to onset of delta wave. Importantly, the recording of a “QS” unipolar electrogram pattern, defined as atrial activation immediately followed by a QS ventricular deflection with an initial steep negative component, is a marker of AP ventricular insertion and successful ablation site. Moreover, absence of a “QS” pattern (i.e., “initial R”) predicts an approximately 90 % chance of unsuccessful ablation [59]. The shortest local atrioventricular interval is defined as the time from the onset of local atrial activation to the onset of local ventricular activation on the bipolar recording. At successful ablation sites this time shortens and electrograms tend to fuse and give an image of continuous electric activity. A local AV time ≤30–40 ms has been identified as a marker of successful ablation site [56, 60]. Although the site of shortest local AV interval is often considered a good marker of successful ablation site, this criterion may be sometimes inaccurate and misleading if the course of the mapped AP is oblique. The oblique course of a pathway can be identified by demonstrating a variation >15 ms in local AV at the site of earliest ventricular activation when reversing the direction of the atrial wave front [9]. In these circumstances, an atrial wave front propagating from the direction of the atrial end of the pathway (concurrent direction) produces an overlapping of atrial and ventricular electrograms and an artificially short local AV interval at the site of earliest ventricular activation, often masking the AP potential. Nevertheless, an atrial wave front propagating in the opposite direction (countercurrent) would lengthen the local AV interval. Interestingly, reversing the direction of the atrial wave front to countercurrent
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direction may help identify the site of successful ablation by exposing the ventricular activation sequence and unmasking an AP potential. Accessory pathway potentials manifest as a sharp narrow deflection recorded between the atrial and ventricular signals on both bipolar and unipolar channels, usually from 10 to 30 ms before the onset of the delta wave. Amplitude of AP potentials at successful ablation sites averages 0.5 to 1 mV. Although the recording of a pathway potential represents a demonstrated predictor of successful outcome, it cannot always be identified [56, 61–65]. Moreover, as components of atrial or ventricular electrograms may mimic a pathway potential, verification of a truly pathway potential with atrial and/or ventricular pacing maneuvers may be required [62, 66, 67]. As validation of signals as true AP potentials may be tedious, difficult to achieve, and questionably practical in the clinical setting, these potentials are preferably referred to as “presumed” or “possible” AP potentials. Mapping catheter stability is crucial to achieve successful ablation at the site with optimal electrogram recordings. It is a demonstrated independent predictor of successful catheter ablation. Catheter stability is determined according to electrogram criteria, defined as <10 % change in both atrial and ventricular electrograms over 5–10 cardiac beats, and is also confirmed fluoroscopically [62].
Mapping Retrograde Conduction of Accessory Pathway Mapping of AP retrograde activation identifies the AP atrial insertion site. Retrograde mapping can serve as an additional mapping approach complementary to antegrade mapping of pathways conducting both antegradely and retrogradely, or the only possible way of mapping for concealed pathways. It can be generally performed during orthodromic reciprocating tachycardia or ventricular pacing. Importantly, fusion of atrial activation caused by simultaneous retrograde conduction over AV node and AP has to be considered when mapping during ventricular pacing, especially with septal pathways, as it can interfere with mapping accuracy. Pacing from areas closer to the AP and pacing maneuvers as introduction of ventricular extrastimuli may help dissociate retrograde conduction over the pathway from that over the AV node. Unipolar recordings are not as helpful for mapping retrograde conduction as they are for mapping pathway antegrade activation. However, as they may still provide useful information, both bipolar and unipolar recordings should be used for retrograde mapping [59, 63]. Some general criteria are used to identify the ventricular insertion of the AP and thus the site of most probable successful ablation: earliest local atrial activation time, shortest local ventriculoatrial (VA) interval, and recording of a presumed AP potential (Fig. 37.6). The earliest local atrial activation site is defined as the one with longest time from the QRS onset to the onset of
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local atrial activation (QRS to A time). Discriminating fused atrial and ventricular components of local electrograms may be challenging when mapping retrograde atrial activation. This problem may be addressed in several ways. Sometimes, the retrograde atrial electrogram may be identified by the unipolar recording as a notch in the ascending limb of local ventricular signal during orthodromic tachycardia or ventricular pacing that is absent during sinus rhythm [63]. Another way that may help differentiate atrial and ventricular components of mapping electrograms consists in comparing local mapping signals during ventricular pacing alone and during simultaneous atrial and ventricular stimulation [68]. Another possible approach is to exploit, when present, the frequent oblique course of the pathway through the annulus. In this situation, a ventricular wave front propagating from the direction of the ventricular end of the pathway (concurrent direction) produces an artificially short local VA interval at the site of earliest atrial activation. As both ventricular and pathway activation propagate parallel at the same time, the ventricular signal often overlaps and masks the atrial signal near the atrial end of the AP. Reversing the ventricular wave front to countercurrent direction by pacing from an opposite site increases the local VA interval all along the pathway exposing the atrial activation sequence and, potentially, the AP potential [9]. The difference between the earliest atrial activation and the shortest local VA interval is important. As the earliest atrial activation is a better marker of a successful ablation site, it should be preferred when both criteria are not met at the same site (Fig. 37.7). The shortest local ventriculoatrial interval is defined as the time from the onset of local ventricular activation to the onset of local atrial activation on the bipolar recording. At successful ablation sites this time shortens and atrial electrogram tends to be inscribed on the terminal portion of the ventricular electrogram, giving an image of continuous electric activity [62, 64]. The identification of the “pseudodisappearance” of a bipolar atrial electrogram during tachycardia or ventricular pacing, but visible during sinus rhythm has been described as a criterion to identify extremely early local atrial activation on a site of probable successful ablation [63]. Nevertheless, some aspects have to be carefully addressed for use of the local VA interval criterion when mapping retrograde pathway conduction. First, short local VA intervals may be potentially observed at multiple sites along the valve annulus as a result of coincident atrial and ventricular activation wave fronts. Another problem is frequent obliquity of APs, which can make the local VA criterion inaccurate and potentially misleading. The presence of an oblique course is a challenge for mapping and a common cause of ablation failure. The optimal ablation site is located near the middle portion of the AP, which can be identified by pacing maneuvers. Importantly, some factors have to be considered when
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Fig. 37.6 Mapping retrograde left lateral pathway activation during orthodromic AV reciprocating tachycardia, using a transaortic approach. Blue lines mark the onset of the QRS on the surface ECG and the onset of atrial activation on the coronary sinus catheter recordings. Red lines
mark the onset of atrial and ventricular electrograms on the bipolar distal mapping electrodes. EAA earliest atrial activation, RAT QRS to local atrium time, VAT local ventriculoatrial time
targeting retrograde atrial activation of an oblique AP. Because of the relatively wide recording range of the 4-mm tip generally used for mapping, the earliest atrial activation during retrograde conduction may be recorded 3–5 mm, or may be more, from the actual atrial insertion. In this situation, ablation is likely to be successful if the tip electrode is displaced 3–5 mm from the atrial insertion in the direction of the ventricular insertion, but probably unsuccessful if displaced in the opposite direction [9]. Additionally, the angle of the AP insertion at the atrium favors a more rapid propagation of atrial activation from the atrial insertion in the same direction of the pathway and moving it away from the midbody of the pathway. In contrast, propagation of atrial activation toward the midbody of the AP may be delayed by the reversal of the direction of atrial activation at the atrial insertion site [69]. These factors have to be also considered when mapping the antegrade conduction of an oblique AP. During antegrade AP conduction, ablation at a site recording earliest ventricular activation is likely to be successful even if the electrode is located 3–5 mm from the ventricular end but in the direction of the atrial insertion and unsuccessful if located in the opposite direction [9]. These factors may help explain
the relatively high rate of ablation failure reported for RF lesions when targeting earliest atrial and ventricular activation times [60, 61, 64] (Fig. 37.7). Accessory pathway potentials are markers of successful ablation sites. However, large ventricular electrograms or fusion of atrial and ventricular electrograms may hinder the recording of these signals. If the course of the AP is oblique, pacing from the side producing the longer local VA interval may facilitate pathway potential identification [9]. Generally, they are not the usual goal for mapping although they are useful, when recorded, to identify the successful ablation site.
General Principles for Ablation Standard 4-mm-tip RF catheters are the first choice to map and ablate a standard AP. In our laboratory, the target temperature is typically set up to 55 °C and the power limit to 50 W. Obtaining a stable position of the catheter and good tissue contact are important for optimal RF delivery. Interruption of AP conduction should ideally occur within the first 6 s of RF delivery. Longer times could be associated with higher recurrences rate [70]. In our laboratory, when AP
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Fig. 37.7 Schematic representation of left free-wall accessory pathway with oblique course. Timing of ventricular (V), atrial (A), and AP potentials changes by reversing the direction of the paced ventricular
wave front. Dashed lines indicate conduction delay associated with reversal in direction. See text for discussion (From Nakagawa and Jackman [69], with permission of Wolters Kluwer Health)
conduction is successfully interrupted within the first 10 s after onset of RF delivery, energy delivery is continued for 60 s. Sometimes, delivery of greater energies with irrigated catheters may be required to create deeper lesions and successfully ablate resistant APs. For irrigated systems we usually target a maximal temperature of 43 °C and maximal power of 30–40 W.
However, accuracy of coronary sinus mapping is limited, as it runs an average of 10–14 mm on the atrial side of true mitral annulus [71]. Left free-wall APs can be mapped using either a retrograde aortic or transseptal approach. The transaortic approach directs the mapping catheter tip perpendicularly to sites beneath the valve. This approach probably allows a slightly worse maneuverability of the mapping catheter but provides higher stability and firmer tissue contact, except for the far lateral and superior mitral annulus. The transseptal approach directs the mapping catheter tip to the atrial side of the mitral annulus or the annulus itself, in a more parallel manner respect to the annulus. This approach may not provide tissue contact as easily as the retrograde approach but allows a better maneuverability of the mapping catheter and provides better access to far lateral and superolateral locations. Other advantages of the transseptal approach are less risk of coronary injury and no need for arterial access. On the other hand, it is associated with a higher risk of air embolism and
Considerations for Mapping and Ablation in Specific Accessory Pathway Location Characteristics of the AP and its relation to the AV annuli, atria, and ventricular myocardium may differ with regard to pathway location.
Left Free-Wall Area The use of a multielectrode diagnostic catheter in the coronary sinus helps mapping along the mitral annulus.
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cardiac perforation. As overall success rates have been found similar with both approaches, the decision regarding which technique to use is based on operator preference and certain patient characteristics, as peripheral vascular disease or aortic valve disease [71–73]. The specific criteria to predict success of ablation when mapping an AP located in the left free-wall area are the following [56, 58, 59, 61, 62, 64, 74–76]: • For mapping either antegrade or retrograde pathway conduction: – Atrial electrogram amplitude >1 mV or A/V amplitude ratio >0.1 when using a retrograde transaortic approach, and A/V ratio = 1 for transseptal mapping – Recording of presumed AP potential – Catheter stability • When mapping antegrade pathway conduction: – Local ventricular activation with a delta-to-V time ≤ 0 ms – Recording of a “QS” pattern on the unipolar recordings – Local AV interval <30–40 ms • When mapping retrograde pathway conduction: – Local atrial activation with QRS to A time <70 ms – Local VA interval <30 ms – The identification of the point of atrial electrogram polarity reversal can be used when performing a transseptal approach. The transseptal approach allows parallel orientation and movement of the mapping electrode bipole along the mitral annulus. The unfiltered bipolar electrograms (bandpass filtering should be set to 0.5–500 Hz) with the mapping bipole oriented parallel to the mitral annulus can be used to localize the atrial insertion of the AP. As the distal tip of the mapping catheter is the negative pole, the bipolar recording will show a negative electrogram when located inferiorly to the AP atrial insertion and a positive electrogram when located superiorly to the atrial insertion. The point at which the atrial electrogram becomes diminished in amplitude, isoelectric, and fractionated marks the atrial insertion and the site for ablation [77].
Right Free-Wall Area Ablation of right free-wall APs is more challenging than in the left side. As previously mentioned, anatomy of the tricuspid valve and the AV junction at the right side of the heart are different from that on the left side. Along the tricuspid annulus, atrial and ventricular myocardia are separated by a poorly defined fibrous component as they fold over one another, creating a folded-over sac. This anatomic configuration facilitates the presence of broad connections with a complex fiber orientation and hinders catheter stability and mapping. Moreover, the course of the pathway may be close to the epicardium in some cases and presence of multiple connections is frequent. Adequate distinction of atrial and ventricular electrograms and identification of AP potentials
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may be prevented by fragmentation of local recordings. This helps explain the lower success rates and more common recurrences for RF ablation in this region. Transient interruption of pathway conduction during RF delivery and prompt resumption of conduction is also frequent. Right free-wall APs can be generally properly approached from the inferior vena cava using, when necessary, long guiding sheaths. These sheaths extend into the right atrium and have distal configurations tailored to specific locations along the annulus, providing support and stability for the mapping catheter. A superior vena cava approach has been also described to allow full exploration of the fold-over sac and the anterior locations of the annulus. Mapping of the tricuspid annulus is usually performed in the LAO view. The tricuspid annulus location is not as easily identified as the mitral annulus, as there is no venous structure to mark with a catheter. The use a circular multipolar diagnostic catheter (Halo®) positioned in the right atrium around the annulus may help pathway localization. However, it is generally used only for selected cases. The specific criteria to predict success of ablation when mapping an AP located in the right free-wall area are [78, 79]: • For mapping either antegrade or retrograde conduction: – Relation A/V electrograms = 1 – Recording of presumed AP potential – Catheter stability • When mapping antegrade conduction: – Local ventricular activation with a delta-to-V time ≤−20 ms. Pre-delta wave activation times are longer in the right side compared to the left side. Even when a negative delta-to-V time is found, the earliest pre-delta time should keep being sought. – Recording of a “QS” pattern on the unipolar recordings, which is usually more pronounced that in the left side. – Local AV interval ≤30 ms. • When mapping retrograde conduction: – Local VA interval ≤40 ms As mentioned, transient interruption of AP conduction during ablation is frequent in the right free wall, more than in the left side. We strongly recommend performing careful and detailed mapping instead of delivering RF in multiple suboptimal sites. In Ebstein anomaly, the annular attachment of tricuspid valve leaflets is typically displaced into the right ventricle. Accessory pathways related to Ebstein anomaly are usually located in the inferior, inferolateral, or inferoparaseptal region and are frequently multiple. Successful ablation is usually achieved at the area of the true tricuspid annulus and not at the lower line of valve leaflet attachment. Extremely careful and detailed mapping is required as it is frequently hindered by fractionation of local electrograms in the area.
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Fig. 37.8 Coronary sinus diverticulum in a patient with an inferoparaseptal accessory pathway. Coronary sinus angiograms during diastole (a) and systole (b) demonstrating myocardial contraction of the diverticulum wall. CT-scan images showing the aneurysm and its relation to nearby structures (c and d). The site of successful ablation was located close to the diverticulum neck (e and f). Earliest ventricular acti-
vation was observed at that site, with continuous electrical activity and an image of a presumed AP potential (APP) between atrial and ventricular signals. The unipolar channel recorded a steep negative deflection (QS pattern) following the presumed AP potential. Irrigated RF was required to achieve successful ablation. RAO right anterior oblique view, LAO left anterior oblique view, ABL ablation, CS coronary sinus
Inferoparaseptal Area The identification of the successful ablation site for APs in the inferoparaseptal area is hindered by its particularly complex anatomy (see General Anatomic Considerations section). In fact, this region is responsible of most of failed AP ablation procedures. Accessory pathways in the inferoparaseptal area can be approached endocardially from the right or left side or epicardially from within the coronary sinus or its branches. However, most of these connections can be successfully ablated from the right endocardium. Some ECG and electrophysiologic criteria have been developed to help discriminate the successful ablation site within this area: Criteria based on ECG findings [80, 81]: • A negative or isoelectric delta wave in V1 suggests a right-sided location. • R/S wave ratio >1 in V1 suggests a left-sided location. • A steep negative delta wave in lead II, a steep positive delta wave in aVR, and a deep S wave (R ≤ S) in V6 suggest an epicardial location within the coronary sinus or its branches. • A long-RP tachycardia suggests a right-sided location. Criteria based on electrophysiologic findings [79, 82, 83]: • Earliest retrograde activation recorded >15 mm far from the coronary sinus ostium suggests a left-sided location.
• Decremental conduction properties exhibited by the AP suggest a right-sided location. • A difference in ventricular-to-atrial conduction time >25 ms, between the His bundle recording site and the earliest site in the coronary sinus during retrograde conduction, suggests a left-sided location. • Left atrium-coronary sinus musculature activation sequence at the site of earliest atrial activation during retrograde conduction. Fragmented or double potentials are frequently recorded in the coronary sinus, with a smaller and blunt component from left atrial myocardium and a larger and sharp signal from the coronary sinus musculature. The recording of a blunt-sharp sequence suggests a left-sided endocardial location, whereas a sharp-blunt sequence is suggestive of either a right-sided endocardial or an epicardial coronary sinus musculature AP. A coronary sinus diverticulum or other anomalies may be present in some cases. The diagnosis can be easily obtained by performing a venogram. As previously mentioned (see General Anatomic Considerations section), anatomic anomalies in the coronary sinus venous system are frequently related to the site of connection of the pathway [11, 33–35, 84]. When a coronary sinus diverticulum is present, the AP is usually located in the neck of the diverticulum (Fig. 37.8).
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We recommend to start mapping with a right-sided endocardial approach unless ECG or electrophysiologic criteria are strongly suggestive of a left-sided location. Mapping in the right side must also include the ostium and the most proximal part of the coronary sinus. If mapping or ablation fails in the right endocardium, the left inferoparaseptal area is then mapped endocardially using either a transaortic or transseptal approach, as described for left free-wall APs. The electrogram criteria used to predict ablation success on the right and left endocardial sides of the inferoparaseptal area are the same as the described for right and left free wall (see above). Ablation along the tricuspid or the mitral annulus can be usually performed with a conventional 4-mm-tip RF catheter. Sometimes, however, irrigated tip catheters may be necessary to achieve successful ablation by creating deeper lesions. If the endocardial approach fails, the presence of an epicardial AP should be considered, and mapping through the coronary sinus and its branches is recommended. As previously mentioned, a coat of striated muscle usually covers the proximal portion of the coronary sinus. This coat, which normally connects with both left and right atria, may also connect with the epicardial aspect of the ventricle, creating an AP. As connections between the coronary sinus and the atria may be multiple and targeting the atrial insertion may be confusing, mapping the ventricular insertion, usually single, is recommended. At the site of earliest ventricular activation, the recording of a venous muscle potential preceding the ventricular endocardial activation is frequently recorded, producing an image similar to an AP potential. Amplitude of these potentials is usually higher than local atrial or ventricular signals. A coronary sinus venogram can be particularly useful in this setting to detect presence of a diverticulum or a venous anomaly and may help guide mapping within the coronary sinus branches (Fig. 37.8). Due to lack of spontaneous cooling, the use of irrigated RF at low power settings may be required when attempting ablation in the coronary sinus, especially for distal locations, in its branches or within a diverticulum. Irrigated ablation within the coronary sinus venous system must be carefully performed limiting power to 15–20 W (not exceeding 30 W) and temperature to 40–45 °C, delivering energy for up to 60 s. Risk of venous occlusion or perforation and risk of coronary artery damage are present when ablating within the veins or a diverticulum [85]. Some authors highly recommend performing coronary angiography previously to RF ablation and avoid sites less than 2 mm away from the right coronary artery and its main branches. As RF delivery at sites less than 2 mm away from the right coronary artery carries a significant risk of arterial injury, switch to a safer approach with cryoablation is recommended.
Septal and Superoparaseptal Area The superoparaseptal area comprises the apex of the triangle of Koch and the area immediately above, in the right atrium.
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The area below the apex of the triangle and above the coronary sinus ostium level constitutes de septal area. Ablation of APs in this region may be extremely challenging because of their proximity to the AV node and the His bundle. Due to this proximity, a His potential may be recorded by the mapping catheter at the site required for successful ablation. A true parahisian pathway is considered when a His potential >0.1 mV is recorded by the mapping catheter at the site required for successful ablation [86]. However, recording of His potential may also be hindered by a large local preexcited ventricular signal. Extremely careful and thorough mapping should be performed before ablation to identify the optimal site for ablation, ensure stability and good tissue contact, and avoid delivering a high number of lesions in such delicate area. The use of long preformed sheaths that extend into the right atrium may help stabilize the position of the mapping catheter. Electroanatomic mapping systems are a helpful tool for tracking the catheter position and monitoring its position relative to the His bundle area. Tagging all sites exhibiting a bundle of His potential creates a “His cloud” on the electroanatomic map, marking the higher-risk area. Moreover, as APs in the septal/superoparaseptal area are frequently superficial and catheter trauma may easily result in block of pathway conduction, mapping systems may help localize and tag this site for subsequent ablation if pathway conduction does not return after a reasonable waiting period [79, 87]. Targeting the ventricular insertion site of the AP instead of the atrial insertion is recommended, when possible, to minimize the risk of damage to the normal conduction system. The electrogram criteria used for mapping antegrade conduction in the presence of ventricular preexcitation are basically the same as those used for mapping APs in the right free wall (see above). However, a more ventricular location, with an atrial/ventricular electrogram ratio <0.4, is considered safer. The His deflection should be identified, when present, and correctly differentiated from a possible pathway potential using maneuvers as atrial burst pacing or atrial extrastimuli. The His bundle electrogram should not exceed 0.2 mV amplitude in the mapping catheter before ablation. Superoparaseptal APs may be ablated with RF energy. A standard 4-mm-tip catheter is used for this purpose. As mentioned, the catheter should be placed in a more ventricular position, beyond the tricuspid annulus or on the annulus itself. Again, catheter stability is very important. Energy delivery may be titrated, starting with 10 W and gradually increasing by 5 W steps up to a maximum of 30 W, completing lesions not longer than 60 s. Integrity of the normal AV conduction system should be carefully monitored during RF delivery. The application should be stopped if no success is observed after 15–20 s. As mentioned, APs are usually superficial in this area and lack of success is usually due to wrong site or poor tissue contact. Use of higher energies, larger tip catheters, or irrigation to make bigger lesions is not appropriate in this region.
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For manifest APs, an increase of the degree of preexcitation should alert of damage on normal AV conduction. Sometimes, pacing from the coronary sinus may decrease the basal degree of preexcitation during sinus rhythm and thus help monitor the AV node and His bundle conduction. Radio-frequency delivery should be immediately stopped with the appearance of junctional rhythm, which results from AV node/His bundle heating. Importantly, this rhythm may be misunderstood as success of the RF application, as it typically produces loss of preexcitation, and wrongly encourage continuing with energy delivery. For concealed APs, the control of conduction through the pathway and through the normal conduction system is more challenging. Ventricular pacing is not useful in this setting as retrograde atrial activation pattern is very similar through both pathway and AV node. Ablation during sinus rhythm allows monitor antegrade AV conduction or appearance of junctional rhythm but does not provide information about lesion effectiveness. One valid option is to perform ablation during orthodromic tachycardia, which allows monitoring of both pathway and AV node conduction. However, the ablating catheter may dislodge with tachycardia cessation during successful ablation, producing an incomplete lesion. This can be addressed by performing atrial entrainment with manifest atrial fusion at a slightly higher rate than the tachycardia during the ablation. At the moment of tachycardia termination, produced by successful ablation, catheter dislodgement will be avoided by fast atrial pacing. At that moment, a change in atrial activation sequence will be observed, translating the termination of the tachycardia and the ablation success. Published data of RF ablation of superoparaseptal and septal APs have shown primary success rates ranging from 71 to 100 %, with recurrence rates of 15–25 % and the risk for AV block varying between 0 and 36 % [70, 86, 88–90]. Although the use of low-energy RF has been recommended to reduce the risk for AV block, this technique is associated with a higher incidence of recurrences and still carries some risk of damage to the AV conduction system [79, 91]. Although RF can be used for ablation of superoparaseptal and septal APs, and some authors do, cryotherapy has emerged as the therapy of choice, as it has demonstrated to be highly effective and safe [92–95]. This technique is performed by combining the cryomapping and cryoablation modalities. A 6-mm-tip catheter is regularly used. With cryomapping, catheter tip temperature drops to – 40 °C during no more than 60 s, producing a reversible lesion on the tissue. If impairment of AV conduction is observed or the lesion is not effective, the catheter can be moved to other site after rewarming. When cryomapping identifies an adequate site for ablation (AP block with no modification of normal AV conduction), cryoablation is initiated and catheter tip temperature drops to – 80 °C for up to 360 s, creating an irreversible lesion. In both modalities, as temperature drops, an ice ball progressively appears at the tip of the catheter and sticks
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to the tissue, avoiding the risk of catheter dislodgement. This phenomenon is marked by the appearance of a noisy signal recorded from the distal catheter bipole. Importantly, the catheter should not be removed until the catheter tip is rewarmed and the ice ball is thawed. In our experience, as the ice ball is created distally to the tip of the catheter, we usually withdraw it a little bit to a slightly more atrial position from the site with optimal electrogram recordings before initiating the application. Transient impairment of normal AV conduction may be observed during cryothermal energy application. However, no permanent damage to the normal conduction system has been described if the application is immediately stopped, even when using cryoablation. Moreover, some variability in the cryothermal energy required to produce a lesion has been described. As this may limit applicability of the cryomapping mode and safety of cryoablation has been also demonstrated, we prefer to use directly the cryoablation mode for mapping and stop the application after 20 s if it does not yield the desired effect. Acute procedural success is higher than 95 % and long-term follow-up recurrences vary from 0 to 27 % in different studies [92, 94, 95].
Clinical Considerations and Role of Catheter Ablation in the Management of Patients Presenting with AV Accessory Pathways As reported in population studies, most patients with an ECG pattern of preexcitation are asymptomatic (ranging from 50 to 80 %) [96, 97]. The diagnosis of WPW syndrome is reserved for patients presenting with both preexcitation and symptomatic arrhythmias. Among patients with WPW syndrome, the most common type of arrhythmia is AVRT. Patients suffering this arrhythmia usually experience welltolerated symptoms, similar to those of typical paroxysmal supraventricular tachycardia. However, sometimes patients may also present with poorly tolerated AVRT, especially in the presence of structural heart disease. Atrial fibrillation is the second most common arrhythmia in patients with WPW syndrome. It may be potentially life threatening in this setting, as rapid repetitive conduction to the ventricles through an AP with a short refractory period may result in a rapid ventricular response and subsequent degeneration to ventricular fibrillation [96, 98, 99]. Interestingly, accessory pathways appear to play a pathophysiological role in the development of atrial fibrillation, especially those that exhibit antegrade conduction [100]. Some factors have been described to help identify patients exposed to a higher risk of cardiac arrest [96, 98, 101–105]: • History of symptomatic tachycardia • Short AP refractoriness: effective refractory period (ERP) <250 ms, or shortest preexcited R-R interval <250 ms during spontaneous or induced atrial fibrillation • Septal location of the accessory pathway
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• Presence of multiple accessory pathways • Ebstein anomaly • Familial WPW syndrome The risk of sudden cardiac death in patients with WPW syndrome has been classically estimated to range from 0.15 to 0.39 % over 3- to 10-year follow-up [106]. In a recent study, 369 symptomatic WPW patients with AVRT that declined catheter ablation were followed up over a 5-year period. Malignant arrhythmias developed in 29 of these patients (0.08 %), resulting in presyncope/syncope (25 patients), hemodynamic collapse (3 patients), or cardiac arrest caused by ventricular fibrillation (1 patient) [105]. The risk of cardiac arrest among asymptomatic patients exhibiting a preexcitation pattern on the ECG is lower than in symptomatic patients, but still not clearly defined. While some series have found no sudden deaths in asymptomatic patients, one study has reported three cases of ventricular fibrillation in a cohort of 162 previously asymptomatic patients [97, 107, 108]. Although it is unusual for cardiac arrest to be the first symptomatic manifestation of WPW syndrome, in more than a half of patients presenting with cardiac arrest, this may be its first clinical manifestation [96, 101]. As conduction properties of APs become poor over time, the risk of suffering arrhythmias decreases with older age at the time of preexcitation pattern detection [96, 109, 110]. In the Olmsted County (Minnesota, USA) population, one third of asymptomatic patients <40 years old at diagnosis of preexcitation pattern eventually had symptoms, whereas no symptomatic patients >40 years old (at diagnosis) developed symptoms [96]. The detection of intermittent preexcitation, characterized by an abrupt loss of delta wave, is a marker of a relatively long AP refractory period and probably translates a low risk for induction of ventricular fibrillation [111]. This is the basis for noninvasive studies as Holter monitoring or stress testing. However, due to their low sensitivity, these studies play a minor role in patient management. The positive predictive value of invasive electrophysiological testing is considered to be too low to justify routine use in asymptomatic patients [106]. According to the guidelines, patients who have WPW syndrome (preexcitation and symptoms) and particularly those with hemodynamic instability during their arrhythmias should undergo catheter ablation as first-line therapy. Catheter ablation is the therapy of choice for APs over pharmacologic therapy, because of its high effectiveness and low risk of complications [106]. In asymptomatic patients, the decision for an approach with catheter ablation should be made on the basis of individual clinical considerations as age <40 years old, familial WPW syndrome, high-risk occupations or high-performance sport, and always balancing its benefit against the risk of major complications. Noninvasive tests as Holter monitoring or stress testing may play a role in stratifying patient risk. Electrophysiological data obtained in
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the course of ablation procedures provide valuable information that may help decision-making, i.e., for challenging APs as parahisian. However, the routine performance of invasive electrophysiological evaluation only for diagnostic purposes is not sufficiently justified.
References 1. Chugh A, Morady F. Atrioventricular reentry and variants. In: Zipes D, editor. Cardiac electrophysiology: from cell to bedside. 5th ed. Philadelphia: WB Saunders; 2009. p. 605–13. 2. Dagres N, Clague JR, Kottkamp H, Hindricks G, Breithardt G, Borggrefe M. Radiofrequency catheter ablation of accessory pathways. Outcome and use of antiarrhythmic drugs during follow-up. Eur Heart J. 1999;20(24):1826–32. doi:10.1053/euhj.1999.1749. S0195668X99917499 [pii]. 3. Schluter M, Schluter CA, Cappato R, Hebe J, Siebels J, Kuck KH. [Anatomic distribution, conduction properties and recurrences after ablation of multiple in comparison with single accessory conduction pathways]. Z Kardiol. 1997;86(3):221–30. 4. Cosio FG, Anderson RH, Kuck KH, Becker A, Benditt DG, Bharati S, et al. ESCWGA/NASPE/P experts consensus statement: living anatomy of the atrioventricular junctions. A guide to electrophysiologic mapping. Working Group of Arrhythmias of the European Society of Cardiology. North American Society of Pacing and Electrophysiology. J Cardiovasc Electrophysiol. 1999;10(8): 1162–70. 5. Klein GJ, Hackel DB, Gallagher JJ. Anatomic substrate of impaired antegrade conduction over an accessory atrioventricular pathway in the Wolff-Parkinson-White syndrome. Circulation. 1980;61(6):1249–56. 6. Sealy WC, Gallagher JJ, Pritchett EL. The surgical anatomy of Kent bundles based on electrophysiological mapping and surgical exploration. J Thorac Cardiovasc Surg. 1978;76(6):804–15. 7. Becker AE, Anderson RH. The Wolff-Parkinson-White syndrome and its anatomical substrates. Anat Rec. 1981;201(1):169–77. doi:10.1002/ar.1092010118. 8. Becker AE, Anderson RH, Durrer D, Wellens HJ. The anatomical substrates of wolff-parkinson-white syndrome. A clinicopathologic correlation in seven patients. Circulation. 1978;57(5):870–9. 9. Otomo K, Gonzalez MD, Beckman KJ, Nakagawa H, Becker AE, Shah N, et al. Reversing the direction of paced ventricular and atrial wavefronts reveals an oblique course in accessory AV pathways and improves localization for catheter ablation. Circulation. 2001; 104(5):550–6. 10. Chauvin M, Shah DC, Haissaguerre M, Marcellin L, Brechenmacher C. The anatomic basis of connections between the coronary sinus musculature and the left atrium in humans. Circulation. 2000;101(6):647–52. 11. Sun Y, Arruda M, Otomo K, Beckman K, Nakagawa H, Calame J, et al. Coronary sinus-ventricular accessory connections producing posteroseptal and left posterior accessory pathways: incidence and electrophysiological identification. Circulation. 2002;106(11): 1362–7. 12. Hwang C, Peter CT, Chen PS. Radiofrequency ablation of accessory pathways guided by the location of the ligament of Marshall. J Cardiovasc Electrophysiol. 2003;14(6):616–20. 13. Aslani A, Moradi M, Kheirkhah J, Haghjoo M. Catheter ablation of an accessory pathway within the marshall vein in a patient with mechanical mitral valve. Pacing Clin Electrophysiol. 2011. doi:10.1111/j.1540-8159.2011.03089.x. 14. Di Biase L, Schweikert RA, Saliba WI, Horton R, Hongo R, Beheiry S, et al. Left atrial appendage tip: an unusual site of
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16.
17.
18. 19.
20.
21.
22.
23.
24. 25.
26.
27.
28.
29.
30.
31.
32. 33.
Location of Accessory Pathways in WPW: What and How Should We Ablate successful ablation after failed endocardial and epicardial mapping and ablation. J Cardiovasc Electrophysiol. 2010;21(2):203–6. doi:10.1111/j.1540-8167.2009.01561.x. JCE1561 [pii]. Mah D, Miyake C, Clegg R, Collins KK, Cecchin F, Triedman JK, et al. Epicardial left atrial appendage and biatrial appendage accessory pathways. Heart Rhythm. 2010;7(12):1740–5. doi:10.1016/j.hrthm.2010.08.013. S1547-5271(10)00823-4 [pii]. Ho SY, Goltz D, McCarthy K, Cook AC, Connell MG, Smith A, et al. The atrioventricular junctions in Ebstein malformation. Heart. 2000;83(4):444–9. Watson H. Natural history of Ebstein’s anomaly of tricuspid valve in childhood and adolescence. An international co-operative study of 505 cases. Br Heart J. 1974;36(5):417–27. Van Lingen B, Bauersfeld SR. The electrocardiogram in Ebstein’s anomaly of the tricuspid valve. Am Heart J. 1955;50(1):13–23. Milstein S, Dunnigan A, Tang C, Pineda E. Right atrial appendage to right ventricle accessory atrioventricular connection: a case report. Pacing Clin Electrophysiol. 1997;20(7):1877–80. Soejima K, Mitamura H, Miyazaki T, Miyoshi S, Murata M, Sato T, et al. Catheter ablation of accessory atrioventricular connection between right atrial appendage to right ventricle: a case report. J Cardiovasc Electrophysiol. 1998;9(5):523–8. Goya M, Takahashi A, Nakagawa H, Iesaka Y. A case of catheter ablation of accessory atrioventricular connection between the right atrial appendage and right ventricle guided by a three-dimensional electroanatomic mapping system. J Cardiovasc Electrophysiol. 1999;10(8):1112–8. Lam C, Schweikert R, Kanagaratnam L, Natale A. Radiofrequency ablation of a right atrial appendage-ventricular accessory pathway by transcutaneous epicardial instrumentation. J Cardiovasc Electrophysiol. 2000;11(10):1170–3. Shah MJ, Garabedian H, Garoutte MC, Cecchin F. Catheter ablation of a right atrial appendage to the right ventricle connection in a neonate. Pacing Clin Electrophysiol. 2001;24(9 Pt 1):1427–9. Anderson RH, Brown NA, Webb S. Development and structure of the atrial septum. Heart. 2002;88(1):104–10. Farre J, Anderson RH, Cabrera JA, Sanchez-Quintana D, Rubio JM, Romero J, et al. Fluoroscopic cardiac anatomy for catheter ablation of tachycardia. Pacing Clin Electrophysiol. 2002;25(1):76–94. Ho SY, Anderson RH. How constant anatomically is the tendon of Todaro as a marker for the triangle of Koch? J Cardiovasc Electrophysiol. 2000;11(1):83–9. Sanchez-Quintana D, Ho SY, Cabrera JA, Farre J, Anderson RH. Topographic anatomy of the inferior pyramidal space: relevance to radiofrequency catheter ablation. J Cardiovasc Electrophysiol. 2001;12(2):210–7. Davis LM, Byth K, Ellis P, McGuire MA, Uther JB, Richards DA, et al. Dimensions of the human posterior septal space and coronary sinus. Am J Cardiol. 1991;68(6):621–5. 0002-9149(91)90354-N [pii]. Sealy WC, Gallagher JJ. The surgical approach to the septal area of the heart based on experiences with 45 patients with Kent bundles. J Thorac Cardiovasc Surg. 1980;79(4):542–51. Sealy WC, Mikat EM. Anatomical problems with identification and interruption of posterior septal Kent bundles. Ann Thorac Surg. 1983;36(5):584–95. Haissaguerre M, Montserrat P, Warin JF, Donzeau JP, Le Metayer P, Massiere JP. Catheter ablation of left posteroseptal accessory pathways and of long RP’ tachycardias with a right endocardial approach. Eur Heart J. 1991;12(8):845–59. von Lüdinghausen M, Ohmachi N, Boot C. Myocardial coverage of the coronary sinus and related veins. Clin Anat. 1992;5:1–15. Schumacher B, Tebbenjohanns J, Pfeiffer D, Omran H, Jung W, Luderitz B. Prospective study of retrograde coronary venography in patients with posteroseptal and left-sided accessory atrioventricular pathways. Am Heart J. 1995;130(5):1031–9.
485
34. Tebbenjohanns J, Pfeiffer D, Schumacher B, Jung W, Manz M, Luderitz B. Direct angiography of the coronary sinus: impact on left posteroseptal accessory pathway ablation. Pacing Clin Electrophysiol. 1996;19(7):1075–81. 35. Weiss C, Cappato R, Willems S, Meinertz T, Kuck KH. Prospective evaluation of the coronary sinus anatomy in patients undergoing electrophysiologic study. Clin Cardiol. 1999;22(8):537–43. 36. Milstein S, Sharma AD, Guiraudon GM, Klein GJ. An algorithm for the electrocardiographic localization of accessory pathways in the Wolff-Parkinson-White syndrome. Pacing Clin Electrophysiol. 1987;10(3 Pt 1):555–63. 37. Xie B, Heald SC, Bashir Y, Katritsis D, Murgatroyd FD, Camm AJ, et al. Localization of accessory pathways from the 12-lead electrocardiogram using a new algorithm. Am J Cardiol. 1994;74(2): 161–5. 38. Fitzpatrick AP, Gonzales RP, Lesh MD, Modin GW, Lee RJ, Scheinman MM. New algorithm for the localization of accessory atrioventricular connections using a baseline electrocardiogram. J Am Coll Cardiol. 1994;23(1):107–16. 39. Chiang CE, Chen SA, Teo WS, Tsai DS, Wu TJ, Cheng CC, et al. An accurate stepwise electrocardiographic algorithm for localization of accessory pathways in patients with WolffParkinson-White syndrome from a comprehensive analysis of delta waves and R/S ratio during sinus rhythm. Am J Cardiol. 1995;76(1):40–6. S000291499980798X [pii]. 40. Arruda MS, McClelland JH, Wang X, Beckman KJ, Widman LE, Gonzalez MD, et al. Development and validation of an ECG algorithm for identifying accessory pathway ablation site in Wolff-Parkinson-White syndrome. J Cardiovasc Electrophysiol. 1998;9(1):2–12. 41. Katsouras CS, Greakas GF, Goudevenos JA, Michalis LK, Kolettis T, Economides C, et al. Localization of accessory pathways by the electrocardiogram: which is the degree of accordance of three algorithms in use? Pacing Clin Electrophysiol. 2004;27(2): 189–93. 42. d’Avila A, Brugada J, Skeberis V, Andries E, Sosa E, Brugada P. A fast and reliable algorithm to localize accessory pathways based on the polarity of the QRS complex on the surface ECG during sinus rhythm. Pacing Clin Electrophysiol. 1995;18(9 Pt 1):1615–27. 43. Fitzgerald DM, Hawthorne HR, Crossley GH, Simmons TW, Haisty Jr WK. P wave morphology during atrial pacing along the atrioventricular ring. ECG localization of the site of origin of retrograde atrial activation. J Electrocardiol. 1996;29(1):1–10. S0022-0736(96)80105-1 [pii]. 44. Tai CT, Chen SA, Chiang CE, Lee SH, Wen ZC, Chiou CW, et al. A new electrocardiographic algorithm using retrograde P waves for differentiating atrioventricular node reentrant tachycardia from atrioventricular reciprocating tachycardia mediated by concealed accessory pathway. J Am Coll Cardiol. 1997;29(2):394–402. S0735109796004901 [pii]. 45. Borggrefe M, Budde T, Podczeck A, Breithardt G. High frequency alternating current ablation of an accessory pathway in humans. J Am Coll Cardiol. 1987;10(3):576–82. 46. Calkins H, Yong P, Miller JM, Olshansky B, Carlson M, Saul JP, et al. Catheter ablation of accessory pathways, atrioventricular nodal reentrant tachycardia, and the atrioventricular junction: final results of a prospective, multicenter clinical trial. The Atakr Multicenter Investigators Group Circulation. 1999;99(2):262–70. 47. Macias Gallego A, Diaz-Infante E, Garcia-Bolao I. [Spanish catheter ablation registry. 10th official report of the Spanish Society of Cardiology Working Group on Electrophysiology and Arrhythmias (2010)]. Rev Esp Cardiol. 2011;64(12):1147–53. doi:10.1016/j. recesp.2011.08.007. S0300-8932(11)00704-4 [pii]. 48. Morady F. Radio-frequency ablation as treatment for cardiac arrhythmias. N Engl J Med. 1999;340(7):534–44. doi:10.1056/ NEJM199902183400707.
486 49. Zhou S, Qi S, Shen X. [Single-catheter approach to radiofrequency current ablation of accessory pathway in Wolff-Parkinson-White syndrome with recurrent rapid atrial fibrillation]. Hunan Yi Ke Da Xue Xue Bao. 1999;24(4):369–70. 50. Brugada J, Garcia-Bolao I, Figueiredo M, Puigfel M, Matas M, Navarro-Lopez F. Radiofrequency ablation of concealed left freewall accessory pathways without coronary sinus catheterization: results in 100 consecutive patients. J Cardiovasc Electrophysiol. 1997;8(3):249–53. 51. Kuck KH, Schluter M. Single-catheter approach to radiofrequency current ablation of left-sided accessory pathways in patients with Wolff-Parkinson-White syndrome. Circulation. 1991;84(6):2366–75. 52. Chen W, Yao Y, Zhang S, He DS. Comparison of operator radiation exposure during coronary sinus catheter placement via the femoral or jugular vein approach. Europace. 2011;13(4):539–42. doi:10.1093/europace/euq515. euq515 [pii]. 53. Chen SA, Tai CT, Chiang CE, Lee SH, Wen ZC, Chiou CW, et al. Electrophysiologic characteristics, electropharmacologic responses and radiofrequency ablation in patients with decremental accessory pathway. J Am Coll Cardiol. 1996;28(3):732–7. 0735-1097 (96)00219-7 [pii]. 54. Cain ME, Luke RA, Lindsay BD. Diagnosis and localization of accessory pathways. Pacing Clin Electrophysiol. 1992;15(5):801–24. 55. Kobza R, Kottkamp H, Piorkowski C, Tanner H, Schirdewahn P, Dorszewski A, et al. Radiofrequency ablation of accessory pathways. Contemporary success rates and complications in 323 patients. Z Kardiol. 2005;94(3):193–9. 56. Xie B, Heald SC, Camm AJ, Rowland E, Ward DE. Successful radiofrequency ablation of accessory pathways with the first energy delivery: the anatomic and electrical characteristics. Eur Heart J. 1996;17(7):1072–9. 57. Szabo TS, Klein GJ, Guiraudon GM, Yee R, Sharma AD. Localization of accessory pathways in the Wolff-Parkinson-White syndrome. Pacing Clin Electrophysiol. 1989;12(10):1691–705. 58. Bashir Y, Heald SC, Katritsis D, Hammouda M, Camm AJ, Ward DE. Radiofrequency ablation of accessory atrioventricular pathways: predictive value of local electrogram characteristics for the identification of successful target sites. Br Heart J. 1993;69(4): 315–21. 59. Barlow MA, Klein GJ, Simpson CS, Murgatroyd FD, Yee R, Krahn AD, et al. Unipolar electrogram characteristics predictive of successful radiofrequency catheter ablation of accessory pathways. J Cardiovasc Electrophysiol. 2000;11(2):146–54. 60. Silka MJ, Kron J, Halperin BD, Griffith K, Crandall B, Oliver RP, et al. Analysis of local electrogram characteristics correlated with successful radiofrequency catheter ablation of accessory atrioventricular pathways. Pacing Clin Electrophysiol. 1992;15(7): 1000–7. 61. Cappato R, Schluter M, Mont L, Kuck KH. Anatomic, electrical, and mechanical factors affecting bipolar endocardial electrograms. Impact on catheter ablation of manifest left free-wall accessory pathways. Circulation. 1994;90(2):884–94. 62. Chen X, Borggrefe M, Shenasa M, Haverkamp W, Hindricks G, Breithardt G. Characteristics of local electrogram predicting successful transcatheter radiofrequency ablation of left-sided accessory pathways. J Am Coll Cardiol. 1992;20(3):656–65. 07351097(92)90021-E [pii]. 63. Villacastin J, Almendral J, Medina O, Arenal A, Merino JL, Peinado R, et al. “Pseudodisappearance” of atrial electrogram during orthodromic tachycardia: new criteria for successful ablation of concealed left-sided accessory pathways. J Am Coll Cardiol. 1996;27(4):853–9. 0735109795005625 [pii]. 64. Calkins H, Kim YN, Schmaltz S, Sousa J, el-Atassi R, Leon A, et al. Electrogram criteria for identification of appropriate target sites for radiofrequency catheter ablation of accessory atrioventricular connections. Circulation. 1992;85(2):565–73.
B. Campos et al. 65. Jackman WM, Wang XZ, Friday KJ, Roman CA, Moulton KP, Beckman KJ, et al. Catheter ablation of accessory atrioventricular pathways (Wolff-Parkinson-White syndrome) by radiofrequency current. N Engl J Med. 1991;324(23):1605–11. doi:10.1056/ NEJM199106063242301. 66. Jackman WM, Friday KJ, Scherlag BJ, Dehning MM, Schechter E, Reynolds DW, et al. Direct endocardial recording from an accessory atrioventricular pathway: localization of the site of block, effect of antiarrhythmic drugs, and attempt at nonsurgical ablation. Circulation. 1983;68(5):906–16. 67. Jackman WM, Friday KJ, Yeung-Lai-Wah JA, Fitzgerald DM, Beck B, Bowman AJ, et al. New catheter technique for recording left free-wall accessory atrioventricular pathway activation. Identification of pathway fiber orientation. Circulation. 1988;78(3):598–611. 68. Nakao K, Seto S, Iliev II, Matsuo K, Komiya N, Isomoto S, et al. Simultaneous atrial and ventricular pacing to facilitate mapping of concealed left-sided accessory pathways. Pacing Clin Electrophysiol. 2002;25(6):922–8. 69. Nakagawa H, Jackman WM. Catheter ablation of paroxysmal supraventricular tachycardia. Circulation. 2007;116(21):2465–78. doi:10.1161/CIRCULATIONAHA.106.655746. 116/21/2465 [pii]. 70. Twidale N, Wang XZ, Beckman KJ, McClelland JH, Moulton KP, Prior MI, et al. Factors associated with recurrence of accessory pathway conduction after radiofrequency catheter ablation. Pacing Clin Electrophysiol. 1991;14(11 Pt 2):2042–8. 71. Shinbane JS, Lesh MD, Stevenson WG, Klitzner TS, Natterson PD, Wiener I, et al. Anatomic and electrophysiologic relation between the coronary sinus and mitral annulus: implications for ablation of left-sided accessory pathways. Am Heart J. 1998;135(1):93–8. S0002-8703(98)70348-5 [pii]. 72. Deshpande SS, Bremner S, Sra JS, Dhala AA, Blanck Z, Bajwa TK, et al. Ablation of left free-wall accessory pathways using radiofrequency energy at the atrial insertion site: transseptal versus transaortic approach. J Cardiovasc Electrophysiol. 1994;5(3):219–31. 73. Natale A, Wathen M, Yee R, Wolfe K, Klein G. Atrial and ventricular approaches for radiofrequency catheter ablation of left-sided accessory pathways. Am J Cardiol. 1992;70(1):114–6. 74. Hindricks G, Kottkamp H, Chen X, Willems S, Haverkamp W, Shenasa M, et al. Localization and radiofrequency catheter ablation of left-sided accessory pathways during atrial fibrillation. Feasibility and electrogram criteria for identification of appropriate target sites. J Am Coll Cardiol. 1995;25(2):444–51. 073510979400363U [pii]. 75. Swartz JF, Tracy CM, Fletcher RD. Radiofrequency endocardial catheter ablation of accessory atrioventricular pathway atrial insertion sites. Circulation. 1993;87(2):487–99. 76. Jackman WM, Friday KJ, Fitzgerald DM, Bowman AJ, Yeung-Lai-Wai JA, Lazzara R. Localization of left free-wall and posteroseptal accessory atrioventricular pathways by direct recording of accessory pathway activation. Pacing Clin Electrophysiol. 1989;12(1 Pt 2):204–14. 77. Fisher WG, Swartz JF. NASPE Young Investigator Awardee 1992. Three-dimensional electrogram mapping improves ablation of left-sided accessory pathways. Pacing Clin Electrophysiol. 1992;15(12):2344–56. 78. Haissaguerre M, Fischer B, Warin JF, Dartigues JF, Lemetayer P, Egloff P. Electrogram patterns predictive of successful radiofrequency catheter ablation of accessory pathways. Pacing Clin Electrophysiol. 1992;15(11 Pt 2):2138–45. 79. Haissaguerre M, Gaita F, Marcus FI, Clementy J. Radiofrequency catheter ablation of accessory pathways: a contemporary review. J Cardiovasc Electrophysiol. 1994;5(6):532–52. 80. Haghjoo M, Mahmoodi E, Fazelifar AF, Alizadeh A, Hashemi MJ, Emkanjoo Z, et al. Electrocardiographic and electrophysiologic predictors of successful ablation site in patients with manifest posteroseptal accessory pathway. Pacing Clin Electrophysiol. 2008;31(1):103–11. doi:10.1111/j.1540-8159.2007.00933.x. PACE933 [pii].
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Location of Accessory Pathways in WPW: What and How Should We Ablate
81. Takahashi A, Shah DC, Jais P, Hocini M, Clementy J, Haissaguerre M. Specific electrocardiographic features of manifest coronary vein posteroseptal accessory pathways. J Cardiovasc Electrophysiol. 1998;9(10):1015–25. 82. Chiang CE, Chen SA, Tai CT, Wu TJ, Lee SH, Cheng CC, et al. Prediction of successful ablation site of concealed posteroseptal accessory pathways by a novel algorithm using baseline electrophysiological parameters: implication for an abbreviated ablation procedure. Circulation. 1996;93(5):982–91. 83. Pap R, Traykov VB, Makai A, Bencsik G, Forster T, Saghy L. Ablation of posteroseptal and left posterior accessory pathways guided by left atrium-coronary sinus musculature activation sequence. J Cardiovasc Electrophysiol. 2008;19(7):653–8. doi:10.1111/j.1540-8167.2008.01103.x. JCE1103 [pii]. 84. Chiang CE, Chen SA, Yang CR, Cheng CC, Wu TR, Tsai DS, et al. Major coronary sinus abnormalities: identification of occurrence and significance in radiofrequency ablation of supraventricular tachycardia. Am Heart J. 1994;127(5):1279–89. 85. Duong T, Hui P, Mailhot J. Acute right coronary artery occlusion in an adult patient after radiofrequency catheter ablation of a posteroseptal accessory pathway. J Invasive Cardiol. 2004;16(11):657–9. 86. Haissaguerre M, Marcus F, Poquet F, Gencel L, Le Metayer P, Clementy J. Electrocardiographic characteristics and catheter ablation of parahissian accessory pathways. Circulation. 1994;90(3):1124–8. 87. Belhassen B, Viskin S, Fish R, Glick A, Glikson M, Eldar M. Catheterinduced mechanical trauma to accessory pathways during radiofrequency ablation: incidence, predictors and clinical implications. J Am Coll Cardiol. 1999;33(3):767–74. S0735-1097(98)00643-3 [pii]. 88. Yeh SJ, Wang CC, Wen MS, Lin FC, Koo CC, Lo YS, et al. Characteristics and radiofrequency ablation therapy of intermediate septal accessory pathway. Am J Cardiol. 1994;73(1):50–6. 89. Lin JL, Huang SK, Lai LP, Cheng TF, Tseng YZ, Lien WP. Radiofrequency catheter ablation of septal accessory pathways within the triangle of Koch: importance of energy titration testing other than the local electrogram characteristics for identifying the successful target site. Pacing Clin Electrophysiol. 1998;21(10):1909–17. 90. Brugada J, Puigfel M, Mont L, Garcia-Bolao I, Figueiredo M, Matas M, et al. Radiofrequency ablation of anteroseptal, paraHisian, and mid-septal accessory pathways using a simplified femoral approach. Pacing Clin Electrophysiol. 1998;21(4 Pt 1):735–41. 91. Tai CT, Chen SA, Chiang CE, Lee SH, Chang MS. Electrocardiographic and electrophysiologic characteristics of anteroseptal, midseptal, and para-Hisian accessory pathways. Implication for radiofrequency catheter ablation. Chest. 1996;109(3):730–40. 92. Bastani H, Insulander P, Schwieler J, Tabrizi F, Braunschweig F, Kenneback G, et al. Cryoablation of superoparaseptal and septal accessory pathways: a single centre experience. Europace. 2010;12(7):972–7. doi:10.1093/europace/euq079. euq079 [pii]. 93. Kimman GP, Szili-Torok T, Theuns DA, Res JC, Scholten MF, Jordaens LJ. Comparison of radiofrequency versus cryothermy catheter ablation of septal accessory pathways. Heart. 2003;89(9):1091–2. 94. Gaita F, Haissaguerre M, Giustetto C, Grossi S, Caruzzo E, Bianchi F, et al. Safety and efficacy of cryoablation of accessory pathways adjacent to the normal conduction system. J Cardiovasc Electrophysiol. 2003;14(8):825–9. 03076 [pii]. 95. Wong T, Markides V, Peters NS, Davies DW. Clinical usefulness of cryomapping for ablation of tachycardias involving perinodal tissue. J Interv Card Electrophysiol. 2004;10(2):153–8. doi:10.1023/B:JICE.0000019269.96323.d0. 5269600 [pii]. 96. Munger TM, Packer DL, Hammill SC, Feldman BJ, Bailey KR, Ballard DJ, et al. A population study of the natural history of Wolff-Parkinson-White syndrome in Olmsted County, Minnesota, 1953-1989. Circulation. 1993;87(3):866–73. 97. Fitzsimmons PJ, McWhirter PD, Peterson DW, Kruyer WB. The natural history of Wolff-Parkinson-White syndrome in 228 military aviators: a long-term follow-up of 22 years.
98.
99.
100.
101.
102.
103.
104.
105.
106.
107.
108.
109.
110.
111.
112.
487
Am Heart J. 2001;142(3):530–6. doi:10.1067/mhj.2001.117779. S0002-8703(01)18940-4 [pii]. Klein GJ, Bashore TM, Sellers TD, Pritchett EL, Smith WM, Gallagher JJ. Ventricular fibrillation in the Wolff-Parkinson-White syndrome. N Engl J Med. 1979;301(20):1080–5. doi:10.1056/ NEJM197911153012003. Dreifus LS, Haiat R, Watanabe Y, Arriaga J, Reitman N. Ventricular fibrillation. A possible mechanism of sudden death in patients and Wolff-Parkinson-White syndrome. Circulation. 1971;43(4):520–7. Della Bella P, Brugada P, Talajic M, Lemery R, Torner P, Lezaun R, et al. Atrial fibrillation in patients with an accessory pathway: importance of the conduction properties of the accessory pathway. J Am Coll Cardiol. 1991;17(6):1352–6. Timmermans C, Smeets JL, Rodriguez LM, Vrouchos G, van den Dool A, Wellens HJ. Aborted sudden death in the WolffParkinson-White syndrome. Am J Cardiol. 1995;76(7):492–4. S0002914999801362 [pii]. Beckman KJ, Gallastegui JL, Bauman JL, Hariman RJ. The predictive value of electrophysiologic studies in untreated patients with Wolff-Parkinson-White syndrome. J Am Coll Cardiol. 1990;15(3):640–7. 0735-1097(90)90639-7 [pii]. Attoyan C, Haissaguerre M, Dartigues JF, Le Metayer P, Warin JF, Clementy J. Ventricular fibrillation in Wolff-Parkinson-White syndrome. Predictive factors. Arch Mal Coeur Vaiss. 1994;87(7): 889–97. Montoya PT, Brugada P, Smeets J, Talajic M, Della Bella P, Lezaun R, et al. Ventricular fibrillation in the Wolff-ParkinsonWhite syndrome. Eur Heart J. 1991;12(2):144–50. Pappone C, Vicedomini G, Manguso F, Baldi M, Pappone A, Petretta A, et al. Risk of malignant arrhythmias in initially symptomatic patients with Wolff-Parkinson-White syndrome: results of a prospective long-term electrophysiological follow-up study. Circulation. 2012;125(5):661–8. Blomstrom-Lundqvist C, Scheinman MM, Aliot EM, Alpert JS, Calkins H, Camm AJ, et al. ACC/AHA/ESC guidelines for the management of patients with supraventricular arrhythmias–executive summary. a report of the American college of cardiology/ American heart association task force on practice guidelines and the European society of cardiology committee for practice guidelines (writing committee to develop guidelines for the management of patients with supraventricular arrhythmias) developed in collaboration with NASPE-Heart Rhythm Society. J Am Coll Cardiol. 2003;42(8):1493–531. S0735109703011410 [pii]. Leitch JW, Klein GJ, Yee R, Murdock C. Prognostic value of electrophysiology testing in asymptomatic patients with WolffParkinson-White pattern. Circulation. 1990;82(5):1718–23. Pappone C, Santinelli V, Rosanio S, Vicedomini G, Nardi S, Pappone A, et al. Usefulness of invasive electrophysiologic testing to stratify the risk of arrhythmic events in asymptomatic patients with Wolff-Parkinson-White pattern: results from a large prospective long-term follow-up study. J Am Coll Cardiol. 2003;41(2): 239–44. S0735109702027067 [pii]. Klein GJ, Yee R, Sharma AD. Longitudinal electrophysiologic assessment of asymptomatic patients with the Wolff-ParkinsonWhite electrocardiographic pattern. N Engl J Med. 1989;320(19): 1229–33. doi:10.1056/NEJM198905113201901. Chen SA, Chiang CE, Tai CT, Lee SH, Chiou CW, Ueng KC, et al. Longitudinal clinical and electrophysiological assessment of patients with symptomatic Wolff-Parkinson-White syndrome and atrioventricular node reentrant tachycardia. Circulation. 1996;93(11):2023–32. Klein GJ, Gulamhusein SS. Intermittent preexcitation in the Wolff-Parkinson-White syndrome. Am J Cardiol. 1983;52(3):292– 6. 0002-9149(83)90125-X [pii]. Basso C, Corrado D, Rossi L, Thiene G. Ventricular preexcitation in children and young adults: atrial myocarditis as a possible trigger of sudden death. Circulation. 2001;103(2):269–75.
VT Ablation: Importance of Linear Lesions and Late Potentials
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Cristiano Pisani, Sissy Lara Melo, Carina Hardy, and Mauricio Scanavacca
Abstract
A reentrant mechanism related to a ventricular scar is the main mechanism of monomorphic VT in the setting of structural heart diseases. The surviving muscles in the scar areas are the main targets for VT ablation, identified as fragmented and late potentials. Identification of critical fibers involved in the circuit is usually performed during stable VT by using traditional entraining techniques. However, since many patients present hemodynamic instability, nonsustained VTs, or multiple morphologies, substrate mapping during sinus rhythm is an acceptable strategy for such patients. Electroanatomic mapping is an essential tool for identifying the possible channels that are targeted by endocardial and epicardial RF linear lesions. Such strategy produces a marked reduction in VT recurrences being increasingly applied for patients with unmappable VT and may be combined with other mapping approaches in patients with mappable VTs. Keywords
Ventricular tachycardia • Radiofrequency ablation • electroanatomic mapping • cardiomyopathy
Sustained monomorphic ventricular tachycardia (VT) is often a clinical manifestation of structural heart disease and scar-related VT. Fibrosis secondary to myocardial infarction, various cardiomyopathies such as Chagas’ disease, or fibrofatty replacement in arrhythmogenic right ventricular cardiomyopathy (ARVC) creates scar regions that enclose multiple reentry circuits that eventually will generate VT. Morphologic studies consistently demonstrate that the myocardial lesion responsible for VT is characterized by islands of surviving ventricular myocardium embedded into C. Pisani, MD • S.L. Melo, MD, PhD • C. Hardy, MD Arrhythmia Clinical Unit, Heart Institute of the University of São Paulo Medical School, São Paulo, Brazil M. Scanavacca, MD, PhD (*) Arrhythmia Clinical Unit, Heart Institute of the University of São Paulo Medical School, Av Dr Eneas Carvalho de Aguiar 44, São Paulo, SP CEP 05403-000, Brazil e-mail:
[email protected] A.S. Kibos et al. (eds.), Cardiac Arrhythmias, DOI 10.1007/978-1-4471-5316-0_38, © Springer-Verlag London 2014
scar tissue [1]. This heterogeneous, abnormal histopathologic arrangement accounts for the lack of uniform intraventricular conduction in the surviving myocardium but electrophysiologically abnormal myocardial tissue. This phenomenon will create slow regional activation and areas of functional block that will promote reentrant excitation [2]. The main objective of VT ablation is to locate such areas that contain heterogeneity of conduction, eliminating all possible circuits and creating a homogenous scar tissue that does not sustain reentry anymore. There are several mapping techniques used to guide VT ablation. If the VT is well tolerated, it can be mapped during tachycardia. Entrainment mapping, activation mapping, and mapping of isolated diastolic potentials are the most frequently used mapping techniques during tachycardia. However, in most cases, at least one VT morphology is unmappable, either due to hemodynamic instability, the induction of only nonsustained VT, a shift in multiple morphologies (circuits), or failure to induce VT. In a large multicentric VT ablation study in patients with ischemic cardiomyopathy, at least one VT was deemed 489
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mappable in 154 patients (67 %), but just 72 (31 %) had only mappable VTs. The majority of patients had unmappable VTs, with 31 % having only unmappable VTs and 38 % having both mappable and unmappable VTs [3]. In this study, VT was unmappable due to hypotension in 78 % and noninducible or nonsustained VT induced in 22 %. When VT is not mappable due to hemodynamic instability, there are alternatives to allow ablation. Vasoactive drugs such as dobutamine and norepinephrine can be used to increase cardiac output and blood pressure during the mapping procedure. Recently, the introduction of mechanical circulatory support that could allow the VT to be mapped even during hemodynamic instability has been shown to be feasible and safe [4–6]. However, the most common alternative to ablating unmappable VT is to use techniques that allow the abnormal tissue to be ablated during sinus rhythm, the so-called substrate mapping. Surviving muscle bundles, commonly located in the subendocardium but also in the intramyocardium and subepicardium, cross the borders and penetrate deeply in the scar. These bundles are characterized by decreased gap junction density, as well as alterations in their distribution, composition, and function. Increased spatial separation of surviving fibers can be identified, with larger amounts of collagen and connective tissue between bundles. These properties, rather than altered action potential characteristics, contribute to the formation of relatively insulated, slow conduction channels through the scar [7]. Reentry is the main mechanism for scarrelated VT; a reentry circuit is composed by at least two paths connected to a slow conduction area, which occur in the setting of different cardiomyopathy. These slow conduction areas can be identified during sinus rhythm or ventricular pacing by analysis of local bipolar electrograms. Low-amplitude and wide-duration electrograms represent those slow conduction areas [8–10] and are identified during mapping in sinus rhythm. During mapping, we can identify late potentials, which are defined as electrical activity extending beyond the end of the surface QRS complex, and fragmented potentials, which are defined as potentials with more than three deflections. Since most patients have extensive scar areas and most of these electrograms are not related to the VT circuit, there are different techniques to identify which electrograms are related to VT, either using pacemapping, the presence of an isolated diastolic potential, locating the border of the scar using electroanatomical mapping (3D mapping), or the combination of these techniques. Electroanatomical mapping is a computerized system that depicts electrophysiological information (such as the amplitude of the electrogram or its activation timing) as a 3D, color-coded, geometric map of the cardiac chambers. It enables identification of the position of the catheter without fluoroscopy and reconstruction of the recorded data from the catheter location and intracardiac electrograms in real time. There are two main electroanatomical mapping systems. One, the Carto™ System (Biosense Webster), uses ultralow
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magnetic fields to locate a sensor positioned near the tip of a regular mapping and ablation catheter [11]. Another, the Ensite™ System (St Jude Medical), involves placing skin patches on the patient’s chest at six different locations that form pairs of opposing patches arranged along three orthogonal axes, comprising a 3D coordinate system that can be used for catheter location and tracking for geometry creation [12]. The cutoff values for electrogram voltage that define scar or normal tissue on electroanatomical mapping are (1) >1.5 mV, normal muscular tissue; (2) <0.5 mV, densely scarred tissue; and (3) >0.5 mV and <1.5 mV, scar tissue. Those electroanatomical mappings are very important to identify different areas of scar, which allows the physician to apply different approaches for substrate ablation.
Linear Ablation Across the Scar Border The first substrate mapping technique used for catheter ablation was described in 2000 by Marchlinsky and colleagues [13] based on electrophysiologically guided surgical procedures [14]. Linear lesions were placed along the scar area using three guiding principles: (1) lesions would extend across the scar borders of the endocardium that demonstrated abnormal bipolar electrogram voltage; (2) lesions would typically extend from the areas demonstrating the lowest amplitude signals (<0.5 mV) to areas demonstrating a distinctly normal signal or to a valve continuity; and (3) lesions would cross through the border zones at sites where pacemapping approximated the QRS morphology during VT. Once the authors identified the extension and position of the scar using electroanatomical mapping, the mapping catheter was placed along the appropriate scar border, and pacemapping was performed to create a 12-lead ECG that approximated the VT morphology. This step was used since the extent of electrogram abnormalities was large, thus allowing for more precise linear lesions around the scar. Sequential RF ablation points created linear lesions of 3–5 cm lengths along all aspects of the scar border. The RF applied in 16 patients created 1–9 linear lesions (median, 4) with an average of 3.9 cm (range 1.4– 9.4 cm). In 8 of 16 patients, the VT was still inducible after the linear lesions’ application. From these 8 patients with persistent inducible VT, 5 had rapid VTs inducible with double (2 patients) or triple (3 patients) extrastimuli. These VTs did not match the cycle length or morphology of the spontaneous arrhythmias. In the remaining three patients, a slower tachycardia was still inducible. In one of these three patients, the induced VT did not match the spontaneous VT. In the second patient, the VT matched a clinical VT morphology but was slower. The total procedure time ranged from 6.0–13.5 h (mean, 8.8 ± 1.9 h). None of the six patients where LV ejection fraction was measured (mean, 24 ± 6.6 %) had cardiac function deterioration after ablation. One patient experienced a cerebrovascular accident with right-sided hemiparesis at the end of the procedure. At a median follow-up of 8 months, 4 of 16 (25 %) patients presented with VT recurrence.
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VT Ablation: Importance of Linear Lesions and Late Potentials
a
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b
Fig. 38.1 Chagas’ disease (LVEF = 28 %) with recurrent VT; multiple unstable VT morphologies were induced. (a) Electroanatomical mapping and voltage map showing left ventricle infero-basal and
mid-lateral scar; (b) linear ablation was performed across the scar border of the larger infero-basal scar connecting it to the mid-lateral scar
Soejima and colleagues [15] studied in patients with previous myocardial infarction and VT a similar technique combined with limited mapping even if VT was not tolerated. Once the scar was defined with the electroanatomical mapping system, they performed pacemapping to identify the area where the morphology was similar to that of the area in which the VT had been previously induced. Then, they reinduced the VT and performed entrainment mapping, followed immediately by an RF application if the site was defined as close to the reentry isthmus. If the site was not defined as reentry isthmus and VT was not tolerated, they continued with pacemapping followed by VT induction and entrainment mapping. If the site was defined as reentry isthmus and VT interrupted, additional RF lesions were applied during sinus rhythm, extending approximately parallel to the border zone of the scar over 1–2 cm, until pacing at 10 mA at 2-ms stimulus strength failed to locally capture. If the target site was within 2–3 cm of the mitral annulus, lesions were extended to the mitral annulus to interrupt a potential perimitral isthmus. Programmed ventricular stimulation was performed to assess VT inducibility, and if VT was not inducible or only hemodynamically untolerated or faster than previously induced, they terminated the procedure. The procedure was considered successful when no monomorphic VT was induced, modified, or if the VT was induced and was different and faster than the previously induced VT. A failure was defined when the VT remained inducible. They studied 40 patients with ischemic cardiomyopathy and 143 different VTs (average of 3.6 ± 2.1 VTs
per patient, range 1–8). Seven (17.5 %) of 40 patients presented only stable VT that was mapped. All VTs were unstable in 13 patients (32.5 %), and both stable and unstable VTs were present in 20 patients (50 %). The isthmus was identified in 25 patients and an initial 3.5 ± 1.2 cm line (11.6 ± 5.7 lesions) was created through the isthmus. After the initial line was performed, the same VT remained inducible in eight patients, a different VT was inducible in four patients, and no VT was inducible in 13. When the VT isthmus was identified, the recurrence rate was 28 %, at a mean follow-up at 288 ± 224 days. In seven patients with incessant VT, no VT recurred in six; isolated episodes were terminated by a defibrillator in one patient; and in the patients who presented recurrence, the frequency of episodes decreased from 9.4 ± 5.3/month to 0.1 ± 0.3/month after ablation (P = 0.0004). In 15 patients where the VT isthmus was not identified and after the initial line guided by pacemapping (16.1 ± 7.7 lesions over 5.2 ± 2.9 cm) was performed, no VT was inducible in four patients and the same VT was inducible in five. Eight patients (53 %) presented recurrence of some type of VT at a mean follow-up of 349 ± 286 days. Figure 38.1 presents a patient with Chagasic cardiomyopathy and a 28 % ejection fraction with recurrent monomorphic VT. Several unstable VT morphologies were induced and RF applications were delivered across the scar border and areas of late potentials. No VT was induced following programmed ventricular stimulation after ablation.
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Late Potential Ablation Late potentials are fragmented potentials that extend beyond the end of the surface QRS complex. As they are located after the end of the QRS, they are also called diastolic late potentials. Ventricular pacing faster than sinus rhythm creates one activation wave across the ventricles. This condition allows late potentials to be identified easier, since during sinus rhythm a different activation wave may mask these potentials. Arenal and colleagues targeted these potentials to ablate unmappable monomorphic ventricular tachycardias in patients with structural heart disease [16]. A ventricular voltage map was constructed during sinus rhythm and right ventricular apex pacing. Once they found electrograms with isolated delayed components, they tagged them on the map and measured their distance from the scar border. After all maps were completed, in order to correlate a particular isolated delayed component area to the clinical VT, pacemapping was performed, starting at the electrogram showing the latest isolated delayed component. After an identical or similarly paced QRS morphology was identified, they tried to induce VT. They assumed that the isolated potential was related to the VT if presystolic or mid-diastolic electrograms could be observed after the induction, even in the presence of nonsustained or non-tolerated VT. If the VT was not inducible, they used pacemapping to define the relationship between this potential and the VT. When the potential was associated with the VT, they performed RF applications until disappearance of all isolated potentials and non-inducibility. Induced VT was well tolerated in five patients allowing entrainment mapping. Four of 24 patients presented two or three different late potential sites, although the area of these sites was smaller than the area of low voltage (<0.5 mV). Most of the isolated potentials were recorded close to the border of the scar, confirming the importance of this site to the VT circuits. Additionally, most of the isolated potential areas (82.7 %) were correlated to the clinical VT. A mean of 11 ± 8 RF applications were applied per patient, rendering the clinical VT non-inducible in all but one patient. A fast and nonclinical VT was induced in five patients. During a mean follow-up of 9 ± 4 months, five (20.8 %) patients presented any VT recurrence, while in three, the same morphology of clinical VT recurred. Four patients died due to heart failure. The same group tried to identify possible conduction channels based on the bipolar electrograms voltage recorded during electroanatomical mapping [17]. Channels were defined as complete if a corridor of continuous electrograms separated from the surrounding scar or the mitral annulus and higher voltage tissue connected to normal myocardium by at least two sites or incomplete if only one site was
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connected to normal tissue. Once they found a channel, they tried to correlate the channel with VT, either by pacemapping in non-inducible VT or mid-diastolic or presystolic potential identification and entrainment mapping in tolerated or non-tolerated, sustained VT. When the channel was correlated to VT, they delivered RF applications in the channel with the endpoint of VT interruption or non-inducibility. In 26 patients, 23 channels were identified in 20 patients; the length of the channel was 23 ± 9 mm and the width was 9 ± 3 mm. A mean of 14 ± 8 RF lesions were applied in each patient, with a mean of 11 ± 6 RF lesions per channel. At a mean of 17 ± 11 months follow-up, there were seven VT recurrence episodes in six patients (23 %). One patient presented two VT episodes before dying from heart failure. Figure 38.2 depicts a patient with ischemic cardiomyopathy (LVEF: 20 %) presenting with ICD shocks. The endocardial voltage map showed two areas of dense scarring with a channel with late potentials and fragmented signals between them. The VT was induced, showing the exit site in that area, and RF applications were delivered with VT interruption. Additional applications were delivered on the channel between scars. A recent study of prophylactic catheter ablation for prevention of defibrillator therapy [18] studied 128 patients at least 1 month after myocardial infarction who underwent ICD implantation for ventricular fibrillation, unstable VT, syncope with inducible VT, or primary prevention ICD with one appropriate shock. Following inclusion, patients were randomized to “prophylactic” VT ablation or medical treatment. The approach of substrate ablation was employed, and numerous strategies to identify the infarct regions that represented the arrhythmogenic tissue were used to target catheter ablation. One was pacemapping along the scar border defined on electroanatomical mapping; once the exit site was identified, linear transecting ablation lesions were applied. Other strategy used in patients with severe ventricular dysfunction was to target late or fragmented potentials deeper within the scar. If the scar was small with poor pacemapping sites and no late potentials, catheter ablation lesions were placed completely around the scar. During a follow-up of 22.5 ± 5.5 months, eight (12 %) patients in the ablation group and 21 (33 %) in the control group presented (P = 0.007) at least one episode of appropriate shock. No significant difference was observed in total mortality (9 % vs. 17 %; P = 0.29) between groups. Listed complications related to the ablation were: pericardial effusion without tamponade, which was managed conservatively; an exacerbation of congestive heart failure requiring prolonged hospitalization; and a deep venous thrombosis requiring prolonged anticoagulation therapy. Table 38.1 shows the recurrence rate after VT ablation according to the etiology and the ablation strategy.
38
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VT Ablation: Importance of Linear Lesions and Late Potentials
Fig. 38.2 Ischemic cardiomyopathy patient (LVEF = 20 %) with recurrent ICD shocks. (a) Endocardial voltage map showing two areas of dense scarring, with a conduction channel between these; (b) The channel entrance showed an isolated diastolic potential and in the middle, a fragmented signal; (c, d) VT was induced, revealing a presystolic potential in the middle of the channel; (e) Four seconds of RF application interrupted VT, which was non-inducible thereafter
a
b
I II III
c
e
avf V1 V6 add
adp
VDP
VDO
VEP
VED
10 mm/mv 25 mm/s
II
RF
4 seg
d
VEP
VED
-61 RF
Which Strategy Is More Effective for Substrate Mapping?
When to Apply Substrate Mapping for VT Ablation
As previously described, there are different strategies for substrate ablation, either by identifying the scar border and performing linear ablation, linear ablation of critical isthmuses, or targeting late potentials. Although most publications present different strategies for substrate mapping and ablation, the results are similar, with an approximately 30 % recurrence rate during follow-up [13, 16, 17, 19]. Additionally, those strategies have not been compared prospectively, and the outcome differences are not apparent in the literature [1]. One such explanation is that all strategies target similar regions, which are areas of less dense scarring, especially on the scar borders.
The main indication for substrate mapping is when the VT is not mappable, although this approach has been employed in the majority of VT ablation procedures. A large number of patients present some mappable VT; most do not present only mappable VT, either due to hemodynamic instability or nonsustained VT. Therefore, even when a mappable VT is ablated, more VTs can be induced due to scar complexity. After interrupting a VT, one should extend the lesions based on the substrate mapping to prevent other circuits from persisting, thus minimizing the risk of VT recurrence.
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Table 38.1 Main studies on “substrate” and VT ablation Author Strategy Marchlinsky [13] Linear ablation across scar border
Etiology Ischemic and nonischemic Ischemic
N 16
Recurrence 25 %
Follow-up 8 months (median)
40
Isth: 228 ± 224 days NoIsth: 349 ± 246 days 9 ± 4 months
Soejima [15]
Linear ablation guided by VT isthmus or scar map
Arenal [16]
Isolated late potentials during V pacing Channel identification (dechanneling) “Prophylactic” ablation Linear ablation across scar border (pace map) Late potentials VT mapping (mappable) or “substrate” (unmap) VT mapping (mappable) or “substrate” (unmap)
Ischemic, nonischemic Ischemic
24
Isthmus identified: 28 % No isthmus identified: 53 % 20.8 %
26
23 %
17 ± 11 months
Ischemic
128 (64 abl + ICD ;64 ICD)
Abl + ICD: 12 % ICD: 33 %
22.5 ± 5.5 months
Ischemic
231 (unmap 69 %) 47 %
6 months
Ischemic
VT: 22pts Subs: 25
VT: 40 % Substrate: 46 % (NS)
Bunch [4]
VT mapping under hemodynamic support or “substrate” mapping (epic map: 29 %)
Ischemic and nonischemic unstable VT
31
Tanner [27]
VT mapping (mappable) Ischemic or “substrate” (unmap) –22 % only unmap
Hemodynamic support: 45 % Substrate: 52 % (NS) 49 %
VT: 24 ± 12 months Subs: 26 ± 14 months 9 ± 3 months
Arenal [17] Reddy [18]
Stevenson [3] Volkmer [26]
Epicardial Substrate Ablation Epicardial ablation is an approach that has been progressively used in the recent years since percutaneous epicardial access through subxiphoid puncture [20] has been shown feasible in most EP labs [21]. However, substrate mapping and ablation on the epicardial surface can have some limitations. One possible limitation is identifying whether the low amplitude of an electrogram indicates a scar or epicardial fat. In a very interesting paper, Desjardins and colleagues [22] showed that a fat tissue 2.8 mm in thickness resulted in voltage attenuation that mimicked scar in electroanatomical mapping. Briefly, they performed a CT scan to identify and tridimensionally reconstruct epicardial fat. Then, they performed epicardial mapping and ablation in 14 patients with drug refractory ventricular or supraventricular tachycardia who had a previous endocardial ablation failure. In patients without cardiomyopathy, the low-voltage area matched well with the area of epicardial fat. In six patients with nonischemic cardiomyopathy, the low-voltage area by far exceeded the area accounted for by epicardial fat; this corresponded to the presence of scar tissue associated with fat.
63
12 ± 3 months
Another limitation for epicardial substrate ablation is the close proximity of coronary arteries and the phrenic nerve. Once the scar is identified, if a linear ablation is planned, those lines should be shorter compared to endocardial lines, and the electrophysiologist should be aware that coronary arteries (Fig. 38.3) and the phrenic nerve could be injured by RF applications in its proximities. Coronary angiogram prior to RF application and pacing at high output using the ablation catheter to exclude phrenic nerve proximity should be performed prior to energy delivery. If there is proximity to phrenic nerve, some alternatives have been described to manage it [23]. Finally, in patients with previous open-heart surgery, pericardial access could be difficult and when obtained, adhesions could limit catheter movement [24]. In some patients, open surgical access to the pericardium can be done [25]. Conclusions
In general, although there are different strategies for substrate-guided VT ablation, a marked reduction in recurrent VT episodes can be achieved with percutaneous catheter ablation. It is a reasonable approach for patients with unmappable VT and may be combined with other mapping approaches in patients with mappable VTs.
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VT Ablation: Importance of Linear Lesions and Late Potentials
Fig. 38.3 (a) Epicardial mapping and ablation in a patient with Chagas’ disease and latero-basal scar with late potentials on the scar border; (b) VT was induced and epicardial mapping showed an early activation site on the inferolatero-basal portion of the LV; red dots represent epicardial RF applications that interrupted VT. Note a line connecting the interruption area with the late potential area across the scar border; (c) coronary angiogram showing left coronary artery distribution; (d) post-processing of electroanatomical and coronary angiogram images showing that the line was close to the circumflex artery and crossed a marginal branch, with no occlusion of the vessel
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a
b
c
d
References 1. Natale A, Raviele A, Al-Ahmad A, Alfieri O, Aliot E, Almendral J, Breithardt G, Brugada J, Calkins H, Callans D, Cappato R, Camm JA, Della Bella P, Guiraudon GM, Haissaguerre M, Hindricks G, Ho SY, Kuck KH, Marchlinski F, Packer DL, Prystowsky EN, Reddy VY, Ruskin JN, Scanavacca M, Shivkumar K, Soejima K, Stevenson WJ, Themistoclakis S, Verma A, Wilber D, Venice Chart M. Venice Chart International Consensus document on ventricular tachycardia/ventricular fibrillation ablation. J Cardiovasc Electrophysiol. 2010;21(3): 339–79. doi:10.1111/j.1540-8167.2009.01686.x. JCE1686 [pii]. 2. de Bakker JM, van Capelle FJ, Janse MJ, Tasseron S, Vermeulen JT, de Jonge N, Lahpor JR. Slow conduction in the infarcted human heart. ‘Zigzag’ course of activation. Circulation. 1993;88(3):915–26. 3. Stevenson WG, Wilber DJ, Natale A, Jackman WM, Marchlinski FE, Talbert T, Gonzalez MD, Worley SJ, Daoud EG, Hwang C, Schuger C, Bump TE, Jazayeri M, Tomassoni GF, Kopelman HA, Soejima K, Nakagawa H, Multicenter Thermocool VTATI. Irrigated radiofrequency catheter ablation guided by electroanatomic mapping for recurrent ventricular tachycardia after myocardial infarction: the multicenter thermocool ventricular tachycardia ablation trial. Circulation. 2008;118(25):2773–82. doi:10.1161/CIRCULATIONAHA.108.788604. CIRCULATIONAHA.108.788604 [pii].
4. Bunch TJ, Darby A, May HT, Ragosta M, Lim DS, Taylor AM, Dimarco JP, Ailawadi G, Revenaugh JR, Weiss JP, Mahapatra S. Efficacy and safety of ventricular tachycardia ablation with mechanical circulatory support compared with substrate-based ablation techniques. Europace. 2011. doi:10.1093/europace/eur347. eur347 [pii]. 5. Friedman PA, Munger TM, Torres N, Rihal C. Percutaneous endocardial and epicardial ablation of hypotensive ventricular tachycardia with percutaneous left ventricular assist in the electrophysiology laboratory. J Cardiovasc Electrophysiol. 2007;18(1):106–9. doi:10.1111/ j.1540-8167.2006.00619.x. JCE619 [pii]. 6. Abuissa H, Roshan J, Lim B, Asirvatham SJ. Use of the Impella microaxial blood pump for ablation of hemodynamically unstable ventricular tachycardia. J Cardiovasc Electrophysiol. 2010;21(4): 458–61. doi:10.1111/j.1540-8167.2009.01673.x. JCE1673 [pii]. 7. Oza S, Wilber DJ. Substrate-based endocardial ablation of postinfarction ventricular tachycardia. Heart Rhythm. 2006;3(5):607–9. doi:10.1016/j.hrthm.2005.11.018. S1547-5271(05)02352-0 [pii]. 8. Brunckhorst CB, Delacretaz E, Soejima K, Jackman WM, Nakagawa H, Kuck KH, Ben-Haim SA, Seifert B, Stevenson WG. Ventricular mapping during atrial and right ventricular pacing: relation of electrogram parameters to ventricular tachycardia reentry circuits after myocardial infarction. J Interv Card Electrophysiol. 2004;11(3):183–91. doi:10.1023/B:JICE.0000048568.83404.59. 5385293 [pii].
496 9. Buxton AE, Kleiman RB, Kindwall KE, Josephson ME. Endocardial mapping during sinus rhythm in patients with coronary artery disease and nonsustained ventricular tachycardia. Am J Cardiol. 1993;71(8):695–8. 10. Henz BD, do Nascimento TA, Dietrich Cde O, Dalegrave C, Hernandes V, Mesas CE, Leite LR, Cirenza C, Asirvatham SJ, de Paola AA. Simultaneous epicardial and endocardial substrate mapping and radiofrequency catheter ablation as first-line treatment for ventricular tachycardia and frequent ICD shocks in chronic chagasic cardiomyopathy. J Interv Card Electrophysiol. 2009;26(3):195–205. doi:10.1007/s10840-009-9433-4. 11. Shpun S, Gepstein L, Hayam G, Ben-Haim SA. Guidance of radiofrequency endocardial ablation with real-time three-dimensional magnetic navigation system. Circulation. 1997;96(6):2016–21. 12. Krum D, Goel A, Hauck J, Schweitzer J, Hare J, Attari M, Dhala A, Cooley R, Akhtar M, Sra J. Catheter location, tracking, cardiac chamber geometry creation, and ablation using cutaneous patches. J Interv Card Electrophysiol. 2005;12(1):17–22. doi:10.1007/ s10840-005-5837-y. 13. Marchlinski FE, Callans DJ, Gottlieb CD, Zado E. Linear ablation lesions for control of unmappable ventricular tachycardia in patients with ischemic and nonischemic cardiomyopathy. Circulation. 2000;101(11):1288–96. 14. Selle JG, Svenson RH, Sealy WC, Gallagher JJ, Zimmern SH, Fedor JM, Marroum MC, Robicsek F. Successful clinical laser ablation of ventricular tachycardia: a promising new therapeutic method. Ann Thorac Surg. 1986;42(4):380–4. 15. Soejima K, Suzuki M, Maisel WH, Brunckhorst CB, Delacretaz E, Blier L, Tung S, Khan H, Stevenson WG. Catheter ablation in patients with multiple and unstable ventricular tachycardias after myocardial infarction: short ablation lines guided by reentry circuit isthmuses and sinus rhythm mapping. Circulation. 2001;104(6):664–9. 16. Arenal A, Glez-Torrecilla E, Ortiz M, Villacastin J, Fdez-Portales J, Sousa E, del Castillo S, de Perez Isla L, Jimenez J, Almendral J. Ablation of electrograms with an isolated, delayed component as treatment of unmappable monomorphic ventricular tachycardias in patients with structural heart disease. J Am Coll Cardiol. 2003;41(1):81–92. doi:S0735109702026232 [pii]. 17. Arenal A, del Castillo S, Gonzalez-Torrecilla E, Atienza F, Ortiz M, Jimenez J, Puchol A, Garcia J, Almendral J. Tachycardia-related channel in the scar tissue in patients with sustained monomorphic ventricular tachycardias: influence of the voltage scar definition. Circulation. 2004;110(17):2568–74. doi:10.1161/01. CIR.0000145544.35565.47. 01.CIR.0000145544.35565.47 [pii]. 18. Reddy VY, Reynolds MR, Neuzil P, Richardson AW, Taborsky M, Jongnarangsin K, Kralovec S, Sediva L, Ruskin JN, Josephson ME. Prophylactic catheter ablation for the prevention of defibrillator
C. Pisani et al.
19.
20.
21.
22.
23.
24.
25.
26.
27.
therapy. N Engl J Med. 2007;357(26):2657–65. doi:10.1056/ NEJMoa065457. 357/26/2657 [pii]. Soejima K, Delacretaz E, Suzuki M, Brunckhorst CB, Maisel WH, Friedman PL, Stevenson WG. Saline-cooled versus standard radiofrequency catheter ablation for infarct-related ventricular tachycardias. Circulation. 2001;103(14):1858–62. Sosa E, Scanavacca M, d’Avila A, Pilleggi F. A new technique to perform epicardial mapping in the electrophysiology laboratory. J Cardiovasc Electrophysiol. 1996;7(6):531–6. Della Bella P, Brugada J, Zeppenfeld K, Merino J, Neuzil P, Maury P, Maccabelli G, Vergara P, Baratto F, Berruezo A, Wijnmaalen AP. Epicardial ablation for ventricular tachycardia: a European multicenter study. Circ Arrhythm Electrophysiol. 2011;4(5):653–9. doi:10.1161/CIRCEP.111.962217. CIRCEP.111.962217 [pii]. Desjardins B, Morady F, Bogun F. Effect of epicardial fat on electroanatomical mapping and epicardial catheter ablation. J Am Coll Cardiol. 2010;56(16):1320–7. doi:10.1016/j.jacc.2010.04.054. S0735-1097(10)02796-8 [pii]. Di Biase L, Burkhardt JD, Pelargonio G, Dello Russo A, Casella M, Santarelli P, Horton R, Sanchez J, Gallinghouse JG, Al-Ahmad A, Wang P, Cummings JE, Schweikert RA, Natale A. Prevention of phrenic nerve injury during epicardial ablation: comparison of methods for separating the phrenic nerve from the epicardial surface. Heart Rhythm. 2009;6(7):957–61. doi:10.1016/j. hrthm.2009.03.022. S1547-5271(09)00297-5 [pii]. Roberts-Thomson KC, Seiler J, Steven D, Inada K, Michaud GF, John RM, Koplan BA, Epstein LM, Stevenson WG, Tedrow UB. Percutaneous access of the epicardial space for mapping ventricular and supraventricular arrhythmias in patients with and without prior cardiac surgery. J Cardiovasc Electrophysiol. 2010;21(4):406–11. doi:10.1111/j.1540-8167.2009.01645.x. JCE1645 [pii]. Michowitz Y, Mathuria N, Tung R, Esmailian F, Kwon M, Nakahara S, Bourke T, Boyle NG, Mahajan A, Shivkumar K. Hybrid procedures for epicardial catheter ablation of ventricular tachycardia: value of surgical access. Heart Rhythm. 2010;7(11):1635–43. doi:10.1016/j.hrthm.2010.07.009. S1547-5271(10)00700-9 [pii]. Volkmer M, Ouyang F, Deger F, Ernst S, Goya M, Bansch D, Berodt K, Kuck KH, Antz M. Substrate mapping vs. tachycardia mapping using CARTO in patients with coronary artery disease and ventricular tachycardia: impact on outcome of catheter ablation. Europace. 2006;8(11):968–76. doi:10.1093/europace/eul109. 8/11/968 [pii]. Tanner H, Hindricks G, Volkmer M, Furniss S, Kuhlkamp V, Lacroix D, DEC C, Almendral J, Caponi D, Kuck KH, Kottkamp H. Catheter ablation of recurrent scar-related ventricular tachycardia using electroanatomical mapping and irrigated ablation technology: results of the prospective multicenter Euro-VT-study. J Cardiovasc Electrophysiol. 2010;21(1):47–53. doi:10.1111/ j.1540-8167.2009.01563.x. JCE1563 [pii].
Programmed Stimulation During Mapping and Ablation of VT
39
Yaariv Khaykin
Abstract
Ventricular tachycardia and ventricular fibrillation are common causes of sudden death among patients with coronary artery disease and ischemic and nonischemic dilated cardiomyopathy and several other groups of patients. Implantable cardioverter defibrillators help save lives in patients with history of VT, but ICD shocks are painful and are associated with increased morbidity and mortality. While antiarrhythmic medications may lessen the likelihood of arrhythmia requiring shock, many patients do not tolerate these. Catheter ablation results from non-randomized registries, and several recent randomized trials are promising and suggest 70–80 % long-term success. The purpose of this chapter is to address application of electrical stimulation during mapping and ablation of ventricular tachyarrhythmias to aid with diagnosis, treatment verification, and avoidance of collateral injury. Keywords
Ventricular tachycardia • Catheter ablation • Antiarrhythmic therapy • Entrainment mapping
Abbreviations
Introduction
AAD ERP LV PPI QoL TCL VF VT
Prophylactic use of implantable cardioverter defibrillators (ICDs) has been shown to prolong survival in patients with left ventricular dysfunction secondary to ischemic or nonischemic cardiomyopathy [1–4]. Most of this benefit is achieved via lifesaving ICD discharges for ventricular tachycardia or fibrillation (VT/VF) with 8–10 % annual shock rate in large clinical trials [1, 2, 5]. There is now a growing body of evidence that shocks received by the ICD patients may be detrimental to their health and actually increase mortality [5]. ICD shocks have long been known to impair the quality of life in ICD patients [6–8]. Recently, however, all-cause mortality was shown to be higher in ICD patients receiving appropriate or inappropriate shocks and higher for patients with multiple compared to single shocks with hazard ratios ranging from 2 for inappropriate shocks to 6 for appropriate shocks and 11 for any shocks vs none [5, 7, 9, 10]. While there is some evidence for increased fibrosis around the shock coil of the transvenous ICD after shock therapy secondary to electroporation-induced local myocardial
Antiarrhythmic drug Effective refractory period Left ventricle Post pacing interval Quality of life Tachycardia cycle length Ventricular fibrillation Ventricular tachycardia
Y. Khaykin, MD, FRCPC, FACC, FHRS Division of Cardiology, Department of Medicine, Southlake Regional Health Center, Newmarket, Toronto, ON, Canada Faculty of Medicine, University of Toronto, Toronto, ON, Canada Heart Rhythm Program, Southlake Regional Health Centre, 105-712 Davis Drive, Newmarket, Toronto, ON L3Y 8C3, Canada e-mail:
[email protected] A.S. Kibos et al. (eds.), Cardiac Arrhythmias, DOI 10.1007/978-1-4471-5316-0_39, © Springer-Verlag London 2014
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necrosis, there is no clear link between shocks and mortality [11, 12]. Prior evidence suggests that there may be a significant rise in troponin with a transvascular shock [12–15]. Transvascular shocks have also been shown to adversely affect cell calcium uptake, shortening fraction, and contractility [16]. In a meta-analysis of four ICD programming trials [10, 17–19] in 2,135 patients, patients treated with a primary shock vs primary antitachycardia pacing therapy were more likely to die with a 20 % increase in mortality for each shocked episode. In fact, there was no difference in mortality between patients who received ATP for VT vs those who did not have any arrhythmia. For patients with fast VT (FVT, 240 ms < cycle length <330 ms), where episode and therapy effects could be uncoupled, ATP-terminated FVT did not increase episode mortality risk, whereas shocked FVT increased this risk by 32 %. Antiarrhythmic medications and particularly amiodarone may lessen the likelihood of arrhythmia requiring shock, but patients, many of whom develop significant toxicity related to long-term amiodarone exposure, do not always tolerate these. Optimal Pharmacological Therapy in Implantable Cardioverter Defibrillator Patients (OPTIC) trial comparing likelihood of ICD shocks between ICD patients randomized to beta-blockers, sotalol, or a combination of amiodarone and beta-blocker found a significant efficacy gradient with hazard ratios (HR) of getting an appropriate shock of 0.30 for patients treated with amiodarone and a beta-blocker and 0.65 for patients treated with sotalol compared to those treated with beta-blockers alone [20]. Several studies evaluated utility of azimilide, a Class III antiarrhythmic agent against standard medical therapy for ICD therapy reduction. In the Azimilide and Recurrent VT in Patients with ICDs study, hazard ratio (HR) for getting a shock on azimilide was 0.31 vs placebo. This study was followed by the Shock Inhibition Evaluation with Azimilide (SHIELD) study showing HR for getting a shock on azimilide or having an episode of symptomatic arrhythmia of 0.43–0.53 vs placebo [21]. Catheter ablation therapy used to modify arrhythmogenic substrate and reduce the arrhythmia burden has developed over the years to help bridge the gap between ineffective or poorly tolerated medications and the safety net provided by the ICD. VT ablation results from non-randomized registries are promising and suggest initial ablation success in 70–80 % of the patients with 20–25 % long-term VT recurrence rates [22–24]. Several approaches to mapping and ablation of ventricular tachyarrhythmia have gained popularity over the years. These range from tools used to map and target the activation sequence of the arrhythmia, identify the circuit, and modify arrhythmogenic substrate.
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Accordingly the purpose of this chapter is to address application of ventricular stimulation during mapping and ablation of VT/VF across the spectrum of therapeutic strategies and stratified by pacing strategies use to aid in diagnosis, treatment verification, and avoidance of collateral injury.
Diagnosis and Prognosis Identification of the Ventricular Arrhythmia Programmed stimulation is the cornerstone of invasive electrophysiology procedures. It is used to diagnose the arrhythmia, uncover the circuit or multiple circuits, guide prognosis, and ablation. Approach to the diagnostic procedure may vary based on patient presentation and comorbid conditions. Young patients with structural heart disease, no documented coronary artery disease and palpitations, documented wide complex tachycardia, or syncope would typically undergo the full diagnostic procedure, whereby several catheters are typically placed transvenously, at the right ventricular apex, the right atrium, His bundle location, and the coronary sinus. The initial stage in the diagnostic procedure involves differentiating ventricular tachyarrhythmia from supraventricular arrhythmia with aberrant conduction. The latter may be secondary to an accessory pathway or differential refractoriness of the HisPurkinje network, frequently producing wide QRS morphology at high ventricular rates. Refractory periods of the different parts of the conduction system are catalogued; abnormal conduction patterns such as those of the accessory pathways or dual AV nodal physiology are identified. Here single premature extrastimuli are typically delivered after a train of several stimuli at one or more cycle lengths, first in the right ventricle, then the right atrium, and/or the coronary sinus. Stimulation is typically delivered at twice the diastolic threshold with a 1 ms pulse width. Older patients, those with history of coronary artery disease and ischemic, nonischemic, dilated, and hypertrophic cardiomyopathy, may have a more focused diagnostic procedure where programmed stimulation is primarily employed to identify whether or not a ventricular tachyarrhythmia is inducible. Patients in the first group may also undergo this procedure if the first diagnostic portion of the study is unrevealing. Several programmed stimulation protocols have been developed to aid with diagnosis and prognostication of the ventricular arrhythmia. These typically involve delivery of two, three, or more premature extrastimuli following a pacing train as well as burst stimulation down to a predefined limit of 1:1 capture of the paced, chamber, 1:1 conduction, ERP, a set cycle length, or induction of the arrhythmia of interest [4]. Ventricular tachycardia is inducible in 70–90 % of the patients using this approach with 2–3 VT morphologies
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documented per patient in most studies [24]. Burst stimulation can also be helpful in testing conduction across the AV node or the accessory pathway in patients where part of the diagnostic question involves discrimination of a rapidly conducting supraventricular arrhythmia with aberrancy vs ventricular arrhythmia. Here, while a negative electrophysiology study is typically associated with favorable outcomes and a relatively lower risk of sudden cardiac death in several populations of patients, a positive study, where one or more ventricular arrhythmia patterns are identified, may be associated with a greater risk of sudden cardiac death [25, 26]. Historically, only studies culminating in the induction of slower monomorphic ventricular tachycardia have been deemed to identify risk of sudden cardiac death and warrant treatment modification. Recently it was recognized that studies leading to the induction of organized ventricular arrhythmia predict future occurrences of VT, whereas induction of a faster and less organized arrhythmia prognosticates future VF episodes [27]. This latter application of programmed stimulation is an intrinsic part of ICD placement guidelines, helping identification of suitable candidates among patients with ischemic cardiomyopathy and ejection fraction between 30 and 40 % as well as other subsets of patients who are thought to benefit from device therapy. Once arrhythmia is induced, electrical stimulation is frequently used in an attempt to terminate it without having to deliver a shock. Cycle length of the pacing train, which succeeds in terminating VT in the electrophysiology laboratory, can then be used to program antitachycardia pacing therapies in the ICD. In some patients, no arrhythmia can be induced in their basal physiologic state. Here addition of sympathetic stimulation with isoproterenol or adrenaline may help bring out reentrant arrhythmia in patients with ischemic substrate, whereas parasympathetic stimulation with agents such as phenylephrine or head-up tilt, when available, may help bring out arrhythmias dependent on automaticity such as those originating in the outflow tracts.
Guidance of Ablation Once one or more ventricular arrhythmias are catalogued and compared with the clinical arrhythmia, and the decision to proceed with the therapeutic portion of the procedure is made, the operator may choose a strategy based on the type of the arrhythmia.
Activation Mapping Slow, hemodynamically stable VT presents an ideal target for activation mapping of the tachycardia circuit. First a fiduciary point in the activation sequence of the arrhythmia is chosen. One can typically use a sharp inflection point on a
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surface QRS of one of the ECG leads to serve this purpose. A roving mapping catheter or a noncontact array is then used to define the path of electrical activation through one or both ventricles typically using a 3D mapping system. A detailed review of this approach to VT diagnosis and treatment is outside of the scope of this review.
Pacemapping In many circumstances, activation mapping approach is impossible or impractical. In one instance, patients with only a few premature ventricular complexes (PVC) or short runs of non-sustained VT present a difficult target for activation mapping. While noncontact mapping may help identify the source of the PVC, many would instead choose pacemapping as the preferred approach. Once the target PVC is identified, the operator may pace from the tip electrode of the ablation catheter to see whether a pacing here would reproduce clinical PVC morphology. It is important to recognize that unipolar stimulation from the tip of the catheter would produce more accurate results than bipolar stimulation, the latter potentially resulting in anodal capture of the “far-field” myocardium at the proximal ring electrode. Stimulation is usually delivered at 10 mA and 2 ms pulse width, but up or down titration of the stimulus may be required to balance local capture against far-field stimulation. Pacing catheter is then moved around the chamber of interest until the site(s) with best match is/are identified and ablated. A good match represents exact reproduction of the QRS morphology in at least 10 of the 12 leads. A number of specialized tools have been developed by several companies to automate template matching of the paced QRS to that of the target PVC. Bard EP Template Matching algorithm allows the user to mark the target PVC using the recording system (Bard, Lowell, Massachusetts). The algorithm then compares paced QRS morphology with that of the PVC and quantifies %-match for each lead and for the entire 12-lead ECG. The system graphically identifies the ECG vectors displaying best match helping the operator direct the catheter to a better site (Fig. 39.1a). PASO algorithm similarly provides template matching between paced and target PVC, but identifies the pacing site graphically on the 3D map (Biosense Webster, Diamond Bar, California; Fig. 39.1b). When a reentrant rather than an automatic arrhythmia is mapped using this approach, mapping involves not only identification of sites producing the clinical QRS morphology but more importantly finding a subset of these sites with a long conduction time from stimulus to QRS. Slow conduction during pacemapping with stimulus to QRS > 40 ms correlates with a reentry circuit site 70 % of the time [28]. Using 3D navigation, pacemapping could identify 11 of the 13 VT isthmus sites with a perfect match between the paced QRS and VT QRS morphology [29]. Pacing during sinus rhythm from sites later identified to be within the reentrant circuit may not always produce a surface QRS
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Fig. 39.1 Automated algorithms for pacemap matching. (a) Bard EP Template Matching. The recording system displays correlation between a template beat and each paced beat for each ECG lead along with
overall match. (b) Biosense Webster PASO algorithm displays colored tags on a 3D map based on the match between a template and a paced beat for each location
identical to that of the tachycardia. This may have several reasons behind it, including different local activation from a point source stimulus as well as different activation at the exit site, multiple exit sites, and rate-related conduction changes in the substrate resulting in functional conduction block during VT which is not present during stimulation in
sinus rhythm. To better approximate QRS morphology in VT and attempt to reproduce functional block if present, one might pace at a rate close to that of the clinical VT [28]. Unfortunately, in a number of patients, this approach may lead to induction of hemodynamically significant arrhythmia, which may require shock for termination. On the other
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Fig. 39.2 Pacemap matching using ICD electrograms. (a) Correlation between the target VT by 12-lead ECG and ICD electrograms. (b) Tags representing pacemapping sites on a 3D map. Blue tags/line represents the area with perfect match based on the 12-lead ECG. Purple line/yellow tags represent the area of perfect pacemap match by ICD EGM
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hand, in a recent study, Tung and colleagues confirmed that ablation at sites where several PVC/VT morphologies are seen and the arrhythmia is induced during pacemapping confers significantly improved freedom from recurrent VT (74 % vs 42 % at 9 months, p = 0.024) [30]. On many occasions the only record of the VT exists in the ICD log of stored electrograms. Unlike the 12-lead ECG, ICD log provides only one or two vectors – typically a narrow-field and a far-field electrogram. Since the ICD analyzer can be connected to a standard recording system, one can use pacemap matching to correlate paced electrogram as “seen” by the ICD with an ICD electrogram template. Using this approach alone, Yoshida and colleagues were able to get to within 8.9 ± 9.0 cm2 (range 0–35 cm2) of the VT exit site (Fig. 39.2) compared to 2.9 ± 4.0 cm2 (range 0–17.5 cm2) for
the 12-lead ECG in patients with ischemic heart disease and 1.8 cm2 in patients without structural heart disease [31]. In this study, investigators documented reduction in spatial resolution of pacemapping close to the healthy tissue – at the VT exit sites with greater resolution within the scar, suggesting that when guided using this approach, more ablation would have to be delivered to achieve success at the scar border than within the scar.
Substrate Mapping Another group of patients have hemodynamically unstable VT requiring assistive devices to maintain circulation during activation mapping or frank VF not amenable to such an approach altogether. Most of these patients have history of occlusive coronary artery disease and suffer from reentrant
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Fig. 39.3 Entrainment mapping. (a) Schematic of scar with multiple areas of conductions demonstrating response to entrainment pacing at each site. AT activation time (electrogram to QRS onset), PPI post pacing interval, ST stimulus time (pacing stimulus to QRS onset), TCL tachycardia cycle length (Reproduced with permission from Wilber [34]). (b) Illustration of entrainment with PPI within 20 ms of TCL and AT = ST (Courtesy of Dr. John Sapp)
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arrhythmias using a meshwork of conducting tissue interlaced with scar. Several pacing approaches have been developed to help identify pathways of conducting tissue responsible for maintenance of the circuit in these patients.
Entrainment Mapping Classic approach to identification of these isthmuses involves entrainment mapping [32]. Patients must have hemodynamically stable monomorphic arrhythmia for this approach to succeed. Here pacing stimuli are delivered during VT from the mapping catheter around the perimeter of the scar as well as from within the scar at a minimum output required to capture local tissue at a rate slightly faster (10–30 ms) than the arrhythmia. The object of this approach is to take over local activation and to (a) determine latency from stimulation to the surface QRS, (b) compare paced vs intrinsic surface QRS morphology, and (c) measure the difference between the
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tachycardia cycle length and the duration of time it takes for the next tachycardia beat to produce local ventricular activation at the pacing site. During reentrant VT, a stable QRS morphology with resumption of tachycardia on termination of pacing indicates that each stimulated wave front has reset the reentry circuit, entraining the tachycardia. Entrainment can be confirmed by the presence of constant fusion, progressive fusion, or evidence of conduction block terminating tachycardia [33]. Best sites, likely responsible for maintaining the VT circuit, would exhibit all of the following characteristics: they would produce a surface QRS identical to that of the tachycardia termed “concealed” rather than “manifest” entrainment, they would conduct to a paced surface QRS with the greatest latency, and they would activate at or close to the tachycardia cycle length following cessation of pacing (Fig. 39.3) [34]. Once identified, these sites can be ablated with well-recognized excellent clinical results. Likelihood of all vs none of the entrainment criteria having been met predict VT termination with ablation 35 % of the
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time [35]. Concealed entrainment can be demonstrated in about 26 % of the successful ablation sites. Success of ablation at sites with concealed entrainment is 35 % [36]. Paced QRS in sinus rhythm matched VT QRS at 21 % of the sites with concealed entrainment [28] bridging the gap between pacemapping and entrainment. Limitations of this approach include termination of the VT during pacing and the fact that it cannot be applied to non-sustained or hemodynamically unstable arrhythmia. Local potential at the site of stimulation can be difficult to separate from the far-field potentials and is frequently masked by the evoked response during relatively high-output stimulation. Furthermore, success is dependent on the assumption that pacing does not affect conduction through the circuit, which may not always hold true.
Identification of Local Fractionation and Delayed Conduction Another approach involves mapping of the ventricular substrate during sinus or paced ventricular rhythm. Here the mapping catheter is used to roam the chamber of interest and document 3D position and electrical signals at each of the sites [23]. These are manually examined and catalogued as exhibiting normal (>1.5 mV) or low-amplitude (<1.5 mV) potentials [37]. Sites found to contain the latter are then further subdivided into sites that show fractionation or multiple discrete or continuous electrograms vs those that show little activity, pathognomonic of scar. Sites exhibiting fractionated potentials are then examined with respect to timing of onset and offset of local activation with respect to the surface QRS or the ventricular pacing spike as well as duration of local activation and degree of fractionation. Specialized algorithms are currently being developed to help better identify these sites. Paced ventricular rhythm is preferred to normal sinus activation using this approach since it forces conduction through ventricular myocardium, rather than the conduction system. As a result, myocardial conduction, ten times slower than that of the Purkinje system, accentuates delayed local activation and fractionation further. Using this approach, one can label sites exhibiting greater amplitude potentials within the scar tissue and between dense scar and anatomic boundaries and thus forming potential arrhythmia circuits. Sites exhibiting late, prolonged, and continuous local electrical activity form prime suspects for isthmuses responsible for the maintenance of the tachycardia circuit (Fig. 39.4). Once these are annotated, automated or manual propagation maps of local activation during remote ventricular stimulation frequently show areas of local conduction block and slow conduction (Fig. 39.5). These can be also highlighted using isochronal mapping as sites with disparate activation timing despite close anatomical proximity.
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Identification of Conducting Myocardium Within the Scar A third approach to identification of the VT circuit involves direct application of high-output unipolar pacing from the mapping catheter to identify myocardial conduction at sites with low-amplitude potentials suggestive of scar. Distinction between unipolar and bipolar stimulation is an important one, since anodal capture of the “far-field” tissue by the proximal electrode of the distal bipole may make the results of bipolar stimulation invalid. Tissue that cannot be captured has been shown to correlate with dense scar. Areas where local tissue can be captured during electrical stimulation while in sinus rhythm, resulting in conduction out of the scar and global myocardial activation, are labeled as potential VT circuit sites and ablated with the goal of no capture within the scar and between the scar and an anatomic barrier such as the mitral annulus. In one study, pacing at 10 mA and 2 ms pulse width helped differentiate between non-excitable scar and conductive tissue with all VT isthmuses identified next to such scar or within the scar [38]. In another study higheroutput bipolar stimulation at 20 mA and pulse width of up to 10 ms was required to uncover some of the sites representing deep-seated VT isthmus sites [39].
Treatment Verification Once catheter ablation lesions have been delivered, it is important to ascertain acute success of the procedure. In most cases, programmed stimulation is used to see whether any further arrhythmia is inducible. Identification of inducible arrhythmia following ablation is typically associated with worse prognosis with a greater likelihood of recurrent VT. Ablation of all hemodynamically stable inducible VT morphologies correlates with lower arrhythmia recurrence rates and better survival in patients with ischemic VT (Table 39.1) [36, 40–42]. As a result, when a VT induction is performed at the beginning of the case, repeat induction using the same approach, i.e., stimulation at two or more ventricular sites with up to three extrastimuli to achieve effective refractory period (ERP) or down to a predefined lower limit to premature extrastimuli, typically 200 ms, with or without concomitant administration of provocative medication such as isoproterenol or adrenaline. Making sure that the delivered lesions are complete is a problem common to all catheter ablation techniques. Since lesions are not directly visualized, alternate methods to establish permanence of the lesions are necessary. In patients where ablation was guided by identification of sites exhibiting low-amplitude delayed, fractionated, and/or continuous electrograms, repeat substrate mapping during ventricular stimulation is helpful to document disappearance of such sites following ablation. Change in the pacing threshold or
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Fig. 39.4 Substrate mapping. Voltage maps with tags identifying areas of local fractionation. (a) Patient 1. (b) Patient 2
disappearance of tissue capture in an area where capture could previously be demonstrated can also be used to verify successful lesion creation as it denotes elimination of conductive tissue close to the source of the stimulus and therefore a requirement for a greater stimulus to capture tissue further away from the stimulation site. In regions of infarction, the relative change in threshold produced by ablation is nearly threefold, substantially larger than the change in bipolar electrogram amplitude shown to decrease by only 17 % in one study, with no correlation between the change in the local
amplitude and capture threshold [43]. In some cases, ongoing electrical stimulation during ablation lesion delivery can also be used to document acute success at that site. Similarly, in patients where high-output unipolar pacing was used to identify critical isthmus sites within the scar, one should document non-capture within the scar following energy delivery. These tools can be used in combination. For instance where far-field potentials might reduce accuracy of local EGM measurement, high-output stimulation to ascertain local myocardial necrosis following ablation can be helpful.
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Fig. 39.5 Propagation mapping during RV apical stimulation showing an area of slow conduction which correlated with local fractionation. (a) Patient 1. (b) Patient 2
Table 39.1 VT recurrences following ablation depending on the initial success of the procedure Borger van der Burg et al. [42] Della Bella et al. [36] Carbucicchio et al. [40] Rothman et al. [41]
Initial success (%) 22 27 16 9
Initial failure (%) 85 60 78 47
Avoidance of Collateral Injury Apart from its utility in diagnosing ventricular arrhythmia and aiding ablation, pacing may help avoid phrenic injury. There is a large body of literature addressing right phrenic palsy during ablation of supraventricular arrhythmia that requires energy delivery in the vicinity of the right phrenic nerve, such as isolation of the right upper pulmonary vein, particularly with balloon cryoablation, isolation of the superior vena cava, and sinus node modification procedures. As it happens, the left phrenic nerve courses over the lateral aspect of the left ventricle [44]. Many electrophysiologists treating heart failure patients with cardiac resynchronization therapy are familiar with it as a source of diaphragmatic stimulation during left ventricular pacing. This nerve is also important to consider when ablating VT coming from the epicardial surface of the
left ventricle. Patients with nonischemic dilated cardiomyopathy frequently have VT originating in the area close to the nerve [45]. High-output pacing to map the course of the nerve prior to ablation as well as during ablation at sites immediately adjacent to the apparent course of the nerve would help avoid diaphragmatic paralysis in these patients (Fig. 39.6). This is particularly important here since most of these patients may have extensive vfunctional impairment as a result of their cardiomyopathy, and diaphragmatic palsy would negate the benefits derived from extinction of the VT circuit.
Summary Electrical stimulation is an integral tool used in treatment and diagnosis of ventricular tachyarrhythmia. Applications of electrical stimulation range from establishing initial diagnosis and prognosis for the patient, identifying the sites responsible for initiation and maintenance of the arrhythmia, verifying efficacy of the delivered therapy, and avoiding collateral injury during ablation. Pacing may also help establish parameters for antitachycardia pacing used by the ICD to terminate clinical arrhythmia down the road. Thorough understanding of the pacing algorithms and application
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Fig. 39.6 Endocardial and epicardial maps of the left ventricle in a patient with nonischemic cardiomyopathy. Black tags represent the course of the phrenic nerve identified via local diaphragmatic
stimulation with high-output pacing. Blue tags represent areas of fractionation and double potentials
during ablation are of paramount importance to electrophysiologists providing care for patients suffering from or at risk of VT/VF.
9. Poole JE, Johnson GW, Hellkamp AS, Anderson J, Callans DJ, Raitt MH, Reddy RK, Marchlinski FE, Yee R, Guarnieri T, Talajic M, Wilber DJ, Fishbein DP, Packer DL, Mark DB, Lee KL, Bardy GH. Prognostic importance of defibrillator shocks in patients with heart failure. N Engl J Med. 2008;359(10):1009–17. 10. Wilkoff BL, Williamson BD, Stern RS, Moore SL, Lu F, Lee SW, Birgersdotter-Green UM, Wathen MS, Van Gelder IC, Heubner BM, Brown ML, Holloman KK. Strategic programming of detection and therapy parameters in implantable cardioverterdefibrillators reduces shocks in primary prevention patients: results from the PREPARE (Primary Prevention Parameters Evaluation) study. J Am Coll Cardiol. 2008;52(7):541–50. 11. Epstein AE, Kay GN, Plumb VJ, Dailey SM, Anderson PG. Gross and microscopic pathological changes associated with nonthoracotomy implantable defibrillator leads. Circulation. 1998;98(15):1517–24. 12. Hurst TM, Hinrichs M, Breidenbach C, Katz N, Waldecker B. Detection of myocardial injury during transvenous implantation of automatic cardioverter-defibrillators. J Am Coll Cardiol. 1999;34(2):402–8. 13. Runsio M, Kallner A, Kallner G, Rosenqvist M, Bergfeldt L. Myocardial injury after electrical therapy for cardiac arrhythmias assessed by troponin-T release. Am J Cardiol. 1997;79(9):1241–5. 14. Dahl CF, Ewy GA, Warner ED, Thomas ED. Myocardial necrosis from direct current countershock. Effect of paddle electrode size and time interval between discharges. Circulation. 1974;50(5):956–61. 15. Barker-Voelz MA, Van Vleet JF, Tacker Jr WA, Bourland JD, Geddes LA, Schollmeyer MP. Alterations induced by a single defibrillating shock applied through a chronically implanted catheter electrode. J Electrocardiol. 1983;16(2):167–79. 16. Stoddard MF, Labovitz AJ, Stevens LL, Buckingham TA, Redd RR, Kennedy HL. Effects of electrophysiologic studies resulting in electrical countershock or burst pacing on left ventricular systolic and diastolic function. Am Heart J. 1988;116(2 Pt 1):364–70. 17. Wathen MS, Sweeney MO, DeGroot PJ, Stark AJ, Koehler JL, Chisner MB, Machado C, Adkisson WO. Shock reduction using antitachycardia pacing for spontaneous rapid ventricular tachycardia in patients with coronary artery disease. Circulation. 2001;104(7):796–801. 18. Wathen MS, DeGroot PJ, Sweeney MO, Stark AJ, Otterness MF, Adkisson WO, Canby RC, Khalighi K, Machado C, Rubenstein DS, Volosin KJ. Prospective randomized multicenter trial of empirical antitachycardia pacing versus shocks for spontaneous rapid
References 1. Kadish A, Dyer A, Daubert JP, Quigg R, Estes NA, Anderson KP, Calkins H, Hoch D, Goldberger J, Shalaby A, Sanders WE, Schaechter A, Levine JH. Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy. N Engl J Med. 2004;350(21):2151–8. 2. Moss AJ, Zareba W, Hall WJ, Klein H, Wilber DJ, Cannom DS, Daubert JP, Higgins SL, Brown MW, Andrews ML. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med. 2002;346(12):877–83. 3. Moss AJ, Hall WJ, Cannom DS, Daubert JP, Higgins SL, Klein H, Levine JH, Saksena S, Waldo AL, Wilber D, Brown MW, Heo M. Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. Multicenter Automatic Defibrillator Implantation Trial Investigators. N Engl J Med. 1996;335(26):1933–40. 4. Buxton AE, Lee KL, Fisher JD, Josephson ME, Prystowsky EN, Hafley G. A randomized study of the prevention of sudden death in patients with coronary artery disease. Multicenter Unsustained Tachycardia Trial Investigators. N Engl J Med. 1999;341(25):1882–90. 5. Moss AJ, Greenberg H, Case RB, Zareba W, Hall WJ, Brown MW, Daubert JP, McNitt S, Andrews ML, Elkin AD. Long-term clinical course of patients after termination of ventricular tachyarrhythmia by an implanted defibrillator. Circulation. 2004;110(25):3760–5. 6. Mark DB, Anstrom KJ, Sun JL, Clapp-Channing NE, Tsiatis AA, Davidson-Ray L, Lee KL, Bardy GH. Quality of life with defibrillator therapy or amiodarone in heart failure. N Engl J Med. 2008;359(10):999–1008. 7. Irvine J, Dorian P, Baker B, O’Brien BJ, Roberts R, Gent M, Newman D, Connolly SJ. Quality of life in the Canadian Implantable Defibrillator Study (CIDS). Am Heart J. 2002;144(2):282–9. 8. Sears Jr SF, Conti JB. Quality of life and psychological functioning of ICD patients. Heart. 2002;87(5):488–93.
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Programmed Stimulation During Mapping and Ablation of VT ventricular tachycardia in patients with implantable cardioverterdefibrillators: Pacing Fast Ventricular Tachycardia Reduces Shock Therapies (PainFREE Rx II) trial results. Circulation. 2004;110(17):2591–6. Wilkoff BL, Ousdigian KT, Sterns LD, Wang ZJ, Wilson RD, Morgan JM. A comparison of empiric to physician-tailored programming of implantable cardioverter-defibrillators: results from the prospective randomized multicenter EMPIRIC trial. J Am Coll Cardiol. 2006;48(2):330–9. Connolly SJ, Dorian P, Roberts RS, Gent M, Bailin S, Fain ES, Thorpe K, Champagne J, Talajic M, Coutu B, Gronefeld GC, Hohnloser SH. Comparison of beta-blockers, amiodarone plus beta-blockers, or sotalol for prevention of shocks from implantable cardioverter defibrillators: the OPTIC Study: a randomized trial. JAMA. 2006;295(2):165–71. Dorian P, Borggrefe M, Al-Khalidi HR, Hohnloser SH, Brum JM, Tatla DS, Brachmann J, Myerburg RJ, Cannom DS, van der Laan M, Holroyde MJ, Singer I, Pratt CM. Placebo-controlled, randomized clinical trial of azimilide for prevention of ventricular tachyarrhythmias in patients with an implantable cardioverter defibrillator. Circulation. 2004;110(24):3646–54. Kuck KH, Schaumann A, Eckardt L, Willems S, Ventura R, Delacretaz E, Pitschner HF, Kautzner J, Schumacher B, Hansen PS. Catheter ablation of stable ventricular tachycardia before defibrillator implantation in patients with coronary heart disease (VTACH): a multicentre randomised controlled trial. Lancet. 2010;375(9708):31–40. Reddy VY, Reynolds MR, Neuzil P, Richardson AW, Taborsky M, Jongnarangsin K, Kralovec S, Sediva L, Ruskin JN, Josephson ME. Prophylactic catheter ablation for the prevention of defibrillator therapy. N Engl J Med. 2007;357(26):2657–65. Calkins H, Epstein A, Packer D, Arria AM, Hummel J, Gilligan DM, Trusso J, Carlson M, Luceri R, Kopelman H, Wilber D, Wharton JM, Stevenson W. Catheter ablation of ventricular tachycardia in patients with structural heart disease using cooled radiofrequency energy: results of a prospective multicenter study. Cooled RF Multi Center Investigators Group. J Am Coll Cardiol. 2000;35(7):1905–14. Denniss AR, Richards DA, Cody DV, Russell PA, Young AA, Cooper MJ, Ross DL, Uther JB. Prognostic significance of ventricular tachycardia and fibrillation induced at programmed stimulation and delayed potentials detected on the signal-averaged electrocardiograms of survivors of acute myocardial infarction. Circulation. 1986;74(4):731–45. Iesaka Y, Nogami A, Aonuma K, Nitta J, Chun YH, Fujiwara H, Hiraoka M. Prognostic significance of sustained monomorphic ventricular tachycardia induced by programmed ventricular stimulation using up to triple extrastimuli in survivors of acute myocardial infarction. Am J Cardiol. 1990;65(16):1057–63. Daubert JP, Zareba W, Hall WJ, Schuger C, Corsello A, Leon AR, Andrews ML, McNitt S, Huang DT, Moss AJ. Predictive value of ventricular arrhythmia inducibility for subsequent ventricular tachycardia or ventricular fibrillation in Multicenter Automatic Defibrillator Implantation Trial (MADIT) II patients. J Am Coll Cardiol. 2006;47(1):98–107. Stevenson WG, Sager PT, Natterson PD, Saxon LA, Middlekauff HR, Wiener I. Relation of pace mapping QRS configuration and conduction delay to ventricular tachycardia reentry circuits in human infarct scars. J Am Coll Cardiol. 1995;26(2):481–8. Brunckhorst CB, Delacretaz E, Soejima K, Maisel WH, Friedman PL, Stevenson WG. Identification of the ventricular tachycardia isthmus after infarction by pace mapping. Circulation. 2004;110(6):652–9. Tung R, Mathuria N, Michowitz Y, Yu R, Buch E, Bradfield J, Mandapati R, Wiener I, Boyle N, Shivkumar K. Functional pacemapping responses for identification of targets for catheter ablation of scar-mediated ventricular tachycardia. Circ Arrhythm Electrophysiol. 2012;5(2):264–72.
507 31. Yoshida K, Liu TY, Scott C, Hero A, Yokokawa M, Gupta S, Good E, Morady F, Bogun F. The value of defibrillator electrograms for recognition of clinical ventricular tachycardias and for pace mapping of post-infarction ventricular tachycardia. J Am Coll Cardiol. 2010;56(12):969–79. 32. Stevenson WG, Khan H, Sager P, Saxon LA, Middlekauff HR, Natterson PD, Wiener I. Identification of reentry circuit sites during catheter mapping and radiofrequency ablation of ventricular tachycardia late after myocardial infarction. Circulation. 1993;88(4 Pt 1):1647–70. 33. Aliot EM, Stevenson WG, Almendral-Garrote JM, Bogun F, Calkins CH, Delacretaz E, Della Bella P, Hindricks G, Jais P, Josephson ME, Kautzner J, Kay GN, Kuck KH, Lerman BB, Marchlinski F, Reddy V, Schalij MJ, Schilling R, Soejima K, Wilber D. EHRA/HRS Expert Consensus on Catheter Ablation of Ventricular Arrhythmias: developed in a partnership with the European Heart Rhythm Association (EHRA), a Registered Branch of the European Society of Cardiology (ESC), and the Heart Rhythm Society (HRS); in collaboration with the American College of Cardiology (ACC) and the American Heart Association (AHA). Heart Rhythm. 2009;6(6):886–933. 34. Wilber DJ. Catheter ablation of ventricular tachycardia: two decades of progress. Heart Rhythm. 2008;5(6 Suppl):S59–63. 35. Stevenson WG, Stevenson LW, Middlekauff HR, Saxon LA. Sudden death prevention in patients with advanced ventricular dysfunction. Circulation. 1993;88(6):2953–61. 36. Della Bella P, De Ponti R, Uriarte JA, Tondo C, Klersy C, Carbucicchio C, Storti C, Riva S, Longobardi M. Catheter ablation and antiarrhythmic drugs for haemodynamically tolerated post-infarction ventricular tachycardia; long-term outcome in relation to acute electrophysiological findings. Eur Heart J. 2002;23(5):414–24. 37. Marchlinski FE, Callans DJ, Gottlieb CD, Zado E. Linear ablation lesions for control of unmappable ventricular tachycardia in patients with ischemic and nonischemic cardiomyopathy. Circulation. 2000;101(11):1288–96. 38. Soejima K, Stevenson WG, Maisel WH, Sapp JL, Epstein LM. Electrically unexcitable scar mapping based on pacing threshold for identification of the reentry circuit isthmus: feasibility for guiding ventricular tachycardia ablation. Circulation. 2002;106(13):1678–83. 39. Sarrazin JF, Kuehne M, Wells D, Chalfoun N, Crawford T, Boonyapisit W, Good E, Chugh A, Oral H, Jongnarangsin K, Pelosi F, Morady F, Bogun F. High-output pacing in mapping of postinfarction ventricular tachycardia. Heart Rhythm. 2008;5(12):1709–14. 40. Carbucicchio C, Santamaria M, Trevisi N, Maccabelli G, Giraldi F, Fassini G, Riva S, Moltrasio M, Cireddu M, Veglia F, Della Bella P. Catheter ablation for the treatment of electrical storm in patients with implantable cardioverter-defibrillators: short- and long-term outcomes in a prospective single-center study. Circulation. 2008;117(4):462–9. 41. Rothman SA, Hsia HH, Cossu SF, Chmielewski IL, Buxton AE, Miller JM. Radiofrequency catheter ablation of postinfarction ventricular tachycardia: long-term success and the significance of inducible nonclinical arrhythmias. Circulation. 1997;96(10):3499–508. 42. Borger van der Burg AE, de Groot NM, van Erven L, Bootsma M, van der Wall EE, Schalij MJ. Long-term follow-up after radiofrequency catheter ablation of ventricular tachycardia: a successful approach? J Cardiovasc Electrophysiol. 2002;13(5):417–23. 43. Delacretaz E, Soejima K, Brunckhorst CB, Maisel WH, Friedman PL, Stevenson WG. Assessment of radiofrequency ablation effect from unipolar pacing threshold. Pacing Clin Electrophysiol. 2003;26(10):1993–6. 44. Stevenson WG, Soejima K. Catheter ablation for ventricular tachycardia. Circulation. 2007;115(21):2750–60. 45. Cano O, Hutchinson M, Lin D, Garcia F, Zado E, Bala R, Riley M, Cooper J, Dixit S, Gerstenfeld E, Callans D, Marchlinski FE. Electroanatomic substrate and ablation outcome for suspected epicardial ventricular tachycardia in left ventricular nonischemic cardiomyopathy. J Am Coll Cardiol. 2009;54(9):799–808.
Catheter Ablation in Pediatric and Congenital Heart Disease
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Steven B. Fishberger
Abstract
Catheter ablation has proven to be a safe and effective method of treatment for the majority of arrhythmias encountered in the pediatric and congenital heart population. The majority of arrhythmias considered for catheter ablation in the pediatric population with a structurally normal heart are accessory pathway-mediated tachycardia or AV node reentry tachycardia. There are a number of practical matters that must be considered when undertaking catheter ablation in a small child or infant including limitations of vascular access and heart size as it relates to AV nodal and coronary injury. Catheter ablation in patients with significant structural congenital heart disease presents a number of challenges related to complex anatomy, more challenging arrhythmia substrates, and limited vascular access. Innovative techniques and technological advances including the availability of three-dimensional electroanatomic mapping and irrigated ablation catheters have resulted in improved outcomes. Keywords
Congenital heart disease • Pediatrics • Ablation
Catheter ablation of cardiac arrhythmias utilizing radiofrequency energy was introduced in 1989 [1]. The relatively small diameter, flexible catheters that deliver a precise endomyocardial lesion made this an attractive option for the treatment of arrhythmias in pediatric patients. Prior definitive therapies required either open-heart cryoablation or the use of a large-lesion, high-risk, DC catheter ablation [2]. Soon after its introduction, radio-frequency catheter ablation was widely adopted by the majority of pediatric arrhythmia centers [3]. It has proven to be a safe, effective method of treatment for the majority of arrhythmias encountered in the pediatric and congenital heart population. The more recent introduction of catheter-based cryoablation attracted many pediatric electrophysiologists when encountering a septal pathway or AV node reentry tachycardia, as this technique was believed to be a safer alternative [4]. S.B. Fishberger, MD Department of Cardiology, Miami Children’s Hospital, Miami, FL, USA e-mail:
[email protected] A.S. Kibos et al. (eds.), Cardiac Arrhythmias, DOI 10.1007/978-1-4471-5316-0_40, © Springer-Verlag London 2014
Specific Considerations for the Pediatric Patient The overwhelming majority of arrhythmias considered for catheter ablation in the pediatric population with a structurally normal heart are accessory pathway-mediated tachycardia or AV node reentry tachycardia [5]. Other substrates include ectopic atrial tachycardia and either right or left idiopathic ventricular tachycardia. There are a number of factors when determining timing of catheter ablation. One important concern is that the substrate for neonatal arrhythmias due to accessory pathways or ectopic atrial tachycardia often resolves by 1 year of age [6]. Attempts to manage these patients medically are usually successful, and catheter ablation is reserved for those who are refractory despite multiple antiarrhythmic medications or those infants who suffer significant hemodynamic compromise or cardiac arrest during an episode of tachycardia. Severe hemodynamic embarrassment is rarely seen, and when it occurs, typically it is in the setting of complex congenital heart disease. 509
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Beyond the first year of age, there is some debate as to when catheter ablation should be performed. The experience of the operator is an important consideration, as many internal medicine-trained electrophysiologists would consider performing catheter ablation on a teenager, though are uncomfortable in a younger child. There are a number of recommendations that have been applied by the pediatric electrophysiology community with respect to the lower limit for “elective” catheter ablation. Data from the Pediatric Radiofrequency Ablation Registry reported that there is a higher incidence of procedure-related complications in patients less than 15 kg [3]. It has been suggested that smaller patients are at an increased risk for AV block, radio-frequency lesion extension, and injury to vascular structures, both cardiac and noncardiac. However, Blaufox and his colleagues at Medical University of South Carolina reviewed that same registry data and concluded that there was not an increase of total or major complications when comparing infants (≤18 months) with noninfants [7]. The groups at the universities of Michigan and Utah reviewed their institutional data and reported no difference in outcomes comparing those less than 15 kg (mean weight 11.9 kg) and those 15–20 kg (mean weight 18.0 kg) [8]. The minimum cutoff remains controversial as highlighted by the published NASPE (now HRS) Expert Consensus Conference in which the use of radiofrequency catheter ablation in children younger than 5 years of age with SVT refractory to drug therapy, including sotalol and amiodarone, was believed to represent a class IIb indication [9]. Class IIb states that there is “clear disagreement of opinion regarding the benefit or medical necessity of catheter ablation.” There are a number of practical matters that must be considered when undertaking catheter ablation in a small child or infant. The size of the veins may make access more challenging and may limit placement of the preferred number of diagnostic catheters. This can be overcome by a variety of techniques. An esophageal catheter can be used for atrial recording and pacing. Additionally, it provides left-sided signals and therefore serves as a partial substitute for a coronary sinus catheter. In a small child, a multipolar catheter can provide simultaneous signals and pacing from the atria, His bundle, and ventricle. Important landmarks such as the His bundle, coronary sinus ostium, and the AV groove can be identified and tagged using a three-dimensional electroanatomic mapping system. Transseptal puncture requires very controlled entry into the left atrium as it can be quite diminutive. There are reports of using a radio-frequency needle to facilitate transseptal puncture in children [10]. The proximity of the coronary arteries to the AV valve annulus in young patients raises the concern of coronary artery injury [11]. Selective coronary artery angiography has been recommended to better define location when there is a concern [12].
S.B. Fishberger
Specific Consideration for the Patient with Congenital Heart Disease Catheter ablation in patients with significant structural congenital heart disease presents a number of challenges. Prior to ablation, it is essential to have a thorough understanding of the patient’s anatomy, both intracardiac and vascular. Patients with complex congenital heart disease may have limited vascular access for a variety of reasons. Congenital venous anomalies that have been observed include an interrupted inferior vena cava with azygous continuation, a leftsided inferior vena cava, a persistent left superior vena cava to the coronary sinus, and absence of the right superior vena cava. Children that have had prior surgery or catheterizations may have suffered severe stenosis or occlusion of previously utilized vessels. Surgical palliation may result in limited access to cardiac structures due to baffling within the atrium (Senning or Mustard operation), anastomosis of the superior vena cava to the pulmonary arteries (bidirectional Glenn), or a total cavopulmonary anastomosis (Fontan operation). Innovative techniques that overcome these obstacles have been described including transhepatic access, transbaffle approach in an extracardiac Fontan (Fig. 40.1), hybrid catheter approach via a sternotomy, and transthoracic percutaneous access [13–15]. Access to the coronary sinus may also be prevented as a result of surgical intervention. The issues associated with intracardiac anatomy goes well beyond access and catheter course. The location of the His bundle and AV node can vary in the setting of corrected transposition of the great arteries (l-looped ventricles), complete or partial AV canal defect, a ventricular septal defect, and the various types of single ventricle anomalies. The presence of a
Fig. 40.1 Fluoroscopic image of transbaffle approach through a stented Fontan conduit in a patient with dextrocardia. The sheath provided access to perform catheter ablation of AVNRT
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Wolff-Parkinson-White accessory pathway, particularly multiple pathways, is increased in patients with Ebstein’s anomaly of the tricuspid valve, corrected transposition, and hypertrophic cardiomyopathy [16]. Atypical atrial flutter, also referred to as intra-atrial reentry tachycardia, is an arrhythmic sequelae associated with previous Fontan operation and a Senning or Mustard operation [16, 17]. Older children and adults who have had surgical repair of tetralogy of Fallot, severe aortic stenosis, or a Senning or Mustard operation are at risk for ventricular tachycardia [16, 17].
Results, Complications, and Advances The Pediatric Electrophysiology Society, since renamed the Pediatric and Adult Congenital Electrophysiology Society (PACES), recognized the need to track outcomes and the evolution of radio-frequency catheter ablation. In 1990, they established the Pediatric Radiofrequency Catheter Ablation Registry, a voluntary registry accepting reports from all pediatric centers. The registry accumulated a large amount of data on the procedures performed at both high- and lowvolume centers. Results including acute procedural success rates, fluoroscopy time, and complications were reported [18]. Comprehensive data regarding follow-up of pediatric ablation procedures, which was not provided in the registry, was targeted with the initiation of a National-Institute-ofHealth-funded trial entitled Prospective Assessment after Pediatric Cardiac Ablation (PAPCA) [19]. This trial evaluated patients at follow-up with echocardiograms and Holter monitors for 2 years. The trial provided data on success and complication rates in the pediatric population and characterized the incidence of recurrence after initially successful ablation by pathway location. It is important to recognize that the PAPCA enrollment was limited to pediatric patients with normal or trivial structural heart disease, while the registry was open to all pediatric ablation patients, including those with complex congenital heart disease.
third degree), catheter perforation/pericardial effusions, and thromboemboli. The PAPCA data reported an acute overall success rate of 95.7 % that was relatively uniform among pathway locations. However recurrence rates at 1 year for acutely successful ablations varied as a function of accessory pathway location [20]. The highest recurrence rates were noted in right septal (24.6 %) and right free wall pathways (15.8 %), while leftsided pathways recurred at a lower rate (left free wall, 9.3 %; left septal, 4.8 %). There has been an ongoing effort to try to improve acute and long-term success and decrease the complication rates associated with accessory pathway ablation in pediatric patients. These include the use of electroanatomic mapping systems, utilizing a 2 French catheter in the right coronary artery to map right free wall pathways, and computer analysis of intracardiac electrograms to facilitate identifying sites for successful accessory pathway ablation (Fig. 40.2) [21, 22]. Perry and colleagues recommended a number of techniques to avoid AV block during radio-frequency catheter ablation of septal substrates including intubation and apnea during ablation, coronary sinus pacing to monitor AV conduction during junctional ectopy, localizing the optimal His electrogram, not ablating during tachycardia, and titrating power output with temperature monitoring [23]. Fluoroscopy time during catheter ablation has shown a study decline. The Pediatric Radiofrequency Ablation Registry reported mean fluoroscopy time of 50.9 min in the early era compared with 40.1 min in the later era [18]. The introduction of an electroanatomic mapping system (EnSite NavX or CARTO) has resulted in a marked decrease in fluoroscopic times. Papagiannis et al. reported fluoroscopy times of 39.8 min in the standard group compared with 8.3 min when combining fluoroscopy with a nonflouroscopic mapping system (NavX) [24]. Clark has demonstrated the ability to safely and successfully eliminate fluoroscopy by utilizing three-dimensional electroanatomic mapping during pediatric catheter ablation [25].
AV Node Reentry Tachycardia Ablation Accessory Pathway Ablation The Pediatric Radiofrequency Ablation Registry grouped data regarding accessory pathway ablation by an early era (1991–1995) and later era (1996–1999) [18]. The overall ablation failure rates fell from 9.6 % in the early era to 4.8 % in the later era. Success rates improved for left free wall (94 % vs. 97 %), right free wall (85 % vs. 95 %), and posterior septal pathways (87 % vs. 93 %). Significant improvement was not noted for ablation of anterior septal accessory pathways (83 % vs. 86 %). The complication rates for the early and later era were 4.2 and 3 %, respectively. The most common complications included AV block (second and/or
Catheter ablation has been established as a safe and effective method of eliminating tachycardia in children with AV node reentry tachycardia (AVNRT) [19, 26]. Radio-frequency catheter ablation of AVNRT has had widespread application in the pediatric population since 1991 [3]. The acute success rates using this approach have been reported to be as high as 97–100 % [20]. Enthusiasm for this approach has been tempered by reports of permanent AV block of up to 2 % in the pediatric population [19]. Children are considered to be particularly vulnerable to this complication given their smaller heart size and limited area of safety to perform slow pathway ablation.
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Fig. 40.2 Electroanatomic images (RAO and LAO) of a right coronary map of a right free wall accessory pathway
The recent introduction of catheter-based cryoablation has been particularly appealing due to the possibility of AV node recovery during rewarming if AV block is promptly recognized [27–29]. This potential benefit has resulted in many pediatric electrophysiologists utilizing cryoablation as the primary approach when ablating AVNRT. A number of single-center and multicenter studies have favorably compared outcomes and complication rates of radio-frequency ablation to cryoablation of AVNRT in pediatric patients [4, 27–29]. However the recurrence rates using cryoablation remain elevated at 9 % at even the most experienced centers, while a recent manuscript utilizing radio-frequency energy reported no recurrences at follow-up [30]. Assessing ablation efficacy may at times be challenging in the setting of AVNRT. In contrast to accessory pathways, defining a successful ablation in patients with AVNRT is based on the lack of inducibility following a lesion. Induction of AVNRT may be difficult or not reproducible during the course of an electrophysiology study. Additionally, the presence of dual AV node physiology is often not present in pediatric patients with AVNRT [31]. The response of junctional acceleration during a radio-frequency lesion provides an additional method of identifying a successful lesion [32]. This response does not occur during cryoablation lesions. While there are no reports of permanent high-grade AV block using cryoablation, there is a relatively high incidence of transient AV block during cryoablation of AVNRT. One high-volume center reported a 6 % incidence of transient third-degree AV block, while another reported a
26 % incidence of second-degree AV block [28, 30]. There was recovery of AV conduction in all patients, though each center had one patient with permanent first-degree AV block. While this supports the notion that AV node injury due to cryoenergy is often reversible, permanent AV block is theoretically possible. In fact, the first reports of AV node ablation utilized a cryosurgical technique [33]. The trend is to use larger-tip cryocatheters which may decrease recurrence rates, though the delivery of a larger lesion may increase the risk of creating permanent AV block [34].
Ablation of Atrial Arrhythmias Ectopic Atrial Tachycardia Ectopic atrial tachycardia arises from an automatic focus within either atrium separate from the sinus node. The arrhythmia typically occurs in children with structurally normal hearts, frequently is incessant, and may result in tachycardia-induced cardiomyopathy. The natural history and response to antiarrhythmic therapy has been reported to vary with age. Children less than 3 years of age are more likely than older children to experience spontaneous resolution (78 % vs. 16 %) and achieve arrhythmia control with medication (91 % vs. 37 %) [6]. Successful catheter ablation of the ectopic focus has improved over time with reported acute success rates of
40 Catheter Ablation in Pediatric and Congenital Heart Disease
94 %. Mapping and ablation has been facilitated by the use of three-dimensional electroanatomic mapping systems. In contrast to many adult patients, this arrhythmia typically cannot be triggered by atrial pacing maneuvers and requires spontaneous tachycardia or at least atrial ectopy to provide an ablation target. This may not be present, particularly under general anesthesia, though the infusion of isoproterenol or the use of single-beat mapping with the balloon-array noncontact system (Ensite, St. Jude Medical, Minneapolis, MN) may provide an opportunity for successful ablation.
Atrial Flutter Atrial flutter, also referred to as intra-atrial reentry tachycardia, is the most common type of atrial arrhythmia in patients with repaired congenital heart disease. This macroreentry atrial arrhythmia typically involves regions of surgical scar, fibrosis, and anatomic barriers [34]. The prevalence of atrial flutter is highest after either an atrial repair of transposition of the great arteries (Mustard or Senning technique) or after the Fontan repair but may occur following a number of intracardiac surgical repairs [16]. Treatment with a number of antiarrhythmic agents has failed to demonstrate long-term efficacy. The atrial-flutter circuit following a Mustard or Senning operation usually courses in the isthmus between the tricuspid valve and the inferior vena cava (IVC), similar to typical atrial flutter in the adult without congenital heart disease [17]. However, accessing the width of the isthmus for catheter ablation is less straightforward, since the intra-atrial baffle which separates the systemic and venous flow prevents direct catheter access via the IVC to the tricuspid valve. Ablating across the full tricuspid valve-IVC isthmus requires either approaching the isthmus from both below the baffle via the IVC and above the baffle retrograde through the aortic valve and right ventricle or with a transseptal procedure across the baffle. Additional circuits may be found by the atriotomy scar, the region of the superior vena cava, or around the mitral annulus [35]. Ablation of atrial flutter in patients following the Fontan operation has proven to be extremely difficult with initial results reporting success rates of approximately 60 % with a greater than 50 % recurrence rate [36]. Challenges facing the interventional electrophysiologist include the presences of multiple circuits or potential circuits, the increased thickness of the atrial myocardium, and the markedly enlarged atrium that must be mapped, particularly in the early version of the Fontan operation. The Fontan operation evolved from a direct atrial pulmonary connection to an intra-atrial baffle to the most recent approach, an extracardiac conduit. While the earliest technique theoretically and practically resulted in a greater incidence of atrial flutter, the development of atrial
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flutter has been shown to be related to the duration of followup [37]. There has been a gradual improvement in the reported success rates of atrial flutter ablation in this population as a result of a better understanding of how to target the circuits, as well as technological advancements that have enhanced mapping and the creation of ablation lesions [38]. The three-dimensional mapping systems have provided the ability to create an electroanatomic map; identifying regions of conduction block (scar and natural barriers) and slowly conducting tissue produce activation maps of the atrial flutter circuits and form images that mark the areas where ablation lesions have been delivered. Pacing maneuvers have helped to identify the circuit through entrainment and measurements of post-pacing intervals [39]. The use of tip cooling of the ablation catheter, typically with an irrigated catheter, has provided the ability to create larger, deeper lesions [40]. Cooling allows for the application of more power to the tip, which causes deeper tissue heating. The combination of these advancements has resulted in acute success rates of up to 90 % with a recurrence rate of only 30 % [17].
Ablation of Ventricular Tachycardia Right Ventricular Outflow Tract Tachycardia Right ventricular outflow tract tachycardia is an automatic tachycardia that occurs in children and adolescents with structurally normal hearts [41]. It tends to be hemodynamically well tolerated and may not cause significant symptoms until the development of tachycardia-induced cardiomyopathy. This arrhythmia is often well controlled with beta blockers or calcium channel blockers, and there is a significant incidence of spontaneous resolution in the pediatric population. Success rates for catheter ablation are very good and further enhanced by the use of three-dimensional mapping systems [42]. As with ectopic atrial tachycardia, one of the biggest challenges faced during ablation of this arrhythmia is the lack of spontaneous ventricular ectopy while the patient is under general anesthesia. Along with the use of isoproterenol and single-beat mapping, pace mapping may be used to identify potential successful targets. It is important to recognize that an arrhythmia that may have the typical appearance of a right ventricular outflow tract origin may actually arise from the left ventricular outflow tract or the region of the coronary cusps of the aortic valve.
Idiopathic Left Ventricular Tachycardia Idiopathic left ventricular tachycardia is also found in the pediatric patient with a structurally normal heart. It is hemodynamically well tolerated though its paroxysmal nature and
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Pulmonary valve
RVOT patch (transannular) TA
[10/11] 2 [4/11]
TA 1 [11/11]
1
3 TA
[11/11] 4 [3/11] RV incision VSD patch
Fig. 40.3 Illustration of lesion set for substrate ablation of ventricular tachycardia in patients with repaired tetralogy of Fallot
rapid rates tend to result in symptoms of palpitations. This arrhythmia is often verapamil sensitive and may be misinterpreted as supraventricular tachycardia. In contrast to right ventricular outflow tract tachycardia, spontaneous resolution is uncommon. Catheter ablation can be very effective with either the region of the left posterior or left anterior fascicle targeted, depending on the site of origin. A Purkinje potential should be identified during tachycardia and/or during sinus rhythm [43]. It is important to distinguish these potentials from the His bundle electrogram, which can be very prominent along the left septal region. Termination of tachycardia and the inability to reinduce tachycardia following ablation are the standard methods of determining procedural efficacy. However, induction may also be difficult in this population and therefore an alternative endpoint is to create either left posterior or anterior hemiblock during ablation.
Tetralogy of Fallot Ventricular tachycardia following surgical repair of tetralogy of Fallot is a function of multiple factors. These include the underlying disease substrate, the progression of right ventricular hypertrophy and dilation, ventricular dysfunction, and the presence of multiple surgically created scars required for repair [17]. The primary approach has been to initially address any residual hemodynamic problems; however recent data has demonstrated that this may not eliminate the risk of ventricular tachycardia [44]. Implantation of an ICD is strongly advised to prevent sudden cardiac death, as medication and catheter ablation may not provide adequate protection. Those patients who have recurrent symptomatic
ventricular tachycardia or multiple ICD discharges are candidates for catheter ablation. Mapping of the arrhythmia circuit can be performed in a method similar to that described for atrial flutter; however this may not be hemodynamically tolerated. Alternatively, substrate mapping can be performed to identify potential circuits, and ablation lines can be created to bridge regions of structural and functional block (Fig. 40.3) [45]. The use of a three-dimensional electroanatomic mapping system and the irrigated catheters may enhance the efficacy of the ablation procedure. Conclusion
The remarkable success and relative safety of catheter ablation has provided the opportunity to cure many pediatric arrhythmias. Catheter ablation of arrhythmias associated with congenital heart disease has proven to be more challenging; however ongoing improvements in arrhythmia mapping, lesion delivery, and hemodynamic support will continue to result in improved outcomes.
References 1. Jackman WM, Wang XZ, Friday KJ, Roman CA, Moulton KP, Beckman KJ, et al. Catheter ablation of accessory atrioventricular pathways (Wolff-Parkinson-White syndrome) by radiofrequency current. N Engl J Med. 1991;324:1605–11. 2. Gallagher JJ, Sealy WC, Anderson RW, Kassel J, Millar R, Campbell RW, et al. Cryosurgical ablation of accessory atrioventricular connections: a method for correction of the pre-excitation syndrome. Circulation. 1977;55:471–9. 3. Kugler JD, Danford DA, Deal BJ, Gillette PC, Perry JC, Silka MJ, et al. Radiofrequency catheter ablation for tachyarrhythmias in children and adolescents. N Engl J Med. 1994;330:1481–7.
40 Catheter Ablation in Pediatric and Congenital Heart Disease 4. Kirsh JA, Gross GJ, O’Connor S, Hamilton RM. Transcatheter cryoablation of tachyarrhythmias in children: initial experience from an international registry. J Am Coll Cardiol. 2005;45:133–6. 5. Kugler JD, Danford DA, Houston K, Felix G. Radiofrequency catheter ablation for paroxysmal supraventricular tachycardia in children and adolescents without structural heart disease. Am J Cardiol. 1997;80:1438–43. 6. Salerno JC, Kertesz NJ, Friedman RA, Fenrich Jr AL. Clinical course of atrial ectopic tachycardia is age dependent: results and treatment in children < 3 or > or = 3 years of age. J Am Coll Cardiol. 2004;43:438–44. 7. Blaufox AD, Felix GL, Saul JP, Pediatric Catheter Ablation Registry. Radiofrequency catheter ablation in infants
515
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
free-wall accessory pathways. J Cardiovasc Electrophysiol. 2009;20:526–9. Ceresnak SR, Gates GJ, Nappo L, Cohen HW, Pass RH. Novel method of signal analysis for ablation of Wolff-Parkinson-White Syndrome. Heart Rhythm. 2012;9:2–7. Pecht B, Maginot KR, Boramanand NK, Perry JC. Techniques to avoid atrioventricular block during radiofrequency catheter ablation of septal tachycardia substrates in young patients. J Interv Card Electrophysiol. 2002;7:83–8. Papagiannis J, Avramidis D, Alexopoulos C, Kirvassilis G. Radiofrequency ablation of accessory pathway in children and congenital heart disease patients: impact of a nonflouroscopic navigation system. Pacing Clin Electrophysiol. 2011;34:1288–96. Smith G, Clark JM. Elimination of flouroscopy use in a pediatric electrophysiology laboratory utilizing three-dimensional mapping. Pacing Clin Electrophysiol. 2007;30:510–8. Strieper MJ, Frias P, Goodwin N, Huber G, Costello L, Balfour G, et al. Radiofrequency modification for inducible and suspected pediatric atrioventricular nodal reentry tachycardia. J Interv Card Electrophysiol. 2005;13:139–43. Collins KK, Dubin AM, Chiesa NA, Avasarala K, Van Hare GF. Cryoablation versus radiofrequency ablation for treatment of pediatric atrioventricular nodal reentrant tachycardia: initial experience with 4-mm cryocatheter. Heart Rhythm. 2006;3:564–70. Avari JN, Jay KS, Rhee EK. Experience and results during transition from radiofrequency ablation to cryoablation for treatment of pediatric atrioventricular nodal reentrant tachycardia. Pacing Clin Electrophysiol. 2008;31:454–60. Khairy P, Novak PG, Guerra PG, Griess I, Macle L, Roy D, et al. Cryothermal slow pathway modification for atrioventricular nodal reentrant tachycardia. Europace. 2007;9:909–14. Fishberger SB, Whalen R, Zahn EM, Welch EM, Rossi AF. Radiofrequency ablation of pediatric AV nodal reentrant tachycardia during the ice age: a single center experience in the cryoablation era. Pacing Clin Electrophysiol. 2009;33:6–10. Burton DJ, Dubin AM, Chiesa NA, Van Hare GF, Collins KK. Characterizing dual atrioventricular nodal physiology in pediatric patients with atrioventricular nodal reentrant tachycardia. J Cardiovasc Electrophysiol. 2006;17:638–44. Jentzer JH, Goyal R, Williamson BD, Man KC, Niebauer M, Daoud E, et al. Analysis of junctional ectopy during radiofrequency ablation of the slow pathway in patients with atrioventricular nodal reentrant tachycardia. Circulation. 1994;90:2820–6. Harrison L, Gallagher JJ, Kasell J, Anderson RH, Mikat E, Hackel DB, et al. Cryosurgical ablation of the A-V node-His bundle: a new method for producing A-V block. Circulation. 1977;55:463–70. Silver ES, Silva JN, Ceresnak SR, Chiesa NA, Rhee EK, Dubin AM, et al. Cryoablation with an 8-mm tip catheter for pediatric atrioventricular nodal reentrant tachycardia is safe and efficacious with a low incidence of recurrence. Pacing Clin Electrophysiol. 2010;33:681–6. Love BA, Collins KK, Walsh EP, Triedman JK. Electroanatomic characterization of conduction barriers in sinus/atrially paced rhythm and association with intra-atrial reentrant tachycardia circuits following congenital heart disease surgery. J Cardiovasc Electrophysiol. 2001;12:17–25. Kannankeril PJ, Anderson ME, Rottman JN, Wathen MS, Fish FA. Frequency of late recurrence of intra-atrial reentry tachycardia after radiofrequency catheter ablation in patients with congenital heart disease. Am J Cardiol. 2003;92:879–81. Fishberger SB, Wernovsky G, Gentles TL, Gauvreau K, Burnett J, Mayer JE, et al. Factors influencing the development of atrial flutter following the Fontan operation. J Thorac Cardiovasc Surg. 1997;113:80–6. Triedman JK, Alexander ME, Love BA, Collins KK, Berul CI, Bevilacqua LM, et al. Influence of patient factors and ablative
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39.
40.
41. 42.
S.B. Fishberger technologies on outcomes of radiofrequency ablation of intra-atrial re-entrant tachycardia in patients with congenital heart disease. J Am Coll Cardiol. 2002;39:1827–35. Triedman JK, Alexander ME, Berul CI, Bevilacqua LM, Walsh EP. Electroanatomic mapping of entrained and exit zones in patients with repaired congenital heart disease and intra-atrial reentrant tachycardia. Circulation. 2001;103:2060–5. Blaufox AD, Numan MT, Laohakunakorn P, Knick B, Paul T, Saul JP. Catheter tip cooling during radiofrequency ablation of intraatrial reentry: effects on power, temperature, and impedance. J Cardiovasc Electrophysiol. 2002;13:783–7. Plammatter JP, Paul T. Idiopathic ventricular tachycardia in infancy and childhood. J Am Coll Cardiol. 1999;33:2067–72. Laohakunakorn P, Paul T, Knick B, Blaufox AD, Long B, Saul JP. Ventricular tachycardia in nonpostoperative pediatric patients: role
of radiofrequency catheter ablation. Pediatr Cardiol. 2003;24: 154–60. 43. Nakagawa H, Beckman KJ, McClelland JH, Wang X, Arruda M, Santoro I, et al. Radiofrequency catheter ablation of idiopathic left ventricular tachycardia guided by a Purkinje potential. Circulation. 1993;88:2607–17. 44. Harrild DM, Berul CI, Cecchin F, Geva T, Gauvreau K, Pigula F, et al. Pulmonary valve replacement in tetralogy of Fallot: impact on survival and ventricular tachycardia. Circulation. 2009;119:445–51. 45. Zeppenfeld K, Schalij MJ, Bartelings MM, Tedrow UB, Koplan BA, Soejima K, et al. Catheter ablation of ventricular tachycardia after repair of congenital heart disease: electroanatomic identification of the critical right ventricular isthmus. Circulation. 2007;116:2241–52.
41
Interventional Electrophysiology in Patients with Congenital Heart Disease Sissy Lara Melo, Cristiano Pisani, Eduardo Sosa, and Mauricio Scanavacca
Abstract
In the last decade, radio-frequency catheter ablation of atrial and ventricular tachycardia has become progressively common, driven predominantly by increasing success and low complication rates. At the same time, there was no significant development in antiarrhythmic drug effectiveness that still present limited efficacy and frequent side effects. As patients with congenital heart disease that have undergone surgical repair or palliation have been getting older, a wide variety of rhythm disturbances have been detected. Although electrophysiological procedures often are problematic due to the complex anatomy of such patients, a high level of success can be achieved with careful attention to surgical history and modern imaging technology. Thus, nowadays, interventional electrophysiological techniques play a major role in their management. Keywords
Congenital heart disease • atrial flutter • ventricular tachycardia • Radiofrequency ablation Cardiac arrhythmias often complicate the evolution of patients with congenital heart disease. Its management is an important clinical challenge, because cardiac dysfunction is common, leading to increased hemodynamic intolerance of individuals to arrhythmia and limits the use of antiarrhythmic drugs [1]. In addition, congenital heart defects are associated with disturbances in the formation and conduction of the stimulus, particularly in patients that underwent surgical treatment, another limiting factor for the use of antiarrhythmic drugs. Antiarrhythmic agents exacerbate sinus node dysfunction, a common problem in patients with extensive surgery in the atrial tissue. In these patients, the need for permanent pacemaker implantation is not uncommon [2]. For these reasons, catheter ablation is an important tool in the management of these patients.
Congenital heart defects (CHD) occur in roughly 0.8 % of live births, and in 30–50 % of these cases, the malformations are severe enough to warrant at least one surgical procedure during early childhood [3]. Table 41.1 lists the main types of CHD in order of prevalence along with an estimate of the relative risk for specific arrhythmias in each condition (Table 41.1). Table 41.1 Relative risk for specific arrhythmias in common congenital heart defects IART + + ++
AF
WPW
VT/SCD +
S.L. Melo, MD, PhD • C. Pisani, MD • E. Sosa, MD, PhD Arrhythmia Clinical Unit, Heart Institute of the University of São Paulo Medical School, São Paulo, SP, Brazil
VSD ASD TOF AS D-TGA(M&S) CAVC SING V(F) L-TGA Ebstein’s anomaly
M. Scanavacca, MD, PhD (*) Arrhythmia Clinical Unit, Heart Institute of the University of São Paulo Medical School, Av Dr Eneas Carvalho de Aguiar 44, São Paulo, SP 05403-000, Brazil e-mail:
[email protected]
IART reentrant atrial tachycardia, AF atrial fibrillation, WPW WolfParkinson-White syndrome, SCD sudden cardiac death, VSD ventricular septal defect, ASD atrial septal defect, TOF tetralogy of Fallot, AS aortic stenosis, M&S after Mustard or Senning operation, CAVC common AV canal defect, SINGV(F) single ventricle after the Fontan operation, +++ high risk, ++ moderate risk, and + slight risk
A.S. Kibos et al. (eds.), Cardiac Arrhythmias, DOI 10.1007/978-1-4471-5316-0_41, © Springer-Verlag London 2014
+ ++ ++ ++
+ +++ + +++ + ++
+ ++ +++
+ + +
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Chronic myocardial hypoxia
Overload pressure and volume
RV dysfunction
Wall stress
Scars of atriotomy and ventriculotomy
Valvular dysfunctions and VSD
Myocardial fibrosis
Substrate for reentry atrial and ventricular
Fig. 41.1 Mechanisms of arrhythmia in patients with congenital heart disease
Pathophysiology A congenital anatomical substrate, such as the presence of accessory atrioventricular conduction pathways (WPW syndrome) or acquired as a scar caused by surgical incision, is an important pathophysiological mechanism of cardiac arrhythmias in patients with CHD. Clinical studies indicate that 20–37 % of patients with Wolff-Parkinson-White additionally present structural heart disease [4, 5]. Now, when analyzing data from patients with structural heart disease, the presence of accessory pathways occurs in 26 % of patients with Ebstein’s anomaly, which often presents multiple accessory pathways [5]. However, chamber dilatation by pressure or volume overload and scar or conduction system disturbances related to surgical suture are functional substrates to cardiac arrhythmias in this setting of patients (Fig. 41.1). Consequently, patients with a history of surgical correction of congenital heart disease are always at risk to develop cardiac arrhythmia, which implies a significant increase in morbidity and mortality in this population. Senning and Mustard surgeries for transposition of great vessels and the Fontan operation for various forms of functional single ventricle are the most frequent examples of this. Another important issue for this population is the risk of recurrent syncope and even sudden cardiac death. The main mechanism is the high ventricular response to atrial arrhythmia caused by hemodynamic compromise that leads to induction of ventricular tachycardia and/or ventricular fibrillation [6]. The changes in surgical techniques lead to a decreased incidence of arrhythmias in the subgroups of patients, such as those undergoing surgical correction of transposition of great vessels with Jatene’s technique, since in this technique there are no surgical incisions in the atrial tissue [7]. Another example is the Fontan technique, in which a cavopulmonary shunt is created. It should be noted that this technique makes it difficult to ablate future atrial arrhythmias due to the exclusion of the atrial chamber’s venous system [8].
The coexistence of severe congenital heart disease with cardiac arrhythmias presents a major challenge when ablation is considered [1]. The main challenge is the technical difficulty of accessing the heart chambers due to the congenital defect itself or surgical correction of it. Additionally, this population presents an inadequate hemodynamic reserve, due to severe structural heart disease, leading to cardiovascular intolerance during sustained episodes of tachycardia, which usually does not occur in people without structural heart disease. Patients with cardiac arrhythmias that require surgical correction of congenital heart defects should be evaluated regarding arrhythmia risk before surgery. This is because the occurrence of arrhythmia in the early postoperative period, in general, is poorly tolerated. It should be treated before or during surgery [1]. For example, a patient at our institution with Ebstein’s anomaly presented symptoms of palpitation with no arrhythmia registration or evidence of pre-excitation on ECG. He underwent an electrophysiological study before surgery with demonstration of posteroseptal right accessory pathway and induction of sustained atrioventricular tachycardia. After ablation of the accessory pathway, the patient underwent surgical repair of Ebstein’s anomaly without postoperative complications. In other situations, depending on the surgical technique, accessing the chamber related to the tachycardia is difficult. As an example, a patient with single ventricle and paroxysmal supraventricular tachycardia with an indication of surgical correction. In this case, the technique consisted of performing programmed Fontan with a side tube. As described in the literature [8], this technique has the lowest incidence of atrial tachycardia on late follow-up. However, once this occurs, it will be more difficult to access the right atrium. Anticipating this, the patient underwent electrophysiological study before the surgery, which showed the presence of dual AV node with the induction of reentrant tachycardia involving both structures. Once the accessory AV node was ablated, the patient underwent the previously scheduled surgical repair. Unfortunately, the patient had recurrence of arrhythmia in the postoperative period that had been controlled with drugs. Therefore, those cases require an observation period to evaluate the result of the ablation. Alternatively, a new electrophysiological study should be performed to document the effectiveness of the procedure before performing the surgical correction for definitive anatomic to prevent such an occurrence. Surgery performed simultaneously with the arrhythmia treatment of congenital heart disease is a strategy used by some specialized services that have surgeons skilled in the treatment of cardiac arrhythmias. Even in these cases, we perform an electrophysiological study before surgical correction and try to ablate the tachycardia in order to decrease the surgical time and minimize complications. We only select the cases of failed percutaneous ablation to simultaneous arrhythmia surgery.
41 Interventional Electrophysiology in Patients with Congenital Heart Disease
As previously discussed, patients with congenital heart disease that have undergone surgical correction are at risk for the development of atrial arrhythmias. The progressive dilations of the chambers, due to the long-lasting pressure and volume overload associated with the creation of anatomical barriers by scar by vena cava cannulation, atrial incision, or interposition of plaque in the atrium, are elements that are related to macroreentrant, the main mechanism of these tachycardias. Another important aspect is the association of the occurrence of atrial arrhythmia with significant morbidity and mortality in the population undergoing surgical correction of congenital heart disease [3]. Some studies have shown that the risk of sudden death in this population is 6–10 %, being related to the association of the tachycardia with hemodynamic collapse or thromboembolic complications [9]. Recently, a published paper by Sing-Chien Yap et al. [10] demonstrated that patients with congenital heart disease associated with atrial tachycardia possessed a higher risk of sudden death when they had one or more risk factors such as poor functional class (NYHA III or IV), single ventricle physiology, pulmonary hypertension, or valvular heart disease.
Electrocardiographic Diagnosis It is important to note that the atrial tachycardia occurring in patients with congenital heart disease usually has a long cycle reentry causing a rapid ventricular response with a conduction ratio of 2:1 or even 1:1 in the absence of medication. In addition, we must remember that most patients have a borderline ventricular function causing debilitating symptoms in this group. Symptoms of hypotension and syncope are common, with reports of 1:1 conduction degenerating into ventricular fibrillation [11]. Sometimes, the electrocardiographic diagnosis of atrial tachycardia becomes difficult because of rapid AV conduction. In these cases, vagal maneuvers or adenosine infusion could help in the diagnosis.
Ablation Techniques With rare exceptions, atrial tachycardia originates in the right atrium in patients with congenital heart disease. This is easily seen in the group that underwent surgical repair of an atrial or ventricular septal defect or a tetralogy of Fallot. In these patients, the caval return to the right atrium occurs in the normal way and the cavotricuspid isthmus (CTI) exists. Most reentrant circuits found in the atrium of these patients did not fundamentally differ from the typical atrial flutter, and they can be ablated using the usual maneuver for the conduction block using the CTI [6]. Although atriotomy scars occasionally involve the circuit along the wall of the right atrium, it is common that these scars work only as
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modulators of functional flutter isthmus, leading the circuit to run over the lateral side of the tricuspid annulus. This is less common when faced with a complex atrial anatomy. For example, patients who underwent Mustard or Senning surgery in which the vena cava flow is directed to the mitral annulus through a big atrial patch. Because of this surgical arrangement, the critical segment of the right atrium containing the CTI is located on the systemic circulation. Although, the CTI continues to be the most likely location of the reentrant circuit, in order to reach this region of the atrium to perform the ablation, the catheter needs to be positioned in the left heart through a “transbaffle” puncture or by retrograde aortic access [12]. Certainly, the most complex trial circuit and anatomy occur in patients with a single ventricle. The surgery used to correct this anatomic defect consists of various modifications of the Fontan operation to direct the flow of the right atrium directly to the pulmonary arteries. In this condition, there is generally no atrioventricular valve into the right atrium and the cavotricuspid isthmus is not present. Alternatively, the reentrant circuit will propagate through areas of fibrosis through the atriotomy scar, atrial septal patch, or the region of the anastomosis with the pulmonary artery (Fig. 41.2). Natural barriers, such as crista terminalis and upper hole and lower vena cava, can also influence the circuit [13]. In this population, it is not rare to find multiple reentrant circuits, leading to very difficult ablation procedures. If a patient starts the procedure in sinus rhythm, it is mandatory to induce the clinical arrhythmia to determine the mechanism and the circuit. Despite previous reports showing the CTI participation in the arrhythmia circuit, we must not forget that is possible for the scar to be related to the reentrant circuit, generating a circuit of eight. In our laboratory, we noted that many times the atrial arrhythmia is CTI dependent; however, when it is blocked, there is a slower atrial arrhythmia, and new maneuvers show a reentrant circuit around the scar of atriotomy. Radio-frequency application from the border of the scar to the inferior vena cava causes interruption of the arrhythmia. The technique used to induce atrial tachycardia in this group of patients consists of continuous rapid atrial pacing until 2:1 atrial capture in different sites of the atria and following isoproterenol infusion. It has proved to be more effective than pacing with extrastimuli. It is essential to use techniques and entrainment extrastimuli during tachycardia to establish the differential diagnosis of tachycardia with accessory pathways and atrioventricular nodal reentrant tachycardia. Note that induction of atrial fibrillation in these patients is not rare, even with far less-aggressive protocols. We must emphasize that the detailed study of the anatomy of the patient before RF ablation, as well as the previous study of vascular access in patients with arrhythmias associated with congenital heart disease, with or without surgical treatment, is of paramount importance. This becomes mandatory in patients with previous Senning, Mustard, and
520 Fig. 41.2 A 23-year-old patient with single ventricle, who underwent a surgical correction with Fontan-Kreutzer technique (atrial-pulmonary shunt) when he was a year old, was referred to catheter ablation due to incessant atrial and important ventricular dysfunction. Procedure was performed with electroanatomic system (Carto 3) assistance. Anatomic reconstruction of right atrium surface on AP (a) and RAO (b) projection shows enlarged RA and the tube communicating the RA and pulmonary artery. The voltage mapping showed a large scar on the posterior and lateral surface of the RA. Atrial tachycardia activation mapping (c) demonstrated fragmented signals and a channel of slow-conducting area through the scar. RF applications on the gap of the dense scar (d) interrupted the atrial tachycardia. Additional RF pulses were delivered to eliminate fractionated and delayed electrograms close to the scar
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Fontan surgery. The reports of the surgical technique used to correct the defect are important to locate the patches and suture lines, which might serve as a substrate for the reentrant circuit. Another important issue is the need to accurately obtain the actual location of the bundle, avoiding damage even when approaching the atrial arrhythmia. This is important, especially in patients with congenital malformation with AV discordance, because it can present a distorted location of the conduction system. Electroanatomic mapping is an important technical resource for ablation of patients with tachycardia associated
b
d
to congenital heart disease. Its use allows better understanding of the complex anatomy and the mechanisms involved. Before its use, the expected success rate was around 60 %. Following its introduction and association with new ablation catheters, such as the irrigation system and longer electrodes, success rates of 90 % for termination of tachycardia and no induction in the end of the procedure could be achieved [14]. However, during a longer follow-up of patients with surgical Fontan, a recurrence rate of around 40 % was observed after 2 years [14]. Patients with two ventricles and less abnormal anatomy present a less frequent recurrence rate of 20 % [14]. Although the recurrence rate is
41 Interventional Electrophysiology in Patients with Congenital Heart Disease
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high, the results are superior compared to clinical treatment only, which presents a recurrence rate of 70 % at 2 years and could be associated with the adverse effects of antiarrhythmic drugs.
population with congenital heart disease and surgical repair because attempting to identify a marker with high sensitivity and specificity for primary prevention in this population is an enormous challenge.
Prevention of the Occurrence of Atrial Arrhythmia
Electrocardiographic Diagnosis
Several factors can be implemented to achieve a lower incidence of atrial tachycardia in the congenital heart disease population. The main method consists of early surgical treatment, as well as some changes in surgical techniques, which will minimize harm to the atrial tissue and the sinus node. For example, changing the surgical technique of Mustard and Senning to the new approach that handles only the blood vessels and the new approach of lateral Fontan, which directs the flow of cava directly to the pulmonary artery [8].
Ablation of Ventricular Tachycardia While considering the tetralogy of Fallot as atypical archetype of lesions in which the ventricular tachycardia occurs in patients with congenital heart disease, ventricular arrhythmias might occur in other kinds of congenital malformations, even in the absence of surgical correction. Some examples include transposition of the great arteries (D or L) when the right ventricle is responsible for the systemic circulation, severe Ebstein’s anomaly, and some forms of single ventricle. The same pathophysiology presented to explain atrial arrhythmias above can be used to understand the occurrence of ventricular tachycardia in patients with congenital heart disease, with or without prior surgical correction. A chronic exposure to volume and pressure overload as well as a history of surgery in patients with congenital heart disease is related to myocardial scarring and fibrosis, which is the main substrate for ventricular tachycardia. The incidence of ventricular tachycardia in patients with tetralogy of Fallot is 11.9 %, and after 35 years of follow-up, there is an 8.3 % risk of sudden death in this same population [15]. A study published by Khairy et al. [16] created a risk score for patients with tetralogy of Fallot who underwent surgical correction. In this work, the authors postulated that the patients who presented the following: (1) previous palliative shunt (2 points), (2) sustained ventricular tachycardia induced on EP study (2 points), (3) QRS duration ≥ 180 ms (1 point), (4) right ventriculotomy incision (2 points), (5) non-sustained VT (2 points), and (6) LVEDP ≥ 12 mmHg (3 points) present low risk of sudden death if the sum is less than 2, intermediate risk between 3 and 5, and high risk between 6 and 12. Several studies try to assess the best way to stratify the risk of sudden death in the
The diagnosis of ventricular tachycardia is given by the presence of wide QRS tachycardia in the presence of AV dissociation on the surface EKG. Although most patients present with VT circuit related to the RV outflow tract, the morphology of the QRS is often not indicative of this site. As described by Horton et al. [17], the morphology of the QRS during VT will depend on the direction of the rotation (clockwise or counterclockwise) around the circuit, as the isthmus is comprised between the right ventricular outflow tract patch and the tricuspid annulus. The tachycardias that have a clockwise rotation have a negative QRS in DI and biphasic in V1, while patients with a counterclockwise rotation presented a QRS morphology of positive DI and completely negative in V1 (LBBB morphology) [17].
Ablation Techniques and Electroanatomic Mapping Electrophysiological studies performed in patients with ventricular tachycardia and a history of surgical repair of tetralogy of Fallot have demonstrated that the basic mechanism of the tachycardia is a macro-reentry involving the outflow tract of the right ventricle at the site of ventriculotomy, which is performed on the anterior wall of the right ventricle or right at the patch placed to correct the ventricular septal defect. The success rate in a series of 30 patients with surgical correction of tetralogy of Fallot who underwent two procedures of sustained ventricular tachycardia ablation was 89 % and the recurrence rate was 20 %. Another series of 11 patients who also sustained ventricular tachycardia and surgical correction of tetralogy of Fallot in that the strategy was substrate mapping and ablation presented an acute success rate of 100 %, with a 9 % recurrence rate after a mean follow-up of 30 months [18]. Several mapping strategies have been described, including activation sequence analysis and entrainment maneuvers. Electroanatomic systems with substrate mapping could also be useful in patients with hemodynamically tolerated VT. Zeppenfeld et al. [19] published an interesting study demonstrating the use of electroanatomic mapping to create a substrate mapping during sinus rhythm and identified the location of important isthmus related to sustained ventricular tachycardia in patients with congenital heart disease. They initially created a bipolar voltage map of the right ventricle, and areas that presented a dense scar and patch location were confirmed by
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Pulmonary valve
RVOT patch (transannular) TA
[10/11] 2 [4/11]
TA 1 [11/11]
1
3 TA
[11/11] 4 [3/11] RV incision VSD patch
Fig. 41.3 Schematic of the localization of anatomic boundaries (blue lines) for VT after repair of CHD and the resulting anatomic isthmuses (red lines); frequency of the distinct isthmuses in brackets (Reproduced from Zeppenfeld et al. [19] with permission)
the loss of capture after high-energy stimulation. The presence of four isthmuses responsible for VT in the population with tetralogy of Fallot was reported (1) between the tricuspid annulus and scar or patch of the anterior wall of the RVOT, (2) between the pulmonary annulus and the scar or patch on the RV free wall, (3) between the pulmonary annulus and septal scar or patch, and (4) among the scar or patch and septal tricuspid annulus (Fig. 41.3). This approach allowed the study of patients with clinical-sustained VT, but not inducible in the EP lab or hemodynamic unstable during the arrhythmia, since the lesions could be based on the substrate during sinus rhythm. We have a case in which a child with previous surgical correction of tetralogy of Fallot and ICD implantation, with many appropriate ICD shocks, underwent invasive electrophysiological study with no VT induction during the procedure. Consequently, RF applications were delivered based on substrate mapping connecting the tricuspid annulus and RVOT. In a follow-up after 2 years, the child had not presented any appropriate ICD therapy since the ablation. Another important consideration in this group is the need for using irrigated tip catheters or longer distal electrodes to generate a deeper lesion, since the patients with pressure overload and pulmonary insufficiency often present an increased thickness of the myocardium as evidenced by the research of Zeppenfeld et al. [19].
Summary The number of patients with congenital heart diseases requiring treatment of cardiac arrhythmias is increasing. Clinical management of these patients is still a challenge, and with
the new era of tools for percutaneous mapping and ablation, catheter ablation is a promising treatment for this population. However, one must not forget that the evolutionary characteristics of these pathologies will require a close follow-up of patients to identify those in risk of sudden cardiac death to be selected to ICD implantation.
References 1. Van Hare GF, Lesh MD, Stanger P. Radiofrequency catheter ablation of supraventricular arrhythmias in patients with congenital heart disease: results and technical considerations. J Am Coll Cardiol. 1993;22(3):883–90. 0735-1097(93)90207-H [pii]. 2. Fish FA, Gillette PC, Benson Jr DW. Proarrhythmia, cardiac arrest and death in young patients receiving encainide and flecainide. The Pediatric Electrophysiology Group. J Am Coll Cardiol. 1991; 18(2):356–65. 3. Hoffman J. Incidence, mortality, and natural history. In: Anderson RHBE, McCarthy FJ, Rigby ML, Shinebourne EA, Tynan M, editors. Paediatric cardiology, vol. 1. 2nd ed. London: Churchill Livingstone; 2002. p. 111–40. 4. Saul JP, Walsh EP, Triedman JK. Mechanisms and therapy of complex arrhythmias in pediatric patients. J Cardiovasc Electrophysiol. 1995;6(12):1129–48. 5. Attenhofer Jost CH, Connolly HM, Edwards WD, Hayes D, Warnes CA, Danielson GK. Ebstein’s anomaly - review of a multifaceted congenital cardiac condition. Swiss Med Wkly. 2005;135 (19–20):269–81. smw-10985 [pii] 2005/19/smw-10985. 6. Triedman J. Atrial reentrant tachycardias. In: Walsh EPSJ, Triedman JK, editors. Cardiac arrhythmias in children and young adults with congenital heart disease. Philadelphia: Lippincott Williams & Wilkins; 2001. p. 137–60. 7. Rhodes LA, Wernovsky G, Keane JF, Mayer Jr JE, Shuren A, Dindy C, Colan SD, Walsh EP. Arrhythmias and intracardiac conduction after the arterial switch operation. J Thorac Cardiovasc Surg. 1995;109(2):303–10. S0022-5223(95)70392-6 [pii].
41 Interventional Electrophysiology in Patients with Congenital Heart Disease 8. Collins KK, Rhee EK, Delucca JM, Alexander ME, Bevilacqua LM, Berul CI, Walsh EP, Mayer JE, Jonas RA, del Nido PJ, Triedman JK. Modification to the Fontan procedure for the prophylaxis of intra-atrial reentrant tachycardia: short-term results of a prospective randomized blinded trial. J Thorac Cardiovasc Surg. 2004;127(3):721–9. doi:10.1016/S0022. S0022522303010559 [pii]. 9. Stephenson EA, Batra AS, Knilans TK, Gow RM, Gradaus R, Balaji S, Dubin AM, Rhee EK, Ro PS, Thogersen AM, Cecchin F, Triedman JK, Walsh EP, Berul CI. A multicenter experience with novel implantable cardioverter defibrillator configurations in the pediatric and congenital heart disease population. J Cardiovasc Electrophysiol. 2006;17(1):41–6. doi:10.1111/j.1540-8167.2005. 00271.x. JCE271 [pii]. 10. Yap SC, Harris L, Chauhan VS, Oechslin EN, Silversides CK. Identifying high risk in adults with congenital heart disease and atrial arrhythmias. Am J Cardiol. 2011;108(5):723–8. doi:10.1016/ j.amjcard.2011.04.021. S0002-9149(11)01605-5 [pii]. 11. Rhodes LA, Walsh EP, Gamble WJ, Triedman JK, Saul JP. Benefits and potential risks of atrial antitachycardia pacing after repair of congenital heart disease. Pacing Clin Electrophysiol. 1995;18(5 Pt 1):1005–16. 12. Perry JC, Boramanand NK, Ing FF. “Transseptal” technique through atrial baffles for 3-dimensional mapping and ablation of atrial tachycardia in patients with d-transposition of the great arteries. J Interv Card Electrophysiol. 2003;9(3):365–9. 5148058 [pii]. 13. Collins KK, Love BA, Walsh EP, Saul JP, Epstein MR, Triedman JK. Location of acutely successful radiofrequency catheter ablation of intraatrial reentrant tachycardia in patients with congenital heart disease. Am J Cardiol. 2000;86(9):969–74. S00029149(00)01132-2 [pii]. 14. Triedman JK, Alexander ME, Love BA, Collins KK, Berul CI, Bevilacqua LM, Walsh EP. Influence of patient factors and ablative
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16.
17.
18.
19.
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technologies on outcomes of radiofrequency ablation of intraatrial re-entrant tachycardia in patients with congenital heart disease. J Am Coll Cardiol. 2002;39(11):1827–35. S07351 09702018582 [pii]. Karamlou T, Silber I, Lao R, McCrindle BW, Harris L, Downar E, Webb GD, Colman JM, Van Arsdell GS, Williams WG. Outcomes after late reoperation in patients with repaired tetralogy of Fallot: the impact of arrhythmia and arrhythmia surgery. Ann Thorac Surg. 2006;81(5):1786–93. doi:10.1016/j.athoracsur.2005.12.039; discussion 1793. S0003-4975(05)02285-X [pii]. Khairy P, Harris L, Landzberg MJ, Viswanathan S, Barlow A, Gatzoulis MA, Fernandes SM, Beauchesne L, Therrien J, Chetaille P, Gordon E, Vonder Muhll I, Cecchin F. Implantable cardioverter-defibrillators in tetralogy of Fallot. Circulation. 2008; 117(3):363–70. doi:10.1161/CIRCULATIONAHA.107.726372. CIRCULATIONAHA.107.726372 [pii]. Horton RP, Canby RC, Kessler DJ, Joglar JA, Hume A, Jessen ME, Scott WP, Page RL. Ablation of ventricular tachycardia associated with tetralogy of Fallot: demonstration of bidirectional block. J Cardiovasc Electrophysiol. 1997;8(4): 432–5. Rostock T, Willems S, Ventura R, Weiss C, Risius T, Meinertz T. Radiofrequency catheter ablation of a macroreentrant ventricular tachycardia late after surgical repair of tetralogy of Fallot using the electroanatomic mapping (CARTO). Pacing Clin Electrophysiol. 2004;27(6 Pt 1):801–4. doi:10.1111/j.1540-8159.2004.00531.x. PACE531 [pii]. Zeppenfeld K, Schalij MJ, Bartelings MM, Tedrow UB, Koplan BA, Soejima K, Stevenson WG. Catheter ablation of ventricular tachycardia after repair of congenital heart disease: electroanatomic identification of the critical right ventricular isthmus. Circulation. 2007;116(20):2241–52. doi:10.1161/CIRCULATIONAHA.107. 723551. CIRCULATIONAHA.107.723551 [pii].
Epicardial Mapping and Ablation of Cardiac Arrhythmias
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Robert Lemery
Abstract
Epicardial mapping and ablation of cardiac arrhythmias has been an important development in interventional electrophysiology. The fibrous and serous pericardia are separated by a space that permits introduction of a guide wire using a subxiphoid percutaneous approach. There are two major sinuses in the pericardial space. A sheath advanced over the guide wire provides a mean to introduce one or more catheters or probes to perform mapping and ablation epicardially. Atrial arrhythmias that require epicardial mapping and ablation include unusual types of atrial tachycardia or accessory pathways. In patients with atrial fibrillation or atypical atrial flutter, epicardial mapping and ablation may be required to obtain isolation or elimination of atrial substrate. In patients with ischemic heart disease and left ventricular dysfunction, as well as in patients with dilated cardiomyopathy, or with infiltrative or unusual forms of heart disease, ventricular tachycardia may originate epicardially or require epicardial mapping prior to performing endocardial ablation. There are numerous considerations requiring safety and management of patients undergoing epicardial mapping and ablation. Newer surgical and hybrid procedures, from the collaboration of electrophysiology and surgery, may also provide new approaches to performing interventional electrophysiology procedures that may require epicardial mapping and ablation. Keywords
Cardiac Mapping • Epicardial • Atrial fibrillation • Ventricular tachycardia • Supraventricular tachycardia
In patients with the Wolff-Parkinson-White syndrome, surgical ablation of accessory pathways was shown to be successful both endocardially and epicardially [1, 2]. The development of catheter ablation allowed for percutaneous endocardial mapping and ablation of cardiac arrhythmias [3], although percutaneous epicardial delivery of low-energy DC in the coronary sinus [4] was initially shown to be safe and effective at eliminating left-sided accessory pathways, followed later by use of irrigated
R. Lemery, MD Division of Cardiology, University of Ottawa Heart Institute, Ottawa, ON K1Y-4W7, Canada e-mail:
[email protected] A.S. Kibos et al. (eds.), Cardiac Arrhythmias, DOI 10.1007/978-1-4471-5316-0_42, © Springer-Verlag London 2014
radiofrequency current [5]. Epicardial mapping and ablation of ventricular tachycardia using percutaneous access to the pericardial space was reported in 1996 [6], in patients with cardiomyopathy associated with Chagas disease.
Anatomic Features and Access to the Pericardial Space The parietal (outer) or fibrous pericardium encloses the heart, and this most outer layer merges and is continuous with the great vessels. The serous (inner) pericardium consists of a double-layered membrane; the most inner aspect is the epicardium, which also merges and is continuous with the great vessels, while the outer aspect is embedded 525
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Fig. 42.1 Fluoroscopic image in an AP view of an epicardial multielectrode electroanatomic mapping catheter positioned in the oblique sinus. The catheter has been inserted from a subxiphoid approach, and a guide wire can be seen in the pericardial space, that may be used as backup for access to the pericardial space. Also shown are other catheters, including a 6 F decapolar catheter positioned in the coronary sinus, an octopolar catheter positioned in the RA, and the endocardial quadripolar electroanatomic mapping catheter advanced through a transseptal sheath to the LA
with the fibrous pericardium [7]. There are extensions of the pericardial cavity called sinuses and recesses [7, 8]. Most importantly are the oblique sinus and transverse sinus (Fig. 42.1). The latter allows access to the right atrium and region of the sinus node, while the former could be seen as the box created or within the four pulmonary veins [9]. Percutaneous access to the pericardial space for cardiac mapping and ablation has generally consisted of the technique outlined by Sosa et al. [6]. Using a subxiphoid approach, a Tuohy needle with a blunt and curved tip is introduced, freely until feeling the resistance from the diaphragmatic muscle, followed by the pulsating heart against the needle. Advancing carefully the needle while applying negative pressure, the pericardial space is entered, removing a few ml of clear fluid and then injecting contrast seen under fluoroscopy to engage the pericardial space. A guide wire is introduced and can be seen on fluoroscopy on the outer aspect of the heart. Inadvertent puncture into the right ventricle would demonstrate during dye injection immediate washout rather than persistence of staining that outlines the heart shadow, while advancing a guide wire into the right ventricle would result in further advancement into the pulmonary artery.
R. Lemery
Once access to the pericardial space has been effectively obtained, a sheath is introduced over the guide wire, often requiring dilation in view of the musculature of the diaphragm. If needed, more than one guide wire may be introduced through the sheath, followed by removal of that sheath to insert two or more sheaths into the pericardial space, to allow for introduction of the mapping and ablation catheter, or a dedicated sheath for fluid drainage or even an instrument such as balloon catheter or an endoscope [10–13]. In patients who have had prior surgical interventions, or who have had pericarditis, there may be significant restriction to catheter movement in the pericardial space; Soejima et al. [14] reported in 2004 of a combined surgical approach of creating a small window in the subxiphoid space to allow for manual lysis of adhesions and introduction of surgical tools or sheaths for creating large access and ease of manipulation of a sheath and catheter. In six patients who had prior cardiac surgery and who failed percutaneous pericardial access, this technique allowed in four patients catheter manipulation in the pericardial space in the region of the anterior and lateral walls, resulting in successful mapping and ablation [14]. More recently, Scanavacca et al. expanded on percutaneous access to the pericardial space endocardially from the right atrial appendage [15, 16]. In a swine model, percutaneous transatrial access to the pericardial space was accomplished by advancing a long transseptal sheath to the right atrial appendage in 16 animals and through the left atrial appendage in one animal [16]. A guide wire and dilator were advanced and perforation was obtained by firmly pressing against the tissue, followed by advancing the guide wire to view it on the outer portion of the heart. Following atrial ablation procedures in these animals, a pigtail catheter was introduced to aspirate blood or fluid. In 13/16 animals, the sheath was removed, while in three animals, patent foramen closure device closed the pericardial access site. The animals were immediately sacrificed. In the latter group, there was one inadvertent placement of the occlusion device in the RV, while in the former group, two of the animals had cardiac tamponade [16].
Physiologic Studies of Endocardial and Epicardial Activation in the Atrium and Ventricle Durrer et al. [17] studied endocardial and epicardial activation on isolated human hearts from seven individuals who died from cerebral conditions. Up to 870 intramural terminals were able to map excitation of the left and right ventricle. In two hearts, atrial activation was also evaluated. An earlier study by Puech et al. [18] in dogs described normal atrial activation using epicardial electrodes.
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With the introduction of 3D non-fluoroscopic mapping systems, Lemery et al. [9] performed an endocardial and epicardial mapping study of the RA and LA is sinus rhythm. Following sinus node onset, there is early epicardial activation of the RA, followed by preferential conduction over Bachmann’s bundle [19] with the earliest left atrial activation being endocardial and anterior. The earliest epicardial LA activation occurs more than half way following onset of the P wave in sinus rhythm, whereas the terminal portion of the P wave is due to late activation of all components of atrial activation, including the RA, LA, coronary sinus, transverse sinus, and oblique sinus [9].
Epicardial Mapping and Ablation of Supraventricular Arrhythmias Infrequently, percutaneous epicardial access to the pericardial space is required for mapping and ablation of accessory pathways or atrial tachycardia [20–25]. In patients with manifest or concealed accessory pathways [20–24], ineffective ablation or instability of catheter positioning against the tricuspid valve annulus for right free wall bypass tracts may be overcome by epicardial mapping and ablation. In rare cases of accessory pathways
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localized in the right atrial appendage [24], use of epicardial mapping can also assist in eliminating conduction over the accessory pathway. Most posteroseptal accessory pathways that are closer to the epicardium than the endocardium are ablated from the coronary sinus, although epicardial mapping and ablation may be required [20–23]. Atrial tachycardia requiring percutaneous epicardial mapping and ablation has also been reported; most patients have a focal atrial tachycardia arising from the region of the left atrial appendage [25]. Atrial fibrillation involves important physiologic mechanisms that are located on the pericardium. The ganglionated plexuses are mostly distributed in the left atrium, and these autonomic sites of innervation can be localized during endocardial or epicardial mapping [26–34]. The Marshall vein and bundle can be targeted endocardially or epicardially and may be important in initiating or maintaining atrial fibrillation [35–37]. Complex fractionated atrial electrograms can be mapped endocardially and epicardially (Fig. 42.2). The transseptal approach to perform circumferential endocardial ablation of the pulmonary veins in patients with atrial fibrillation requires delivery of energy to regions of the left atrium that are associated with greater recurrences of conduction (ridge, carina), that may require epicardial mapping and ablation [38–40].
I II III V1 V6 ABL 1 2 CS 1,2
Fig. 42.2 Surface ECG leads I, II, and III V1 and V6 in a patient with epicardial and endocardial mapping of atrial fibrillation. The catheters record bipolar electrograms and are positioned in the coronary sinus (CS, distal to proximal 1–2 to 9–10), oblique sinus (Epi, 1–2 to 7–8), high right atrium (HRA 3–4), and His bundle region (His 1–2 and 3–4). The ablation catheter (ABL 1–2) is positioned in the antral region of the left superior pulmonary vein (left panel) and left inferior pulmonary vein (right panel). Complex fractionated atrial electrograms are observed at different time intervals, but distinct isoelectric periods are also observed
CS 3,4 CS 5,6 CS 7,8 CS 9,10 Epi 1 2 Epi 3 4 Epi 5 6 Epi 7 8 MAP 1 2 MAP 3 4 hRA 3 4 HIS 1 2 HIS 3 4
200 ms
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The esophageal position in the posterior left atrium may result in the inability to deliver high enough energies to obtain pulmonary vein isolation. Percutaneous techniques to protect the esophagus by use of a balloon catheter or use of extra pericardial fluid have been described [12, 13, 39]. Combined endocardial-epicardial percutaneous mapping and ablation procedures in patients with atrial fibrillation have been reported [39]. However, development of hybrid techniques involving surgical access to the pericardial space using minimally invasive techniques, combined with electrophysiological mapping and ablation during or following surgical ablation, may provide more comprehensive end points, especially in patients with persistent atrial fibrillation requiring a maze-like procedure [41, 42].
Epicardial Mapping and Ablation of Ventricular Arrhythmias Ventricular arrhythmias associated with cardiomyopathies were initially reported as having an increased incidence of epicardial foci. In the original report a direct subxiphoid percutaneous approach by Sosa et al. [6], ventricular tachycardia was associated with Chagas cardiomyopathy. In this trypanosomiasis, cardiac involvement often results in a basal inferolateral scar, associated with ventricular tachycardia that can be reproducibly induced during programmed electrical stimulation. Subepicardial reentry may result in unsuccessful ablation from the endocardium; in a series of 257 consecutive patients with VT, epicardial VT occurred in 37 % with Chagas disease, as compared with 28 % in patients with ischemic VT, and 24 % in patients with idiopathic dilated cardiomyopathy [43]. Although significant reduction in shocks from an implantable defibrillator in patients with Chagas disease has been shown following combined endocardial-epicardial VT ablation procedures, recurrence rates remain elevated during long-term follow-up [43]. Patients with ischemic [44, 45] or idiopathic cardiomyopathies showing a predominant left ventricular involvement or patients with arrhythmogenic right ventricular cardiomyopathy may also require epicardial mapping and ablation [46–49]. In a recent report of 22 patients with epicardial VT associated with idiopathic dilated cardiomyopathy [47], the epicardial regions showing low voltages were significantly larger and more adjacent than those seen on the endocardium. In approximately half of patients with an epicardial origin of VT, low-voltage regions were mapped in close proximity to the aortic or mitral valve [47]. In patients with arrhythmogenic right ventricular cardiomyopathy, epicardial mapping has demonstrated significant scarring, beyond the endocardial regions of abnormal low voltage [48, 49]. In 13 patients with arrhythmogenic right ventricular cardiomyopathy who failed endocardial VT ablation [48], epicardial
Fig. 42.3 Carto PA (anatomic) view of the epicardium, with the pulmonary veins and RA
mapping and ablation was associated with no recurrence of VT in 10/13 patients (77 %) during a mean follow-up of 18 months (range 5–41). Patients with nonischemic VT occurring in patients without overt heart disease typically have VT occurring from the outflow tract in the RV or LV. Infrequently, these patients may have an epicardial origin of their VT from the anterior interventricular vein or distal great cardiac vein or other unusual left ventricular myocardial sites [50]. When the venous anatomy does not allow for adequate positioning of the mapping and ablation catheter, a percutaneous approach to the epicardium may result in successful mapping and ablation of VT [50]. In patients with VT, an epicardial focus is typically associated with specific electrocardiographic features [50–52]. These include a pseudo delta wave of 34 ms or greater, an intrinsicoid deflection of 85 ms or greater, and a precordial RS complex duration of 121 ms or greater. In addition, the paced QRS complex has been shown to be significantly longer from paced epicardial sites as compared with endocardial sites of pacing [50–52]. Mapping and ablation in patients with an epicardial origin of VT requires attention to numerous details [53, 54]. Most patients have significant LV dysfunction; use of an intraaortic balloon catheter or other methods of LV assistance may be required. An underlying ICD is frequently present, and specific coronary anatomic features can be delineated during pre-procedure coronary angiography or CT angiography. Figure 42.3 shows a Carto map view of the epicardium.
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Epicardial Mapping and Ablation of Cardiac Arrhythmias
Energy Sources The pericardial space has several limitations to energy delivery during ablation [55, 56]. Anatomic considerations such as coronary anatomy, phrenic nerve, or esophagus may limit the site of energy delivery [56–59], while epicardial fat may be associated with ineffective energy delivery [60]. The closed space of the pericardium with absence of circulating blood flow may result in electrode temperature increase, requiring low-power applications. The latter may limit effective energy delivery, resulting in need for irrigated radiofrequency energy delivery [55]. Regular drainage of pericardial fluid throughout the mapping and ablation procedure is necessary.
Complications and Post-procedure Management Access to the pericardial space may result in inadvertent puncture of the left lobe of the liver or of the abdominal cavity [54, 61]. In patients with a megacolon with underlying Chagas disease [43] or with previous abdominal surgery, inadvertent puncture through the bowel may result in air under the diaphragm, or abdominal hemorrhage may occur. These patients may be managed conservatively, but abdominal interventions may be required. Access to the pericardial space may be associated with inadvertent puncture of the RV. Generally, if a guide wire has been introduced in the RV, removal and continuation of the procedure can generally be done. Insertion of a sheath in the RV may require surgical intervention for closure of the hole. A case of epicardial laceration of a coronary artery has also been described [62]. Collateral damage from mapping and ablation in the epicardial space includes injury to the coronary arteries, phrenic nerve, lungs, esophagus, and vagus nerve [56–59, 61, 62]. Post-procedure pericarditis usually responds to nonsteroidal anti-inflammatories. Intrapericardial use of 0.5–1.0 mg/kg of methylprednisolone may reduce the risks of post-procedure pericarditis or the development of significant pericardial effusions [63].
Future Perspectives and Hybrid SurgicalInterventional Electrophysiological Collaboration Percutaneous epicardial mapping and ablation for the treatment of selected cardiac arrhythmias will likely grow in importance over the next years. Specific approaches and tools for working in the pericardial space will need to be developed. Remote magnetic navigation applications to epicardial mapping and ablation may facilitate catheter
navigation and provide favorable vector orientations for catheter energy delivery [64]. New hybrid surgicalelectrophysiological procedures may also result in improved patient outcomes [42, 65].
References 1. Sealy WC, Gallagher JJ, Wallace AG. The surgical treatment of Wolff-Parkinson-White syndrome: evolution of improved methods for identification and interruption of the Kent bundle. Ann Thorac Surg. 1976;22:443. 2. Guiraudon GM, Klein GJ, Gulamhusein S, Jones DL, Yee R, Perkins DG, Jarvis E. Sureical reDair of Wolff-Parkinson-White syndrome: a new closed-heart technique. Ann Thorac Surg. 1984;37:67. 3. Jackman WM, Wang X, Friday KJ, Roman CA, Moulton KP, Beckman KJ, McClelland JH, Twidale N, Hazlitt A, Pior MI, Margolis D, Calame JD, Overholt ED, Lazarra R. Catheter ablation of accessory atrioventricular pathways (Wolff-Parkinson-White syndrome) by radiofrequency current. N Engl J Med. 1991;324: 1605–11. 4. Lemery R, Talajic M, Roy D, Coutu B, Lavoie L, Lavallee E, Cartier R. Success, safety, and late electrophysiological outcome of low-energy direct-current ablation in patients with the WolffParkinson-White syndrome. Circulation. 1992;85:957–62. 5. Yamane T, Jais P, Shah DC, Hocini M, Peng JT, Deisenhofer I, Clementy J, Haissaguerre M. Efficacy and safety of an irrigated-tip catheter for the ablation of accessory pathways resistant to conventional radiofrequency ablation. Circulation. 2000;102:2565–8. 6. Sosa E, Scanavacca M, d’Avila A, Pilleggi F. A new technique to perform epicardial mapping in the electrophysical laboratory. J Cardiovasc Electrophyisol. 1996;7:537–8. 7. McAlpine WA. Heart and coronary arteries: an anatomical atlas for clinical diagnosis, radiological investigation, and surgical treatment. Berlin/New York: Springer; 1975. 8. D’Avila A, Scanacca M, Sosa E, Ruskin JE, Reddy VY. Pericardial anatomy for the interventional electrophysiologist. J Cardiovasc Electrophysiol. 2003;14:422–30. 9. Lemery R, Birnie D, Tang A, Green M, Gollob M, Hendry M, Lau E. Normal atrial activation and voltage during sinus rhythm in the human heart. J Cardiovasc Electrophysiol. 2007;18:402–8. 10. Nazarian S, Kantsevoy SV, Zviman MM, Matsen FA, Calkins H, Berger RD, Halperin HR. Feasibility of endoscopic guidance for nonsurgical transthoracic atrial and ventricular epicardial ablation. Heart Rhythm. 2008;5(8):1115–9. 11. Nagashima K, Watanabe I, Okumura Y, Ohkubo K, Kofune M, Ohya T, Kasamaki Y, Hirayama A. Efficacy and feasibility of pericardial endoscopy by subcutaneous approach. Europace. 2011;13: 1501–3. 12. Buch E, Nakahara S, Shivkumar K. Intra-pericardial balloon retraction of the left atrium. A novel method to prevent esophageal injury during catheter ablation. Heart Rhythm. 2008;5(10):1473–5. 13. Nakahara S, Ramirez R, Buch E, Michowitz Y, Vaseshi M, de Diego C, Boyle N, Mahajan A, Shivkumar K. Intrapericardial balloon placement for prevention of collateral injury during catheter ablation of the left atrium in a porcine model. Heart Rhythm. 2010;7:81–7. 14. Soejima K, Couper G, Coopr JM, Sapp JL, Epstein LM, Stevenson WG. Subxiphoid surgical approach for epicardial catheter-based mapping and ablation in patients with prior cardiac surgery or difficult pericardial access. Circulation. 2004;110:1197–201. 15. Verner RL, Waxman S, Lovett EG, Moreno R. Transatrial access to the normal pericardial space: an approach for diagnostic sampling,
530
16.
17.
18. 19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30. 31. 32.
33.
34.
R. Lemery pericardiocentesis, and therapeutic interventions. Circulation. 1998;98(21):2331–3. Scanavacca M, Vanancio A, Pisani C, Lara S, Hachul D, Darrieux F, Hardy C, Paola E, Aiello V, Mhapatra S, Sosa E. Percutaneous transatrial access to the pericardial space for epicardial mapping and ablation. Circ Arrhytm Electrophysiol. 2011;4:331–6. Durrer D, Van Dam RT, Freud GE, Janse MJ, Meijler FL, Arzbaecher C. Total excitation of the isolated human heart. Circulation. 1970;41:899–912. Puech P, Esclavissat M, Sodi-Pollares D, Cisneros F. Normal auricular activation in the dog’s heart. Am Heart J. 1954;47:174–91. Lemery R, Guiraudon G, Veinot JP. Anatomic description of Bachmann’s bundle and its relation to the atrial septum. Am J Cardiol. 2003;91:1482–5. Schweikert RA, Saliba WI, Tomassoni G, Marrouche NF, Cole CR, Dressing TJ, Tchou PJ, Bash D, Beheiry S, Lam C, Kanagarathan L, Natale A. Percutaneous pericardial instrumentation for endoepicardial mapping of previously failed ablations. Circulation. 2003;108(11):1329–35. Valderrabano M, Cessario DA, Ji S, Shannon K, Weiner I, Swerdlow CD, Oral H, Morady F, Shivkumar K. Percutaneous epicardial mapping during ablation of difficult accessory pathways as an alternative to cardiac surgery. Heart Rhythm. 2004;1(3):311–6. Ho I, D’Avila A, Ruskins J, Mansour M. Images in cardiovascular medicine. Percutaneous epicardial mapping and ablation of a posteroseptal accessory pathway. Circulation. 2007;115:e418–21. de Paloa AAV, Leite LR, Mesas CE. Nonsurgical transthoracic epicardial ablation for the treatment of a resistant posteroseptal accessory pathway. Pacing Clin Electrophysiol. 2004;27:259–61. Lam C, Schweikert R, Kanagaratnam L, Natale A. Radiofrequency ablation of a right atrial appendage-ventricular accessory pathway by transcutaneous epicardial instrumentation. J Cardiovasc Electrophysiol. 2000;11:1170–3. Phillips KP, Natale A, Sterba R, Saliba WI, Burkhardt JD, Wazni O, Liberman L, Schweikert RA. Percutaneous pericardial instrumentation for catheter ablation of focal atrial tachycardias arising from the left atrial appendage. J Cardiovasc Electrophysiol. 2008;19: 430–3. Armour JA, Murphy DA, Yuan BX, Macdonald S, Hopkins DA. Gross and microscopic anatomy of the human intrinsic cardiac nervous system. Anat Rec. 1997;247(2):289–98. Scherlag BJ, Nakagawa H, Jackman WM, Yamanashi WS, Patterson E, Po S, Lazzara R. Electrical stimulation to identify neural elements on the heart: their role in atrial fibrillation. J Interv Card Electrophysiol. 2005;13 Suppl 1:37–42. Lemery R, Birnie D, Tang SL, Green M, Gollob M. Feasibility study of endocardial mapping of ganglionated plexuses during catheter ablation of atrial fibrillation. Heart Rhythm. 2006;3:387–96. Scanavacca M, Pisani CF, Hachul D, Lara S, Hardy C, Darrieux F, Trombetta I, Negrao CE, Sosa E. Selective atrial vagal denervation guided by evoked vagal reflex to treat patients with paroxysmal atrial fibrillation. Circulation. 2006;114:876–85. Lemery R. How to perform ablation of the parasympathetic ganglia of the left atrium. Heart Rhythm. 2006;3(10):1237–9. Scherlag BJ, Po S. The intrinsic cardiac nervous system and atrial fibrillation. Curr Opin Cardiol. 2006;21(1):51–4. Pokushalov E, Romanov A, Shugayev P, Artymenko S, Shirokova N, Turov A, Katritsis DG. Selective ganglionated plexi ablation for paroxysmal atrial fibrillation. Heart Rhythm. 2009;6(9):1257–64. Pokushalov E, Romanov A, Artyomenko S, Shirokva N, Turov A, Karaskov S, Katritsis D, Po SS. Ganglionated plexi ablation directed by high-frequency stimulation and complex fractionated atrial electrograms for paroxysmal atrial fibrillation. Pacing Clin Electrophysiol. 2012;35:776–84. Lemery R. Autonomics and ablation of paroxysmal atrial fibrillation. Pacing Clin Electrophysiol. 2012;35:773–5.
35. Doshi RN, Wu TJ, Yashima M, Kim YH, Ong JJ, Cao JM, Hwang C, Yashar P, Fishbein MC, Karagueuzian HS, Chen PS. Relation between ligament of Marshall and adrenergic atrial tachyarrhythmia. Circulation. 1999;100:876–83. 36. Hwang C, Wu TJ, Doshi RN, Peter CT, Chen PS. Vein of Marshall cannulation for the analysis of electrical activity in patients with focal atrial fibrillation. Circulation. 2000;101:1503–5. 37. Valderrabano M, Liu X, Sasaridis C, Sidhu J, Little S, Khoury DS. Ethanol infusion in the vein of Marshall: adjunctive effects during ablation of atrial fibrillation. Heart Rhythm. 2009;6:1552–8. 38. Reddy VY, Neuzil P, Ruskin JN. Extra-ostial pulmonary venous isolation: use of epicardial ablation to eliminate a point of conduction breakthrough. J Cardiovasc Electrophysiol. 2003;14(6): 663–6. 39. Pak HN, Hwang C, Lim HE, Kim JS, Kim YH. Hybrid epicardial and endocardial ablation of persistent or permanent atrial fibrillation: a new approach to difficult cases. J Cardiovasc Electrophysiol. 2007;18(9):917–23. 40. Reddy V, Neuzil P, d’Avila A, JN R. Isolating the posterior left atrium and pulmonary veins with a “box” lesion set: use of epicardial ablation to complete electrical isolation. J Cardiovasc Electrophysiol. 2008;19(3):326–9. 41. Shivkumar K. Percutaneous epicardial ablation of atrial fibrillation. Heart Rhythm. 2008;5:152–4. 42. Krul SPJ, Driessen AHG, van Boven WJ, Linnebank AC, Geuzebroek GSC, Jackman WM, Wilde AAM, de Bakker JMT, de Groot JR. Thoracoscopic video-assisted pulmonary vein antrum isolation, ganglionated plexus ablation, and periprocedural confirmation of ablation lesions: first results of a hybrid surgicalelectrophysiological approach for atrial fibrillation. Circ Arrhythm Electrophysiol. 2011;4:262–70. 43. Scanavacca M, Sosa E. Epicardial ablation of ventricular tachycardia in Chagas heart disease. Cardiac Electrophysiol Clin. 2010;2: 55–67. 44. Sosa E, Scanavacca M, d’Avila A, Oliveira F, Ramires JAF. Nonsurgical transthoracic epicardial ablation to treat recurrent ventricular tachycardia occurring late after myocardial infarction. J Am Coll Cardiol. 2000;35(6):1442–9. 45. Brugada J, Berruezo A, Cuesta A, Osca J, Chueca E, Fosch X, Waynar L, Mont L. Nonsurgical transthoracic epicardial radiofrequency ablation: an alternative in incessant ventricular tachycardia. J Am Coll Cardiol. 2003;41(11):2036–43. 46. Soejima E, Stevenson WG, Sapp JL, Selwyn AP, Couper G, Epstein LM. Endocardial and epicardial radiofrequency ablation of ventricular tachycardia associated with dilated cardiomyopathy: the importance of low-voltage scars. J Am Coll Cardiol. 2004;43: 1834–42. 47. Cano O, Hutchinson M, Lin D, Garcia F, Zado E, Bala R, Riley M, Cooper J, Dixit S, Gerstenfeld E, Callans D, Marchlinski FE. Electroanatomic substrate and ablation outcome for suspected epicardial ventricular tachycardia in left ventricular non-ischemic cardiomyopathy. J Am Coll Cardiol. 2009;54(9):799–808. 48. Farcia FC, Bazan V, Zado ES, Ren JF, Marchlinksi FE. Epicardial substrate and outcome with epicardial ablation of ventricular tachycardia in arrhythmogenic right ventricular cardiomyopathy/dysplasia. Circulation. 2009;120:366–75. 49. Berruezo A, Fernandez-Armenta J, Mont L, Zeliko H, Andreu D, Herczku C, Boussy T, Tolosana JM, Arbelo E, Brugada J. Combined endocardial and epicardial ablation in arrhythmogenic right ventricular dysplasia incorporating scar dechanneling technique. Circ Arrhythm Electrophysiol. 2012;5:111–21. 50. Daniels DV, Lu YY, Morton JB, Santucci P, Akar JG, Green AI, Wilber DJ. Idiopathic epicardial left ventricular tachycardia originating remote from the sinus of valsalva electrophysiological characteristics, catheter ablation, and identification from the 12-lead electrocardiogram. Circulation. 2006;113:1659–66.
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51. Berruezo A, Mont L, Nava S, Cheuca E, Bartholomay E, Brugada J. Electrocardiographic recognition of the epicardial origin of ventricular tachycardias. Circulation. 2004;109:1842–7. 52. Bazan V, Gertsenfeld E, Garcia F, Bala R, Rivas N, Dixit S, Zado E, Callans D, Marchlinski E. Site-specific twelve-lead ECG features to identify an epicardial origin for left ventricular tachycardia in the absence of myocardial infarction. Heart Rhythm. 2007;4:1403–10. 53. Aliot EM, Stevenson WG, Almendral-Garrote JM, Bogun F, Calkins CH, Delacretaz E, Della Bella P, Hindricks G, Jails P, Josephson MF, Kautzner J, Kay GN, Kuck KH, Lerman BB, Marchlinski F, Reddy V, Schalij MJ, Schilling R, Soejima K, Wilber D. EHRA/ESC/HRS/ACC/AHA expert consensus on catheter ablation of ventricular arrhythmias. Heart Rhythm. 2009;6: 886–933. 54. Sacher F, Roberts-Thomson K, Maury P, Tedro U, Nault I, Steven D, Hocini M, Koplan B, Lerpux L, Derval N, Seiler J, Wright MJ, Epstein L, Haissaguerre M, Jais P, Stevenson WG. Epicardial ventricular tachycardia ablation of multicenter safety study. J Am Coll Cardiol. 2010;55:2366–72. 55. d’Avila A, Houghtaling C, Gutierrez P, Vragovic O, Ruskin JN, Josephson ME, Reddy VY. Catheter ablation of ventricular epicardial tissue. A comparison of standard and cooled-tip radiofrequency energy. Circulation. 2004;109:2363–9. 56. d’Avila A, Gutierrez P, Scanavacca M, Reddy V, Lustgarten BDL, Sosa E, Ramires JA. Effects of radiofrequency pulses delivered in the vicinity of the coronary arteries: implication for nonsurgical transthoracic epicardial catheter ablation to treat ventricular tachycardia. Pacing Clin Electrophysiol. 2002;25:1488–95. 57. Buch E, Vaseghi M, Cesario DA, Shivkumar K. A novel method for preventing phrenic nerve injury during catheter ablation. Heart Rhythm. 2007;4:95–8. 58. Di Biase L, Burkhardt JD, Pelargonio G, Dello Russo A, Casella M, Santarelli P, Horton R, Sanchez J, Gallinghouse JG, Al-Ahmad A, Wang P, Cummings JE, Schweikert RA, Natale A. Prevention of
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61.
62.
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phrenic nerve injury during epicardial ablation: comparison of methods for separating the phrenic nerve from the epicardial surface. Heart Rhythm. 2009;6:957–61. Sanchez-Quintana D, Cabrera JA, Climent V, Murillo M, Cabrera JA. Anatomic evaluation of the left phrenic nerve relevant to epicardial and endocardial catheter ablation: implications for phrenic nerve injury. Heart Rhythm. 2009;6:764–8. Tung R, Nakahara S, Ramirez R, Lai C, Fishbein MC, Shivkumar K. Distinguishing epicardial fat from scar: analysis of electrograms using high-density electroanatomic mapping in a novel porcine infarct model. Heart Rhythm. 2010;7:389–95. Koruth J, Aryana A, Dukkipati S, Pak HN, Kim YH, Sosa EA, Scanavacca M, Mahapatra S, Ailawadi G, Reddy V, d’Avila A. Unusual complications of percutaneous epicardial access and epicardial mapping and ablation of cardiac arrhythmias. Circ Arrhythm Electrophysiol. 2011;4:882–8. Hsieh CH, Ross DL. Case of coronary perforation with epicardial access for ablation of ventricular tachycardia. Heart Rhythm. 2011;8:318–21. D’Avila A, Neuzil P, Thaigalingam A, Gutierrez P, Aleong R, Ruskin J, Reddy V. Experimental efficacy of pericardial instillation of anti-inflammatory agents during percutaneous epicardial catheter ablation to prevent postprocedure pericarditis. J Cardiovasc Electrophysiol. 2007;18:1178–83. Di Biase L, Santangeli P, Astudillo V, Conti S, Mohanty P, Sanchez J, Horton R, Thomas B, Burkhardt JD, Natale A. Endoepicardial ablation of ventricular arrhythmias in the left ventricle with the Remote Magnetic Navigation System and the 3.5-mm open irrigated magnetic catheter: results from a large single-center case–control series. Heart Rhythm. 2010;7:1029–35. Gersak B, Pernat A, Robic B, Sinkovec M. Prospective long-term outcomes after atrial fibrillation treatment using the convergent epicardial and endocardial ablation procedure. J Cardiovasc Electrophysiol. 2012;23(10):1059–66. doi:10.1111/j.1540-8167.2012.02355.x.
Robotic Ablation in Electrophysiology
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Ferdi Akca, Lara Dabiri, and Tamas Szili-Torok
Abstract
Catheter ablation has gone through great improvement recent years and it has become a well-established therapeutic treatment for various arrhythmias. Cardiac robotic systems became more important in clinical electrophysiology and have several advantages over manual catheter ablation. The Stereotaxis Niobe Magnetic Navigation System (RMN) consists of two permanent external magnets that generate a magnetic field and allows the operator to manipulate the catheter tip. It provides unrestricted catheter movements with enhanced stability. The RMN significantly decreases the use of fluoroscopy for both patient and physician and allows safe procedures with no risk of acute perforation. Studies reveal that comparable success rates are obtained using RMN in treatment of atrial arrhythmias, AV nodal reentrant tachycardias, circus movement tachycardias, and ventricular tachycardias. Another robotic system is the Hansen Sensei Robotic System (HSRS) that provides improved positioning and control of the catheters within the heart. The HSRS consists of a remote catheter manipulator that allows for three-dimensional motion in response to the operator’s hand motion. An estimation can be made of the applied force and therefore of lesion formation. It decreases the use of fluoroscopy and the operator’s exposure can be reduced by 77 % when using HSRS. In atrial fibrillation similar efficacy was achieved using HSRS when compared to conventional methods. However, when we evaluate robotic technology, we must conclude that it creates a less efficient workflow and specially designed hardware and catheters are required for the procedures. Nevertheless, these technologies are able to increase safety and efficacy of ablation procedures. Keywords
Catheter ablation • Robotic ablation • Robotics • Robotic navigation • Remote magnetic navigation • Stereotaxis • Hansen Sensei
Abbreviations
F. Akca • L. Dabiri, MD • T. Szili-Torok, MD, PhD (*) Department of Clinical Electrophysiology, Thoraxcenter, Erasmus MC, S Gravendijkwal 230, Kamer BD416, Postbus 2040, Rotterdam, CA 3000, The Netherlands e-mail:
[email protected] A.S. Kibos et al. (eds.), Cardiac Arrhythmias, DOI 10.1007/978-1-4471-5316-0_43, © Springer-Verlag London 2014
AF HSRS ICMP NICMP RF RMN SGC SNH VT
Atrial fibrillation Hansen Sensei Robotic System Ischemic cardiomyopathy Nonischemic cardiomyopathy Radio frequency Remote magnetic navigation Steerable guide catheter Structurally normal hearts Ventricular tachycardia 533
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Introduction Catheter ablation was introduced into clinical electrophysiology in the 1980s. Since then it has become an established curative treatment for various arrhythmias. It is considered first-line therapy for many types of arrhythmias, including atrioventricular nodal reentrant tachycardia, circus movement tachycardia, and cavotricuspid isthmus-dependent atrial flutter. Furthermore, it also became a well-founded therapeutic option for the treatment of atrial fibrillation, atrial tachycardia, and ventricular tachycardia. Important developments such as electroanatomical mapping, integration of cardiac imaging, and improved catheter design have been implemented. These technological progressions significantly improved catheter ablation in general, and it became a dependable solution for treating cardiac arrhythmias. Until recently, developments in catheter ablation were based on refining manual catheter navigation within the heart. However, some issues in manual catheter ablation limit patient safety and procedure efficacy. Furthermore, standardization of the procedures is required to reduce interoperator variability. These clinical needs paved the road for the development of cardiac robotic systems. Currently there are four systems available for clinical electrophysiology: the Stereotaxis remote magnetic navigation system, Hansen Sensei robotic system, Magnetecs robotic catheter guidance control and imaging system, and the Amigo remote robotic arm. Since no published experience is available on the last
Fig. 43.1 Stereotaxis remote magnetic navigation system
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two systems, we will exclusively focus on the first two robotic systems.
Stereotaxis Remote Magnetic Navigation System Description of the System The Stereotaxis Niobe Magnetic Navigation System (Stereotaxis, Inc., Saint Louis, MO, USA) was introduced in 2002. The remote magnetic navigation (RMN, Fig. 43.1) consists of two permanent external magnets located on either side of the patient which generate a magnetic field (0.08 or 0.1 T) within the patient. Navigation of the ablation catheter is obtained by changing the magnetic field orientation from a computer-controlled workstation (Fig. 43.2). The atraumatic catheter incorporates three magnets in the distal segment, which allow the catheter to be manipulated remotely by the directional magnetic fields. By altering the vector of the magnetic field, the catheter tip will align with this vector. This allows the operator to navigate the distal tip of the catheter. Initially, ablation catheters contained one magnet at the tip. In order to increase stability, later generation catheters were built with two magnets. Currently, three magnets are incorporated in the distal part of the ablation catheter attaining more precision. The RMN incorporates a feature which stores magnetic vectors for repeated access
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Fig. 43.2 Control room of the cathlab with the remote magnetic navigation system
with automatic catheter navigation. Advancement and retraction of the catheter are operated separately by a joystick-controlled motor drive (Cardiodrive, Stereotaxis, Inc., Saint Louis, MO). Images from three-dimensional mapping systems, real-time fluoroscopy, and CT scans can be integrated, thus facilitating fully remote-controlled mapping and ablation procedures. One of the most significant features of the RMN is the ability to decrease fluoroscopy exposure for both patient and operator. Manipulation of the magnetic ablation catheter is safe with no risk of perforation. To localize the catheter tip, an integrated three-dimensional mapping system (CARTO RMT, Biosense Webster, Inc., Diamond Bar, CA, USA) can be used. Manipulation of the catheter does not need continuous fluoroscopy and is generally used only to confirm localization prior to an application. Although RMN is associated with longer ablation times, fluoroscopy time is considerably shorter as compared to manual ablation. Differences of up to 29 min of fluoroscopy are described [1]. Furthermore, with increased experience, fluoroscopy time for magnetically guided atrial fibrillation ablation decreases [2].
Rationale of RMN Accurate mapping and ablation of the area of interest can be complex. Even for experienced operators, procedures can be very challenging and multiple difficulties must be overcome in order to achieve successful outcome without unnecessary
adverse events. Crucial requirements for successful catheter ablation are stability in difficult anatomical locations (with continuous cardiac and respiratory movements), catheter maneuverability to access target regions, and reproducibility of catheter location. When using manual ablation, issues regarding catheter control are often encountered. Manual catheters are limited in their freedom of movement by their predefined curve. In certain anatomical structures, maneuvering within the heart can be extremely difficult, and on occasion, regions of interest remain unreachable (e.g., outflow tract regions and arrhythmogenic substrates in patients with congenital heart diseases and cardiac abnormalities). RMN catheters are not restricted in their movements, and the improved navigation capabilities allow appropriate energy delivery. Increased catheter stability can provide constant tissue contact during ablation. A constant magnetic vector stabilizes the catheter, leading to little displacement during an application. In complex anatomical locations like the mitral valve and highly trabeculated myocardium, this enhanced wall contact and stability could lead to better energy delivery [3, 4]. In contrast to manual catheters, which can be anchored in the tissue by applying torque to the catheter, the RMN catheter has a lower but constant contact force and results in less tissue deformation by the applied magnetic force. On the endocardial surface, the contact force applied by the Stereotaxis RMN system is approximately 10–15 g. This value is substantially less than with conventional ablation catheters [5]. However, this decrease in contact force does
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not result in less effective lesions. The stability of the catheter results in less variation in contact force, whereas conventional techniques have shown intermittent or variable contact forces. Lesion formation is thought to be a function of both contact force and applied energy. However, it has been shown that stability combined with lower contact force can produce efficacious lesions [6]. This decreased variation of contact force will create more transmural and larger-volume lesions at comparable forces. In order to create similar lesions using conventional manual catheters, higher forces are required [7]. This means that for a given force, RMN may attain better energy delivery as compared to manual catheters. However, despite these theoretical advantages, RMN-guided AF ablation was associated with longer total application times in most studies [8, 9]. Most likely there are still difficult regions where the RMN cannot provide sufficient contact force, resulting in less energy delivery. These regions which are difficult to reach are identical for RMN and manual ablations. The significant difference is that, until now, RMN does not provide the possibility to adjust and improve contact force and increase lesion size. There are three options to increase lesion formation: (1) longer application time, (2) higher power output, and (3) switch to a manual ablation catheter. Although the use of RMN is an intuitive system with a steep learning curve, it is related to longer procedure times for AF [1, 10]. Initially this was thought to be due to the learning curve for a new technology. However, recent data suggest that procedure times are 35–60 min longer using RMN. No learning curve for procedure duration has been observed [2]. Also ablation times, defined as time from the first to the last ablation point, are higher with RMN. This could be explained by a slower navigation speed in the left atrium (and other chambers) using RMN compared to experienced manual operators. The stepwise changing of the magnetic vector, followed by adjustment of the two magnets and subsequently catheter movement, will increase the time spent on navigating the catheter and thus the procedure and ablation time.
Safety Manual navigation of catheters in the human heart has further limitations. Some regions are difficult to access, and compromised catheter positioning may result in insufficient lesion formation. Catheter movement in some positions is accompanied by the risk of major complications, including pericardial effusion or tamponade. Although several predefined catheter curves were introduced to aid appropriate lesion delivery, there are no optimal curves available for all subgroups of patients (small hearts, patients with complex congenital heart defects, or for patients with extremely dilated hearts). During manipulation of the catheter, high contact forces are often applied and this can be a risk for perforating the myocardium.
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The introduction and utilization of RMN was aimed to surmount these difficulties. It has been demonstrated that RMN procedures are safe due to the flexible catheter design, and no pericardial effusion or tamponade was reported related to catheter navigation using RMN. However tamponade is described as a complication in RMN AF ablations. These traumas were delayed and probably related to prolonged ablation and not to acute perforation with the RMN-guided catheter tip. Recent data suggests that RMN can be associated with changes in esophageal temperatures causing acute esophageal injury. These lesions all had complete remission within 14 days and were comparable to those from a conventional approach [11]. In addition, non-fluoroscopic imaging and software-based automated functions such as auto-mapping and stored magnetic vectors may allow for reductions in fluoroscopy time for both operator and patient. Stored magnetic vectors also make it possible to re-navigate to spots previously stored during the procedure.
Efficacy in Relation to Specific Arrhythmias Atrial Fibrillation After the introduction of the irrigated RMN ablation catheters, several studies evaluated the efficacy of RMN in paroxysmal atrial fibrillation (AF) [12–14]. It can be concluded that good acute success rates were achieved using RMN and this was sustained over time. After the procedures complete pulmonary vein isolation was reached in 96 % of the patients. During a mean follow-up period of 11.6 months, 76.3 % of the patients remained free of recurrence. These numbers are comparable to those obtained from conventional techniques. Longer duration of total radiofrequency (RF) current has been described in AF ablation. To realize equally effective ablation lesions, more RF current needs to be delivered as compared to the conventional approach. It was suggested that the RMN was not sufficiently effective in making ablation lines. This statement was based on using a 4- or 8-mm non-irrigated RMN ablation catheter. However, these results were confirmed by longer RF application times when using an irrigated RMN catheter as well. Data suggest that RMN requires more total application time than manual procedures and may be less effective in creating linear lesions; however, the long-term outcome is equivalent [8]. Ventricular Tachycardia For ablation of ventricular tachycardia (VT) in ischemic cardiomyopathy (ICMP), success rates ranging from 71 to 80 % are achieved using RMN. In patients with structurally normal hearts (SNH), RMN VT ablation was successful in 86–100 %. Although the studies on RMN on idiopathic VTs were evaluated in a relatively small number of patients, they demon-
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strate the feasibility of RMN for successful ablation of right and left outflow tracts and left fascicular and aortic cusp VT. In nonischemic cardiomyopathy (NICMP), effective VT ablation procedures were performed (e.g., arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy, sarcoidosis). However, these studies included a minimal number of patients and more research is needed in this patient population in order to draw conclusions. Recurrence was experienced in 0–30 % of the ICMP patients following acute successful ablation procedures. Recurrence rates ranging from 14 to 50 % were reported for the NICMP population. For patients with SNH, recurrence rates ranged from 0 to 17 % after VT ablation procedures.
Congenital Heart Disease In patients with surgically repaired congenital heart disease, it may be necessary to perform a baffle puncture during the ablation procedure. The retrograde approach to the left side of the heart due to the flexibility of the RMN catheter can be used to avoid this puncture. This mostly benefits patients with structural cardiac abnormalities. Fewer transseptal punctures are needed and therefore the risk of complications is decreased. However, it should be taken into account that these studies on safety included a limited number of patients and are retrospective in nature. In order to really understand the effect on safety using RMN, randomized trials need to be executed.
Fig. 43.3 The Stereotaxis Vdrive remote robotic manipulator with a specially designed interface to contain the circular mapping catheter
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The decrease in fluoroscopy times is a crucial feature in congenital patients due to the number of young and pediatric patients and the need for repetitive ablation procedures. For other arrhythmias (e.g., atrial flutter, atrial tachycardia, AV nodal reentrant tachycardia, circus movement tachycardia), comparable results were reported using RMN and manual ablation techniques. Overall, less fluoroscopy is used during the procedure and less major complications are described.
New Developments for Fully Remote RMN Procedures New developments are made to make the ablation procedure fully remote controlled. Optimal outcomes of AF ablation with the RMN require manual manipulations of the circular mapping catheter. Although some groups do catheter ablation of AF without the use of a circular mapping catheter, it can be a tool to evaluate complete pulmonary vein isolation at the end of the ablation procedure. Until recently, it was not possible to navigate the circular mapping catheter from the remote RMN workstation. Recently, the Vdrive system (Stereotaxis, Inc., Saint Louis, MO, USA) has been introduced to permit remote manipulation of specialized diagnostic catheters (Fig. 43.3). The operator in the remote workstation utilizes a remote controller to manipulate the catheter movements (Fig. 43.4).
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Fig. 43.4 Vdrive controller and variable loop functionality
The catheter can be advanced, retracted, rotated, and deflected. The loop size of the circular mapping catheter can also be modified. The Vdrive can be used for navigation between PVs, mapping of the chambers, and identifying gaps with segmental isolation. The Vdrive is a very promising tool for making AF ablation fully remote and appears to be useful to reduce procedure times. However, more research is necessary to assess the true value of this system.
Hansen Sensei Robotic System Description of the System The introduction of the Hansen Sensei Robotic System in 2007 (HSRS, Hansen Medical, Inc., Mountain View, CA, USA) was a revolutionary development within clinical electrophysiology. The system was designed to improve positioning and control of the catheters within the heart. The HSRS consists of a physician workstation and includes a remote catheter manipulator, a setup joint, a steerable guide catheter
(SGC), and steerable sheath (Artisan; Hansen Medical). Currently, the HSRS is fully integrated with Philips (Best, The Netherlands) and St. Jude (St Paul, MN, USA) systems. The workstation is a mobile console and can be positioned anywhere to decrease fluoroscopy exposure to the physician. The catheter can be moved within the body by maneuvering the handle of the intuitive motion controller device on the master console (Fig. 43.5). The physician can orientate the position of the catheter by using the displayed fluoroscopy images, intracardiac echocardiography, cardiac electrograms and three-dimensional electroanatomical maps (EnSite NavX, St. Jude Medical, St Paul, MN, USA). The mapping and ablation catheters are controlled via a master–slave electromechanical system (Fig. 43.6). The movements of the physician are translated to the steerable sheath, which is connected to the slave remote catheter manipulator at the patient’s bedside. The hollow steerable Artisan sheath containing the SGC can be operated from the workstation. This sheath system allows for three-dimensional motion in response to the operator’s hand motion and allows 270° of bend articulation to access difficult to reach anatomical locations.
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Fig. 43.5 Mobile workstation of the Hansen robotic system
Fig. 43.6 The remote catheter manipulator at the patient’s bedside
Rationale of HSRS At the workstation a panel is incorporated on which instantaneous catheter tip pressure is displayed in grams. This allows the operator to safely manipulate the catheter and provide sufficient contact force during ablation. An estimation can be made of the applied force and thus lesion formation [15].
Operators cannot always make a reliable estimation of the applied contact force with the ablation catheter. Low contact force during ablation can result in ineffective lesions and can cause reconduction or the substrate for new arrhythmias. Studies have demonstrated that HSRS procedures have a decreased power output and total RF ablation time (mean RF duration time could be lowered by up to 35 %) [16]. Due to
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the robotic stability of the system, the power settings could be lowered without compromising lesion formation, monitored by the attenuation of the myocardial signals on the intracardiac electrograms. HSRS procedures are associated with significantly decreased use of fluoroscopy for atrial fibrillation and atrial flutter ablation procedures. Studies report 16–45 % less use of fluoroscopy [17, 18]. The exposure to the operator can be reduced by 77 % when using HSRS [16]. Since the learning curve of the system is steep, a significant reduction of radiation times can be expected during the learning experience. However, procedure times are comparable to conventional procedures but could be expected to decline with experience.
Safety Several studies have reported that the same complications can occur with HSRS and conventional techniques and show comparable rates. It must be noted that a good understanding of the atrial anatomy is crucial during robotic catheter ablation. The HSRS has beneficial properties for providing sufficient contact force to make transmural lesions. However, just like manual ablation catheters, the stiff nature of the steerable sheath could be a cause for tamponade and physicians should be well aware of this possibility. As has been discussed before, the HSRS has an improved energy delivery as compared to conventional catheters and this has considerable consequences for the power settings of the ablation catheter. For instance, to minimize the risk of PV stenosis, it is recommended to lower the power output when ablating along the PV rims as is necessary in posterior portions of the left PVs [19]. Furthermore, during ablation with the robotic system at the posterior wall, power outputs of 30 W should be avoided to minimize esophageal temperature rise.
Efficacy Atrial Fibrillation So far, most of the studies evaluating HSRS were for atrial fibrillation procedures. HSRS AF ablation resulted in an arrhythmia-free rate of about 76 % after one procedure. The efficacy of the robotic approach is therefore comparable to the manual approach. After 3 months of follow-up, 67–91 % of the patients were free of symptoms or documented atrial tachyarrhythmias. During follow-up of 239 days, the proportion of patients remaining free of paroxysmal AF is 76 and 68 % for persistent AF. Ventricular Tachycardia Very limited data is available on HSRS for treating VT. Some initial experience resolves that after the ablation procedure,
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all hemodynamically tolerable VTs were noninducible. At average follow-up of 13.4 ± 6.7 months recurrence occurred in 13 % of the patients. However, more research is necessary to evaluate the true value of HSRS for this group of patients.
Limitations of Robotic Navigation Systems As we evaluate robotic technology, we realize that there are some limitations related to the systems as compared to conventional catheter ablation. First, the use of a robotic navigation system might create a less efficient workflow. For instance, when a circular mapping catheter is used in the pulmonary veins during RMN or HSRS procedure, the operator needs to leave the control room in order to manually manipulate this mapping catheter. Given that manipulation of the catheter needs to be performed several times, it could be more time consuming than during a manual ablation procedure (sterility considerations). Therefore development of a robotic system that controls both the ablation catheter and the circular mapping catheter has been developed. Especially for RMN procedures, preparation time and manipulating the magnetic ablation catheter could be slower as compared to manually controlled catheters resulting in longer procedure times. Altering the alignment of the catheter tip is separated from the back and forward movements, which are performed by a separate device, performed by a separate device, and therefore requires extra time. Furthermore, in order to make use of the RMN and HSRS, expensive hardware and specially designed catheters or sheaths are required for the procedures.
References 1. Kim AM, Turakhia M, Lu J, Badhwar N, Lee BK, Lee RJ, et al. Impact of remote magnetic catheter navigation on ablation fluoroscopy and procedure time. Pacing Clin Electrophysiol. 2008;31(11):1399–404. 2. Luthje L, Vollmann D, Seegers J, Dorenkamp M, Sohns C, Hasenfuss G, et al. Remote magnetic versus manual catheter navigation for circumferential pulmonary vein ablation in patients with atrial fibrillation. Clin Res Cardiol. 2011;100(11):1003–11. 3. Faddis MN, Blume W, Finney J, Hall A, Rauch J, Sell J, et al. Novel, magnetically guided catheter for endocardial mapping and radiofrequency catheter ablation. Circulation. 2002;106(23):2980–5. 4. Thornton AS, Jordaens LJ. Remote magnetic navigation for mapping and ablating right ventricular outflow tract tachycardia. Heart Rhythm. 2006;3(6):691–6. 5. Kuck KH, Reddy VY, Schmidt B, Natale A, Neuzil P, Saoudi N, et al. A novel radiofrequency ablation catheter using contact force sensing: Toccata study. Heart Rhythm. 2012;9:18–23. 6. Kuck KH. Comparison of catheter stability between magnetically guided and manual cooled-tip ablation catheters. Presented at: Heart Rhythm 2008, San Fransisco, 14 May–17 May 2008; 2008. 7. Burkhardt JD, Natale A. New technologies in atrial fibrillation ablation. Circulation. 2009;120(15):1533–41.
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8. Arya A, Zaker-Shahrak R, Sommer P, Bollmann A, Wetzel U, Gaspar T, et al. Catheter ablation of atrial fibrillation using remote magnetic catheter navigation: a case–control study. Europace. 2011;13(1):45–50. 9. Solheim E, Off MK, Hoff PI, De Bortoli A, Schuster P, Ohm OJ, et al. Remote magnetic versus manual catheters: evaluation of ablation effect in atrial fibrillation by myocardial marker levels. J Interv Card Electrophysiol. 2011;32(1):37–43. 10. Bauernfeind T, Akca F, Schwagten B, de Groot N, Van Belle Y, Valk S, et al. The magnetic navigation system allows safety and high efficacy for ablation of arrhythmias. Europace. 2011;13(7):1015–21. 11. Konstantinidou M, Wissner E, Chun JK, Koektuerk B, Metzner A, Tilz RR, et al. Luminal esophageal temperature rise and esophageal lesion formation following remote-controlled magnetic pulmonary vein isolation. Heart Rhythm. 2011;8:1875–80. 12. Sorgente A, Chierchia GB, Capulzini L, Yazaki Y, Muller-Burri A, Bayrak F, et al. Atrial fibrillation ablation: a single center comparison between remote magnetic navigation, cryoballoon and conventional manual pulmonary vein isolation. Indian Pacing Electrophysiol J. 2010;10(11):486–95. 13. Pappone C, Vicedomini G, Frigoli E, Giannelli L, Ciaccio C, Baldi M, et al. Irrigated-tip magnetic catheter ablation of AF: a long-term prospective study in 130 patients. Heart Rhythm. 2011;8(1):8–15. 14. Miyazaki S, Shah AJ, Xhaet O, Derval N, Matsuo S, Wright M, et al. Remote magnetic navigation with irrigated tip catheter for
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15.
16.
17.
18.
19.
ablation of paroxysmal atrial fibrillation. Circ Arrhythm Electrophysiol. 2010;3(6):585–9. Okumura Y, Johnson SB, Bunch TJ, Henz BD, O’Brien CJ, Packer DL. A systematical analysis of in vivo contact forces on virtual catheter tip/tissue surface contact during cardiac mapping and intervention. J Cardiovasc Electrophysiol. 2008;19(6): 632–40. Steven D, Rostock T, Servatius H, Hoffmann B, Drewitz I, Mullerleile K, et al. Robotic versus conventional ablation for common-type atrial flutter: a prospective randomized trial to evaluate the effectiveness of remote catheter navigation. Heart Rhythm. 2008;5(11):1556–60. Kautzner J, Peichl P, Cihak R, Wichterle D, Mlcochova H. Early experience with robotic navigation for catheter ablation of paroxysmal atrial fibrillation. Pacing Clin Electrophysiol. 2009;32 Suppl 1:S163–6. Di Biase L, Wang Y, Horton R, Gallinghouse GJ, Mohanty P, Sanchez J, et al. Ablation of atrial fibrillation utilizing robotic catheter navigation in comparison to manual navigation and ablation: single-center experience. J Cardiovasc Electrophysiol. 2009;20(12):1328–35. Wazni OM, Barrett C, Martin DO, Shaheen M, Tarakji K, Baranowski B, et al. Experience with the hansen robotic system for atrial fibrillation ablation – lessons learned and techniques modified: Hansen in the real world. J Cardiovasc Electrophysiol. 2009;20(11):1193–6.
Strategies for Restoring Cardiac Synchrony by Cardiac Pacing
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Gabriel Cristian, Ecaterina Bontas, Liviu Chiriac, Silviu Ionel Dumitrescu, and Ion C. T¸intoiu
Abstract
As already demonstrated, the restoring of cardiac synchrony is a complex process which implies a detailed assessment of the pathology that needs to be restructured (such as cardiac conduction abnormalities, heart failure) and a particularized analysis of pacing alternatives. In brief, this predecisional analysis involves the anticipation of the hemodynamic response for each type of cardiac pacing. The two most corrected pacing parameters are the atrioventricular and interventricular delay; however, their optimization process is often difficult because of the lack of an exclusive pacing system optimization by which the cardiac parameters can be improved. In general, the optimization methods are classified as echocardiographic and non-echocardiographic methods, but the most used is the echocardiographic evaluation. Cardiac resynchronization therapy is basically the pacing of the free wall region of the left ventricle with a lead. It is of interest that the transvenous approach is the most frequently utilized method. Even so, the right ventricle apex lead insertion may have negative effects on the cardiac function as a result of negative effects on myocardial contractility. Conversely, the left ventricle lead insertion may have variable effects that depend on various factors such as coronary sinus anatomy, the degree of atrioventricular and interventricular dyssynchrony, and location of scars due to myocardial infarction. Lastly, cardiac pacing is the key element for assessing the responder or nonresponder status in case of patients diagnosed with heart failure, being achieved by a team that includes an electrophysiologist and a specialist in cardiac hemodynamic assessment by echocardiography. Keywords
Dyssynchrony • Cardiac pacing • Asynchrony • Device optimization • Cardiac resynchronization therapy • Leads • Pacemaker
G. Cristian, MD, PhD, FESC • L. Chiriac, MD, PhD, FESC “Acad. Vasile Candea” Emergency Clinical Center for Cardiovascular Diseases, “Titu Maiorescu” University, Faculty of Medicine, Calea Plevnei 134, Bucharest, Romania E. Bontas, MD “Prof. Dr. C.C. Iliescu” Institute for Cardiovascular Diseases, Sos. Fundeni 258, Bucharest, Romania S.I. Dumitrescu, MD, PhD “Acad. Vasile Candea” Emergency Clinical Center for Cardiovascular Diseases, “Titu Maiorescu” University, Faculty of Medicine, Calea Plevnei 134, Bucharest, Romania A.S. Kibos et al. (eds.), Cardiac Arrhythmias, DOI 10.1007/978-1-4471-5316-0_44, © Springer-Verlag London 2014
I.C. T¸intoiu, MD, PhD, FESC (*) “Acad. Vasile Candea” Emergency Clinical Center for Cardiovascular Diseases, “Carol Davila” University of Medicine and Pharmacy, “Titu Maiorescu” University, Faculty of Medicine, Calea Plevnei 134, Bucharest, Romania e-mail:
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Introduction Theoretically, the normal human heart has a synchronous activity between electrical and contractile activity of the cardiac muscle. The physiological pacemaker of the human heart known as the sinoatrial node (SAN) was firstly described in 1907 by Arthur Keith and Martin Flack [1]. As a result, this natural pacemaker generates the normal sinus rhythm that is spreading all over the right atrium and the left atrium, determining the contraction of both atria myocardium. Further, electrical impulse is transmitted forward to the atrioventricular node (AVN) and its distal part named bundle of His that divides inside the interventricular septum, in two branches, into left bundle and right bundle branches. The electrical impulse generated by the SAN has a relative rate of 60–100 bpm, and this electrical activation usually arises within 40 ms through the Purkinje fibers being considered a synchronous regional mechanical contraction. In fact, AVN delays the electrical impulse with 40 ms with the direct benefit of a synchronous mechanical contraction of the atria and the ventricles. It should be stressed that a normal heart has a synchrony between electrical and contractile activity of the cardiac muscle. If the activity of SAN fails or is blocked, the AVN will become the heart’s pacemaker [2]. Again, if the AVN stops, Purkinje fibers or the bundle of His is able to overtake its activity as the pacemaker. As expected, myocardial diseases may induce alterations in cardiac structure and its function that may give rise to regions with early and late contraction, known as dyssynchrony [3]. These associations are well known from a long time, and heart failure due to various mechanisms has allowed the research of various parameters of dyssynchrony concerning electrical and mechanical activity with negative consequences upon cardiac function. The mechanical efficiency of the heart may be disturbed by a disruption of the physiological relations between atrial and ventricular contraction (atrioventricular dyssynchrony or AV dyssynchrony), among the right ventricle and the left ventricle contractions (interventricular dyssynchrony or VV dyssynchrony), and in the normal sequence of activation and contraction of segments of the LV wall (intraventricular dyssynchrony or IV dyssynchrony) [4]. Basically, the dyssynchrony is defined as the nonsynchronous myocardial contractions which may comprise three mechanisms [5]: the primary electrical dyssynchrony or electrical conduction delay due to non-homogeneous synchronization of myocyte depolarization, the primary mechanical dyssynchrony or abnormal myocardial contractility and load with local blockage in initiation of the systole, and the excitation–contraction coupling abnormalities. So far, the primary electrical dyssynchrony is typically illustrated by left bundle branch block (LBBB), but the primary mechanical dyssynchrony is usually represented by ischemic process [6]. Conversely, it is accepted that the electrical dyssynchrony (prolonged QRS complex) is not the
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same with the mechanical dyssynchrony, and in reality significant dyssynchrony may be demonstrated on echocardiograms associated with narrow QRS duration on ECG. Also, the heart failure with impaired left ventricle ejection fraction can show damaged electromechanical coupling, which may further damage left ventricle function [7]. Importantly, electrical dyssynchrony leads to mechanical dyssynchrony that further may cause the alteration of cardiac function proven by the benefits of pacing devices [8]. As a rule, this electromechanical coupling process takes place in the interatrial, atrioventricular, intraventricular, and interventricular levels, and the development of dyssynchrony at any level may be isolated or coexistent (Fig. 44.1). Moreover, the term asynchrony is identical with the term dyssynchrony, but it is not the same thing with dyssynergy [9]. Of note, dyssynergy indicates variation in cardiac function illustrated by the peak systolic velocity or strain parameters [10, 11]. Similarly, gaps in synchronizing of the segmental mechanical activity may not be exactly attributed to the electrical activation delay. No matter of dyssynchrony mechanism, there is a dyssynchronous left ventricle contraction that leads to decreased left ventricle systolic function with enlarged left ventriclular endsystolic volume and delayed relaxation [12]. As a result, a decreased diastolic filling time with mitral regurgitation can be initiated or enhanced by the incoordination of papillary muscle contraction [13]. Finally, the impaired systolic and diastolic ventricular function may induce severe heart failure. Intraatrial and interatrial dyssynchrony are usual anomalies of heart failure [14, 15]. It seems that underlying advanced atrial myocardial disease and previous surgery such as mitral valve replacement or maze procedure are often associated with intra- and interatrial dyssynchrony. Atrioventricular dyssynchrony (AV dyssynchrony) defines the dyssynchrony between both the sinoatrial node and the atrioventricular node that often generates an increased atrioventricular conduction delay. Furthermore, sinus node dysfunctions may induce a chronotropic failure that determines the AV dyssynchrony delay between atrial and ventricular contraction [4]. Therefore, the consequences are same for both situations with shortened ventricular filling time [16], with atrial contraction overlaid on early passive filling, and reduced left ventricle filling. Secondary, diastolic mitral regurgitation may develop [4]. AV dyssynchrony is often a diagnosis of patients with heart failure [17], dilated cardiomyopathy, or the first-degree atrioventricular block [18]. Interestingly, the primary goal of cardiac resynchronization therapy (CRT) was AV dyssynchrony by bicameral pacemakers in the early 1990s [18]. Recall that the atrioventricular node delays the electrical impulse with 40 ms in a normal heart with a synchronous mechanical contraction of the atria and the ventricles. Therefore, longer AV delay produces a delayed onset of ventricular systole with decreased diastolic filling time [19] and may cause the joining
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Fig. 44.1 The levels of dyssynchrony and the corresponding optimization targets in dilated cardiomyopathy
of the E wave and A wave of mitral valve inflow. This further causes the development of left ventricle–atrial pressure gradient due to increased left ventricle end-diastolic pressure with partial mitral valve closing [18]. Consequently, it decreases the preload and the filling of the left ventricle [20], higher pulmonary capillary wedge pressure, lower cardiac output, lower systolic blood pressure [21], and late diastolic mitral regurgitation. Accordingly to published data, pacing with short AV delay at an interval of 100 ms may abolish diastolic mitral regurgitation in these patients [16]. Alternatively, a shorter AV delay triggers earlier ventricular contraction with increased diastolic filling period and with separated E wave and A wave of the mitral valve inflow. In spite of this, enddiastolic filling is stopped by the beginning of ventricular systole and by the earlier mitral valve closing, revealed by the truncation of A wave at echocardiographic evaluation. Interventricular dyssynchrony or VV delay is the asynchrony between the right and the left ventricle that happens when both ventricles do not contract simultaneously, and a postponed contraction of the left ventricle compared with the right ventricle occurs [22]. It is often in addition to the left bundle branch block when the contraction of the right ventricle precedes the left ventricle contraction, causing abnormal septal motion, inconsistent left ventricle contraction, and a reduced left ventricle ejection fraction. Interventricular conduction delay varies broadly in patients with heart failure [23]. Normally, the right ventricular contraction occurs before the left ventricular contraction by milliseconds [24]. Clearly, this dyssynchrony leads to premature contraction of the right
ventricle that shifts interventricular septum toward the left ventricle giving rise to asynchrony inside the left ventricle [25]. The asynchronous electrical activation of the left ventricle has a distorted contraction model. To begin with, the septum decreases during the isovolumic contraction period, triggering an early systolic contraction of the posterolateral wall [26]. Obviously, a poor interventricular septal motion may influence its involvement to left ventricle ejection [4]. Moreover, the load alterations of a single ventricle induce the pressure variation of another ventricle [27]. At the present moment, CRT may partially diminish the electrical asynchrony by cardiac pacing. The last class of CRT devices permits to adjust the interval between the right and left ventricle (VV interval) reproducing the normal process [28]. By convention, a negative value specifies that the left ventricle contraction comes before the right ventricle contraction. Intraventricular dyssynchrony (IV dyssynchrony) suggests the variation in the synchronization of myocardial parts [8]. When a part of the left ventricle is too early activated, numerous regions with different timing of contraction occur causing an impaired left ventricle function [29]. As previously demonstrated, the left ventricle uses a significant energy to modify its shape but fails to eject proper volume of blood with IV dyssynchrony [30, 31]. As well, it is important to underline that IV dyssynchrony commonly implicates papillary muscles causing mitral regurgitation [30, 31]. Current research suggests that IV dyssynchrony is an important pathophysiological abnormality that leads to the heart failure progression.
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Without a doubt, CRT is a successful therapy for heart failure from 25 years [32]. However, as previously stated, cardiac pacing has been utilized as therapy of bradyarrhythmias from over 50 years [5]. In particular, cardiac pacing is based on the discharge of an electrical discharge from an electrode placed directly on the myocardium, and further, with the initiation of the cardiac contraction [33]. The perfect cardiac pacing system for arrhythmias and conduction disorders will be the one which is able to reproduce the native physiological conduction system, a hard thing to obtain, since there is not yet an optimal system to achieve this goal. It is important to state that nowadays, CRT is a well-known therapeutic option for severe heart failure with ventricular conduction delay unresponsive to drugs [34, 35]. As can be appreciated, CRT devices are designed to improve left ventricle function by reestablishing the cardiac synchrony from atrioventricular, interventricular, and intraventricular levels, which later rises left ventricle filling period, diminishes mitral regurgitation with septal dyskinesis restitution [36]. As discussed above, the benefits derived from CRT utilized in heart failure with coexistent intraventricular conduction delay or LBBB are considerable alongside the improvement of left ventricle function [37–39]. Even further, cardiac pacing is well related to invert ventricular remodeling from heart failure disease [38–47]. For instance, experimental research data confirms that CRT decreases regional and global molecular remodeling by consistent activation of stress kinases and decreasing apoptosis [48]. Despite the encouraging results and beneficial response to CRT that it is similar to medically treated heart failure patients [49, 50], the individual responses to CRT vary significantly [51]. The reaction to CRT counts on many features, for instance, the left ventricle dyssynchrony, optimization of the AV interval and IV interval, the LV pacing lead location, or the extent and location of nonviable scarred tissue [10, 52–57]. A positive answer to CRT is defined as reverse left ventricle remodeling that is the decreasing of left ventricle end-systolic volume (LVESV) greater than 10 %. In fact, responders to CRT are described as patients with a reduction over ≥15 % in LVESV over 6 months of reexamination [58]. When patients with CRT have a decrease in LVESV ≥30 %, they are called superresponders [59]. This subgroup of patients showed the highest survival rates. More importantly, the study demonstrated that long-term survival after CRT device was independently determined by the extent of LV reverse remodeling [59]. Also, patients with a significant recovery of left ventricle ejection fraction ≥5 % after 3 months from CRT are called echocardiographic responders [60]. Therefore, according to these data, reverse remodeling of the left ventricle is an accurate surrogate end point to evaluate the usefulness of cardiac resynchronization therapy in heart failure treatment in contrast with clinical parameters [61].
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Conversely, it is essential to take into consideration that over 30 % of patients with CRT are nonresponders [30, 50, 62]. Interestingly, about a third from patients with an increased QRS interval does not demonstrate interventricular or intraventricular dyssynchrony [63, 64]. However, the left ventricular end-diastolic diameter ≥75 mm, ischemic heart disease, and severe mitral regurgitation are identified as independent clinical predictors for nonresponders to CRT [62]. The goal of CRT is coordination of the left ventricle contraction by cardiac pacing with the latest activated segment from the left ventricle, obtaining a superior synchronization of every left ventricle segment in systole. It follows from above that CRT causes increased stroke volume, stabilizes the diastolic filling time, and diminishes mitral regurgitation by synchronized papillary muscle activation. Indeed, patients with conduction abnormalities as wide QRS complex, low left ventricle ejection fraction, and symptomatic heart failure benefit from CRT [50]. During performing the cardiac pacing, it is necessary to do the optimization process that is very important for the improvement and the recovery of cardiac function parameters. Clearly, the goal of the optimization process at different dyssynchrony levels (Fig. 44.1) is to improve the heart failure of patients. This cardiac optimization process is carried out by multiple evaluation techniques for cardiac dyssynchrony, mostly by echocardiographic and non-echocardiographic evaluations. On the other hand, the best method for device optimization is not established. Undoubtedly, the best optimization method should be noninvasive, easy to be applied in clinical settings, and reproducible. The most used optimization method is echocardiographic evaluation, even if it has disadvantages being time-consuming and operator dependent [65]. Invasive hemodynamic assessment of cardiac optimization remains the gold standard, although it may have technical complications and is not appropriate for the clinical follow-up that needs constant optimizations at different periods of time [65]. Ideally, CRT implies both pre-implant evaluation of dyssynchrony and the clinical follow-up with frequent optimizations at different periods of time. Briefly, AV dyssynchrony is accomplished by correcting the AV delay so that the atria and the ventricles work together, and VV dyssynchrony is corrected by changing the VV interval so that the right ventricle and the left ventricle operate together. Usually, the right ventricle contracts earlier than the left ventricle by 20 ms. Intraventricular dyssynchrony is best accomplished by a good location of catheter often on the lateral and posterolateral walls so that the segments of the left ventricle perform altogether.
Assessment of Optimization Methods Optimization process starts with a comprehensive assessment of comorbid conditions that may make implantation difficult or reduce response rates. Obviously, imaging
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Table 44.1 Outline of atrioventricular (AV), interventricular (VV), and intraventricular (IV) optimization techniques AV optimization Echocardiographic methods 2D echocardiography LV systolic function LV dP/dtmax LVOT-VTI Aortic VTI LV diastolic filling Iterative method Ritter method Mitral inflow VTI Meluzin’s method LV global function MPI TDI 2D-STE (strain, strain rate) RT3DE
VV optimization
IV optimization
2D echocardiography LV systolic function LV dP/dtmax LVOT-VTI Aortic VTI LV diastolic filling Iterative method Ritter method Mitral inflow VTI Meluzin’s method LV global function MPI PW TDI 2D-STE RT3DE
M-mode: SPWMD M-mode and PW Doppler: LWPSD M-mode and color TDI
PW TDI Color TDI-derived SRI Color TVI 2D-STE (strain, strain rate) RT3DE
Non-echocardiographic methods Invasive dP/dtmax Invasive dP/dtmax Impedance cardiography Radionuclide ventriculography Acoustic cardiography Finger photo-plethysmography Invasive LV pressure–volume loops Surface ECG Finger photo-plethysmography Impedance cardiography Surface ECG (QRS morphology) Acoustic cardiography CCT Blood pressure CMR SPECT Intracardiac electrograms or device-based algorithms (IEGM) QuickOptTM Smart DelayTM SonR QuickOptTM NICOM SonRTM NICOM EEHFTM
Invasive dP/dtmax Radionuclide ventriculography CCT CMR
VTI velocity–time integral, MPI myocardial performance index, RT3DE real-time 3D echocardiography, TDI tissue Doppler imaging, TVI tissue velocity imaging, STE speckle-tracking echocardiography, IEGM intracardiac electrograms, ECG electrocardiogram, NICOM noninvasive cardiac output measurements, CCT cardiac computed tomography, CMR cardiac MRI, SPECT single-photon emission CT, PW TDI pulsed wave tissue Doppler imaging, SPWMD septal-posterior wall motion delay, EEHF Expert Ease for Heart Failure, LWPSD lateral wall postsystolic displacement, 2D-STE 2D speckle-tracking echocardiography
techniques and electrophysiological evaluation, including baseline electrocardiogram (ECG) and history of arrhythmias or prior device therapy, are significant to carry out the pacing device selection, lead placement, and programming of the implanted device [32]. Conventionally, only wide QRS interval (>120–150 ms) on ECG was considered a marker of LV dyssynchrony in large trials [38, 50, 66–69]. However, it seems that the longestablished marker of left ventricle dyssynchrony that was a QRS complex over >120–150 ms does not effectively distinguish left ventricle dyssynchrony [70–74]. What is more, numerous studies confirmed that severe LV dyssynchrony is associated with narrow QRS interval in 20–50 % of cases [70–72, 74]. Of note, the greatest benefit from CRT is for patients with QRS complex ≥150 ms [75–78].
Several methods are designed for the optimization of dyssynchrony at atrioventricular, interventricular and intraventricular levels (Table 44.1). Despite the fact of a poor accord among various methods accessible for asynchrony diagnosis [79], the most used method is echocardiography because it is noninvasive and easily performed and offers relative good information about cardiac function evaluation after the use of different pacing techniques. Indeed, echocardiography may correspond to catheter-based techniques but without the risks and cost of these invasive procedures [80]. New indices such as tissue velocities, torsion, and deformation (strain and strain rate) release distinctive possibilities to evaluate global and regional myocardial performance. RT3DE (real-time three-dimensional echocardiography) has recently emerged into routine practice
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and provides unique anatomic perspectives unobtainable heretofore. Apart from non-echocardiographic techniques, the invasive procedures represent the gold standard because they provide accurate information about the cardiac function. However, it is difficult to carry them out for each step of optimization process. Other non-echocardiographic methods stated by current evidence are the surface electrocardiogram (ECG), the intracardiac electrogram (IEGM), cardiac computed tomography (CCT), cardiac magnetic resonance (CMR) [81], scintigraphy [82], single-photon emission computed tomography (SPECT), finger plethysmography, acoustic, and impedance cardiography [83], etc. Conversely, present trend on diagnostic work-up of optimization often involves techniques based on intracardiac electrograms (Smart Delay, Quick Opt) that are using an algorithmic principle that is included in the device structure (device-based algorithm). For instance, the newest emerged are SonR and NICOM systems. In this view, it should be emphasized that the optimization process has no standard cutoff values, and consequently there are still many questions regarding the best technique of optimization assessment at levels of dyssynchrony (AV, VV, and IV).
Echocardiographic Methods Various methods are certified for the diagnosing and measuring of the left ventricle asynchrony in patients with CRT. Among these numerous methods, echocardiography is regarded as the most valuable diagnostic method in the assessment of heart failure for detection of LV dyssynchrony [84, 85]. Therefore, it is important to underline the recognized role of echocardiography in CRT assessment [86]. Latest studies pointed out that election of patients highly responsive to CRT is achievable with the newest echocardiographic techniques [36] (Table 44.1). Echocardiographic evaluation before and after cardiac pacing comprises standard and/or specific applications extending from M-mode, pulsed wave Doppler (PW Doppler), continuous wave Doppler (CW Doppler), pulsed wave tissue Doppler imaging (PW TDI), the offline analysis of color-coded tissue Doppler imaging, strain imaging, and RT3DE (real-time 3D echocardiography) [4, 36, 42, 87, 88]. The most valuable echocardiographic and non-echocardiographic methods to detect LV asynchrony in CRT patients are highlighted and summarized in Table 44.1. On this basis, a large number of echocardiographic indices are regarded as parameters of successful CRT [89]. To sum up, the most frequently utilized echocardiographic techniques to evaluate left ventricle dyssynchrony and optimization can be classified as M-mode echocardiography, pulsed wave tissue Doppler imaging, color-coded tissue Doppler imaging, tissue synchronization imaging (TSI), and strain imaging by TDI, 2D-STE, and RT3DE.
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M-Mode Echocardiography Without bias, M-mode is the simplest method to quantify LV dyssynchrony along one line of interrogation with the ultrasound beam. The advantages of M-mode echocardiography are significant. Firstly, its superior temporal resolution is greater than 2D echocardiography with a frame rate of 30–100 frames per second [90]. However, it can only show the dyssynchrony of the anterior septum or posterior wall. Technically, M-mode is using two echocardiographic views: parasternal long-axis view of the left ventricle and parasternal short-axis view of the mid-ventricular level (papillary muscle level). By using M-mode echocardiography, it can be determined by two dyssynchrony indices: septal-toposterior wall motion delay (SPWMD) and lateral wall postsystolic displacement (LWPSD). SPWMD measures intraventricular mechanical delay (IVMD) by locating the M-mode cursor at the base of the left ventricle, vertical on the interventricular septum, and posterior wall at the mid-ventricular level (papillary muscle level), from the parasternal long-axis view of the left ventricle or the parasternal short-axis view with a sweep speed at 50–100 mm/s. SPWMD is estimated as the measuring of the time interval from the maximum posterior displacement of the interventricular septum to the highest displacement of the LV posterior wall. A value of SPWMD >130 ms means a significant LV asynchrony [91]. However, SPWMD may be false positive in patients with previous septal myocardial infarctions, and it does not take in consideration the evaluation of the lateral wall that is often the latest stimulated site. Importantly, a longer SPWMD is related to extensive reverse remodeling [92]. LWPSD measures IV dyssynchrony, and it is defined as the difference estimated from QRS beginning to peak systolic displacement of the basal left ventricle lateral wall measured by M-mode in the apical four-chamber view and from QRS onset to the onset of transmitral E velocity (mitral valve opening) evaluated by PW Doppler of mitral valve inflow. For instance, a positive value of the difference is a sign of the coexistence of segmental postsystolic contraction and diastolic relaxation [93]. It appears that LWPSD could predict CRT response but studies are needed.
Pulsed Wave Tissue Doppler Imaging (PW TDI) and Color-Coded Tissue Doppler Imaging (Color-Coded TDI) Pulsed wave tissue Doppler imaging (PW TDI) and colorcoded tissue Doppler imaging (color-coded TDI) are both derived from TDI. Consequently, TDI uses PW TDI or color TDI, and it is based on the evaluation by autocorrelation technique of the mean myocardial instantaneous velocities which are low velocity (on average <15 cm/s) with highamplitude signals. It has to be noted that signals from intracardiac blood flow determined by classic Doppler have in normal approximately 1 m/s and have low amplitudes. Also, it is worth to be revealed that the myocardial velocities
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Fig. 44.2 Longitudinal strain evaluation by 2D-STE in apical four chambers using Philips, QLAB, segmentation model. During isovolumic relaxation period, about 40 % of global left ventricle untwisting arises (BAL basal anterolateral, MAL medium anterolateral, ApL apical lateral, BIS basal interventricular septum, MIS medium interventricular septum, ApS apical septum)
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Apex ApL
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evaluated by color TDI are about 20 % lower in comparison with the myocardial velocities evaluated by PW TDI [94]. Thus, myocardial TDI quantifies the highest systolic myocardial velocity and the synchronization of this highest velocity with respect to QRS on ECG [95]. It is a method with good spatial resolution but poorer temporal resolution because it needs >100 frames/s. Limitations of TDI include cardiac rotation, translation, and segmental tethering. TDI is very important in the evaluation and dyssynchrony optimization.
Tissue Synchronization Imaging (TSI) Tissue synchronization imaging (TSI) operates with colorcoded time-to-peak tissue Doppler velocities, showing areas of asynchrony in real time by overlaying of sequential motion information on the 2D echocardiographic images [96, 97]. Strain Imaging As already described, myocardial fibers are distributed in two transmural layers, in which subendocardium has a righthanded twist orientation and subepicardium has a left-handed twist orientation. During cardiac cycle, myofiber orientation transforms step by step from a right-handed twist of subendocardium to a left-handed twist of subepicardium [98]. Evaluation of myocardial velocities and myocardial deformation allows the evaluation of myocardial dysfunction in a large number of cardiovascular diseases as coronary artery disease, valvular diseases, hypertension, dilated or non-dilated cardiomyopathy, and amyloidosis [99].
Basically, the motion is described by displacement and velocity, whereas the deformation is described by strain and strain rate. By definition, strain and strain rate estimate myocardial deformation. Myocardial deformation takes place in three-dimensional space, and therefore, strain evaluates tissue deformation in three-dimensional space being defined as the variation in length compared to the initial length, otherwise known also as shortening of myocardial fibers. Strain is unitless being expressed in percent. In relation to the original length, positive strain is expansion and negative strain is reduction. For instance, myocardial thickening during systole is a positive strain. Strain rate is the variation of deformation with reference to time, and the unit of strain rate is s–1. The strain rate is negative during reduction and positive during extension. Historically, Mirsky and Parmley studied the elastic structure of the myocardium by using strain [100]. Subepicardium and subendocardium fibers have longitudinal contraction, but middle fibers have radial and circumferential contraction. In fact, the heart undergoes deformation in three-dimensional space, as in the longitudinal direction with reduction/enlargement, as in the radial direction with thickening/slimming, and as in the circumferential direction with shortening/lengthening. Meanwhile, the torsion motion of the heart develops along with the base and the apex (Fig. 44.2) [101]. Precisely, if the heart is observed from the apex, twisting happens during systole when the apex twists counterclockwise and the base twists clockwise. Consequently, untwisting is the opposed motion that appears in diastole.
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Strain and strain rate are obtained by using color TDI (based on myocardial velocity measurements) and by using 2D-STE (2D speckle-tracking echocardiography) that is a tissue tracking method. Strain derived from tissue velocity measurements using color TDI quantifies the deformation of the myocardium during systole and diastole along the longitudinal axis (best seen in the apical views from base to apex). The method can estimate regional electromechanical delay by offline study of longitudinal strain imaging. The normal values of strain are 15–25 % and of strain rate is 1–1.5/s [102]. Unfortunately, same to all Doppler methods, it is angle dependent [103], along with the fact that the regional left ventricle torsional mechanisms cannot be assessed. Also, cardiac cycle and respiratory movements may induce shifting of the strain curve during acquirement. Strain derived from the tissue tracking method is the newest method that measures strain and strain rate being angle independent and validated against MRI [104, 105]. In fact, this technique is an offline analysis based on 2D speckletracking echocardiography (2D-STE) that is founded on the recognition of tissue speckles. Particularly, the reflected ultrasound echoes from myocardial structures produce an irregular random-speckled pattern that is unique for every region of the myocardium. Speckles in ultrasound images are determined by the interfering of the wave’s energy from erratically distributed scatters, and they are traced during the cardiac cycle step by step. The amount of rotation about a fixed axis of these pixels traced from the basal, mid-ventricle, and apex segments can be plotted over time. Also, averaging rotation of these pixels can offer for each segment a measurement of rotational motion [104, 105]. 2D-STE is angle independent, being achieved at lower frame rates (40–90 frames/s) but with lower accuracy in timing mechanical events as TDI. Further, speckle displacement may be used to estimate tissue velocity and strain [106]. It is evident that 2D-STE permits accurate estimation of left ventricle mechanics, along with regional deformation estimation in circumferential, longitudinal, and radial directions [107– 109]. Consequently, 2D-STE allows the assessment of global left ventricle twist and of the parameters of the left ventricle mechanics in the subendocardium and subepicardium layers [110]. Using offline 2D-STE analysis, speckle-tracking radial dyssynchrony is estimated based on the mid-ventricular short-axis views [111].
Real-Time 3D Echocardiography (RT3DE) Real-time 3D echocardiography (RT3DE) is obtained from one single acquisition, the complete volume data sets in realtime imaging by using the matrix array transducers [112]. Precisely, these real-time images might be analyzed offline. Therefore, the endocardial border is detected by semiautomated edge detection algorithms that create a 3D dynamic mesh of the left ventricle cavity using the voxel data from
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one single acquisition. RT3DE has the capacity to display all left ventricle walls without foreshortening, but also, it permits analysis of regional myocardial function. Moreover, it has high accuracy for global and regional measurement of the left ventricle being validated against the gold standard in diagnostic imaging that is the magnetic resonance imaging (MRI) [113]. Furthermore, RT3DE is superior to cardiac computed tomography in left ventricle ejection fraction and left ventricle volumes evaluation [114]. Because of its highest accuracy in estimation of left ventricle ejection fraction, RT3DE might manage the proper choice of patients for ICD and CRT therapy. In case of dyssynchrony, RT3DE can estimate the systolic dyssynchrony index. Importantly, in line with above information, these echocardiographic methods have many advantages and disadvantages in the evaluation of AV, VV, and IV optimization and mechanical dyssynchrony assessment (Table 44.2).
Evaluation of Left Ventricle Diastolic Function The Iterative Method (Transmitral Flow Method) The iterative method (transmitral flow method) evaluates the optimal AV interval (Fig. 44.3) based on LV diastolic filling using PW Doppler transmitral inflow [38]. Firstly, this method starts with the programming of a long AV delay that usually begins with an AV delay of 200 ms, and then it is reduced step by step with 20 ms until the emerging of A wave truncation [38]. At this moment, optimal AV delay (usually a minimum AV delay as short as 60 ms) is established by gradual rising of the AV delay with 10 ms additions until A wave truncation stops [89]. The smallest AV delay that permits clear separation of E and A waves and ending of A wave at approximately 40–60 ms prior to the beginning of the QRS would be regarded as the best AV interval [116]. The iterative method was utilized for optimizing the AV delay in the case of patients integrated in the CARE-HF trial, and it has proven useful [117]. Conversely, there are no reported outcomes of routinely used AV delay optimization for the left ventricle systolic function or left ventricle remodeling.
Ritter Method (Transmitral Flow Method or Mitral Inflow Method) AV delay optimization is usually completed by the Ritter method [118, 119] that estimates mitral valve inflow using PW Doppler. To begin with, the Ritter method was derived from dual-chamber pacing studies [50, 120–122] that comprised patients with normal left ventricle ejection fraction and atrioventricular block. Later, it was utilized into
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Table 44.2 Advantages and disadvantages of echocardiographic methods for the assessment of mechanical dyssynchrony Methods M-mode echocardiography
Advantages No specific ultrasound equipment is needed Easy to perform
Disadvantages Difficult to determine the timing of inward motion if the wall is akinetic or has plateau in motion Only can assess limited walls (anteroseptal and inferolateral wall)
High temporal resolution (>1,000–3,000 fps) Tissue velocity imaging Pulsed wave Doppler
High temporal resolution Does not require specific ultrasound equipment
Color-coded tissue Doppler
Tissue synchronization imaging
Strain imaging TDI derived
Relatively high temporal resolution (>100 fps) Allows sampling of multiple segments simultaneously from one image Allows further parameter processing by offline analysis (displacement, strain rate, strain) Same as color-coded TDI Enables quick measurement of timing Allows visual assessment of both temporal severity and spatial distribution of time delay by color coding Relatively high temporal resolution (>200 fps for individual wall imaging, >100 for whole apical views) Less affected by translational and tethering motion
Speckle tracking
Less affected by translational and tethering motion Nearly automated analysis: less variability
3D echocardiography
Enables the dyssynchrony assessment in one image Nearly automated analysis Option to display the temporal and spatial distribution of timing in bull’s eye plot
Does not allow simultaneous sampling in multiple segments Requires multiple imaging to map the entire heart Susceptible to translational motion or tethering effect Requires high-end ultrasound equipment Susceptible to translational motion or tethering effect
Same as color-coded TDI Color coding can change substantially depending on time window setting Time-consuming image analysis High angle dependency: difficult in spherical heart Less reproducibility Requires specific software Highly dependent on image quality: not feasible in all patients Less time resolution (>40–80 fps) Requires specific software Highly dependent on 2D image quality: not feasible in all patients Low temporal (15–25 fps) and spatial resolution Requires high-end ultrasound equipment and probe Highly dependent on image quality Incomplete inclusion of dilated apex Requires several regular heart beats: cannot perform in atrial fibrillation or frequent ectopic beats
Anderson et al. [115] with permission
numerous multicenter trials (MUSTIC, MIRACLE, InSync III) [50, 66, 123]. The Ritter method tries to best possible match up the end of atrial contraction with the beginning of ventricular systole [124]. Particularly, the LV diastolic filling ending or the A wave ending has to overlay with mitral valve closing; therefore, the longest LV end-diastolic filling happens before LV systole. In essence, two AV intervals thresholds are considered, prolonged AV period with A wave reduction (AVlong) and small AV period with A wave truncation (AVshort), whereas their influence is assessed on the end-diastolic filling period. Specifically, in case of every AV delay, the period from the QRS beginning to the end of the A wave is calculated. The best AV time is con-
sidered based on the method AVopt = AVshort + [(AVlong + QAlong) − (AVshort + QAshort) [50, 66, 123, 124], in which QA is the time interval from the beginning of QRS to the A wave ending. The abridged equation is AVopt = AVlong − (QAshort − QAlong) [121, 125]. Nevertheless, the significance of the Ritter technique may have limits. It is difficult to be applied on patients with high heart rates [126]. Also, contradictory data support that the hemodynamic benefits are not optimal [127]. Furthermore, it is also difficult to be completed in case of patients with an AV interval <150 ms. In turn, Gold et al. demonstrated in the comparative study of AV optimization methods (QuickOpt and AV-VTI using LVdP/dtmax) that Ritter method has less accuracy [128].
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E IVCT
IVRT
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Mitral inflow VTI
Fig. 44.4 Diagram of mitral inflow VTI method by tracing the envelope of mitral valve inflow (green color) . See text for details Short AV
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Optimal AV A E
Fig. 44.3 Diagram of AV optimization by iterative method. See text for details
Meluzin’s Method or Simplified Mitral Inflow Method An additional technique to synchronize AV interval was proposed by Meluzin, and it consists in the superimposing of the atrial wave ending with mitral valve closing [129] based on the transmitral flow lasting 5–10 s with a measurable mitral regurgitation signal. By definition, it estimates the time between the ending of the A wave and the beginning of mitral regurgitation [26]. Essentially, the best AV interval is obtained with the equation optimal AV = “long AV delay”−“t1,” where “long AV delay” is the AV time that permits a complete ventricular beat reduced by 5–10 ms and “t1” that is the time interval from the A wave ending to the beginning of mitral regurgitation. Unfortunately, data about this optimization method are still lacking. There is a single report that applied synchronization of CRT devices based on the Meluzin’s method [129].
Method of Mitral Inflow VTI (Velocity–Time Integral Method) AV delay optimization is frequently completed with the measure of VTI of flow through the left ventricle outflow tract,
mitral valve (Fig. 44.4), or aortic valve [36, 127, 130–135]. As such, VTI determination is directly proportional to the stroke volume of the left ventricle. In order to understand and operate with these velocity–time integral methods, Jansen et al. [127] estimated AV delay optimization by numerous echocardiographic methods to establish what method causes the greatest invasive LVdP/dtmax calculated with a wire tipped with pressure sensor in 30 patients with heart failure during first day of CRT. Echocardiographic methods applied in this study comprised VTI of mitral inflow, VTI of the LV outflow tract, or VTI of aorta, Ritter method, and diastolic filling time. The highest VTI of mitral inflow is established as technique with highest accuracy compared with the invasively measured dP/dtmax of the left ventricle. Therefore, the best AV interval is related to the biggest VTI. The measurement of the VTI by PW Doppler of the transmitral inflow is a substitute for LV filling volume, but the estimation of stroke volume from the mitral VTI is not accurate. Usually, the mitral inflow VTI is acquired from the apical four-chamber view by PW Doppler, and both diastolic E wave and A wave are integrated in the measuring of VTI.
Diastolic Mitral Regurgitation (Ishikawa) Method Patients diagnosed with heart failure have diastolic mitral regurgitation because of elevated LV end-diastolic pressure. Diastolic mitral regurgitation (Ishikawa) method was developed with the aim to minimize diastolic mitral regurgitation by selecting an optimal AV time in case of patients with DDD pacemakers [136, 137]. By this method, a longer AV interval is elected for generating diastolic mitral regurgitation, and the optimal AV interval is considered the difference from the initial long AV interval of the diastolic mitral regurgitation length. So that, Ishikawa et al. established the formula for calculating the best AV interval using Doppler echocardiography: optimal AV delay = slightly extended AV
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Strategies for Restoring Cardiac Synchrony by Cardiac Pacing
delay – mitral regurgitation length (the period from the atrial kick ending and the mitral valve closing) [136]. Ultimately, the AV delay is increased starting from 65 ms with 25 ms increments with a fixed pacing rate at 70–80 beats/min, and the measurements are carried out at each 5 min pacing cycle [138]. Therefore, an optimal AV delay causes a complete end-diastolic transmitral filling flow before ventricular systole providing the longest filling time [138]. When diastolic mitral regurgitation appears, a better cardiac function may be obtained decreasing AV delay below the PQ interval that generates diastolic mitral regurgitation [136]. The method seems simple and not time-consuming (usually less than 5 min) being useful for the examination of heart failure with BiV [139]. Moreover, there is no important association between the PQ interval that produces diastolic mitral regurgitation and pulmonary capillary wedge pressure in patients with DDD pacemakers [140]. In spite of this, AV sequential pacing may be ineffective or even harmful for patients without diastolic mitral regurgitation [138].
Ismer’s Method It is a complex method based on a bipolar esophageal electrode that provides the left-atrial electrogram together with the PW Doppler of mitral valve inflow; therefore, real-time pacemaker data are provided by the esophageal electrode [141]. As a final point, a difficult method based on the above evaluations is utilized in assessing the best AV interval. Overall, evaluation of the optimal AV delay in line with Ismer et al. [142] is based on next constituents: (1) pacemaker-related interatrial conduction interval (IACT) → VDD pacing, MA-LA measured between right-atrial senseevent marker (MA) and the onset of left-atrial deflection (LA) in esophageal electrogram DDD pacing and SA-LA measured between right-atrial pacing stimulus (SA) and the onset of left-atrial deflection (LA) in esophageal electrogram; (2) left-atrial electromechanical action (LA-EAClong) → measured during a nonphysiologically long-programmed AV delay between the beginning of left-atrial deflection (LA) in esophageal electrogram and the end of the left-atrial contribution (EAC) in transmitral flow; and (3) left ventricular electromechanical latency period (Sv-EACshort) → measured during nonphysiologically short programmed AV delay between ventricular pacing stimulus (Sv) and the end of the left-atrial contribution (EAC) in mitral valve inflow. Derived from above data, optimal AV delay is considered for VDD (atrial triggered) and DDD (atrial paced) mode using next the formulas AVDOPT VDD = MA-LA + LA-EAClong − SvEACshort and AVDOPT DDD = SA-LA + LA-EAClong − Sv-EACshort. Despite its difficulty, this is the single technique that permits independent evaluations of the three AV intervals, such as the pacemaker-related interatrial conduction time, the leftatrial electromechanical action, and the left ventricular
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latency period [141]. Moreover, AV delay optimization by Ismer’s method [142] is confirmed for BiV pacing in addition to the right ventricular DDD pacing. To date, Ismer’s method was applied for AV delay optimization in DDD pacemakers with normal left ventricular function [142, 143].
Evaluation of Left Ventricle Systolic Function Echocardiographic methods using the left ventricle hemodynamics to synchronize AV delay comprise the estimation of stroke volume by PW Doppler or CW Doppler at the level of the LV outflow tract (LVOT) or the noninvasive estimation of LV dP/dtmaxbyCW Doppler of mitral regurgitation [144].
Continuous Wave Aortic Valve Velocity Time Integral (CW Aortic VTI) Variation in aortic VTI determined by CW Doppler can be a substitute for the stroke volume changes which are entirely associated with the LVOT-VTI. Further, aortic VTI determined by CW Doppler is much accurate than VTI of LV outflow tract evaluated by PW Doppler. In this perspective, it is essential to mention that Sawhney et al. compared an empirical AV interval (120 ms) with aortic VTI-optimized AV delay in a one-blind randomized study of 40 subjects that illustrated an upgrading of QOL (quality of life) and of NYHA functional classification over 3 months, in patients with aortic VTI-optimized AV delay [145]. Further, same group studied the aortic VTI-optimized AV delay against Ritter method. Needlessly, the study demonstrated that a greater rise in systolic performance was obtained using aortic VTI-optimized AV delay [119].
Left Ventricular Outflow Tract Velocity Time Integral (LVOT-VTI) It is the most used method for the synchronization of AV delay and VV delay, when the optimal AV interval and the optimal VV interval are described by the largest stroke volume. In simple terms, LVOT-VTI or “stroke distance” by PW Doppler can be estimated by acquiring in the parasternal long-axis view of the left ventricle the diameter of the LV outflow tract to estimate its area. LV outflow tract is examined with PW Doppler in the apical five-chamber view to acquire its VTI. A normal range of LVOT-VTI is 18–22 cm [146]. The result of LV outflow tract area multiplied with its VTI provides stroke volume [147, 148]. Optimal VV interval is the largest LVOT-VTI. Same to AV delay, interventricular interval is modified to enlarge echocardiographic cardiac output. Cardiac output is computed from the product of stroke volume with heart rate. This method is
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ECG
IVCT
IVRT
Sm Time to peak Sm
Am Em
Time to onset Sm
Em
Fig. 44.5 PW TDI where are illustrated: Am myocardial atrial velocity, Em myocardial early diastolic velocity, Sm myocardial systolic velocity, IVCT isovolumic contraction time, IVRT isovolumic relaxation time, time-to-peak Sm, and time-to-onset Sm
confirmed in patients with severe heart failure compared with the Fick oxygen as criterion [149]. On the whole, several limitations are relevant. The echocardiographic acquirement of LVOT-VTI may have significant errors. Also, cardiac output determined by echocardiographic methods varies with cardiac drugs [150], exercise [151], and body position [152]. There are three small studies with no randomization that synchronized VV delay using LVOT-VTI [130, 134], but further randomized studies are necessary for an appropriate interpretation. The InSync III study evaluated the VV optimization obtained by LVOT-VTI (stroke volume) in patients with simultaneous biventricular pacing and showed improvements only in 6MWT versus control group. Also, the results showed no major distinction regarding quality of life or NYHA functional classification [153]. Further, the RHYTHM II ICD trial utilized LVOT-VTI in the synchronization of the VV delay but found no benefits compared with simultaneous ventricular pacing [135].
timing of this peak velocity with regard to electrical activity (QRS on ECG) [95]. PW TDI (Fig. 44.5) estimates the peak annular myocardial velocities in case of intraventricular mechanical dyssynchrony (IVMD) [94]. TDI is applied in assessing the interventricular dyssynchrony in the basal segment of RV free wall and septal and lateral walls of LV, and further, by establishing the time difference in the beginning of RV–LV walls mechanical activation [155]. Two studies synchronized the VV interval using TDI methods [156, 157]. Only one study that attempted the optimization of interventricular asynchrony utilizing strain imaging showed increased cardiac output (4.6 ± 0.3 vs. 4.3 ± 0.3 L/min) [157]. However, it should be established if the estimation of interventricular asynchrony is an efficient method for analyzing the positive outcome in CRT.
Global Evaluation of LV Function Doppler-Derived dP/dTmax
Tissue Doppler imaging (TDI) Tissue Doppler imaging (TDI) is based on the measurement of the myocardial velocities which are low velocity <15 cm/s. As well, TDI operates with pulsed TDI or with color TDI. As well, TDI allows location of the delayed left ventricle segment and may be helpful for the placement of left ventricle lead insertion [154]. In case of dyssynchrony, myocardial TDI quantifies the peak systolic myocardial velocity and the
Atrioventricular delay optimization can be guided by the estimation of the left ventricle dP/dtmax (LVdP/dtmax) that is defined as the peak rate of pressure rise in the left ventricle during isovolumetric contraction being an accurate index of left ventricle function. LVdP/dtmax can be estimated by invasive technique by cardiac catheterization, although it is estimated noninvasively by the CW Doppler of mitral regurgitation signal (Fig. 44.6) [158].
Velocity (m/s)
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Strategies for Restoring Cardiac Synchrony by Cardiac Pacing
ECG
E
E A
A
Mitral regurgitation
4 mmHg
1
2 3
Δt
dp/dt=32/Δt
36 mmHg
Fig. 44.6 Diagram and CW Doppler measurement of the LV dP/dtmax from mitral regurgitation signal, noninvasive method. See text for details
The mitral regurgitation signal acquired by CW Doppler signifies the instant systolic pressure gradient between the left ventricle and left atrium. Therefore, this noninvasive estimation of LVdP/dtmax is carried out on the mitral regurgitation signal by CW Doppler. Firstly, the time difference (dt) is measured between two points from mitral regurgitation signal that the left ventricle typically corresponds between 1 and 3 m/s [158, 159]. After that, the pressure gradient of two points is considered based on the modified Bernoulli equation. Of note, both two points denote left ventricle–left atrium pressure gradients for 4 and 36 mmHg, based on the modified Bernoulli equation (where pressure gradient is 4v2). As a result, dP is a constant of 32 mmHg [160]. A normal value of LVdP/dtmax is considered >1,200 mmHg. The optimal AV interval is the highest value of LVdP/ dtmax; therefore, the AV interval is tailored to generate the maximum dP/dtmax [158]. LVdP/dtmax is load independent, but significant aortic stenosis and systemic hypertension may have normal LVdP/dtmax. Conversely, LV dP/dtmax is markedly reduced in LBBB. Importantly, this index ameliorates with cardiac resynchronization [161], and it has the best consistency with LVOT-VTI in distinguishing the optimal VV interval [162]. Without a doubt, left ventricular dP/dtmax is measured accurately by CW Doppler of mitral regurgitation velocity curves [159] being validated against LV dP/dtmax invasively measured by cardiac catheterization in subjects with heart failure [160].
The method is restricted by the condition of measurable mitral regurgitation signal, even if up to 45 % of patients suitable for CRT do not present mitral regurgitation [163].
Myocardial Performance Index (MPI) or Tei Index It is a global evaluation of systolic and diastolic function [164, 165] being used for the AV interval optimization. The best AV interval is identified by the lowest MPI. MPI is estimated as the sum of isovolumic contraction time (IVCT) and the isovolumic relaxation time (IVRT) subdivided by ejection time (ET) based on the equation MPI = IVCT + IVRT/ET [133, 166]. MPI is unitless. Also, the Tei index is calculated from the ratio of time intervals (a–b/b) where the interval a is formed from the IVCT, ET, and IVRT, and interval b is ET, being averaged of three to five cycles with held end expiration. These values may be adjusted for heart rate, IVCT-c = IVCT/√RR, where IVCT is addressed in milliseconds and RR in seconds [167]. Both equations of MPI = IVCT + IVRT/ET = a–b/b may be derived by four methods [168]. However, at the present, two methods are used routinely during echocardiographic examination. Also, both methods may be applied separately for the left ventricle or the right ventricle to estimate LV-MPI and RV-MPI.
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E
ECG
E IVCT
A
IVRT
A
a
MPI=a–b/b
ET = b
MPI=IVCT+IVRT/ET
b
Tei index by PW Doppler
Fig. 44.7 Diagram of Tei index calculation by PW Doppler method. Isovolumic contraction time (IVCT) is calculated from the end of mitral A wave to the beginning of aortic flow. Isovolumic relaxation time
Measurement of the MPI by Spectral Doppler (Fig. 44.7). MPI by PW Doppler implies acquiring of the mitral valve inflow (E and A waves) by PW Doppler into the apical fourchamber view at mitral valve tip level. Normal MPI of LV by PW Doppler is 0.39 ± 0.09 [164]. Abnormal LV-MPI is >0.50 when IVCT is increasing and ET decreases. Measurement of the MPI by the DTI method (Fig. 44.8) is based on using PW DTI at mitral annuli in the apical fourchamber view with the sample volume placed in the basal segment of interventricular septum. The early diastolic wave (Em) and late diastolic wave (Am) and the systolic wave (Sm) are measured with their peak velocities. It seems that estimation of MPI by DTI method is a regional measurement and may not be an index of the global ventricular function. Also, it has been observed that by this DTI method, the systolic periods are longer and the diastolic periods are shorter [169]. MPI is notably correlated with the maximum rate of pressure rise (dP/dtmax) during isovolumic systole, with peak rate of pressure decrease (peak − dP/dtmax), and with the time constant of pressure reduction during isovolumic relaxation time (tau), stating that it is a reliable measure of the globally left ventricle function [170]. Two published surveys have optimized CRT using MPI [133, 171]. Both applied MPI in AV and VV delay optimization, although it seems to be the index that provides information about both systolic and diastolic functions, and it is relatively easy to calculate. Both studies of AV and VV delay optimization did not have randomization or well-defined end points [133, 171].
(IVRT) is considered from the end of aortic flow to the beginning of the mitral E wave. Ejection time is the period from the start to the end of aortic flow
ECG IVCT
IVRT
a MPI=a–b/b MPI=IVCT+IVRT/ET
Sm
Am Em
b
Em
Tei index by DTI
Fig. 44.8 Diagram of Tei index calculation by TDI method. See text for details
Non-echocardiographic Methods Invasive Methods Invasive Left Ventricle dP/dtmax (LV dP/dtmax) Invasive LV dP/dtmax assesses the acute hemodynamic consequences of CRT, by the evaluation of the peak first time secondary to the LV pressure curve [172] during the isovolumic
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Strategies for Restoring Cardiac Synchrony by Cardiac Pacing
contraction time of cardiac cycle. LV dP/dtmax is a good surrogate for LV function [173, 174]. Moreover, LV dP/dtmax is an accurate method for assessing dyssynchrony [175]. Even if the acute rise of LVdP/dtmax (or highest LVdP/dtmax value) is considered as a preference in assessing the acute response to CRT or recent optimization methods [127], a gold standard criterion for resynchronization is still not available or recommended [176]. Based on published data, LVdP/dtmax may carry out optimal placement of the LV lead [177] and may optimize AV and VV delay [178–182]. To avoid heart rate control on the LVdP/dtmax, pacing of atrium at five to ten beats over the native rate is needed. Conversely, to assure constant capture in case of atrial fibrillation, ventricular pacing/stimulation is achieved over the intrinsic rate. The optimization process starts with a baseline LVdP/dtmax estimated and stabilized over a number of cardiac cycles with the elimination of premature and post-extrasystolic beats. The initial LVdP/dtmax determination is preceded by AV optimization that is accomplished initially during CRT. After the best AV interval with the maximum value of LVdP/dtmax is elected, then VV optimization is achieved. According to published data, invasive LVdP/dtmax is correlated to clinical consequences of CRT patients on long term [176, 183]. It remains to be established if guided CRT optimization by LVdP/dtmax optimization improves individual outcome [176], even if the invasive determination of LV dP/dtmax is restrictive.
LV Pressure–Volume Loops Stroke work resulting from merged estimation of LV pressure and volume (pressure–volume loops) may be regarded as superior compared with LV dP/dtmax since it integrates the LV function during the cardiac cycle [184]. The conversion of intraventricular signal in pressure loop is done by specialized software and covers the systolic and diastolic phases of cardiac cycle [185]. Consequently, the study of Kass et al. evaluating the optimization efficacy of LV dP/dtmax and pressure–volume loops demonstrated that these methods are useful and equal in the initial stage of CRT implantation [186]. Unfortunately, in terms of longtime hemodynamic response, the data of studies are not convincing to do a comprehensive approach [26].
Device-Based Algorithms SMART-AV (Boston Scientific Corporation, St. Paul, MN, USA) SMART-AV is an electrogram optimization process that calculates the best AV interval using the sensing and pacing of native AV delays with the extent of intrinsic VV interval based on the intracardiac electrograms (IEGMs). Basically, SMART-AV is based on the use of thoracic electrical bioimpedance known as impedance cardiography (ICG).
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Impedance cardiography was originally designed to synchronize AV interval from dual-chamber pacemakers [121, 187] by estimating the variations of the impedance when an alternating current is put on the patient thorax. Impedance variations denote the cardiac output. Using this type of intracardiac electrogram, the synchronization of AV delay evaluates the electrical conduction intervals (QRS duration, AV delay) with the aim to increase left ventricle hemodynamics [188]. IEGM was initially utilized for the synchronization of AV interval in subjects with dual-chamber pacemakers [121, 187]. However, it has already established a good correlation between Smart Delay’s determinations and echocardiographic measurements through aortic VTI and mitral valve inflow (Ritter) techniques, except with the fact that the greatest association was with LV dP/dtmax determined invasively [128]. Further, Gold et al. evaluated on 28 patients, the AV optimization by echocardiographic methods (Ritter and aortic VTI) against electrogram optimization algorithm (SMART-AV). They confirmed a superior correlation between SMART-AV and LV dP/dtmax [128]. Another randomized, multicenter trial (SMART-AV) applied on 1,014 patients who received CRT-DI evaluated the AV optimization by Smart Delay compared with echocardiographic methods and a fixed empirical AV interval of 120 ms. The conclusion was the synchronization of AV interval by Smart Delay is not inferior to other methods and may be utilized in nonresponders to CRT [188].
QuickOptTM (St. Jude Medical, St. Paul, MN, USA) QuickOpt or timing cycle optimization is an automatic programming algorithm for best synchronization of AV interval and VV interval derived from the measurement of a native atrial depolarization with the help of a right-atrial electrode electrogram. Also, QuickOpt may optimize AV and VV intervals for responders and nonresponders with great time efficiency for routine practice. Synchronization of both AV and VV intervals by means of an IEGM technique has newly been explained [189]. Optimization with QuickOpt can increase outcomes of patients with CRT by suggesting optimal AV and VV intervals. Importantly, it is clinically proven that QuickOpt correlates with echocardiography-based optimization. For instance, the study of Gold et al. showed that QuickOpt is correlated with estimated synchronized AV intervals using aortic VTI ranges, excluding the association with invasive estimations as LVdP/dtmax or other echocardiographic methods [128]. Subsequently, the preliminary data of FREEDOM trial shows that QuickOptTM optimization has improved clinical response in higher percentage (71.3 %) in comparison with conventional treatment (68.8 %) at patients with CRT-D device, even if these data are not statistically
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significant. Moreover, the highest benefit from QuickOptTM optimization is for nonresponder patients with CRT [50, 190, 191]. Interestingly, this optimization method demonstrated to decrease LV dyssynchrony and increase systolic function determined by RT3DE [192].
resulting from acute hemodynamic information offered by the PATH-CHF II studies, where the best VV interval is determined by the formula VVopt = −0.333 × (RV−LV electrical delay)−20 ms [199].
SonR (Sorin Biomedica, Saluggia, Italy) SonR® is an automatic system designed for weekly optimization as an alternative to echocardiographic optimization methods, the measurements of SonR being correlated with LVdP/dtmax. It is made of a special sensor fixed in a pacing lead that is inserted with the CRT device. Based on the peak endocardial acceleration (PEA), this sensor senses the mechanical speeding up of the heart via a microaccelerometer positioned in one end of the ventricular pacing lead. Also, the maximum value of the PEA signal changes with myocardial contraction and corrects the device by hemodynamic signals for each patient in part. It should also be emphasized that the CLEAR study showed that the SonR optimization of the device’s atrioventricular and interventricular delays causes a significant improvement of cardiac function at patients with CRT [122, 124, 188, 190, 193].
Synchrony Restoring
NICOM NICOM (noninvasive cardiac output measurement) is a noninvasive technique to acquire hemodynamic assessment, as well as the cardiac output. Overall, NICOM is a portable bioreactance system that it is composed from a device that generates high-frequency (75 kHz) sine waves with four electrodes contained by the left and right side of body [194]. In particular, bioreactance systems evaluate cardiac output by the determination of real-time variations of the recorded signal corresponding to the utilized signal. It permits the regular optimization of the AV interval and VV interval during routine examination visits of all patients with CRT [195]. This device optimization is mainly based on the cardiac output assessment, and its application in case of CRT is connected with the improvement of clinical and echocardiographic parameters [196]. In fact, NICOM system may establish cardiac function indexes as cardiac output, stroke volume, left ventricular ejection time, and systemic vascular resistance with cardiac beat [189, 197, 198].
EEHFTM (Expert Ease for Heart FailureTM Algorithm) EEHFTM estimates VV interval derived from the native VV interval evaluated by the device in the course of insertion. Actually, the Expert Ease for Heart FailureTM algorithm is
The reestablishing of synchrony for the AV, VV, and IV dyssynchrony is usually a complex process that aims to optimize these parameters based on the severity of dyssynchrony for each level and to acquire the best parameters of cardiac performance. The procedures by which CRT achieves the atrioventricular, interventricular, and intraventricular resynchronizations with secondary reverse remodeling of the left ventricle are successively carried out for each level of dyssynchrony. Further, every level of dyssynchrony has specific physiopathological mechanisms (Fig. 44.9), so that the atrioventricular resynchronization in CRT or DDD mode generates decreasing of left-atrial pressure initiating the decrease of left ventricle end-diastolic volume (LVEDV) and the raising of left ventricle filling pressure all along causing benefits to the LV reverse remodeling process. Indeed, an increasing of RV cardiac output is achieved through interventricular resynchronization with significant global outcome on cardiac performance. Also, the intraventricular resynchronization of LV segments causes the increasing of cardiac output by the enhancement of cardiac contraction, the rise of the left ventricle ejection fraction (LVEF), and the rise of the LVdP/ dtmax. Moreover, all these above mechanisms produce mitral regurgitation lessening and left ventricle end-systolic volume (LVESV) decreasing which in conjunction with LVEDV reduction produce reverse remodeling of the left ventricle.
Atrioventricular Delay Optimization Basically, atrioventricular optimization is valuable in case of the patients with atrioventricular block with adequate cardiac function in which a VDD or DDD cardiac pacemaker may be implanted but also in case of the patients with CRT and cardiac failure or ventricular dyssynchrony. In practice, AV optimization is achieved during CRT insertion with an initial empirically setting of AV >120 ms [145, 158, 200]. Therefore, adjusting limits of AV delay include longer or shorter interval at first programming, being optimized for each patient in part (“individualized AV delay optimization”). Thus, a short AV delay determines premature ventricular contractions and interrupts the filling with the early closure of mitral valve. A long AV delay slows down the ventricular contraction with reduction of the diastolic filling. Importantly, AV delay optimization has to enlarge the diastolic filling time with a complete end-diastolic filling time [201].
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Fig. 44.9 The effects of the optimization of each dyssynchrony level are convergent and contribute to left ventricular reverse remodeling. CRT cardiac resynchronization therapy, LA left atrium, MI mitral insufficiency, LVEF left ventricular ejection fraction, CO cardiac output, LA left atrium, LVED left ventricular end-diastolic volume, LVESV left ventricular end-systolic volume, RVCO right ventricular cardiac output (Adapted from Yu et al. [43] with permission)
Interventricular dyssynchrony
559
Atrioventricular dyssynchrony
CRT
Intraventricular synchrony
↑dP/dT, ↑LVEF, ↑CO, (Pulse pressure)
DDD-VDD
Atrioventricular synchrony
↓ MI
↓ LVESV
Intraventricular dyssynchrony
↓ LA pressure
Interventricular synchrony
↑ LV Filling pressure
↑ RVEV
↓ LVEDV
Inverse remodeling
Echocardiographic synchronization may evaluate the optimization of atrial and ventricular mechanical events from estimation of left ventricular filling time (LVFT) ratio, defined as the LV filling divided by the RR interval. The value of LVFT <40 % is typically for AV dyssynchrony [202]. Supporting data for AV delay optimization during CRT insertion are derived from dual-chamber pacing studies. Even if, echocardiographic optimization method is largely used (Table 44.3) the information about improvement in clinical outcome is not sufficient [201]. Furthermore, the initial optimization of AV delay is most likely followed by another one that is different for each patient in part. Invasive dP/dtmax is rarely used despite its higher accuracy for optimal AV delay. Clearly, the PATCH-CHF and PATHCHF II trials demonstrated good outcomes when AV delay optimization by dP/dtmax was evaluated against the empirical AV optimization [76, 178, 208]. AV optimization techniques by using intracardiac electrogram (QuickOpt, Smart Delay) have the benefit of being easy to be used during CRT, although more data are needed for an accurate interpretation. In summary, AV delay optimization methods are numerous, but the absence of an up-to-date general consensus looking their use is still missing.
Interventricular (Ventriculoventricular) Delay Optimization Interventricular dyssynchrony is a prolonged delay between mechanical activations of the RV and the LV. As well, in a normal heart, the depolarization of RV comes first with few milliseconds before of LV. As a consequence, the RV contracts with −20 ms before of the LV, where negative value of VV delay signifies that the LV is initially activated and the positive value means the opposing ventricle. In case of patients diagnosed with heart failure, the VV conduction time may be broad. A value >40 ms for VV delay is abnormal [209]. Values for optimal VV delay are rather restricted, usually being within 20 ms for LV preexcitation [123, 131]. Conversely, the optimization of VV delay (Table 44.4) are based on echocardiographic methods (by cardiac output measuring, TDI), blood pressure, invasive dP/dtmax, radionuclide ventriculography, finger photo-plethysmography, surface ECG, impedance cardiography, acoustic cardiography, and intracardiac electrograms. The most frequent techniques utilized to synchronize VV delay are using the measurement of substitutes for stroke volume, cardiac output, or the mechanical asynchrony measurement.
Myocardial performance index LVOT-VTI
LVOT CO
Ritter method or iterative method
(1) LVPEI, (2) IVD, (3) FTc, (4) MPI
18
21
36
19
5
40
11
30
40
215
26
22
Meluzin et al. [129]
Porciani et al. [132]
Scharf et al. [203]
Riedlbauchova et al. [133]
Inoue et al. [139]
Donnell [204]
Melzer et al. [141]
Jansen et al. [127]
Kerlan et al. [119])
Kedia et al. [205]
Stockburger et al. [171]
Porciani et al. [132]
Myocardial performance index
(2) Ritter method
(1) Aortic valve VTI
(2) DFT (3) Aortic valve VTI (4) Ritter method
(1) Mitral VTI
Ismer’s method
Ritter method
Ishikawa diastolic MR
Mitral inflow
n 40
Reference Sawhney et al. [145]
Echocardiographic optimization method Aortic valve VTI
<24 h
Not stated
<24 h
Not stated
Not stated
Not stated
<24 h
3 months
Timing of optimization after implant <24 h
No mortality difference +9 % of patients ≥1 diastolic stage −27 ms LVPEI, −43 ms IVD, +0.09 FTc, −0.36 MPI −0.40 MPI, 82 % of patients required re-optimization
<1 week
<3 days
<30 days
(1) +19 % aortic <24 h valve VTI, (2) +12 % aortic valve VTI
+0.047 cm/s LVOT-VTI per 10 bum increase per 20 ms increase AV delay +0.6 L/min LVOT CO, +2.7 % LVEF, −1 NYHA +0.8 L/min LVOT CO, +38 ms DFT, −22.2 NYHA 93 % of patients required re-optimization +12 % LVEF, echo dyssynchrony nonsignificant +233 dyn/s (+32 %), (1)> (2)> (3)> (4) correlation with invasive LV dP/ dTmax
Effect of optimization +10 points QOL, +0.6 NYHA, +4.4 % LVEF +0.2 L/min CO by Swan Ganz −0.49 MPI
Table 44.3 Echocardiographic optimization of AV delay in cardiac resynchronization therapy
115 ± 24
Not stated
135 ± 40
119 ± 34
120 ± 26
106 ± 38
126
133 ± 66
140
99 ± 19
97 ± 27
148 ± 17
Yes
No
No
No
Yes
No
Yes
No
Yes
No
Yes
No
Mean AV VV delay delay (ms) optimized 119 ± 34 No
No
No
No
No
No
No
No
No
No
No
No
No
Randomized Yes
No
No
No
No
No
No
Yes
No
No
Yes
No
Yes
Blinded Yes
12
21
13
None
None
None
9
28
6
None
None
None
Mean follow-up (months) 3
Yes
Not stated
Not stated
–
–
–
Yes
Yes
Not stated
–
–
–
Further optimization Yes
560 G. Cristian et al.
28
31
100
33
Gold [128]
Zhang et al. [206]
Vidal et al. [156]
Hardt et al. [207]
LVOT-VTI
Iterative
(1) Ritter method (2) Aortic valve VTI (3) EEHF+ Ritter method
Doppler dP/dtmax
56 % of patients required re-optimization +0.7 L/min CO by aortic valve VTI,+52 m 6MWT +26 m 6MWT, −599 ng/L NT-proBNP
+0.9 NYHA, +4.6 % LVEF Maximal invasive LV, dP/dTmax max using EEHF+
31 ± 8 weeks
24–72 h
<24 h
Not stated
2–4 months
Not stated
137
99 ± 30
134 ± 45
103
No
Yes
No
No
No
No
No
No
No
No
No
No
Yes
No
Single
43 days
6
16
None
6
Not stated
Not stated
Yes
–
Not stated
Stanton et al. [201] with permission AVD atrioventricular delay, CO cardiac output, dP/dtmax maximal change in pressure/change in time, E maximum E wave from mitral inflow, Ea maximum E wave derived from tissue Doppler imaging of the mitral annulus, EEHFa Expert Ease for Heart Failure algorithm, FTc left ventricular filling fraction, IVD interventricular delay, LVEF left ventricular ejection fraction, LVOT left ventricular outflow tract, LVPEI left ventricular pre−ejection interval, MPI myocardial performance index, NT-proBNP N-terminal pro-brain natriuretic peptide, NYHA New York Heart Association, QOL quality of life by Minnesota Living with Heart Failure Questionnaire, VTI velocity–time integral
41
Morales et al. [158]
44 Strategies for Restoring Cardiac Synchrony by Cardiac Pacing 561
Echocardiographic LVOT-VTI Tissue Doppler imaging
20
100
20
34
Radionuclide ventriculography Finger photo-plethysmography
53
22
27
van Gelder et al. [182]
Kurzidim et al. [212] Burri et al. [213] +4 mmHg systolic BP
+3 % invasive dP/dt +0.4 % LVEF
+8 % invasive dP/dTmax
Simultaneous optimal
+26 % LVOT-VTI +3.9 % LVEF +7 % DFT +0.7 L/min CO AV-VTI +0.3 L/min CO by Fick +6 % invasive dP/dTmax
+7.3 6MWT
+8.6 % stroke volume +15.1 m 6MWT +0.8 L/min CO by LVOT-VTI +0.1 NYHA
15.4 ± 10.7
Not stated
Not stated
Discharge: +27.4 ms 3 months: +22.7 ms Not stated
3–30 months
<3 days
−8 ms
Not stated
Ischemic: –52 ms Idiopathic: –28 ms Time of implant −37 ms
<24 h
Time of implant Not stated
Time of implant −25 ms
3 months
24–72 h
24 h
2–5 days
Predischarge
Optimal preexcitation LV/ Sim/RV (%) Not stated 35/28/34
Not stated
44/33/22
64/32/4
83/11/6
33/67/0
75/25/0
14/2/0
72/21/6
45/0/55
60/25/15
38/21/41
61/15/24
None stated 58/19/23
Mean VV delay (ms) 48 ± 14 Not stated
Time of implant Not stated
Predischarge
Timing of optimization after implant 2 weeks Predischarge
FPPG
Ritter method
Invasive dP/dt
Invasive dP/dt
No
Meluzin’s method Invasive dP/dt
Iterative
Ritter method
Ritter method
Ritter method
Ritter method
Ritter method
AV delay optimized EEHF+ Ritter method
No
No
No
No
No
No
No
No
No
No
No
No
No
Randomized Yes Yes
No
No
No
No
No
No
No
No
No
No
No
No
No
Blinded Double Single
None
None
None
None
None
None
None
6
3
6
6
3
6
Mean follow-up (months) 6 6
–
–
−
–
–
–
–
–
Not stated
Not stated
3 months
Not stated
Not stated
Further optimization – No
Stanton et al. [201] with permission 6MWT Six-minute walk test, CO cardiac output, DFT diastolic filling time, EEHF Expert Ease for Heart Failure algorithm, LVEF left ventricle ejection fraction, LVOT left ventricle outflow tract, NYHA New York Heart Association, VTI velocity–time integral, LV left ventricle, RV right ventricle, FPPG finger photo-plethysmography
15
Invasive dP/dtmax
9
Hay et al. [211]
Whinnett et al. [214]
Invasive dP/dtmax Invasive dP/dtmax Invasive dP/dtmax
12
Perego et al. [28]
Tissue Doppler synchrony Strain rate synchrony
Echocardiographic LVOT-VTI Echocardiographic LVOT-VTI
41
359
Optimization method EEHF+ Echocardiographic LVOT-VTI Echocardiographic LVOT-VTI
n 306 121
Novak et al. [157] 16
Vidal et al. [156]
Vanderheyden et al. [134] Sogaard et al. [210]
Bordachar et al. [130] Mortensen et al. [131]
Reference Rao et al. [199] Boriani et al. [135] Leon et al. [123]
Effect of optimization None significant None significant
Table 44.4 Optimization of interventricular delay in CRT
562 G. Cristian et al.
44
Strategies for Restoring Cardiac Synchrony by Cardiac Pacing
Interventricular dyssynchrony may be obviously observed as a large QRS complex on the electrocardiogram [73]. The interventricular mechanical delay (IVMD) is achieved from measuring with PW Doppler of pulmonary blood flow of the RV and aortic blood flow of LV outflow tract. The interval from the QRS beginning to the pulmonary/aortic blood flow onset is considered as RV pre-ejection time period and LV pre-ejection time period. The difference from LV pre-ejection interval to RV preejection interval is an index of IVMD with a cutoff value of ≥40 ms regarded as interventricular dyssynchrony [73, 74]. Briefly, echocardiographic optimization for VV delay has two parts: optimization of LV systolic function by LVOTVTI and optimization of LV mechanical dyssynchrony using next dyssynchrony indices [83]; interventricular dyssynchrony (difference between aortic and pulmonary preejection intervals); time-to-peak systolic velocity by TDI that is time difference between two or four opposing walls; standard deviation of 12 LV segments; radial, longitudinal, and circumferential dyssynchrony by 2D-STE; and systolic dyssynchrony index by RT3DE. Interventricular dyssynchrony is the difference of electromechanical coupling times of RV and LV by TDI [215]. Electromechanical coupling time is the interval defined from the beginning of the QRS complex to the onset of myocardial systolic shortening velocity, determined at the basal segment of the RV lateral wall and the most delayed LV segment. A cutoff value of 56 ms suggests IV dyssynchrony [215]. The modern CRT devices permit the adjusting of VV interval with the reproducing of physiological activation [28]. But, the benefits of VV delay optimization are not established. A summary of large nonrandomized studies has demonstrated benefits from VV delay optimization and improved exercise capacity [123, 131]. Despite these data, large randomized studies (e.g., RHYTHM II ICD, RESPONSE-HF) have been shown the absence of benefits from sequential versus biventricular pacing with optimal VV delay even though VV delay optimization improved LVEF, cardiac output, and stroke volume (Table 44.4) [135, 216]. Also, it has been revealed that reverse remodeling of the left ventricle and enhanced left ventricle function secondary to CRT is connected with decreasing of VV dyssynchrony [215]. Alternatively, the majority of proof advocates that optimization of VV dyssynchrony is not as valuable to anticipate the positive outcomes to CRT as compared with left ventricle IV dyssynchrony [89].
Sequential Versus Simultaneous BiV Pacing Interventricular resynchronization in patients with CRT may be achieved by two ways: simultaneous and sequential pacing of the right and left ventricles. Moreover, current studies revealed higher benefits of simultaneous pacing by improvement of
563
global left ventricular function with mortality regression [50, 66, 217–223]. The DECREASE-HF trial included 360 randomized subjects with LVEF ≤35 % and QRS ≥150 ms, with sequential BiV pacing, simultaneous BiV pacing, and LV pacing based on echocardiographic methods for optimization (LV internal dimension, LV volume, LVEF, Doppler measurements of systolic function, cardiac output, mitral regurgitation, or dP/ dtmax). Transmitral Doppler flow and myocardial performance index demonstrated in both groups of patients decreased LV end-systolic and end-diastolic diameters (p < 0.001) and a raise of the stroke volume (p < 0.01) and of the LVEF (p < 0.001). Clearly, results of the study advocate that there is no distinction between simultaneous BiV pacing and sequentially BiV pacing mode for VV delay optimization [199]. However, all three pacing modes determined recovery in ventricular size and systolic function, and moreover, simultaneous pacing had a higher rise of ventricular volume [199]. On the contrary, there are studies that using sequential pacing showed diminishing of the heart failure and improvement of the systolic and diastolic left ventricular function [210, 224]. It seems that the sequential pacing is a physiological way of resynchronization, since a normal delay of a few milliseconds exists between the right ventricle and the left ventricle. To a great extent, about 422 nonrandomized patients with moderate-to-severe heart failure and prolonged QRS from InSync III had sequential cardiac resynchronization therapy. The results demonstrated that the optimization of the sequential pacing improved stroke volume in 77 % of patients and greater exercise capacity [123]. The benefits of tissue tracking by TDI and RT3DE echocardiography as optimization method were explored on a group of 20 patients with heart failure and LBBB, in which VV resynchronization by simultaneous and sequential pacing were applied too. Interestingly, both pacing methods considerably improved the systolic and diastolic left ventricle function, albeit the sequential CRT had a greater increasing of left ventricular systolic and diastolic performance. Furthermore, tissue tracking is confirmed as valuable method for VV delay synchronization programming during sequential CRT [210]. By contrast, the RHYTHM II ICD study failed to prove the advantage of sequential pacing over the simultaneous pacing [135]. Obviously, even if the results are conflicting, they may be justified by the used optimization methods of the VV delay. However, a new noninvasive method based on the electrocardiography imaging (ECGI) that utilizes electrophysiological response of cardiac depolarization by electrophysiological epicardial imaging for the period of a single beat has emerged [225]. From epicardial data supplied by ECGI, pacing leads position is compared with the equivalent position established from computed tomographic images. Jia et al. examined the benefits of different pacing methods: right ventricular (RV), single LV, biventricular, simultaneous, and sequential (Fig. 44.10). It seems that one patient
564
G. Cristian et al. Left lateral
Anterior
a
RV pacing
(Esyn:–76 ms)
Posterior ms
40
54
68
82
96
110 124 138 152 166 180 194 208 222 QRSd 160 ms
LV pacing
(Esyn:12 ms) QRSd 240 ms
b
Biv simulataneous (Esyn:–73 ms) QRSd 160 ms
c
Biv sequential LV-RV 80 ms
(Esyn:–39 ms) QRSd 230 ms
d
Front
Fig. 44.10 Epicardial isochrones maps during right ventricular (RV) pacing (a), left ventricular (LV) pacing (b), simultaneous biventricular pacing (c), and sequential biventricular pacing (d). During sequential pacing, LV is paced 80 ms earlier than RV. Epicardial surfaces of both ventricles are displayed in three views: anterior, left lateral, and poster. Left anterior descending coronary artery (LAD) shown. The approximate valve region is covered by gray. Thick black markings indicate
Left
Back
line/region of conduction block. All isochrones maps show sequential ventricular activation of the right ventricle (RV) followed by a much delayed left ventricular (LV) activation. Esyn electrical synchrony index (the mean activation time difference between lateral RV and LV free walls and lower absolute value corresponds to greater synchrony), QRSd QRS duration. Pacing sites are marked by asterisks (Jia et al. [225] with permission)
44
Strategies for Restoring Cardiac Synchrony by Cardiac Pacing
Fig. 44.11 The simultaneous and sequential pacing mode of CRT, where LVOT (left ventricular output tract) diameter and VTI (velocity–time integral) of the LVOT by PW Doppler are used to estimate stroke volume and cardiac performance measurement. Using these parameters can be determined interventricular interval delay (VV). Importantly, VV affects stroke volume by the accuracy of VTI regarded as a surrogate marker for resynchronization. In the above picture, it can be seen that the optimal interventricular interval is when RV pacing precedes with 40 ms LV pacing. Conversely, the optimal atrioventricular delay derives from (optimal AS-VP) 40 ms (interventricular interval). AS atrial sensed, LVP monochamber left ventricular pacing (Gassis and Leon [226] with permission)
565
0.785 x diameterLVOT2 x VTILVOT = stroke volume
–80 ms
–40 ms
Simulataneous
+40 ms
+80 ms
VV delay RV pre-excitation
LV pre-excitation
LVOT VTI VV time corresponding to the greatest stroke volume
with simultaneous biventricular pacing from this study was nonresponsive, the ECGI having the same aspect with the RV pacing. In case of sequential biventricular pacing, the first one paced is RV with 30 ms before LV pacing. In spite of this, sequential biventricular pacing of LV produces no benefit. Conversely, biventricular pacing of LV with 80 ms earlier than RV causes same activation for both biventricular pacing and LV pacing, along with better benefits for biventricular sequential pacing in comparison with the simultaneous biventricular pacing, lower efficiency for the RV pacing, and limitation of CRT efficiency by mechanisms same to the electrophysiological and pathological substrate of LV [225]. By this method, the electrical synchrony index (Esyn) that is the difference of average activation time between lateral RV and LV free walls can be achieved. Esyn is a quantitative index attained from the heart surface of interventricular synchrony. As well as, the minimum value of Esyn characterizes a greater synchrony. However, Esyn is not used in the assessment of intraventricular electrical synchrony due to its limitation to offer data about interventricular septum. On the other hand, intraventricular mechanical synchrony is better described by hemodynamic improvement than the interventricular mechanical synchrony [130]. The value of VV delay optimization by simultaneous and sequential CRT (Fig. 44.11) corresponds to the maximum stroke volume and cardiac output (Fig. 44.11).
Taken together, the above data strongly suggest that atrioventricular and interventricular delay optimization is a vital process of CRT with obvious improvement of cardiac performance. The stages of optimization process include individual optimization steps, taking into account the large number of the optimization methods for clinical practice. Usually, it is using a phased optimization program with a specific pathophysiological sequence to obtain the best cardiac performance. The most used methods are based on the echocardiographic evaluation for cardiac function evaluation, which are described above, and surface electrocardiogram. Principally, the AV and VV optimization process is achieved based on four steps in successive phases (Fig. 44.12).
Intraventricular Delay Optimization Intraventricular dyssynchrony is defined by early or delayed contraction of left ventricle segments because of the delayed electrical conduction within LV [29]. However, the role for routine IV optimization is not established when most patients appear to benefit from LV pre-excitation or simultaneous activation [182]. IV optimization may be done by simple M-mode, PW TDI, or better and most often by color tissue velocity imaging (TVI), SRI, and RT3DE. IV dyssynchrony is usually
G. Cristian et al.
566 Step 1: interrogation of pacing mode and history Parameters • LV-RV pacing interval • Frequency of atrial sensing vs pacing • Frequency of ventricular sensing vs pacing • Range of sensed and paced rates • Sensed and paced AV intervals Step 2: Optimization of LV-RV interval Parameters: • LV M-mode via parasternal window • LV regional strain (speckeld tracking) • LV dp/dt (spectral Doppler)
Step 3: Optimization of AV interval -targeted 10 msec incrementation of AV intervals Parameters • LV inflow PW Doppler velocities • PV flow PW Doppler velocities • LVOT PW Doppler TVI
Step 4: Optimization of pacing rate -targeted 10 ppm incrementation of pacing rate Parameters: • LV inflow PW Doppler velocities • PV flow PW Doppler velocities • LVOT PW Doppler TVI
Fig. 44.12 Systematic approaches to pacemaker optimization of systolic and diastolic function. PW pulsed wave Doppler, RV right ventricular, PV pulmonary valve, LV dP/dt, the peak rate of pressure rise in left ventricle (Marcus et al. [227], with permission)
noticed with severe myocardial disease from heart failure [228], but there is no correlation with reverse LV remodeling after CRT [58, 130, 228]. On the other hand, apical rocking showed by the 2D echocardiographic images is newly recommended as prospective sign for CRT response [229, 230]. Septal-to-posterior wall motion delay (SPWMD) estimates time between peak displacement of the septum and peak displacement of the posterior wall on M-mode, being considered significant intraventricular dyssynchrony when delay is ≥130 ms [91, 231]. The early activation of the septum (septal flash) is defined as an early septal thickening during IVCT and can be seen on parasternal long-axis or short-axis view by 2D or tissue Doppler color M-mode. Highest displacement of early radial septal velocities quantifies septal flash. More importantly, this parameter of IV dyssynchrony has 64 % sensitivity and 55 % specificity to anticipate CRT response [232].
Using TDI, longitudinal systolic velocities of opposite LV walls can be estimated. Therefore, from the apical fourchamber view, apical long-axis view, and apical two-chamber view, three types of IV dyssynchrony indices can be derived: a two-site method (septal–lateral walls), a four-site method (within septal–lateral and anterior–inferior walls), and the six-site method (septal–lateral and anterior–inferior and anterior septal–posterior walls). No matter what method, the time difference from the beginning of QRS to peak systolic velocity of the basal regions is estimated. Significant IV dyssynchrony estimates CRT response when time-to-peak delay is ≥65 ms [58]. Likewise, the 6-segment model that measures the six basal left ventricle segments has a SD cutoff ≥36.5 ms for CRT response [233]. Further, dyssynchrony index (DI) measures standard deviation of time-to-peak velocities by TDI. DI is the standard deviation (SD) of the average time from the beginning of QRS to peak longitudinal velocity during the ejection phase (Ts), from the basal and midsegments of the lateral, septal, anterior, and posterior walls in a 12-segment model. The cutoff value of DI ≥32.6 ms is a clue of IV dyssynchrony for CRT response [234]. Septal-to-posterior wall delay of radial strain based on 2D-STE from the short-axis mid-ventricular level is utilized to estimate LV dyssynchrony. Mean data about radial strain values are displayed into six segmental time-strain curves. Therefore, a time difference ≥130 ms of peak strain between the anterior-septal and posterior wall is classified as the cutoff value for IV dyssynchrony in patients with CRT [111]. Strain delay index (SDI) or longitudinal strain delay index is estimated by 2D speckle-tracking imaging (2D-STE). Precisely, longitudinal strain measured by 2D-STE in a 16-segment model estimates the sum of the difference between peak and end-systolic strain [235]. It seems that a cutoff of SDI ≥25 % predicts CRT response in cardiomyopathy [235]. Systolic dyssynchrony index by RT3DE is based on regional volume variation related to the cardiac cycle in a 16-segment model. Therefore, it estimates for each myocardial segment the interval of time to the smallest regional volume. Theoretically, each myocardial segment attains the smallest volume in the course of cardiac cycle. So that ranges of time distribution to the smallest regional volume correlates with IV dyssynchrony [236]. In this case, systolic dyssynchrony index (SDI) is the standard deviation of the mean time necessary to achieve the smallest systolic volume for 16 left ventricular segments with a cutoff value ≥5.6 % for predicting CRT response [237]. The newest approach of IV dyssynchrony combined radial 2D-STE and longitudinal color TDI dyssynchrony. This technique uses 2D-STE involving the anterior-septal and posterior wall peak radial strain delay with cutoff value ≥130 ms and a two-site (septal–lateral) systolic longitudinal velocity delay with the cutoff value ≥ 60 ms. It seems that patients diagnosed with both longitudinal dyssynchrony and radial dyssynchrony established highest recovery in NYHA functional class when measured up to either radial or longitudinal dyssynchrony [238].
44
Strategies for Restoring Cardiac Synchrony by Cardiac Pacing
567
Fig. 44.13 Color DTI velocity tracings of the basal septal and lateral wall segments. Normal subject (top) and a patient with significant delay in lateral wall contraction (bottom). Red arrows indicate the difference in the timing of peak septal and lateral velocities (Mor-Avi V et al. [243] with permission)
Triplane TDI evaluates IV dyssynchrony and is a novel 3D TDI technique that acquires TDI from left ventricle segments on the same cardiac beat together with measuring of volumes in 3D [238]. So that, the triplane colorcoded TDI data set estimates myocardial velocity curves from 12 left ventricle segments, and the SD of time-topeak systolic velocities (Ts) is considered as the dyssynchrony index. Information is presented in a bulls’ eye plot and a cutoff value of Ts-SD ≥33 ms may anticipate the CRT response [239]. At present, the data of published studies do not advocate DTI or M-mode evaluations for QRS complex <120 ms for a possible CRT [240]. For the most part, the method of assessment both radial and longitudinal dyssynchrony is much higher correlated with the CRT response [238]. It should be
taken into consideration that excepting mechanical dyssynchrony, a large number of factors may anticipate the response to CRT. Alternatively, one current single-center study with QRS complex of 100–130 ms has demonstrated that radial dyssynchrony obtained by 2D-STE is useful to anticipate variation of left ventricle volumes and LVEF after CRT [241]. Further, it is also confirmed that the strain-derived dyssynchrony index discriminated IV dyssynchrony more accurately in comparison with TDI parameters [242]. Color TDI (Fig. 44.13) may estimate the peak systolic myocardial velocity and the timing of this peak velocity in relation to electrical activity (QRS on ECG) [95]. Since there is no general consensus to guide the application of a specific echocardiographic method for the evaluation of intraventricular dyssynchrony, the most used methods
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G. Cristian et al.
Table 44.5 Echocardiographic studies for intraventricular synchrony Author Pitzalis et al. [91]
No. of patients 20
Dyssynchrony criterion (method) Septal-to-posterior wall motion delay (M-mode ≥130 ms)
Aetiology IDCM/NIDCM
Follow-up months 1
Sogaard et al. [244]
25
Delayed longitudinal contraction (% basal LV) [tissue Doppler imaging]
IDCM/NIDCM
6–12
Breithardt et al. [245]
34
Difference in septal and lateral wall motion phase angles to establish dyssynchrony Systolic dyssynchrony index (time-to-peak systolic contraction 32.6 ms) [tissue Doppler imaging] Peak septum strain–peak lateral wall strain pre-CRT vs. peak septum strain–peak lateral wall strain post-CRT LV dyssynchrony (≥65 ms, septal-to-lateral delay) [tissue velocity imaging]
IDCM/NIDCM
1
Yu et al. [223]
30
IDCM/NIDCM
3
After CRT: ↓ LVESV
Breithardt et al. [246]
18
IDCM/NIDCM
Acute
CRT reverts strain patterns
Bax et al. [58]
85
IDCM/NIDCM
6
After CRT: ↓ NYHA class ↓ LVESV
Penicka et al. [215]
49
LV + LV-RV asynchrony (sum asynchrony ≥102 ms) [tissue Doppler imaging]
IDCM/NIDCM
6
Time-to-peak velocities of opposing ventric. wall ≥65 ms [tissue synch imaging] Standard deviation of TS time-to-peak myocardial velocity: 31.4 ms [tissue Doppler imaging] Intra-LV delay peak, intra-LV delay onset [tissue Doppler imaging]
IDCM/NIDCM
5±2
After CRT: ↑ LVEF (25 %) ↓LV end-systolic/diastolic volumes After CRT: ↑ LVEF
Gorcsan et al. [96]
29
Yu et al. [222]
54
IDCM/NIDCM
3
After CRT: ↓ LVESV
Bordachar et al. [130]
41
IDCM/NIDCM
3
After CRT: ↓ LV volumes ↑ LVEF
Yu et al. [247]
141
10 % reduction of LVESV, mortality and heart failure events Evaluation of septal-toposterior wall motion delay to predict CRT response
IDCM/NIDCM
−6
IDCM/NIDCM
6
10 % reduction in LVESV predicts lower long-term mortality and heart failure events Septal-to-posterior wall motion delay did not predict reverse remodeling or clinical improvement
Marcus et al. [92]
79
Comment Septal-to-posterior wall motion index ≥130 ms predicts ↓ LVESV index (≥15 %) after CRT ↑ LVEF ↓LV end-systolic/diastolic volumes Acute benefit of CRT in patients with greater dyssynchrony
Vardas et al. [5] with permission Q-Ao QRS onset-to-onset of aortic flow, Q-Pulm QRS onset-to-onset of pulmonary flow, Q-Mit QRS onset-to-onset of mitral annulus systolic wave, Q-Tri QRS onset-to-onset of tricuspid annulus systolic wave, IMD interventricular electromechanical delay, IDCM ischemic-dilated cardiomyopathy, NICM nonischemic-dilated cardiomyopathy, LVESV left ventricular end-systolic volume, LV left ventricular, LVEF left ventricular ejection fraction, NYHA New York Heart Association
are represented by PW TDI, color DTI with peak velocity, color TDI for 12 segments, color TDI by strain and strain rate, and RT3DE by radial dyssynchrony index. Numerous echocardiographic parameters (Table 44.5) are proposed to be utilized for the quantification of the intraventricular dyssynchrony or for follow-up of CRT benefits, but each echocardiographic method has its limitations. That is why, nowadays, there are no established indices by a general
consensus to observe the effects induced by CRT, as over 30 % of the patients with CRT are nonresponders [50, 217]. Based on the aforementioned findings, there are even now numerous controversies about the evaluation of interventricular dyssynchrony and about their selecting criteria, in particular in case of methods which assess physiopathology factors as the LV lead placing or the size of the myocardial scar. This topic is approached in the next chapter.
44
Strategies for Restoring Cardiac Synchrony by Cardiac Pacing efficiency
Stretch (locally different)
lo n fu cha nc n tio ne n l
ar ul ric n nt atio Ve ilat d
is in che fa m r c ia tio , n
Ne u ac roh tiv um at o io ra n l
Coronary reserve
Wall stress
Pump function
Contractile remodelling
Hypertrophy (asymmetric)
Fig. 44.14 Mechanisms of ventricular remodeling and progressive reduction in pump function during mechanical dyssynchrony induced by ventricular conduction delay (LBBB, RVA pacing) (Sweeney and Prinzen [248] with permission)
Optimizing Hemodynamic by Pacing Lead Location Right Ventricular Pacing Site Right Ventricular Apex Pacing (RVA)-Detrimental Outcomes The insertion of lead in the pacing of right ventricular apex is the most used method for pacing in VVI(R) mode, for VDD(R) mode, for ICD mode and CRT. It appears that various studies revealed the negative effects of RVA on cardiac performance, because of the consequences caused by the right ventricular pacing (Fig. 44.14), for instance, LBBB [249]. RVA pacing can induce interventricular and intraventricular dyssynchrony. The presence of mechanical dyssynchrony is related with reduced left ventricular systolic function in VVI (R) pacing mode. Moreover, the negative effects as a consequence of right ventricle apex pacing (RVA) dyssynchrony are evaluated by large randomized clinical trials (RCTs). It follows from it that detrimental effects caused by RVA are better described by mechanisms of ventricular remodeling with gradual decrease of cardiac function [250]. Numerous randomized clinical trials proposed a connection of RVA pacing with cardiac mortality and morbidity from RVA permanent pacing. These RCTs implied that this type of pacing generates mechanical dyssynchrony associated with decreased left ventricle function and heart failure
569
development. For instance, the MOST study (Mode Selection Trial) showed clear correlation of RVA pacing with heart failure development and atrial fibrillation [251]. As well, same study has observed that over 40 % from DDDR group had a higher risk of heart failure hospitalization (p < 0.005) and in case of VVIR group with more than 80 % (p < 0.005).
Upgrade of RVA Pacing to CRT Numerous studies (Table 44.6) indicate that resynchronization by CRT causes significant improvement of left ventricular systolic function by reverse remodeling of the LV [257–259] with important mitral regurgitation reducing [260–263]. Further data achieved from DAVID trial [264] assessed patients with left ventricular dysfunction with both VVI and DDDR paced modes. Clearly, the results of trial pointed out that RVA increases the risk of heart failure. Another prospective study “PAVE Study Group” that evaluated RVA in patients with chronic biventricular pacing who undergone atrioventricular nodal ablation for chronic atrial fibrillation demonstrated that biventricular pacing induces a noteworthy enhancement of left ventricle ejection fraction relative to RVA pacing [254]. Ventricular dyssynchrony caused by RVA pacing exists in over 50 % of patients with RVA pacing being related with increasing of left ventricle internal dimensions and impairment of the left ventricle systolic function [257, 265, 266]. Besides, the mechanical dyssynchrony caused by RVA pacing was extensively studied on medium and long term in relation to CRT, studies that demonstrated that CRT is advanced over RV apical pacing (Table 44.6). To sum up, RVA pacing has numerous side effects such as iatrogenically intraventricular conduction delay, electrical and mechanical dyssynchrony of the left ventricle, left ventricle systolic dysfunction and left ventricle diastolic dysfunction, LV remodeling, functional mitral regurgitation, higher risk for atrial fibrillation in sick sinus syndrome and normal QRS complex, left-atrial enlargement, regional walls motion abnormalities of LV, and congestive heart failure [250].
Alternative RVA Pacing Sites Due to the side effects of RVA pacing, alternative positions for pacing were considered as the right ventricular septum, direct pacing of His bundle, the right ventricular outflow tract, bifocal right ventricular pacing, and biventricular pacing and left ventricular pacing. It seems that extensive data from studies that compared alternative RVA pacing sites demonstrated the deterrence of the right ventricular pacing strategies and of echocardiographic parameters for cardiac function improvement.
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G. Cristian et al.
Table 44.6 Clinical trials comparing RV apical pacing versus CRT Trial (ref. #) MUSTIC [252]
n 43
Design Crossover
Inclusion criteria Chronic heart failure
Primary end point 6MWT
LV systolic dysfunction Persistent AF
OPSITE [253]
56
Crossover
QOL
Ventricular pacing QRS >200 ms 6MWT <450 m AVN ablation and PM QOL implantation CRT 6MWT
PAVE [254]
184
Parallel arms
AVN ablation and PM 6MWT implantation
HOBIPACE [255]
30
Crossover
LV systolic LVESV dysfunction Permanent ventricular LVEF pacing Peak Vo2
Albertsen et al. [256] 50
Parallel arms
High-grade AV block
Secondary end point Peak Vo2
LVEF
Comment CRT modestly superior over RV pacing for 6 MWT and peak Vo2 No difference in QOL
Heart failure hospitalization Mortality Patient pacing preferences Subgroup analysis of: QOL 6MWT QOL LVEF NYHA functional class QOL NT-proBNP Exercise capacity LV dyssynchrony LV dyssynchrony LV diastolic function
CRT modestly superior over RV pacing for QOL and 6MWT CRT superior over RV pacing for 6MWT and LVEF No difference in QOL CRT superior over RV pacing for LVESV, LVEF, peak Vo2 CRT superior over RV pacing for secondary end points
No difference in LVEF No differences in secondary end points
LA volumes LV dimensions NT-proBNP 6MWT Tops et al. [249] with permission AF atrial fibrillation, AV atrioventricular, AVN atrioventricular node, CRT cardiac resynchronization therapy, HOBIPACE Homburg Biventricular Pacing Evaluation, LA left atrial, LVESV left ventricular end-systolic volume, MUSTIC Multisite Stimulation in Cardiomyopathies Study, NTproBNP N-terminal pro-B-type natriuretic peptide, OPSITE Optimal Pacing SITE, PAVE Left Ventricular-Based Cardiac Stimulation Post AV Nodal Ablation Evaluation, PM pacemaker
Right Ventricular Septal Location Septal location of RV pacing generates the decrease of perfusion defects with positive outcomes on cardiac performance and LV remodeling when compared with apical location [267]. What is more, long-term studies showed that septal location is superior to apical location, mainly explained by physiological sequence of pacing [268]. Furthermore, same positive outcomes for the septal catheter location were observed for short-time studies maybe because septal location produces less ventricular dyssynchrony when compared with apical location [269].
His Bundle or Para-Hisian Pacing Para-Hisian placement of catheter causes ventricular pacing same to native pacing. Thereby, His bundle pacing allows
preserving of cardiac performance at higher parameters than apical location. The His bundle location and the septal location are of value because they do not generate interventricular or intraventricular dyssynchrony when compared with apical location [269, 270].
RV Outflow Tract The placement of catheter in right ventricle outflow tract (RVOT) has positive outcomes since its activation is similar to physiological contraction when compared with apical location with reduced ventricular dyssynchrony. Therefore, RVOT pacing is often used in RV pacing because it is technologically easy to perform. Further, a meta-analysis consisting of nine trials which evaluated the apical location of catheter against the RVOT location demonstrated that the RVOT location has better outcomes due to positive effect on
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Fig. 44.15 Typical lead locations in Tri-V in the right anterior oblique view (a) and left anterior oblique view (b). RVA right ventricular apex, RVOT right ventricular outflow tract, LV left ventricle (Yoshida et al. [281] with permission)
cardiac index [271–273]. In addition, other studies failed to show the advantage of RVOT catheter location when compared with RVA location with regard to the ventricular dyssynchrony [274]. As well, when the apical location was upgraded in CRT, it has been shown good outcomes by reverse of LV remodeling and by decreasing of left ventricle end-systolic volume and end-diastolic volume [249].
Bifocal Right Ventricular Pacing With the purpose of reducing the detrimental consequences of apical RV lead position, some trials studied the effect of bifocal RV pacing by introducing of the second catheter in right ventricle outflow tract. This option was tailored mainly for the complex from CRT-like phrenic nerve stimulation, absence of venous branch to place the lead, or when the coronary sinus cannulation could not be done. In particular, bifocal location was evaluated in studies based on the echocardiographic optimization methods against the apical location of catheter. Interestingly, the results illustrated that bifocal location has good outcomes in terms of cardiac performance [275–277]. Conversely, ROVA trial undergone on 103 patients with heart failure and atrial fibrillation showed no statistically significant difference between the RV bifocal location pacing (RVA and RVOT) and RVA pacing (p = 0.03) [278]. It appears that Zamparelli et al. studied the apical catheter location versus bifocal location (RV apex and interventricular septum) in a group of 25 patients with standard recommendation of CRT such as dilated cardiomyopathy, LBBB, or mitral regurgitation.
After 18 months of follow-up, their deductions were that bifocal location by mechanisms of interventricular and intraventricular resynchronization (shortening of interventricular and intraventricular delays) is diminishing mitral regurgitation, increases LV cardiac performance, and shortens QRS duration [279]. Remarkably, the group of Anouma et al. studied 13 patients by clinical and echocardiographic evaluation for trifocal location (RVA, RVOT and LV), and they found considerable improvements of LV hemodynamic parameters [280]. In conclusion, it is important to note that RV pacing lead location produces significant effects on cardiac performance level, especially in case of the apical position that may generate heart failure on long term. It is noteworthy that the rest of locations as septal, RVOT, and His bundle prove favorable outcomes when compared with apical location. Moreover, studies of alternative locations pacing (left ventricle, left ventricle and biventricular, RVA+ RVOT RVA, RVA + RV His bundle, RVA + LV + RVOT) demonstrated the advantages of these locations when compared with RVA pacing.
Triangle Ventricular Pacing Triangle ventricular pacing (Tri-V), known also as “triplesite pacing” (Fig. 44.15), is done by placing one catheter in RVA, and the LV catheter is introduced same to standard CRT, so that RVA is anode and LV is cathode, but the third catheter is located in RVOT being connected with the LV catheter [281]. With other words, BiV cathodal pacing of RV and LV is associated with anodal RVA. This pacing design is
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Fig. 44.16 Angiographic classification of left ventricular lead position. (a) Right anterior oblique (RAO) view representative of the long axis of the heart. This view enables segmentation of the heart into basal, mid-ventricular (MID), and apical segments. (b) Left anterior oblique (LAO) view used to divide the left ventricular wall along the short axis
of the heart into five equal parts; anterior, anterolateral, lateral, posterolateral, and posterior. For the analysis, the anterolateral, lateral, and posterolateral segments were grouped together as the lateral wall. AIV indicates anterior interventricular vein, CS coronary sinus, and MCV middle cardiac vein (Singh et al. [282] with permission)
organized from anodal RVA lead and LV and RVOT leads as cathode (Fig. 44.15). As well as, it is of interest that Tri-V was considered based on the hypothesis that a double location of RV pacing may improve the benefits from CRT [281]. Yoshida K. et al. [281] evaluated on 21 patients the effect of Tri-V on cardiac performance against typical BiV. Efficiency assessment of parameters has been studied by various echocardiographic techniques such as TDI, but also by invasive methods, mainly by dP/dtmax, pulmonary capillary wedge pressure (PCWP), and cardiac output (CO). It seems that both types of CRT (BiV and Tri-V) enhanced cardiac output, but in patients with Tri-V, the value of cardiac output was greater (baseline 3.1 ± 1.0, BiV 3.4 ± 1, and Tri-V 3.8 ± 1.2l) and dP/dtmax significantly increased (p = 0.002). Notably, Tri-V improves LV function when compared with standard BiV.
Essentially, the cardiac segments with maximal mechanical delay and those with scar tissue should be distinguished. Of note, these assessments from CRT may be responsible of the responders or nonresponders clustering (reverse or without reverse LV remodeling) subsequent to CRT. What is more, left ventricular lead position is very important for cardiac pacing because of the specific patient characteristics, heart failure classification and myocardial structure (various different grades of regional wall motion abnormalities). Furthermore, left ventricular lead position is also reliant on coronary sinus anatomy which can be approached from different territories (Fig. 44.16). Theoretically, the location of leads is preferably in the segments with maximal mechanical delay. Likewise, the complete process involves a pre-CRT evaluation of cardiac function, venous sinus anatomy with its branches, so that the catheter location will be in the LV segments with damaged contraction, altogether with at least one echocardiographic control of optimization. Practically, the most utilized locations with CRT are the anterior and lateral walls of LV, where the lateral location is superior to the anterior wall. This routine is derived from the principle that in dilated cardiomyopathy with left bundle branch block, there is a delayed activation of the lateral wall; therefore, pacing location at this level should be optimal [283]. In patients with myocardial scar as a result of myocardial infarction, the placement of catheter will be made in healthy myocardium tissue at a distance of 9.3 ± 3.6 cm [284, 285]. If there is no myocardial
Left Ventricular Lead Position Intraventricular dyssynchrony is frequent in chronic heart failure which has the criteria for CRT. Basically, it defines the delay in cardiac contraction of different segments versus other segments (“incomplete dyssynchrony”) or the delay of all segments (“global dyssynchrony”) that often meet in dilated cardiomyopathy. Before doing CRT, the analysis of parameters that describe the cardiac segmental function is needed for the optimal location establishing of the LV catheter.
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scar (dilated cardiomyopathy), the recent general consent is placement of the LV catheter within lateral or posterolateral branch of the coronary sinus [283]. Not surprisingly, these locations of catheter within the most delayed sites have a better clinical outcome, higher reverse remodeling of LV, and lower mortality and hospitalizations secondary to heart failure [55, 286]. In fact, using RT3DE tissue synchronization imaging, Murphy et al. showed that the highest clinical and hemodynamic benefit of CRT is present in patients who were paced at the latest mechanical activation but poorer response in patients with left ventricle paced out of latest mechanical activation [286]. Using TDI optimization method, Ansalone et al. confirmed that the latest wall activated before insertion is usually the lateral (35 %), anterior (26 %), posterior (23 %), and inferoseptal (16 %) walls [287]. Moreover, the highest clinical outcomes were in case of LV lead location within or nearby the latest mechanical activated wall. Optimal pacing location is evaluated before lead insertion by finding out of points with highest dyssynchrony; however, this periprocedural insertion of LV lead nearest to the point of highest dyssynchrony and AV optimization for the individual patients may be done postprocedural [288]. Supplementary, patients with optimal lead location respond better to CRT [289]. It is generally accepted that the best sweet spot for LV lead location is on the lateral or posterolateral wall of LV. In fact, estimation of time-to-peak radial strain is determined by 2D-STE; after that, patients undergo echo-guided LV lead position insertion in the latest segment of mechanical activation [290]. Of interest, MADIT-CRT trial that evaluated the impact of the LV catheter position over the outcome of 799 patients followed up to 29 ± 11 months after CRT. The classification of LV lead insertion was completed in short axis (anterior, lateral, or posterior position) and long axis (basal, midventricular, and apical position). Once again, CRT had similar benefits for the anterior, lateral, or posterior LV lead location (p = 0.652) [282]. Whereas, apical position of catheter produces a significant rise of the heart failure risk or mortality when compared with non-apical position (basal or mid-ventricular; p = 0.019) [282]. For the anterior, lateral, or posterior positions of the catheter, the outcomes are similar, but the apical position is a reason of nonresponders after CRT [282]. Thus the study reckons that the apical positions do not have a positive benefit on the cardiac function when compared with the non-apical positions. To date, LV catheter location within lateral or posterolateral branch of the coronary sinus is generally acknowledged [63, 178], but the concept that these locations are optimal for all patients is not still proven by hemodynamic studies [291, 292] and therefore the location of the catheter in the LV should be individualized for each patient depending on clinical status, hemodynamic, and venous sinus anatomy. The TARGET trial undergone on 220 patients was designed to
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establish the optimal lead position by echocardiographic control against empirical guidance (non-echocardiographic guidance). Here, the interventricular dyssynchrony was defined by echocardiographic criterion as time difference from QRS onset to the pulmonary and aortic outflow tracts obtained by CW Doppler. Also, the dyssynchrony quantification was made by radial strain speckle-tracking analysis, and it is defined by more than 130 ms delay between anteroseptal and posterolateral LV segments in mid-ventricular short-axis images. By this study, it was shown that the echocardiographic guidance in placement of the LV leads have higher percentage of responders when compared with the empirical placement (70 % vs. 55 % p = 0.031) and the clinical response was also better in the group with echocardiographic guidance (85 % vs. 65 % p = 0.003) [293]. In addition, Suffoletto et al. have confirmed that the catheter localization in the LV segments with lower motion is superior to the empirical one (10 ± 5 % vs. 6 ± 5 %, p < 0.05) [111].
LV Leads Position and Myocardial Scar Tissue Existence of the myocardial scar tissue due to the myocardial infarction generates heart failure by intraventricular dyssynchrony which it is different from intraventricular dyssynchrony of dilated cardiomyopathy because myocardial scar has segments with normal contractile activity and therefore catheter position in this area generates nonresponders. Actually, status of responder versus nonresponder to CRT in patients with transmural and non-transmural scar was studied by the group of Bleeker [53]. They studied 40 patients with heart failure and myocardial infarction for 6 months observing a higher rate of nonresponder patients in transmural scar group (>50 %) compared with no transmural scar group (14 % vs. 81 %; p < 0.001) [53]. Another significant benefit of cardiac pacing is reverse remodeling that is lower in ischemic heart failure with myocardial scar compared with no ischemic heart failure [44, 294]. As shown by MIRACLE trial with 228 patients with heart failure, cardiac volumes after CRT are higher reduced in nonischemic cardiomyopathy [44]. In accordance with this, patients with myocardial scar may be initially included in nonresponder group. Supplementary, the group of Ypenburg et al. using contrast-enhanced MRI in 34 patients with ischemic cardiomyopathy proved after 6 months of follow-up an important decrease of LV volumes (53 % of patients) correlated with postinfarction scar size [295]. In order to completely understand and take advantage of above data, it has to underline that assessment of LV scar size is important in CRT recommendation indication, and having a precisely myocardial scar evaluation technique plays a major task. Among the techniques used in detecting myocardial scar, contrast echocardiography, SPECT, and positron
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a
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Epicardial CS pacing site Endocardial site facing CS
Base
Basal (4 sites) Anterior Lateral
* * Mid-cavity (4 sites)
Septal
Anterior
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Lateral Septal Inferior Apex
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Fig. 44.17 Distribution of LV pacing sites and catheter position (a) Predetermined left ventricular (LV) pacing site used during the study. The LV cavity was divided into 9 zones: 4 basal, 4 mid-cavity (inferior, lateral, anterior, and septal aspects), and 1 apex. One site was epicardial
in a lateral branch of the coronary sinus (CS), and 1 site was endocardial just facing the CS pacing site. (b) Catheter position during study (Derval et al. [302] with permission)
emission tomography have a significant role too [296–299]. For instance, to assess the site of LV lead positioning is important to evaluate venous sinus anatomy that may be estimated before CRT by venography using a 64-slice computed tomography [300] or by an up-to-date three-dimensional mapping method. It is important to point out that location, size, and degree of mechanical dyssynchrony produced by myocardial scar can be the decisive factor for assessing the indication of CRT. Another major feature is to emphasize the fact that multiple approaches were developed to decrease the number of nonresponders after CRT, plus the improvement of patient selection; the optimization of AV, VV, and intraventricular delay; and the synchronization of LV lead position. Derived from numerous analyses, the current general consent about the LV catheter placement is the lead insertion in lateral or posterolateral branch of the coronary sinus [63, 178]. On the other hand, these lead locations may not be optimal for all patients, but several hemodynamic studies demonstrated that LV pacing site is major for CRT [291, 292]. Taken together, these above facts advocate that the correlation between the catheter location in areas with dyssynchrony and the discordant localization of the lead has a prognostic value regarding hospitalization and mortality rates. Moreover, the optimal lead location in LV is achieved by sophisticated echocardiographic techniques during preoperative evaluation and intraoperatory and postoperatory phases. Nevertheless, it can be sometimes unfeasible due to the venous sinus anatomy which sometimes rules out optimal location and the venous anatomy description that is performed intraoperatory by retrograde demography.
Where Is the Best and Worst Site Within the Left Ventricle? Various trials have been shown that CRT reduces heart failure symptomatology and diminishes the mortality and morbidity [38, 66, 67, 76, 181, 232, 301], but after these studies, about 20–40 % of patients are nonresponders to CRT. Among the factors responsible for nonresponders are the selection criterion of patients, the anatomy of coronary sinus, and the accurate quantification of LV segments with dyssynchrony, but the most important is the left ventricular lead position. It should be emphasized that the current general agreement is the insertion of the lead in lateral and posterior branches of coronary sinus, with the notice that even these lead locations may be associated with nonresponders patients [178, 287]. This further implies the important need for better optimal LV site reevaluation studies, especially when hemodynamic assessments suggest that location of LV catheter in the left ventricle is very important in CRT response. For instance, the study of Derval et al. [302] using the echocardiographic methods (TDI) and hemodynamic parameters (+dP/dtmax, −dP/dtmax, pulse pressure = PP, and end-systolic pressure = ESP) in 35 patients with nonischemic-dilated cardiomyopathy evaluated several approaches as individualized lead location for each patient related with the maximum increase of dP/dtmax. And the usual approach, directed by echocardiographic criteria in which optimal lead site was defined as the latest mechanical activated segment and the catheter location in the lateral area (basal and mid-lateral sites). Dividing left ventricle cavity in nine areas (Fig. 44.17) where the catheter can be placed, four basal areas (anterior, inferior, septal,
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Mid 2
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Fig. 44.18 Quadripolar left ventricular lead. (a) Right anterior oblique projection of balloon occlusive venogram shows multiple (CS) branches available. (b) Posterior–anterior view of the final Quartet lead position in a high lateral branch of the CS. (c) About ten vectors are available using
the three-ring electrodes and distal tip of the Quartet lead and the RV coil: 1. distal 1 (D1) to mid 2 (M2), 2. D1 to proximal 4 (P4), 3. D1–RV coil, 4. M2–P4; 5. M2–RV coil, 6. Mid 3 (M3) to M2, 7. M3–P4, 8. M3–RV coil, 9. P4–M2, and 10. P4–RV (Shetty et al. [308] with permission)
lateral), four mid-cavity areas (anterior, inferior, lateral, septal), and one apical, and using four approaches, the authors proved that the optimal pacing site principles are as follows: LV pacing site is the most important element in CRT response; the interindividual and intraindividual variations determine positive response in CRT; individually based strategy is superior, but this cannot be established from the previous; and endocardial location is superior to epicardial location. This study proved that 1. LV pacing site is the most important parameter in assessing the hemodynamic response, and 2. there are variations between intraindividual and interindividual responses based on the lead location [302]. Lastly, it seems obvious that the LV pacing sites must be specified and described because the coronary sinus pacing is rarely optimal and there is no information about switching of a nonresponder to a responder in CRT.
In summary, the best or optimal site for the LV pacing is still theoretical: (1) latest electrical activation [303], (2) latest mechanical activation [57, 304–307], (3) bypassing of slow electrical conduction area [291], (4) bypassing of myocardial scar [304, 308], and (5) highest performance of hemodynamic parameters as CO, SV, LV dP/dtmax, and LVEF [111, 302].
Quadripolar Left Ventricular Pacing Lead Recently, a new technique was introduced in routine practice based on the using of a quadripolar (Fig. 44.18) electrode which is inserted in the coronary sinus. Its structure has four poles assigned to the catheter shaft to 20, 10, and 17 in. from
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distal pole, being able to pace by four cathodal electrodes in the left ventricle, two anodal electrodes in the left ventricle and the right ventricle. Further, four electrodes of catheter are positioned within middle, distal, and proximal. The quadripolar LV lead has ten various pacing models (Fig. 44.18); therefore, the electrophysiologist may change the vector close to myocardial scar and may avoid phrenic nerve stimulation with ruling out of the LV lead relocation [309]. Information about routine clinical practice using this catheter in resynchronization therapy with CRT and CRT-D
is still limited. However, recently multicenter studies [309– 311] proved the advantages of this new catheter, but structured scientific assessment of this new quadripolar lead concept is required. To sum up, there are many controversies in the optimal therapy with pacing devices, and the newest guidelines from European Heart Rhythm Association (ERHA) and Heart Rhythm Society (HRS) introduced an up-to-date consensus statement for CRT [32] (Table 44.7), but it fails to work out the problems of switching the nonresponders into responders.
Table 44.7 New EHRA and HRS consensus statement on CRT Recommendations Pre-implant
Is recommended A careful evaluation of comorbidities and an estimate of life expectancy are recommended
May be useful Pre-implant formal functional status testing including a QOL measure may be useful for monitoring CRT response
Are not recommended CRT implant should be deferred in patients with acutely decompensated heart failure, who are dependent on inotropes, or who have unstable ventricular arrhythmias until their medical status is improved A thorough pre-implant history and physical Cardiac MRI may be useful to assess Echocardiographic examination including review of vital signs cardiac function and provide detailed dyssynchrony and laboratory tests are recommended information about viable myocardium in assessment should not be distribution of a CS branch vein considered used to exclude patients for LV lead implant from consideration for CRT CRT candidates should have stable heart Venous anatomic mapping using CT failure status on guideline-directed medical angiography may be useful in certain therapy prior to implant patient populations. These include patients with prior LV lead implant failure or those at risk for abnormal venous anatomy A pre-implant comprehensive echocardiogram Development of a pre-implant strategy for quantification of LVEF and assessment of should be considered to identify and cardiac size and function is recommended manage atrial fibrillation or frequent PVCs that may impair the ability of CRT to deliver therapy continuously A pre-implant 12-lead ECG including QRS In patients at low-to-moderate duration measure (>120–130 ms) and thromboembolic risk on oral anticoagulant characterization of QRS morphology is therapy with warfarin, continuing at recommended reduced dosage (INR 1.5–2) or withholding therapy 3–5 days preoperatively can be useful to minimize bleeding risk In patients at high thromboembolic risk on In patients at low–moderate oral anticoagulant therapy with warfarin, thromboembolic risk on direct thrombin continuing therapy at reduced dosage with or factor Xa inhibitor agents, close monitoring of INR (INR 2–3) is withholding such therapy 2–3 days recommended perioperatively. Postoperative before surgery can be useful to minimize use of heparin is discouraged bleeding risk Preoperative treatment with an antibiotic that has in vitro activity against staphylococci is recommended for infection prophylaxis
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Table 44.7 (continued) Recommendations CRT implant
Predischarge evaluation
CRT follow-up
Is recommended Intraoperative hemodynamic monitoring including careful attention of volume status is recommended The RV lead is recommended as the first intracardiac lead implanted
CS venography is recommended to create a roadmap that guides lead selection and assists with navigation LV lead testing is recommended to assure an adequate safety margin for capture and avoidance of PNS Careful discussion with patients regarding the risk and benefits of CRT-D vs. CRT-P device implant is recommended prior to the decision as to the type of CRT device implanted A physical examination, device interrogation, chest X-ray, and surface ECG are recommended prior to discharge Careful attention to volume status is recommended after the implantation procedure as an acute response to CRT may include significant dieresis A standard echocardiographic assessment is recommended prior to discharge if a procedural complication is suspected on the basis of patient symptoms or clinical findings An assessment to assure 100 % biventricular capture is recommended prior to discharge The majority of patients implanted with CRT should remain in the hospital overnight after implant to observe clinical status A close degree of cooperation is recommended in the follow-up of the CRT recipient between the heart failure and electrophysiology follow-up physician A minimum in-clinic follow-up interval of 6 months is strongly recommended for CRT recipients Remote monitoring and follow-up in addition to in-clinic follow-up are recommended. Patients should be encouraged to initiate a remote transmission if new symptoms or concerns arise Follow-up visits that include a patient history, physical examination, device interrogation and testing, and systematic analysis of device data are recommended Optimization including upward titration of heart failure drug therapies, if appropriate, is recommended to maximize response to CRT Evaluation of LV function or other adjuncts to assess heart failure progression or regression is recommended during follow-up
May be useful Are not recommended General anaesthesia may be considered for It is not recommended to CRT implants place the LV lead in an apical position Controversy exists regarding the value of routine acute defibrillation testing but major CRT trials included DFT testing. The decision to perform DFT testing should be made on an individual basis by the treating physician
Catheter ablation of the AV node in the setting of atrial fibrillation with native conduction can be useful if CRT is not being delivered consistently
(continued)
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Table 44.7 (continued) Recommendations CRT management
Is recommended Assessment of patient response to CRT, including an evaluation of symptoms and functional response and echocardiographic measures of cardiac function, is recommended An assessment of potentially reversible causes for nonresponse is recommended in patients without demonstrable improvement in heart failure status after CRT implant A device interrogation is recommended to assess for atrial and ventricular arrhythmias, quality of CRT delivery (% effective biventricular capture), and response rate
Special considerations
May be useful Are not recommended Echocardiographically directed or empiric AV or VV timing optimization or LV lead repositioning may be considered in selected patients, but their role in improving response has not been proven Discontinuation of CRT by programming off LV stimulation may be considered if there is no clear evidence of response to therapy or concern exists that LV pacing is introducing risk In patients who do not respond to CRT and continue to experience heart failure symptoms, alternative treatment options should be considered such as placement of a LV assist device or cardiac transplantation
Optimization of medical therapy, assurance of appropriate and consistent biventricular pacing, and treatment of arrhythmias are recommended Pre-implant patient education including information about the need and function of the CRT device and follow-up plan is recommended. There are a variety of digital patient educational tools that can be utilized to fully inform the patient as to the risks and benefits of CRT or CRT-D therapy
Daubert et al. [32] with permission
References 1. Boyett MR, Dobrzynski H. The sinoatrial node is still setting the pace 100 years after its discovery. Circ Res. 2007;100(11):1543–5. 2. Kim D, Shinohara T, Joung B, Maruyama M, Choi EK, On YK. Calcium dynamics and the mechanisms of atrioventricular junctional rhythm. J Am Coll Cardiol. 2010;56(10):805–12. 3. Grines CL, Bashore TM, Boudoulas H, Olson S, Shafer P, Wooley CF. Functional abnormalities in isolated left bundle branch block. The effect of interventricular asynchrony. Circulation. 1989;79(4):845–53. 4. Bax JJ, Ansalone G, Breithardt OA, Derumeaux G, Leclercq C, Schalij MJ, Sogaard P, St John Sutton M, Nihoyannopoulos P. Echocardiographic evaluation of cardiac resynchronization therapy: ready for routine clinical use? A critical appraisal. J Am Coll Cardiol. 2004;44(1):1–9. 5. Vardas PE, Auricchio A, Blanc JJ, Daubert JC, Drexler H, Ector H, Gasparini M, Linde C, Morgado FB, Oto A, Sutton R, Trusz-Gluza M, European Society of Cardiology, European Heart Rhythm Association. Guidelines for cardiac pacing and cardiac resynchronization therapy: The Task Force for Cardiac Pacing and Cardiac Resynchronization Therapy of the European Society of Cardiology. Developed in collaboration with the European Heart Rhythm Association. Eur Heart J. 2007;28(18):2256–95. 6. Smiseth OA, Russell K, Skulstad H. The role of echocardiography in quantification of left ventricular dyssynchrony: state of the art and future directions. Eur Heart J Cardiovasc Imaging. 2012;13(1):61–8. 7. Epstein AE, DiMarco JP, Ellenbogen KA, Estes 3rd NA, Freedman RA, Gettes LS, Gillinov AM, Gregoratos G, Hammill SC, Hayes DL, Hlatky MA, Newby LK, Page RL, Schoenfeld MH, Silka MJ,
8.
9. 10.
11.
Stevenson LW, Sweeney MO, Smith Jr SC, Jacobs AK, Adams CD, Anderson JL, Buller CE, Creager MA, Ettinger SM, Faxon DP, Halperin JL, Hiratzka LF, Hunt SA, Krumholz HM, Kushner FG, Lytle BW, Nishimura RA, Ornato JP, Page RL, Riegel B, Tarkington LG, Yancy CW, American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices), American Association for Thoracic Surgery, Society of Thoracic Surgeons. ACC/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/ AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices) developed in collaboration with the American Association for Thoracic Surgery and Society of Thoracic Surgeons. J Am Coll Cardiol. 2002;51(21): e1–62. Nagueh SF. Mechanical dyssynchrony in congestive heart failure: diagnostic and therapeutic implications. J Am Coll Cardiol. 2008;51(1):18–22. Kass DA. An epidemic of dyssynchrony: but what does it mean? J Am Coll Cardiol. 2008;51(1):12–7. Bax JJ, Gorcsan III J. Echocardiography and noninvasive imaging in cardiac resynchronization therapy: results of the PROSPECT (Predictors of Response to Cardiac Resynchronization Therapy) study in perspective. J Am Coll Cardiol. 2009;53(21): 1933–43. Sanderson JE. Echocardiography for cardiac resynchronization therapy selection: fatally flawed or misjudged? J Am Coll Cardiol. 2009;53(21):1960–4.
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Strategies for Restoring Cardiac Synchrony by Cardiac Pacing
12. Spragg DD, Kass DA. Pathobiology of left ventricular dyssynchrony and resynchronization. Prog Cardiovasc Dis. 2006;49(1):26–41. 13. Kanzaki H, Bazaz R, Schwartzman D, Dohi K, Sade LE, Gorcsan 3rd J. A mechanism for immediate reduction in mitral regurgitation after cardiac resynchronization therapy: insights from mechanical activation strain mapping. J Am Coll Cardiol. 2004;44(8):1619–25. 14. Sanders P, Morton JB, Davidson NC, Spence SJ, Vohra JK, Sparks PB, Kalman JM. Electrical remodeling of the atria in congestive heart failure: electrophysiological and electroanatomic mapping in humans. Circulation. 2003;108(12):1461–8. 15. Van Beeumen K, Duytschaever M, Tavernier R, Van de Veire N, De Sutter J. Intra- and interatrial asynchrony in patients with heart failure. Am J Cardiol. 2007;99(1):79–83. 16. Brecker SJ, Xiao HB, Sparrow J, Gibson DG. Effects of dualchamber pacing with short atrioventricular delay in dilated cardiomyopathy. Lancet. 1992;340(8831):1308–12. 17. Schoeller R, Andresen D, Büttner P, Oezcelik K, Vey G, Schröder R. First- or second-degree atrioventricular block as a risk factor in idiopathic dilated cardiomyopathy. Am J Cardiol. 1993;71(8): 720–6. 18. Nishimura RA, Hayes DL, Holmes Jr DR, Tajik AJ. Mechanism of hemodynamic improvement by dual-chamber pacing for severe left ventricular dysfunction: an acute Doppler and catheterization hemodynamic study. J Am Coll Cardiol. 1995;25(2):281–8. 19. Panidis IP, Ross J, Munley B, Nestico P, Mintz GS. Diastolic mitral regurgitation in patients with atrioventricular conduction abnormalities: a common finding by Doppler echocardiography. J Am Coll Cardiol. 1986;7(4):768–74. 20. Xiao HB, Lee CH, Gibson DG. Effect of left bundle branch block on diastolic function in dilated cardiomyopathy. Br Heart J. 1991; 66(6):443–7. 21. Auricchio A, Fantoni C, Steinberg JS. Acute and chronic sequelae of ventricular dyssynchrony. Prog Cardiovasc Dis. 2006;48(4): 227–31. 22. Hawkins NM, Petrie MC, MacDonald MR, Hogg KJ, McMurray JJ. Selecting patients for cardiac resynchronization therapy: electrical or mechanical dyssynchrony? Eur Heart J. 2006;27(11): 1270–81. 23. Auricchio A, Salo RW. Acute hemodynamic improvement by pacing in patients with severe congestive heart failure. Pacing Clin Electrophysiol. 1997;20:313–24. 24. Hirschfeld S, Meyer R, Schwartz DC, Korfhagen J, Kaplan S. Measurement of right and left ventricular systolic time intervals by echocardiography. Circulation. 1975;51(2):304–9. 25. Bordachar P, Garrigue S, Lafitte S, Reuter S, Jaïs P, Haïssaguerre M, Clementy J. Interventricular and intra-left ventricular electromechanical delays in right ventricular paced patients with heart failure: implications for upgrading to biventricular stimulation. Heart. 2003;89(12):1401–5. 26. Houthuizen P, Bracke FA, van Gelder BM. Atrioventricular and interventricular delay optimization in cardiac resynchronization therapy: physiological principles and overview of available methods. Heart Fail Rev. 2011;16(3):263–76. 27. Weber KT, Janicki JS, Shroff S, Fishman AP. Contractile mechanics and interaction of the right and left ventricles. Am J Cardiol. 1981;47(3):686–95. 28. Perego GB, Chianca R, Facchini M, Frattola A, Balla E, Zucchi S, Cavaglià S, Vicini I, Negretto M, Osculati G. Simultaneous vs. sequential biventricular pacing in dilated cardiomyopathy: an acute hemodynamic study. Eur J Heart Fail. 2003;5(3):305–13. 29. Prinzen FW, Augustijn CH, Arts T, Allessie MA, Reneman RS. Redistribution of myocardial fiber strain and blood flow by asynchronous activation. Am J Physiol. 1990;259(2 Pt 2):H300–8. 30. Leclercq C, Faris O, Tunin R, Johnson J, Kato R, Evans F, Spinelli J, Halperin H, McVeigh E, Kass DA. Systolic improvement and
579
31.
32.
33. 34.
35.
36.
37.
38.
mechanical resynchronization does not require electrical synchrony in the dilated failing heart with left bundle-branch block. Circulation. 2002;106(14):1760–3. Turner MS, Bleasdale RA, Mumford CE, Frenneaux MP, MorrisThurgood JA. Left ventricular pacing improves haemodynamic variables in patients with heart failure with a normal QRS duration. Heart. 2004;90(5):502–5. European Heart Rhythm Association, European Society of Cardiology, Heart Rhythm Society, Heart Failure Society of America, American Society of Echocardiography, American Heart Association, European Association of Echocardiography, Heart Failure Association, Daubert JC, Saxon L, Adamson PB, Auricchio A, Berger RD, Beshai JF, Breithard O, Brignole M, Cleland J, Delurgio DB, Dickstein K, Exner DV, Gold M, Grimm RA, Hayes DL, Israel C, Leclercq C, Linde C, Lindenfeld J, Merkely B, Mont L, Murgatroyd F, Prinzen F, Saba SF, Shinbane JS, Singh J, Tang AS, Vardas PE, Wilkoff BL, Zamorano JL. EHRA/HRS expert consensus statement on cardiac resynchronization therapy in heart failure: implant and follow-up recommendations and management. Heart Rhythm. 2012;9(9):1524–76. Winfree AT. The electrical thresholds of ventricular myocardium. J Cardiovasc Electrophysiol. 1990;1:393–410. Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, Jessup M, Konstam MA, Mancini DM, Michl K, Oates JA, Rahko PS, Silver MA, Stevenson LW, Yancy CW. 2009 Focused update incorporated into the ACC/AHA 2005 guidelines for the diagnosis and management of heart failure in adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the International Society for Heart and Lung Transplantation. Circulation. 2009;119(14):e391–479. Epstein AE, DiMarco JP, Ellenbogen KA, Estes 3rd NA, Freedman RA, Gettes LS, Gillinov AM, Gregoratos G, Hammill SC, Hayes DL, Hlatky MA, Newby LK, Page RL, Schoenfeld MH, Silka MJ, Stevenson LW, Sweeney MO, Smith Jr SC, Jacobs AK, Adams CD, Anderson JL, Buller CE, Creager MA, Ettinger SM, Faxon DP, Halperin JL, Hiratzka LF, Hunt SA, Krumholz HM, Kushner FG, Lytle BW, Nishimura RA, Ornato JP, Page RL, Riegel B, Tarkington LG, Yancy CW, American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices), American Association for Thoracic Surgery, Society of Thoracic Surgeons. ACC/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices): developed in collaboration with the American Association for Thoracic Surgery and Society of Thoracic Surgeons. Circulation. 2002;117(21):e350–408. Bax JJ, Abraham T, Barold SS, Breithardt OA, Fung JW, Garrigue S, Gorcsan 3rd J, Hayes DL, Kass DA, Knuuti J, Leclercq C, Linde C, Mark DB, Monaghan MJ, Nihoyannopoulos P, Schalij MJ, Stellbrink C, Yu CM. Cardiac resynchronization therapy: part 1–issues before device implantation. J Am Coll Cardiol. 2005;46(12):2153–67. Kerwin WF, Botvinick EH, O’Connell JW, Merrick SH, DeMarco T, Chatterjee K, Scheibly K, Saxon LA. Ventricular contraction abnormalities in dilated cardiomyopathy: effect of biventricular pacing to correct interventricular dyssynchrony. J Am Coll Cardiol. 2000;35(5):1221–7. Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, Tavazzi L, Cardiac Resynchronization-Heart Failure (CARE-HF) Study Investigators. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med. 2005;352(15):1539–49.
580 39. St John Sutton MG, Plappert T, Abraham WT, Smith AL, DeLurgio DB, Leon AR, Loh E, Kocovic DZ, Fisher WG, Ellestad M, Messenger J, Kruger K, Hilpisch KE, Hill MR, Multicenter InSync Randomized Clinical Evaluation (MIRACLE) Study Group. Effect of cardiac resynchronization therapy on left ventricular size and function in chronic heart failure. Circulation. 2003;107(15):1985–90. 40. Auricchio A, Abraham WT. Cardiac resynchronization therapy: current state of the art: cost versus benefit. Circulation. 2004; 109(3):300–7. 41. Leclercq C, Hare JM. Ventricular resynchronization: current state of the art. Circulation. 2004;109(3):296–9. 42. Saxon LA, De Marco T, Schafer J, Chatterjee K, Kumar UN, Foster E, VIGOR Congestive Heart Failure Investigators. Effects of longterm biventricular stimulation for resynchronization on echocardiographic measures of remodeling. Circulation. 2002;105(11): 1304–10. 43. Yu CM, Chau E, Sanderson JE, Fan K, Tang MO, Fung WH, Lin H, Kong SL, Lam YM, Hill MR, Lau CP. Tissue Doppler echocardiographic evidence of reverse remodeling and improved synchronicity by simultaneously delaying regional contraction after biventricular pacing therapy in heart failure. Circulation. 2002; 105(4):438–45. 44. Sutton MG, Plappert T, Hilpisch KE, Abraham WT, Hayes DL, Chinchoy E. Sustained reverse left ventricular structural remodeling with cardiac resynchronization at one year is a function of etiology: quantitative Doppler echocardiographic evidence from the Multicenter InSync Randomized Clinical Evaluation (MIRACLE). Circulation. 2006;113(2):266–72. 45. Donal E, Leclercq C, Linde C, Daubert JC. Effects of cardiac resynchronization therapy on disease progression in chronic heart failure. Eur Heart J. 2006;27(9):1018–25. 46. Zhang Q, Fung JW, Auricchio A, Chan JY, Kum LC, Wu LW, Yu CM. Differential change in left ventricular mass and regional wall thickness after cardiac resynchronization therapy for heart failure. Eur Heart J. 2006;27(12):1423–30. 47. Bleeker GB, Mollema SA, Holman ER, Van de Veire N, Ypenburg C, Boersma E, van der Wall EE, Schalij MJ, Bax JJ. Left ventricular resynchronization is mandatory for response to cardiac resynchronization therapy: analysis in patients with echocardiographic evidence of left ventricular dyssynchrony at baseline. Circulation. 2007;116(13):1440–8. 48. Chakir K, Daya SK, Tunin RS, Helm RH, Byrne MJ, Dimaano VL, Lardo AC, Abraham TP, Tomaselli GF, Kass DA. Reversal of global apoptosis and regional stress kinase activation by cardiac resynchronization. Circulation. 2008;117(11):1369–77. 49. Gheorghiade M, Bonow RO. Chronic heart failure in the United States: a manifestation of coronary artery disease. Circulation. 1998;97(3):282–9. 50. Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E, Kocovic DZ, Packer M, Clavell AL, Hayes DL, Ellestad M, Trupp RJ, Underwood J, Pickering F, Truex C, McAtee P, Messenger J, MIRACLE Study Group. Multicenter InSync Randomized Clinical Evaluation. Cardiac resynchronization in chronic heart failure. N Engl J Med. 2002;346(24):1845–53. 51. Bradley DJ, Bradley EA, Baughman KL, Berger RD, Calkins H, Goodman SN, Kass DA, Powe NR. Cardiac resynchronization and death from progressive heart failure: a meta-analysis of randomized controlled trials. JAMA. 2003;289(6):730–40. 52. Bleeker GB, Schalij MJ, Van Der Wall EE, Bax JJ. Postero-lateral scar tissue resulting in non-response to cardiac resynchronization therapy. J Cardiovasc Electrophysiol. 2006;17(8):899–901. 53. Bleeker GB, Kaandorp TA, Lamb HJ, Boersma E, Steendijk P, de Roos A, van der Wall EE, Schalij MJ, Bax JJ. Effect of posterolateral scar tissue on clinical and echocardiographic improvement after cardiac resynchronization therapy. Circulation. 2006;113(7):969–76.
G. Cristian et al. 54. Ypenburg C, Schalij MJ, Bleeker GB, Steendijk P, Boersma E, Dibbets-Schneider P, Stokkel MP, van der Wall EE, Bax JJ. Impact of viability and scar tissue on response to cardiac resynchronization therapy in ischaemic heart failure patients. Eur Heart J. 2007; 28(1):33–41. 55. Ypenburg C, van Bommel RJ, Delgado V, Mollema SA, Bleeker GB, Boersma E, Schalij MJ, Bax JJ. Optimal left ventricular lead position predicts reverse remodeling and survival after cardiac resynchronization therapy. J Am Coll Cardiol. 2008;52(17):1402–9. 56. Fung JW, Lam YY, Zhang Q, Yip GW, Chan WW, Chan GC, Chan JY, Yu CM. Effect of left ventricular lead concordance to the delayed contraction segment on echocardiographic and clinical outcomes after cardiac resynchronization therapy. J Cardiovasc Electrophysiol. 2009;20(5):530–5. 57. Becker M, Hoffmann R, Schmitz F, Hundemer A, Kühl H, Schauerte P, Kelm M, Franke A. Relation of optimal lead positioning as defined by three-dimensional echocardiography to longterm benefit of cardiac resynchronization. Am J Cardiol. 2007; 100(11):1671–6. 58. Bax JJ, Bleeker GB, Marwick TH, Molhoek SG, Boersma E, Steendijk P, van der Wall EE, Schalij MJ. Left ventricular dyssynchrony predicts response and prognosis after cardiac resynchronization therapy. J Am Coll Cardiol. 2004;44(9):1834–40. 59. Ypenburg C, van Bommel RJ, Borleffs CJ, Bleeker GB, Boersma E, Schalij MJ, Bax JJ. Long-term prognosis after cardiac resynchronization therapy is related to the extent of left ventricular reverse remodeling at midterm follow-up. J Am Coll Cardiol. 2009; 53(6):483–90. 60. Mangiavacchi M, Gasparini M, Faletra F, Klersy C, Morenghi E, Galimberti P, Genovese L, Regoli F, De Chiara F, Bragato R, Andreuzzi B, Pini D, Gronda E. Clinical predictors of marked improvement in left ventricular performance after cardiac resynchronization therapy in patients with chronic heart failure. Am Heart J. 2006;151(2):477.e1–6. 61. Anand IS, Florea VG, Fisher L. Surrogate end points in heart failure. J Am Coll Cardiol. 2002;39(9):1414–21. 62. Chung ES, Leon AR, Tavazzi L, Sun JP, Nihoyannopoulos P, Merlino J, Abraham WT, Ghio S, Leclercq C, Bax JJ, Yu CM, Gorcsan 3rd J, St John Sutton M, De Sutter J, Murillo J. Results of the predictors of response to CRT (PROSPECT) trial. Circulation. 2008;117(20):2608–16. 63. Ansalone G, Giannantoni P, Ricci R, Trambaiolo P, Fedele F, Santini M. Biventricular pacing in heart failure: back to basics in the pathophysiology of left bundle branch block to reduce the number of nonresponders. Am J Cardiol. 2003;91(9A):55F–61. 64. Emkanjoo Z, Esmaeilzadeh M, Mohammad Hadi N, Alizadeh A, Tayyebi M, Sadr-Ameli MA. Frequency of inter- and intraventricular dyssynchrony in patients with heart failure according to QRS width. Europace. 2007;9(12):1171–6. 65. Ginks MR, Sciaraffia E, Karlsson A, Gustafsson J, Hamid S, Bostock J, Simon M, Blomström-Lundqvist C, Rinaldi CA. Relationship between intracardiac impedance and left ventricular contractility in patients undergoing cardiac resynchronization therapy. Europace. 2011;13(7):984–91. 66. Cazeau S, Leclercq C, Lavergne T, Walker S, Varma C, Linde C, Garrigue S, Kappenberger L, Haywood GA, Santini M, Bailleul C, Daubert JC, Multisite Stimulation in Cardiomyopathies (MUSTIC) Study Investigators. Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay. N Engl J Med. 2001;344(12):873–80. 67. Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De Marco T, Carson P, DiCarlo L, DeMets D, White BG, DeVries DW, Feldman AM, Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) Investigators. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med. 2004;350(21):2140–50.
44
Strategies for Restoring Cardiac Synchrony by Cardiac Pacing
68. Strickberger SA, Conti J, Daoud EG, Havranek E, Mehra MR, Piña IL, Young J, Council on Clinical Cardiology Subcommittee on Electrocardiography and Arrhythmias and the Quality of Care and Outcomes Research Interdisciplinary Working Group, Heart Rhythm Society. Patient selection for cardiac resynchronization therapy: from the Council on Clinical Cardiology Subcommittee on Electrocardiography and Arrhythmias and the Quality of Care and Outcomes Research Interdisciplinary Working Group, in collaboration with the Heart Rhythm Society. Circulation. 2005;111(16):2146–50. 69. Swedberg K, Cleland J, Dargie H, Drexler H, Follath F, Komajda M, Tavazzi L, Smiseth OA, Gavazzi A, Haverich A, Hoes A, Jaarsma T, Korewicki J, Lévy S, Linde C, Lopez-Sendon JL, Nieminen MS, Piérard L, Remme WJ, Task Force for the Diagnosis and Treatment of Chronic Heart Failure of the European Society of Cardiology. Guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 2005): The Task Force for the Diagnosis and Treatment of Chronic Heart Failure of the European Society of Cardiology. Eur Heart J. 2005; 26(11):1115–40. 70. Bleeker GB, Schalij MJ, Molhoek SG, Verwey HF, Holman ER, Boersma E, Steendijk P, Van Der Wall EE, Bax JJ. Relationship between QRS duration and left ventricular dyssynchrony in patients with end-stage heart failure. J Cardiovasc Electrophysiol. 2004;15(5):544–9. 71. Yu CM, Lin H, Zhang Q, Sanderson JE. High prevalence of left ventricular systolic and diastolic asynchrony in patients with congestive heart failure and normal QRS duration. Heart. 2003;89(1): 54–60. 72. Bleeker GB, Schalij MJ, Molhoek SG, Holman ER, Verwey HF, Steendijk P, van der Wall EE, Bax JJ. Frequency of left ventricular dyssynchrony in patients with heart failure and a narrow QRS complex. Am J Cardiol. 2005;95(1):140–2. 73. Rouleau F, Merheb M, Geffroy S, Berthelot J, Chaleil D, Dupuis JM, Victor J, Geslin P. Echocardiographic assessment of the interventricular delay of activation and correlation to the QRS width in dilated cardiomyopathy. Pacing Clin Electrophysiol. 2001;24(10): 1500–6. 74. Ghio S, Constantin C, Klersy C, Serio A, Fontana A, Campana C, Tavazzi L. Interventricular and intraventricular dyssynchrony are common in heart failure patients, regardless of QRS duration. Eur Heart J. 2004;25(7):571–8. 75. Dickstein K, Vardas PE, Auricchio A, Daubert JC, Linde C, McMurray J, Ponikowski P, Priori SG, Sutton R, van Veldhuisen DJ, ESC Committee for Practice Guidelines. 2010 focused update of ESC guidelines on device therapy in heart failure: an update of the 2008 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure and the 2007 ESC guidelines for cardiac and resynchronization therapy. Europace. 2010;12(11):1526–36. 76. Auricchio A, Stellbrink C, Butter C, Sack S, Vogt J, Misier AR, Böcker D, Block M, Kirkels JH, Kramer A, Huvelle E, Pacing Therapies in Congestive Heart Failure II Study Group; Guidant Heart Failure Research Group. Clinical efficacy of cardiac resynchronization therapy using left ventricular pacing in heart failure patients stratified by severity of ventricular conduction delay. J Am Coll Cardiol. 2003;42(12):2109–16. 77. Moss AJ, Hall WJ, Cannom DS, Klein H, Brown MW, Daubert JP, Estes 3rd NA, Foster E, Greenberg H, Higgins SL, Pfeffer MA, Solomon SD, Wilber D, Zareba W, MADIT-CRT Trial Investigators. Cardiac-resynchronization therapy for the prevention of heart-failure events. N Engl J Med. 2009;361(14):1329–38. 78. Linde C, Abraham WT, Gold MR, Daubert C, REVERSE Study Group. Cardiac resynchronization therapy in asymptomatic or mildly symptomatic heart failure patients in relation to etiology: results from the REVERSE (REsynchronization reVErses Remodeling in Systolic Left vEntricular Dysfunction) study. J Am Coll Cardiol. 2010;56(22):1826–31.
581 79. Perez de Isla L, Florit J, Garcia-Fernandez MA, Evangelista A, Zamorano J, RAVE (Registro de Asincronía Ventricular en España-Spanish Ventricular Asynchrony Registry) study investigators. Prevalence of echocardiographically detected ventricular asynchrony in patients with left ventricular systolic dysfunction. J Am Soc Echocardiogr. 2005;18(8):850–9. 80. Ho KK, Anderson KM, Kannel WB, Grossman W, Levy D. Survival after the onset of congestive heart failure in Framingham heart study subjects. Circulation. 1993;88(1):107–15. 81. Curry CW, Nelson GS, Wyman BT, Declerck J, Talbot M, Berger RD, McVeigh ER, Kass DA. Mechanical dyssynchrony in dilated cardiomyopathy with intraventricular conduction delay as depicted by 3D tagged magnetic resonance imaging. Circulation. 2000;101(1):E2. 82. Fauchier L, Marie O, Casset-Senon D, Babuty D, Cosnay P, Fauchier JP. Reliability of QRS duration and morphology on surface electrocardiogram to identify ventricular dyssynchrony in patients with idiopathic dilated cardiomyopathy. Am J Cardiol. 2003;92(3):341–4. 83. Bertini M, Delgado V, Bax JJ, Van de Veire NR. Why, how and when do we need to optimize the setting of cardiac resynchronization therapy? Europace. 2009;11 Suppl 5:v46–57. 84. Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, Jessup M, Konstam MA, Mancini DM, Michl K, Oates JA, Rahko PS, Silver MA, Stevenson LW, Yancy CW, Antman EM, Smith Jr SC, Adams CD, Anderson JL, Faxon DP, Fuster V, Halperin JL, Hiratzka LF, Jacobs AK, Nishimura R, Ornato JP, Page RL, Riegel B, American College of Cardiology, American Heart Association Task Force on Practice Guidelines, American College of Chest Physicians, International Society for Heart and Lung Transplantation, Heart Rhythm Society. Guideline update for the diagnosis and management of chronic heart failure in the adult: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation. 2005;112(12): e154–235. 85. Bleeker GB, Yu CM, Nihoyannopoulos P, de Sutter J, Van de Veire N, Holman ER, Schalij MJ, van der Wall EE, Bax JJ. Optimal use of echocardiography in cardiac resynchronisation therapy. Heart. 2007;93(11):1339–50. 86. Yu CM, Bax JJ, Monaghan M, Nihoyannopoulos P. Echocardiographic evaluation of cardiac dyssynchrony for predicting a favourable response to cardiac resynchronisation therapy. Heart. 2004;90 Suppl 6:vi17–22. 87. Waggoner AD, Agler DA, Adams DB. Cardiac resynchronization therapy and the emerging role of echocardiography (part 1): indications and results from current studies. J Am Soc Echocardiogr. 2007;20(1):70–5. 88. Agler DA, Adams DB, Waggoner AD. Cardiac resynchronization therapy and the emerging role of echocardiography (part 2): the comprehensive examination. J Am Soc Echocardiogr. 2007;20(1):76–90. 89. Gorcsan 3rd J, Abraham T, Agler DA, Bax JJ, Derumeaux G, Grimm RA, Martin R, Steinberg JS, Sutton MS, Yu CM, American Society of Echocardiography Dyssynchrony Writing Group. Echocardiography for cardiac resynchronization therapy: recommendations for performance and reporting–a report from the American Society of Echocardiography Dyssynchrony Writing Group endorsed by the Heart Rhythm Society. J Am Soc Echocardiogr. 2008;21(3):191–213. 90. Bonita A. Echocardiography: the normal examination and echocardiographic measurements. Second edition. MGA Graphics; 2007. ISBN 9780646468631.
582 91. Pitzalis MV, Iacoviello M, Romito R, Massari F, Rizzon B, Luzzi G, Guida P, Andriani A, Mastropasqua F, Rizzon P. Cardiac resynchronization therapy tailored by echocardiographic evaluation of ventricular asynchrony. J Am Coll Cardiol. 2002;40(9):1615–22. 92. Marcus GM, Rose E, Viloria EM, Schafer J, De Marco T, Saxon LA, Foster E, VENTAK CHF/CONTAK-CD Biventricular Pacing Study Investigators. Septal to posterior wall motion delay fails to predict reverse remodeling or clinical improvement in patients undergoing cardiac resynchronization therapy. J Am Coll Cardiol. 2005;46(12):2208–14. 93. Sassone B, Capecchi A, Boggian G, Gabrieli L, Saccà S, Vandelli R, Petracci E, Mele D. Value of baseline left lateral wall postsystolic displacement assessed by M-mode to predict reverse remodeling by cardiac resynchronization therapy. Am J Cardiol. 2007;100(3):470–5. 94. Kukulski T, Hubbert L, Arnold M, Wranne B, Hatle L, Sutherland GR. Normal regional right ventricular function and its change with age: a Doppler myocardial imaging study. J Am Soc Echocardiogr. 2000;13(3):194–204. 95. Waggoner AD, Bierig SM. Tissue Doppler imaging: a useful echocardiographic method for the cardiac sonographer to assess systolic and diastolic ventricular function. J Am Soc Echocardiogr. 2001;14(12):1143–52. 96. Gorcsan 3rd J, Kanzaki H, Bazaz R, Dohi K, Schwartzman D. Usefulness of echocardiographic tissue synchronization imaging to predict acute response to cardiac resynchronization therapy. Am J Cardiol. 2004;93(9):1178–81. 97. Yu CM, Zhang Q, Fung JW, Chan HC, Chan YS, Yip GW, Kong SL, Lin H, Zhang Y, Sanderson JE. A novel tool to assess systolic asynchrony and identify responders of cardiac resynchronization therapy by tissue synchronization imaging. J Am Coll Cardiol. 2005;45(5):677–84. 98. Sengupta PP, Korinek J, Belohlavek M, Narula J, Vannan MA, Jahangir A, Khandheria BK. Left ventricular structure and function: basic science for cardiac imaging. J Am Coll Cardiol. 2006;48(10):1988–2001. 99. Bijnens BH, Cikes M, Claus P, Sutherland GR. Velocity and deformation imaging for the assessment of myocardial dysfunction. Eur J Echocardiogr. 2009;10(2):216–26. 100. Mirsky I, Parmley WW. Assessment of passive elastic stiffness for isolated heart muscle and the intact heart. Circ Res. 1973;33(2):233–43. 101. Abraham TP, Dimaano VL, Liang HY. Role of tissue Doppler and strain echocardiography in current clinical practice. Circulation. 2007;116(22):2597–609. 102. Sun JP, Popović ZB, Greenberg NL, Xu XF, Asher CR, Stewart WJ, Thomas JD. Noninvasive quantification of regional myocardial function using Doppler-derived velocity, displacement, strain rate, and strain in healthy volunteers: effects of aging. J Am Soc Echocardiogr. 2004;17(2):132–8. 103. Urheim S, Edvardsen T, Torp H, Angelsen B, Smiseth OA. Myocardial strain by Doppler echocardiography. Validation of a new method to quantify regional myocardial function. Circulation. 2000;102(10):1158–64. 104. Helle-Valle T, Crosby J, Edvardsen T, Lyseggen E, Amundsen BH, Smith HJ, Rosen BD, Lima JA, Torp H, Ihlen H, Smiseth OA. New noninvasive method for assessment of left ventricular rotation: speckle tracking echocardiography. Circulation. 2005;112(20):3149–56. 105. Notomi Y, Lysyansky P, Setser RM, Shiota T, Popović ZB, MartinMiklovic MG, Weaver JA, Oryszak SJ, Greenberg NL, White RD, Thomas JD. Measurement of ventricular torsion by twodimensional ultrasound speckle tracking imaging. J Am Coll Cardiol. 2005;45(12):2034–41. 106. Leitman M, Lysyansky P, Sidenko S, Shir V, Peleg E, Binenbaum M, Kaluski E, Krakover R, Vered Z. Two-dimensional strain-a novel software for real-time quantitative echocardiographic assessment of myocardial function. J Am Soc Echocardiogr. 2004; 17(10):1021–9.
G. Cristian et al. 107. Becker M, Hoffmann R, Kühl HP, Grawe H, Katoh M, Kramann R, Bücker A, Hanrath P, Heussen N. Analysis of myocardial deformation based on ultrasonic pixel tracking to determine transmurality in chronic myocardial infarction. Eur Heart J. 2006; 27(21):2560–6. 108. Chan J, Hanekom L, Wong C, Leano R, Cho GY, Marwick TH. Differentiation of subendocardial and transmural infarction using two-dimensional strain rate imaging to assess short-axis and long-axis myocardial function. J Am Coll Cardiol. 2006;48(10): 2026–33. 109. Gjesdal O, Hopp E, Vartdal T, Lunde K, Helle-Valle T, Aakhus S, Smith HJ, Ihlen H, Edvardsen T. Global longitudinal strain measured by two-dimensional speckle tracking echocardiography is closely related to myocardial infarct size in chronic ischaemic heart disease. Clin Sci (Lond). 2007;113(6):287–96. 110. Goffinet C, Chenot F, Robert A, Pouleur AC, le Polain de Waroux JB, Vancrayenest D, Gerard O, Pasquet A, Gerber BL, Vanoverschelde JL. Assessment of subendocardial vs. subepicardial left ventricular rotation and twist using two-dimensional speckle tracking echocardiography: comparison with tagged cardiac magnetic resonance. Eur Heart J. 2009;30(5):608–17. 111. Suffoletto MS, Dohi K, Cannesson M, Saba S, Gorcsan 3rd J. Novel speckle-tracking radial strain from routine black-and-white echocardiographic images to quantify dyssynchrony and predict response to cardiac resynchronization therapy. Circulation. 2006; 113(7):960–8. 112. Sugeng L, Weinert L, Lang RM. Left ventricular assessment using real time three dimensional echocardiography. Heart. 2003;89 Suppl 3:iii29–36. 113. Jenkins C, Bricknell K, Hanekom L, Marwick TH. Reproducibility and accuracy of echocardiographic measurements of left ventricular parameters using real-time three-dimensional echocardiography. J Am Coll Cardiol. 2004;44(4):878–86. 114. Sugeng L, Mor-Avi V, Weinert L, Niel J, Ebner C, SteringerMascherbauer R, Schmidt F, Galuschky C, Schummers G, Lang RM, Nesser HJ. Quantitative assessment of left ventricular size and function: side-by-side comparison of real-time threedimensional echocardiography and computed tomography with magnetic resonance reference. Circulation. 2006;114(7):654–61. 115. Anderson LJ, Miyazaki C, Sutherland GR, Oh JK. Patient selection and echocardiographic assessment of dyssynchrony in cardiac resynchronization therapy. Circulation. 2008;117(15):2009–23. 116. Oh JK, Hatle L, Tajik AJ, Little WC. Diastolic heart failure can be diagnosed by comprehensive two-dimensional and Doppler echocardiography. J Am Coll Cardiol. 2006;47(3):500–6. 117. Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, Klein W, Tavazzi L, CARE-HF study Steering Committee and Investigators. The CARE-HF study (CArdiac REsynchronisation in Heart Failure study): rationale, design and end-points. Eur J Heart Fail. 2001;3(4):481–9. 118. Ritter P, Dib JC, Mahaux V, Lelièvre T, Soyeur D, Lavergne T, Cazeau S, Guize L, Rabine LM, Daubert JC. New method for determining the optimal atrio-ventricular delay in patients paced in DDD mode for complete atrio-ventricular block (abstract). Pacing Clin Electrophysiol. 1995;18:855. 119. Kerlan JE, Sawhney NS, Waggoner AD, Chawla MK, Garhwal S, Osborn JL, Faddis MN. Prospective comparison of echocardiographic atrioventricular delay optimization methods for cardiac resynchronization therapy. Heart Rhythm. 2006;3(2):148–54. 120. Ritter P, Lelieve T, Lavergne T. Quick determination of the optimal AV delay at rest in patients paced in DDD mode for complete AV block. Eur J Cardiac Pacing Electrophysiol. 1994;4:P54. 121. Kindermann M, Fröhlig G, Doerr T, Schieffer H. Optimizing the AV delay in DDD pacemaker patients with high degree AV block: mitral valve Doppler versus impedance cardiography. Pacing Clin Electrophysiol. 1997;20(10 Pt 1):2453–62.
44
Strategies for Restoring Cardiac Synchrony by Cardiac Pacing
122. Dupuis JM, Kobeissi A, Vitali L, Gaggini G, Merheb M, Rouleau F, Leftheriotis G, Ritter P, Victor J. Programming optimal atrioventricular delay in dual chamber pacing using peak endocardial acceleration: comparison with a standard echocardiographic procedure. Pacing Clin Electrophysiol. 2003;26(1 Pt 2):210–3. 123. León AR, Abraham WT, Brozena S, Daubert JP, Fisher WG, Gurley JC, Liang CS, Wong G, InSync III Clinical Study Investigators. Cardiac resynchronization with sequential biventricular pacing for the treatment of moderate-to-severe heart failure. J Am Coll Cardiol. 2005;46(12):2298–304. 124. Ritter P, Padeletti L, Gillio-Meina L, Gaggini G. Determination of the optimal atrioventricular delay in DDD pacing. Comparison between echo and peak endocardial acceleration measurements. Europace. 1999;1(2):126–30. 125. Burri H, Sunthorn H, Shah D, Lerch R. Optimization of device programming for cardiac resynchronization therapy. Pacing Clin Electrophysiol. 2006;29(12):1416–25. 126. Barold SS, Ilercil A, Herweg B. Echocardiographic optimization of the atrioventricular and interventricular intervals during cardiac resynchronization. Europace. 2008;10 Suppl 3:iii88–95. 127. Jansen AH, Bracke FA, van Dantzig JM, Meijer A, van der Voort PH, Aarnoudse W, van Gelder BM, Peels KH. Correlation of echo-Doppler optimization of atrioventricular delay in cardiac resynchronization therapy with invasive hemodynamics in patients with heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol. 2006;97(4):552–7. 128. Gold MR, Niazi I, Giudici M, Leman RB, Sturdivant JL, Kim MH, Yu Y, Ding J, Waggoner AD. A prospective comparison of AV delays programming methods for hemodynamic optimization during cardiac resynchronization therapy. J Cardiovasc Electrophysiol. 2007;18(5):490–6. 129. Meluzín J, Novák M, Müllerová J, Krejcí J, Hude P, Eisenberger M, Dusek L, Dvorák I, Spinarová L. A fast and simple echocardiographic method of determination of the optimal atrioventricular delay in patients after biventricular stimulation. Pacing Clin Electrophysiol. 2004;27(1):58–64. 130. Bordachar P, Lafitte S, Reuter S, Sanders P, Jaïs P, Haïssaguerre M, Roudaut R, Garrigue S, Clementy J. Echocardiographic parameters of ventricular dyssynchrony validation in patients with heart failure using sequential biventricular pacing. J Am Coll Cardiol. 2004;44(11):2157–65. 131. Mortensen PT, Sogaard P, Mansour H, Ponsonaille J, Gras D, Lazarus A, Reiser W, Alonso C, Linde CM, Lunati M, Kramm B, Harrison EM. Sequential biventricular pacing: evaluation of safety and efficacy. Pacing Clin Electrophysiol. 2004;27(3):339–45. 132. Porciani MC, Dondina C, Macioce R, Demarchi G, Pieragnoli P, Musilli N, Colella A, Ricciardi G, Michelucci A, Padeletti L. Echocardiographic examination of atrioventricular and interventricular delay optimization in cardiac resynchronization therapy. Am J Cardiol. 2005;95(9):1108–10. 133. Riedlbauchová L, Kautzner J, Frídl P. Influence of different atrioventricular and interventricular delays on cardiac output during cardiac resynchronization therapy. Pacing Clin Electrophysiol. 2005;28 Suppl 1:S19–23. 134. Vanderheyden M, De Backer T, Rivero-Ayerza M, Geelen P, Bartunek J, Verstreken S, De Zutter M, Goethals M. Tailored echocardiographic interventricular delay programming further optimizes left ventricular performance after cardiac resynchronization therapy. Heart Rhythm. 2005;2(10):1066–72. 135. Boriani G, Müller CP, Seidl KH, Grove R, Vogt J, Danschel W, Schuchert A, Djiane P, Biffi M, Becker T, Bailleul C, Trappe HJ, Resynchronization for the HemodYnamic Treatment for Heart Failure Management II Investigators. Randomized comparison of simultaneous biventricular stimulation versus optimized interventricular delay in cardiac resynchronization therapy. The Resynchronization for the HemodYnamic Treatment for Heart
583
136.
137.
138.
139.
140.
141.
142.
143.
144.
145.
146.
147. 148.
149.
150.
Failure Management II implantable cardioverter defibrillator (RHYTHM II ICD) study. Am Heart J. 2006;151(5):1050–8. Ishikawa T, Sumita S, Kimura K, Kuji N, Nakayama R, Nagura T, Miyazaki N, Tochikubo O, Usui T, Kashiwagi M, et al. Critical PQ interval for the appearance of diastolic mitral regurgitation and optimal PQ interval in patients implanted with DDD pacemakers. Pacing Clin Electrophysiol. 1994;17(11 Pt 2):1989–94. Ishikawa T, Sumita S, Kimura K, Kikuchi M, Kosuge M, Kuji N, Endo T, Sugano T, Sigemasa T, Kobayashi I, Tochikubo O, Usui T. Prediction of optimal atrioventricular delay in patients with implanted DDD pacemakers. Pacing Clin Electrophysiol. 1999;22(9):1365–71. Ishikawa T, Sumita S, Kimura K, Kikuchi M, Kosuge M, Nakagawa T, Matsushita K, Usui T, Umemura S. Efficacy of atrioventricular sequential pacing and diastolic mitral regurgitation in patients with intrinsic atrioventricular conduction. Jpn Circ J. 2000;64(8):579–82. Inoue N, Ishikawa T, Sumita S, Nakagawa T, Kobayashi T, Matsushita K, Matsumoto K, Ohkusu Y, Taima M, Kosuge M, Uchino K, Kimura K, Umemura S. Long-term follow-up of atrioventricular delay optimization in patients with biventricular pacing. Circ J. 2005;69(2):201–4. Ishikawa T, Kimura K, Nihei T, Usui T, Kashiwagi M, Ishii M. Relationship between diastolic mitral regurgitation and PQ intervals or cardiac function in patients implanted with DDD pacemakers. Pacing Clin Electrophysiol. 1991;14(11 Pt 2):1797–802. Melzer C, Knebel F, Ismer B, Bondke H, Nienaber CA, Baumann G, Borges AC. Influence of the atrio-ventricular delay optimization on the intra left ventricular delay in cardiac resynchronization therapy. Cardiovasc Ultrasound. 2006;4:5. Ismer B, von Knorre GH, Voß W, Körber T. Definition of the optimal atrioventricular delay by simultaneous measurement of electrocardiographic and Doppler-echocardiographic parameters. Prog Biomed Res. 2003;7:116–20. Ismer B, Von Knorre GH, Voss W, Grille W, Klenke G, Pulya K, Koglek W, Suntinger A, Luessow H. Exercise induced sympathetic influences do not change interatrial conduction times in VDD and DDD pacing. Pacing Clin Electrophysiol. 1996;19(11 Pt 2):1786–90. Ypenburg C, Van De Veire N, Westenberg JJ, Bleeker GB, Marsan NA, Henneman MM, Van Der Wall EE, Schalij MJ, Abraham TP, Barold SS, Bax JJ. Noninvasive imaging in cardiac resynchronization therapy–part 2: follow-up and optimization of settings. Pacing Clin Electrophysiol. 2008;31(12):1628–39. Sawhney NS, Waggoner AD, Garhwal S, Chawla MK, Osborn J, Faddis MN. Randomized prospective trial of atrioventricular delay programming for cardiac resynchronization therapy. Heart Rhythm. 2004;1(5):562–7. Goldman JH, Schiller NB, Lim DC, Redberg RF, Foster E. Usefulness of stroke distance by echocardiography as a surrogate marker of cardiac output that is independent of gender and size in a normal population. Am J Cardiol. 2001;87(4):499–502, A8. Coats AJ. Doppler ultrasonic measurement of cardiac output: reproducibility and validation. Eur Heart J. 1990;11(Suppl I):49–61. Dubin J, Wallerson DC, Cody RJ, Devereux RB. Comparative accuracy of Doppler echocardiographic methods for clinical stroke volume determination. Am Heart J. 1990;120(1):116–23. Gola A, Pozzoli M, Capomolla S, Traversi E, Sanarico M, Cobelli F, Tavazzi L. Comparison of Doppler echocardiography with thermodilution for assessing cardiac output in advanced congestive heart failure. Am J Cardiol. 1996;78(6):708–12. Harrison MR, Smith MD, Nissen SE, Grayburn PA, DeMaria AN. Use of exercise Doppler echocardiography to evaluate cardiac drugs: effects of propranolol and verapamil on aortic blood flow velocity and acceleration. J Am Coll Cardiol. 1988;11(5): 1002–9.
584 151. Wong M, Matsumura M, Omoto R. Left and right ventricular flows by Doppler echocardiography: serial measurements in patients with aortic regurgitation during exercise, cold pressor stimulation, and vasodilatation. J Am Soc Echocardiogr. 1990;3(4):285–93. 152. Wish M, Fletcher RD, Gottdiener JS, Cohen AI. Importance of left atrial timing in the programming of dual-chamber pacemakers. Am J Cardiol. 1987;60(7):566–71. 153. León AR, Abraham WT, Curtis AB, Daubert JP, Fisher WG, Gurley J, Hayes DL, Lieberman R, Petersen-Stejskal S, Wheelan K, MIRACLE Study Program. Safety of transvenous cardiac resynchronization system implantation in patients with chronic heart failure: combined results of over 2,000 patients from a multicenter study program. J Am Coll Cardiol. 2005;46(12):2348–56. 154. Dohi K, Suffoletto M, Ganz L, Zenati M, Gorcsan 3rd J. Utility of echocardiographic tissue synchronization imaging to redirect left ventricular lead placement for improved cardiac resynchronization therapy. Pacing Clin Electrophysiol. 2005;28(5):461–5. 155. Bleeker GB, Bax JJ, Schalij MJ, van der Wall EE. Tissue Doppler imaging to assess left ventricular dyssynchrony and resynchronization therapy. Eur J Echocardiogr. 2005;6(5):382–4. 156. Vidal B, Sitges M, Marigliano A, Delgado V, Díaz-Infante E, Azqueta M, Tamborero D, Tolosana JM, Berruezo A, Pérez-Villa F, Paré C, Mont L, Brugada J. Optimizing the programation of cardiac resynchronization therapy devices in patients with heart failure and left bundle branch block. Am J Cardiol. 2007;100(6):1002–6. 157. Novák M, Lipoldová J, Meluzín J, Krejcí J, Hude P, Feitová V, Dusek L, Kamarýt P, Vítovec J. Contribution to the V-V interval optimization in patients with cardiac resynchronization therapy. Physiol Res. 2008;57(5):693–700. 158. Morales MA, Startari U, Panchetti L, Rossi A, Piacenti M. Atrioventricular delay optimization by Doppler-derived left ventricular dP/dt improves 6-month outcome of resynchronized patients. Pacing Clin Electrophysiol. 2006;29(6):564–8. 159. Bargiggia GS, Bertucci C, Recusani F, Raisaro A, de Servi S, Valdes-Cruz LM, Sahn DJ, Tronconi L. A new method for estimating left ventricular dP/dt by continuous wave Dopplerechocardiography. Validation studies at cardiac catheterization. Circulation. 1989;80(5):1287–92. 160. Chung N, Nishimura RA, Holmes Jr DR, Tajik AJ. Measurement of left ventricular dp/dt by simultaneous Doppler echocardiography and cardiac catheterization. J Am Soc Echocardiogr. 1992;5(2): 147–52. 161. Breithardt OA, Sinha AM, Schwammenthal E, Bidaoui N, Markus KU, Franke A, Stellbrink C. Acute effects of cardiac resynchronization therapy on functional mitral regurgitation in advanced systolic heart failure. J Am Coll Cardiol. 2003;41(5):765–70. 162. Thomas DE, Yousef ZR, Fraser AG. A critical comparison of echocardiographic measurements used for optimizing cardiac resynchronization therapy: stroke distance is best. Eur J Heart Fail. 2009;11(8):779–88. 163. Tournoux FB, Alabiad C, Fan D, Chen AA, Chaput M, Heist EK, Mela T, Mansour M, Reddy V, Ruskin JN, Picard MH, Singh JP. Echocardiographic measures of acute haemodynamic response after cardiac resynchronization therapy predict long-term clinical outcome. Eur Heart J. 2007;28(9):1143–8. 164. Tei C, Ling LH, Hodge DO, Bailey KR, Oh JK, Rodeheffer RJ, Tajik AJ, Seward JB. New index of combined systolic and diastolic myocardial performance: a simple and reproducible measure of cardiac function–a study in normals and dilated cardiomyopathy. J Cardiol. 1995;26(6):357–66. 165. Tei C. New non-invasive index for combined systolic and diastolic ventricular function. J Cardiol. 1995;26(2):135–6. 166. Porciani MC, Fantini F, Musilli N, Sabini A, Michelucci A, Colella A, Pieragnoli P, Demarchi G, Padeletti L. A perspective on atrioventricular delay optimization in patients with a dual chamber pacemaker. Pacing Clin Electrophysiol. 2004;27(3):333–8.
G. Cristian et al. 167. Yoshifuku S, Otsuji Y, Takasaki K, Yuge K, Kisanuki A, Toyonaga K, Lee S, Murayama T, Nakashima H, Kumanohoso T, Minagoe S, Tei C. Pseudonormalized Doppler total ejection isovolume (Tei) index in patients with right ventricular acute myocardial infarction. Am J Cardiol. 2003;91(5):527–31. 168. Tham EB, Silverman NH. Measurement of the Tei index: a comparison of M-mode and pulse Doppler methods. J Am Soc Echocardiogr. 2004;17(12):1259–65. 169. Rojo EC, Rodrigo JL, Pérez de Isla L, Almería C, Gonzalo N, Aubele A, Cinza R, Zamorano J, Macaya C. Disagreement between tissue Doppler imaging and conventional pulsed wave Doppler in the measurement of myocardial performance index. Eur J Echocardiogr. 2006;7(5):356–64. 170. Tei C, Nishimura RA, Seward JB, Tajik AJ. Noninvasive Dopplerderived myocardial performance index: correlation with simultaneous measurements of cardiac catheterization measurements. J Am Soc Echocardiogr. 1997;10(2):169–78. 171. Stockburger M, Fateh-Moghadam S, Nitardy A, Langreck H, Haverkamp W, Dietz R. Optimization of cardiac resynchronization guided by Doppler echocardiography: haemodynamic improvement and intraindividual variability with different pacing configurations and atrioventricular delays. Europace. 2006;8(10):881–6. 172. Auricchio A, Stellbrink C, Sack S, Block M, Vogt J, Bakker P, Mortensen P, Klein H. The Pacing Therapies for Congestive Heart Failure (PATH-CHF) study: rationale, design, and endpoints of a prospective randomized multicenter study. Am J Cardiol. 1999; 83(5B):130D–5. 173. Nelson GS, Curry CW, Wyman BT, Kramer A, Declerck J, Talbot M, Douglas MR, Berger RD, McVeigh ER, Kass DA. Predictors of systolic augmentation from left ventricular preexcitation in patients with dilated cardiomyopathy and intraventricular conduction delay. Circulation. 2000;101(23):2703–9. 174. Mason DT. Usefulness and limitations of the rate of rise of intraventricular pressure (dp-dt) in the evaluation of myocardial contractility in man. Am J Cardiol. 1969;23(4):516–27. 175. Verbeek XA, Vernooy K, Peschar M, Van Der Nagel T, Van Hunnik A, Prinzen FW. Quantification of interventricular asynchrony during LBBB and ventricular pacing. Am J Physiol Heart Circ Physiol. 2002;283(4):H1370–8. 176. Bogaard MD, Houthuizen P, Bracke FA, Doevendans PA, Prinzen FW, Meine M, van Gelder BM. Baseline left ventricular dP/dtmax rather than the acute improvement in dP/dtmax predicts clinical outcome in patients with cardiac resynchronization therapy. Eur J Heart Fail. 2011;13(10):1126–32. 177. Gold MR, Auricchio A, Hummel JD, Giudici MC, Ding J, Tockman B, Spinelli J. Comparison of stimulation sites within left ventricular veins on the acute hemodynamic effects of cardiac resynchronization therapy. Heart Rhythm. 2005;2(4):376–81. 178. Butter C, Auricchio A, Stellbrink C, Fleck E, Ding J, Yu Y, Huvelle E, Spinelli J, Pacing Therapy for Chronic Heart Failure II Study Group. Effect of resynchronization therapy stimulation site on the systolic function of heart failure patients. Circulation. 2001;104(25):3026–9. 179. Bogaard MD, Doevendans PA, Leenders GE, Loh P, Hauer RN, van Wessel H, Meine M. Can optimization of pacing settings compensate for a non-optimal left ventricular pacing site? Europace. 2010;12(9):1262–9. 180. Auricchio A, Stellbrink C, Block M, Sack S, Vogt J, Bakker P, Klein H, Kramer A, Ding J, Salo R, Tockman B, Pochet T, Spinelli J. Effect of pacing chamber and atrioventricular delay on acute systolic function of paced patients with congestive heart failure. The Pacing Therapies for Congestive Heart Failure Study Group. The Guidant Congestive Heart Failure Research Group. Circulation. 1999;99(23):2993–3001. 181. Auricchio A, Stellbrink C, Sack S, Block M, Vogt J, Bakker P, Huth C, Schöndube F, Wolfhard U, Böcker D, Krahnefeld O,
44
182.
183.
184.
185.
186.
187.
188.
189.
190.
191.
192.
193.
Strategies for Restoring Cardiac Synchrony by Cardiac Pacing Kirkels H, Pacing Therapies in Congestive Heart Failure (PATHCHF) Study Group. Long-term clinical effect of hemodynamically optimized cardiac resynchronization therapy in patients with heart failure and ventricular conduction delay. J Am Coll Cardiol. 2002;39(12):2026–33. van Gelder BM, Bracke FA, Meijer A, Lakerveld LJ, Pijls NH. Effect of optimizing the VV interval on left ventricular contractility in cardiac resynchronization therapy. Am J Cardiol. 2004;93(12): 1500–3. Suzuki H, Shimano M, Yoshida Y, Inden Y, Muramatsu T, Tsuji Y, Tsuboi N, Hirayama H, Shibata R, Murohara T. Maximum derivative of left ventricular pressure predicts cardiac mortality after cardiac resynchronization therapy. Clin Cardiol. 2010;33(12):E18–23. de Roest G, Knaapen P, Götte M, Hendriks T, Allaart C, de Cock C, van Rossum A. Stroke work or systolic dP/dtmax to evaluate acute response to cardiac resynchronization therapy: are they interchangeable? Eur J Heart Fail. 2009;11(7):706–8. Kass DA, Maughan WL, Guo ZM, Kono A, Sunagawa K, Sagawa K. Comparative influence of load versus inotropic states on indexes of ventricular contractility: experimental and theoretical analysis based on pressure-volume relationships. Circulation. 1987;76(6):1422–36. Kass DA, Chen CH, Curry C, Talbot M, Berger R, Fetics B, Nevo E. Improved left ventricular mechanics from acute VDD pacing in patients with dilated cardiomyopathy and ventricular conduction delay. Circulation. 1999;99(12):1567–73. Crystal E, Ovsyshcher IE. Cardiac output-based versus empirically programmed AV interval–how different are they? Europace. 1999;1(2):121–5. Ellenbogen KA, Gold MR, Meyer TE, Fernndez Lozano I, Mittal S, Waggoner AD, Lemke B, Singh JP, Spinale FG, Van Eyk JE, Whitehill J, Weiner S, Bedi M, Rapkin J, Stein KM. Primary results from the SmartDelay determined AV optimization: a comparison to other AV delay methods used in cardiac resynchronization therapy (SMART-AV) trial: a randomized trial comparing empirical, echocardiography-guided, and algorithmic atrioventricular delay programming in cardiac resynchronization therapy. Circulation. 2010;122(25):2660–8. Baker 2nd JH, McKenzie 3rd J, Beau S, Greer GS, Porterfield J, Fedor M, Greenberg S, Daoud EG, Corbisiero R, Bailey JR, Porterfield L. Acute evaluation of programmer-guided AV/PV and VV delay optimization comparing an IEGM method and echocardiogram for cardiac resynchronization therapy in heart failure patients and dual-chamber ICD implants. J Cardiovasc Electrophysiol. 2007;18(2):185–91. Abraham WT, Gras D, Yu CM, Guzzo L, Gupta MS, FREEDOM Steering Committee. Rationale and design of a randomized clinical trial to assess the safety and efficacy of frequent optimization of cardiac resynchronization therapy: the Frequent Optimization Study Using the QuickOpt Method (FREEDOM) trial. Am Heart J. 2010;159(6):944–948.e1. Abraham William T, et al. Results from the FREEDOM Trial Assess the Safety and Efficacy of Frequent Optimization of Cardiac Resynchronization Therapy. SP08. Late-Breaking Clinical Trials. Denver: HRS; 2010. Porciani MC, Rao CM, Mochi M, Cappelli F, Bongiorno G, Perini AP, Lilli A, Ricciardi G, Hashtroudi L, Silvestri P, Barold SS, Padeletti L. A real-time three-dimensional echocardiographic validation of an intracardiac electrogram-based method for optimizing cardiac resynchronization therapy. Pacing Clin Electrophysiol. 2008;31(1):56–63. Leung SK, Lau CP, Lam CT, Ho S, Tse HF, Yu CM, Lee K, Tang MO, To KM, Renesto F. Automatic optimization of resting and exercise atrioventricular interval using a peak endocardial acceleration sensor: validation with Doppler echocardiography and direct cardiac output measurements. Pacing Clin Electrophysiol. 2000;23(11 Pt 2):1762–6.
585 194. Khan FZ, Virdee MS, Pugh PJ, Read PA, Fynn SP, Dutka DP. Non-invasive cardiac output measurements based on bioreactance for optimization of atrio- and interventricular delays. Europace. 2009;11(12):1666–74. 195. Gras D, Gupta MS, Boulogne E, Guzzo L, Abraham WT. Optimization of AV and VV delays in the real-world CRT patient population: an international survey on current clinical practice. Pacing Clin Electrophysiol. 2009;32 Suppl 1:S236–9. 196. Khan FZ, Virdee MS, Hutchinson J, Smith B, Pugh PJ, Read PA, Fynn SP, Dutka DP. Cardiac resynchronization therapy optimization using noninvasive cardiac output measurement. Pacing Clin Electrophysiol. 2011;34(11):1527–36. 197. Ritter P, Delnoy PP, Padeletti L, Lunati M, Naegele H, BorriBrunetto A, Silvestre J. A randomized pilot study of optimization of cardiac resynchronization therapy in sinus rhythm patients using a peak endocardial acceleration sensor vs. standard methods. Europace. 2012;14(9):1324–33. 198. Keren H, Burkhoff D, Squara P. Evaluation of a noninvasive continuous cardiac output monitoring system based on thoracic bioreactance. Am J Physiol Heart Circ Physiol. 2007;293(1):H583–9. 199. Rao RK, Kumar UN, Schafer J, Viloria E, De Lurgio D, Foster E. Reduced ventricular volumes and improved systolic function with cardiac resynchronization therapy: a randomized trial comparing simultaneous biventricular pacing, sequential biventricular pacing, and left ventricular pacing. Circulation. 2007;115(16):2136–44. 200. Naqvi TZ, Rafique AM. Novel insights on effect of atrioventricular programming of biventricular pacemaker in heart failure– a case series. Cardiovasc Ultrasound. 2006;4:38. 201. Stanton T, Hawkins NM, Hogg KJ, Goodfield NE, Petrie MC, McMurray JJ. How should we optimize cardiac resynchronization therapy? Eur Heart J. 2008;29(20):2458–72. 202. Cazeau S, Bordachar P, Jauvert G, Lazarus A, Alonso C, Vandrell MC, Mugica J, Ritter P. Echocardiographic modeling of cardiac dyssynchrony before and during multisite stimulation: a prospective study. Pacing Clin Electrophysiol. 2003;26(1 Pt 2):137–43. 203. Scharf C, Li P, Muntwyler J, Chugh A, Oral H, Pelosi F, Morady F, Armstrong WF. Rate-dependent AV delay optimization in cardiac resynchronization therapy. Pacing Clin Electrophysiol. 2005; 28(4):279–84. 204. O’Donnell D, Nadurata V, Hamer A, Kertes P, Mohamed U. Longterm variations in optimal programming of cardiac resynchronization therapy devices. Pacing Clin Electrophysiol. 2005;28 Suppl 1:S24–6. 205. Kedia N, Ng K, Apperson-Hansen C, Wang C, Tchou P, Wilkoff BL, Grimm RA. Usefulness of atrioventricular delay optimization using Doppler assessment of mitral inflow in patients undergoing cardiac resynchronization therapy. Am J Cardiol. 2006;98(6):780–5. 206. Zhang Q, Fung JW, Chan YS, Chan HC, Lin H, Chan S, Yu CM. The role of repeating optimization of atrioventricular interval during interim and long-term follow-up after cardiac resynchronization therapy. Int J Cardiol. 2008;124(2):211–7. 207. Hardt SE, Yazdi SH, Bauer A, Filusch A, Korosoglou G, Hansen A, Bekeredjian R, Ehlermann P, Remppis A, Katus HA, Kuecherer HF. Immediate and chronic effects of AV-delay optimization in patients with cardiac resynchronization therapy. Int J Cardiol. 2007;115(3):318–25. 208. Auricchio A, Ding J, Spinelli JC, Kramer AP, Salo RW, Hoersch W, KenKnight BH, Klein HU. Cardiac resynchronization therapy restores optimal atrioventricular mechanical timing in heart failure patients with ventricular conduction delay. J Am Coll Cardiol. 2002;39(7):1163–9. 209. Naqvi TZ. Echocardiography-guided biventricular pacemaker optimization. JACC Cardiovasc Imaging. 2010;3(11):1168–80. 210. Sogaard P, Egeblad H, Pedersen AK, Kim WY, Kristensen BO, Hansen PS, Mortensen PT. Sequential versus simultaneous biventricular resynchronization for severe heart failure: evaluation by tissue Doppler imaging. Circulation. 2002;106(16):2078–84.
586 211. Hay I, Melenovsky V, Fetics BJ, Judge DP, Kramer A, Spinelli J, Reister C, Kass DA, Berger RD. Short-term effects of right-left heart sequential cardiac resynchronization in patients with heart failure, chronic atrial fibrillation, and atrioventricular nodal block. Circulation. 2004;110(22):3404–10. 212. Kurzidim K, Reinke H, Sperzel J, Schneider HJ, Danilovic D, Siemon G, Neumann T, Hamm CW, Pitschner HF. Invasive optimization of cardiac resynchronization therapy: role of sequential biventricular and left ventricular pacing. Pacing Clin Electrophysiol. 2005;28(8):754–61. 213. Burri H, Sunthorn H, Somsen A, Zaza S, Fleury E, Shah D, Righetti A. Optimizing sequential biventricular pacing using radionuclide ventriculography. Heart Rhythm. 2005;2(9):960–5. 214. Whinnett ZI, Davies JE, Willson K, Manisty CH, Chow AW, Foale RA, Davies DW, Hughes AD, Mayet J, Francis DP. Haemodynamic effects of changes in atrioventricular and interventricular delay in cardiac resynchronisation therapy show a consistent pattern: analysis of shape, magnitude and relative importance of atrioventricular and interventricular delay. Heart. 2007;92(11):1628–34. 215. Penicka M, Bartunek J, De Bruyne B, Vanderheyden M, Goethals M, De Zutter M, Brugada P, Geelen P. Improvement of left ventricular function after cardiac resynchronization therapy is predicted by tissue Doppler imaging echocardiography. Circulation. 2004;109(8):978–83. 216. Weiss R, Malik R, Wish M, Dinerman J, Lee LY, Petrutiu S, Khoo MSC. V-V Optimization in Cardiac Resynchronization Therapy Non-Responders: RESPONSE-HF Trial Results [Abstract]. Heart Rhythm. 2010;7(5 Suppl):S26. 217. Young JB, Abraham WT, Smith AL, Leon AR, Lieberman R, Wilkoff B, Canby RC, Schroeder JS, Liem LB, Hall S, Wheelan K, Multicenter InSync ICD Randomized Clinical Evaluation (MIRACLE ICD) Trial Investigators. Combined cardiac resynchronization and implantable cardioversion defibrillation in advanced chronic heart failure: the MIRACLE ICD trial. JAMA. 2003;289(20):2685–94. 218. Cazeau S, Ritter P, Lazarus A, Gras D, Backdach H, Mundler O, Mugica J. Multisite pacing for end-stage heart failure: early experience. Pacing Clin Electrophysiol. 1996;19(11 Pt 2):1748–57. 219. Leclercq C, Cazeau S, Le Breton H, Ritter P, Mabo P, Gras D, Pavin D, Lazarus A, Daubert JC. Acute hemodynamic effects of biventricular DDD pacing in patients with end-stage heart failure. J Am Coll Cardiol. 1998;32(7):1825–31. 220. Saxon LA, Kerwin WF, Cahalan MK, Kalman JM, Olgin JE, Foster E, Schiller NB, Shinbane JS, Lesh MD, Merrick SH. Acute effects of intraoperative multisite ventricular pacing on left ventricular function and activation/contraction sequence in patients with depressed ventricular function. J Cardiovasc Electrophysiol. 1998;9(1):13–21. 221. Gras D, Mabo P, Tang T, Luttikuis O, Chatoor R, Pedersen AK, Tscheliessnigg HH, Deharo JC, Puglisi A, Silvestre J, Kimber S, Ross H, Ravazzi A, Paul V, Skehan D. Multisite pacing as a supplemental treatment of congestive heart failure: preliminary results of the Medtronic Inc. InSync Study. Pacing Clin Electrophysiol. 1998;21(11 Pt 2):2249–55. 222. Nelson GS, Berger RD, Fetics BJ, Talbot M, Spinelli JC, Hare JM, Kass DA. Left ventricular or biventricular pacing improves cardiac function at diminished energy cost in patients with dilated cardiomyopathy and left bundle-branch block. Circulation. 2000;102(25):3053–9. 223. Gras D, Leclercq C, Tang AS, Bucknall C, Luttikhuis HO, Kirstein-Pedersen A. Cardiac resynchronization therapy in advanced heart failure the multicenter InSync clinical study. Eur J Heart Fail. 2002;4(3):311–20. 224. O’Cochlain B, Delurgio D, Leon A, Langberg J. The effect of variation in the interval between right and left ventricular activation on
G. Cristian et al.
225.
226.
227.
228.
229.
230.
231.
232.
233.
234.
235.
236.
237.
238.
paced QRS duration. Pacing Clin Electrophysiol. 2001;24(12): 1780–2. Jia P, Ramanathan C, Ghanem RN, Ryu K, Varma N, Rudy Y. Electrocardiographic imaging of cardiac resynchronization therapy in heart failure: observation of variable electrophysiologic responses. Heart Rhythm. 2006;3(3):296–310. Gassis S, León AR. Cardiac resynchronization therapy: strategies for device programming, troubleshooting and follow-up. J Interv Card Electrophysiol. 2005;13(3):209–22. Marcus RH, Harry MJ, Lang RM. Pacemaker therapy in refractory heart failure: a systematic approach to electromechanical optimization of diastolic function. JACC Cardiovasc Imaging. 2009;2(7):908–13. Bader H, Garrigue S, Lafitte S, Reuter S, Jaïs P, Haïssaguerre M, Bonnet J, Clementy J, Roudaut R. Intra-left ventricular electromechanical asynchrony. A new independent predictor of severe cardiac events in heart failure patients. J Am Coll Cardiol. 2004;43(2): 248–56. Voigt JU, Schneider TM, Korder S, Szulik M, Gürel E, Daniel WG, Rademakers F, Flachskampf FA. Apical transverse motion as surrogate parameter to determine regional left ventricular function inhomogeneities: a new, integrative approach to left ventricular asynchrony assessment. Eur Heart J. 2009;30(8):959–68. Szulik M, Tillekaerts M, Vangeel V, Ganame J, Willems R, Lenarczyk R, Rademakers F, Kalarus Z, Kukulski T, Voigt JU. Assessment of apical rocking: a new, integrative approach for selection of candidates for cardiac resynchronization therapy. Eur J Echocardiogr. 2010;11(10):863–9. Pitzalis MV, Iacoviello M, Romito R, Guida P, De Tommasi E, Luzzi G, Anaclerio M, Forleo C, Rizzon P. Ventricular asynchrony predicts a better outcome in patients with chronic heart failure receiving cardiac resynchronization therapy. J Am Coll Cardiol. 2005;45(1):65–9. Parsai C, Bijnens B, Sutherland GR, Baltabaeva A, Claus P, Marciniak M, Paul V, Scheffer M, Donal E, Derumeaux G, Anderson L. Toward understanding response to cardiac resynchronization therapy: left ventricular dyssynchrony is only one of multiple mechanisms. Eur Heart J. 2009;30(8):940–9. Yu CM, Fung JW, Zhang Q, Chan CK, Chan YS, Lin H, Kum LC, Kong SL, Zhang Y, Sanderson JE. Tissue Doppler imaging is superior to strain rate imaging and postsystolic shortening on the prediction of reverse remodeling in both ischemic and nonischemic heart failure after cardiac resynchronization therapy. Circulation. 2004;110(1):66–73. Yu CM, Fung WH, Lin H, Zhang Q, Sanderson JE, Lau CP. Predictors of left ventricular reverse remodeling after cardiac resynchronization therapy for heart failure secondary to idiopathic dilated or ischemic cardiomyopathy. Am J Cardiol. 2003;91(6):684–8. Lim P, Buakhamsri A, Popovic ZB, Greenberg NL, Patel D, Thomas JD, Grimm RA. Longitudinal strain delay index by speckle tracking imaging: a new marker of response to cardiac resynchronization therapy. Circulation. 2008;118(11):1130–7. Kapetanakis S, Kearney MT, Siva A, Gall N, Cooklin M, Monaghan MJ. Real-time three-dimensional echocardiography: a novel technique to quantify global left ventricular mechanical dyssynchrony. Circulation. 2005;112(7):992–1000. Marsan NA, Bleeker GB, Ypenburg C, Ghio S, van de Veire NR, Holman ER, van der Wall EE, Tavazzi L, Schalij MJ, Bax JJ. Realtime three-dimensional echocardiography permits quantification of left ventricular mechanical dyssynchrony and predicts acute response to cardiac resynchronization therapy. J Cardiovasc Electrophysiol. 2008;19(4):392–9. Gorcsan 3rd J, Tanabe M, Bleeker GB, Suffoletto MS, Thomas NC, Saba S, Tops LF, Schalij MJ, Bax JJ. Combined longitudinal and radial dyssynchrony predicts ventricular response after resynchronization therapy. J Am Coll Cardiol. 2007;50(15):1476–83.
44
Strategies for Restoring Cardiac Synchrony by Cardiac Pacing
239. Van de Veire NR, Bleeker GB, Ypenburg C, De Sutter J, Ajmone Marsan N, Holman ER, van der Wall EE, Schalij MJ, Bax JJ. Usefulness of triplane tissue Doppler imaging to predict acute response to cardiac resynchronization therapy. Am J Cardiol. 2007;100(3):476–82. 240. Beshai JF, Grimm RA, Nagueh SF, Baker 2nd JH, Beau SL, Greenberg SM, Pires LA, Tchou PJ, RethinQ Study Investigators. Cardiac-resynchronization therapy in heart failure with narrow QRS complexes. N Engl J Med. 2007;357(24):2461–71. 241. Oyenuga O, Hara H, Tanaka H, Kim HN, Adelstein EC, Saba S, Gorcsan 3rd J. Usefulness of echocardiographic dyssynchrony in patients with borderline QRS duration to assist with selection for cardiac resynchronization therapy. JACC Cardiovasc Imaging. 2010;3(2):132–40. 242. Miyazaki C, Powell BD, Bruce CJ, Espinosa RE, Redfield MM, Miller FA, Hayes DL, Cha YM, Oh JK. Comparison of echocardiographic dyssynchrony assessment by tissue velocity and strain imaging in subjects with or without systolic dysfunction and with or without left bundle-branch block. Circulation. 2008;117(20):2617–25. 243. Mor-Avi V, Lang RM, Badano LP, Belohlavek M, Cardim NM, Derumeaux G, Galderisi M, Marwick T, Nagueh SF, Sengupta PP, Sicari R, Smiseth OA, Smulevitz B, Takeuchi M, Thomas JD, Vannan M, Voigt JU, Zamorano JL. Current and evolving echocardiographic techniques for the quantitative evaluation of cardiac mechanics: ASE/EAE consensus statement on methodology and indications endorsed by the Japanese society of echocardiography. J Am Soc Echocardiogr. 2011;24(3):277–313. 244. Søgaard P, Egeblad H, Kim WY, Jensen HK, Pedersen AK, Kristensen BØ, Mortensen PT. Tissue Doppler imaging predicts improved systolic performance and reversed left ventricular remodeling during long-term cardiac resynchronization therapy. J Am Coll Cardiol. 2002;40(4):723–30. 245. Breithardt OA, Stellbrink C, Kramer AP, Sinha AM, Franke A, Salo R, Schiffgens B, Huvelle E, Auricchio A, PATH-CHF Study Group. Pacing therapies for congestive heart failure. Echocardiographic quantification of left ventricular asynchrony predicts an acute hemodynamic benefit of cardiac resynchronization therapy. J Am Coll Cardiol. 2002;40(3):536–45. 246. Breithardt OA, Stellbrink C, Herbots L, Claus P, Sinha AM, Bijnens B, Hanrath P, Sutherland GR. Cardiac resynchronization therapy can reverse abnormal myocardial strain distribution in patients with heart failure and left bundle branch block. J Am Coll Cardiol. 2003;42(3):486–94. 247. Yu CM, Bleeker GB, Fung JW, Schalij MJ, Zhang Q, van der Wall EE, Chan YS, Kong SL, Bax JJ. Left ventricular reverse remodeling but not clinical improvement predicts long-term survival after cardiac resynchronization therapy. Circulation. 2005;112(11): 1580–6. 248. Sweeney MO, Prinzen FW. Ventricular pump function and pacing: physiological and clinical integration. Circ Arrhythm Electrophysiol. 2008;1(2):127–39. 249. Tops LF, Schalij MJ, Bax JJ. The effects of right ventricular apical pacing on ventricular function and dyssynchrony implications for therapy. J Am Coll Cardiol. 2009;54(9):764–76. 250. Manolis AS. The deleterious consequences of right ventricular apical pacing: time to seek alternate site pacing. Pacing Clin Electrophysiol. 2006;29(3):298–315. 251. Sweeney MO, Hellkamp AS, Ellenbogen KA, Greenspon AJ, Freedman RA, Lee KL, Lamas GA, MOde Selection Trial Investigators. Adverse effect of ventricular pacing on heart failure and atrial fibrillation among patients with normal baseline QRS duration in a clinical trial of pacemaker therapy for sinus node dysfunction. Circulation. 2003;107(23):2932–7. 252. Leclercq C, Walker S, Linde C, Clementy J, Marshall AJ, Ritter P, Djiane P, Mabo P, Levy T, Gadler F, Bailleul C, Daubert JC. Comparative effects of permanent biventricular and right-
587
253.
254.
255.
256.
257.
258.
259.
260.
261.
262.
263.
264.
265.
266.
univentricular pacing in heart failure patients with chronic atrial fibrillation. Eur Heart J. 2002;23(22):1780–7. Brignole M, Gammage M, Puggioni E, Alboni P, Raviele A, Sutton R, Vardas P, Bongiorni MG, Bergfeldt L, Menozzi C, Musso G, Optimal Pacing SITE (OPSITE) Study Investigators. Comparative assessment of right, left, and biventricular pacing in patients with permanent atrial fibrillation. Eur Heart J. 2005;26(7):712–22. Doshi RN, Daoud EG, Fellows C, Turk K, Duran A, Hamdan MH, Pires LA, PAVE Study Group. Left ventricular-based cardiac stimulation post AV nodal ablation evaluation (the PAVE study). J Cardiovasc Electrophysiol. 2005;16(11):1160–5. Kindermann M, Hennen B, Jung J, Geisel J, Böhm M, Fröhlig G. Biventricular versus conventional right ventricular stimulation for patients with standard pacing indication and left ventricular dysfunction: the Homburg Biventricular Pacing Evaluation (HOBIPACE). J Am Coll Cardiol. 2006;47(10):1927–37. Albertsen AE, Nielsen JC, Poulsen SH, Mortensen PT, Pedersen AK, Hansen PS, Jensen HK, Egeblad H. Biventricular pacing preserves left ventricular performance in patients with high-grade atrio-ventricular block: a randomized comparison with DDD(R) pacing in 50 consecutive patients. Europace. 2008;10(3):314–20. Tops LF, Suffoletto MS, Bleeker GB, Boersma E, van der Wall EE, Gorcsan 3rd J, Schalij MJ, Bax JJ. Speckle-tracking radial strain reveals left ventricular dyssynchrony in patients with permanent right ventricular pacing. J Am Coll Cardiol. 2007;50(12):1180–8. Leon AR, Greenberg JM, Kanuru N, Baker CM, Mera FV, Smith AL, Langberg JJ, DeLurgio DB. Cardiac resynchronization in patients with congestive heart failure and chronic atrial fibrillation: effect of upgrading to biventricular pacing after chronic right ventricular pacing. J Am Coll Cardiol. 2002;39(8):1258–63. Witte KK, Pipes RR, Nanthakumar K, Parker JD. Biventricular pacemaker upgrade in previously paced heart failure patients– improvements in ventricular dyssynchrony. J Card Fail. 2006;12(3): 199–204. Valls-Bertault V, Fatemi M, Gilard M, Pennec PY, Etienne Y, Blanc JJ. Assessment of upgrading to biventricular pacing in patients with right ventricular pacing and congestive heart failure after atrioventricular junctional ablation for chronic atrial fibrillation. Europace. 2004;6(5):438–43. Eldadah ZA, Rosen B, Hay I, Edvardsen T, Jayam V, Dickfeld T, Meininger GR, Judge DP, Hare J, Lima JB, Calkins H, Berger RD. The benefit of upgrading chronically right ventricle-paced heart failure patients to resynchronization therapy demonstrated by strain rate imaging. Heart Rhythm. 2006;3(4):435–42. Marai I, Gurevitz O, Carasso S, Nof E, Bar-Lev D, Luria D, Arbel Y, Freimark D, Feinberg MS, Eldar M, Glikson M. Improvement of congestive heart failure by upgrading of conventional to resynchronization pacemakers. Pacing Clin Electrophysiol. 2006;29(8):880–4. Leclercq C, Cazeau S, Lellouche D, Fossati F, Anselme F, Davy JM, Sadoul N, Klug D, Mollo L, Daubert JC. Upgrading from single chamber right ventricular to biventricular pacing in permanently paced patients with worsening heart failure: the RD-CHF study. Pacing Clin Electrophysiol. 2007;30 Suppl 1:S23–30. Wilkoff BL, Cook JR, Epstein AE, Greene HL, Hallstrom AP, Hsia H, Kutalek SP, Sharma A, Dual Chamber and VVI Implantable Defibrillator Trial Investigators. Dual-chamber pacing or ventricular backup pacing in patients with an implantable defibrillator: the Dual Chamber and VVI Implantable Defibrillator (DAVID) Trial. JAMA. 2002;288(24):3115–23. Thambo JB, Bordachar P, Garrigue S, Lafitte S, Sanders P, Reuter S, Girardot R, Crepin D, Reant P, Roudaut R, Jaïs P, Haïssaguerre M, Clementy J, Jimenez M. Detrimental ventricular remodeling in patients with congenital complete heart block and chronic right ventricular apical pacing. Circulation. 2004;110(25):3766–72. Tops LF, Schalij MJ, Holman ER, van Erven L, van der Wall EE, Bax JJ. Right ventricular pacing can induce ventricular
588
267.
268.
269.
270.
271.
272.
273.
274.
275. 276.
277.
278.
279.
280.
281.
G. Cristian et al. dyssynchrony in patients with atrial fibrillation after atrioventricular node ablation. J Am Coll Cardiol. 2006;48(8):1642–8. Yu CC, Liu YB, Lin MS, Wang JY, Lin JL, Lin LC. Septal pacing preserving better left ventricular mechanical performance and contractile synchronism than apical pacing in patients implanted with an atrioventricular sequential dual chamber pacemaker. Int J Cardiol. 2007;118(1):97–106. Kypta A, Steinwender C, Kammler J, Leisch F, Hofmann R. Long-term outcomes in patients with atrioventricular block undergoing septal ventricular lead implantation compared with standard apical pacing. Europace. 2008;10(5):574–9. Victor F, Mabo P, Mansour H, Pavin D, Kabalu G, de Place C, Leclercq C, Daubert JC. A randomized comparison of permanent septal versus apical right ventricular pacing: short-term results. J Cardiovasc Electrophysiol. 2006;17(3):238–42. Zanon F, Bacchiega E, Rampin L, Aggio S, Baracca E, Pastore G, Marotta T, Corbucci G, Roncon L, Rubello D, Prinzen FW. Direct His bundle pacing preserves coronary perfusion compared with right ventricular apical pacing: a prospective, cross-over mid-term study. Europace. 2008;10(5):580–7. Occhetta E, Bortnik M, Magnani A, Francalacci G, Piccinino C, Plebani L, Marino P. Prevention of ventricular desynchronization by permanent para-Hisian pacing after atrioventricular node ablation in chronic atrial fibrillation: a crossover, blinded, randomized study versus apical right ventricular pacing. J Am Coll Cardiol. 2006;47(10):1938–45. de Cock CC, Giudici MC, Twisk JW. Comparison of the haemodynamic effects of right ventricular outflow-tract pacing with right ventricular apex pacing: a quantitative review. Europace. 2003;5(3): 275–8. Vanerio G, Vidal JL, Fernández Banizi P, Banina Aguerre D, Viana P, Tejada J. Medium- and long-term survival after pacemaker implant: improved survival with right ventricular outflow tract pacing. J Interv Card Electrophysiol. 2008;21(3):195–201. ten Cate TJ, Scheffer MG, Sutherland GR, Verzijlbergen JF, van Hemel NM. Right ventricular outflow and apical pacing comparably worsen the echocardiographic normal left ventricle. Eur J Echocardiogr. 2008;9(5):672–7. Clay SC. Alternate site biventricular pacing: Bi-V in the RV–is there a role? Pacing Clin Electrophysiol. 2004;27(5):567–9. Pachón JC, Pachón EI, Albornoz RN, Pachón JC, Kormann DS, Gimenes VM, Medeiros PT, Silva MA, Sousa JE, Paulista PP, Souza LC, Jatene AD. Ventricular endocardial right bifocal stimulation in the treatment of severe dilated cardiomyopathy heart failure with wide QRS. Pacing Clin Electrophysiol. 2001;24(9 Pt 1): 1369–76. O’Donnell D, Nadurata V, Hamer A, Kertes P, Mohamed U. Bifocal right ventricular cardiac resynchronization therapies in patients with unsuccessful percutaneous lateral left ventricular venous access. Pacing Clin Electrophysiol. 2005;28 Suppl 1:S27–30. Stambler BS, Ellenbogen K, Zhang X, Porter TR, Xie F, Malik R, Small R, Burke M, Kaplan A, Nair L, Belz M, Fuenzalida C, Gold M, Love C, Sharma A, Silverman R, Sogade F, Van Natta B, Wilkoff BL, ROVA Investigators. Right ventricular outflow versus apical pacing in pacemaker patients with congestive heart failure and atrial fibrillation. J Cardiovasc Electrophysiol. 2003;14(11):1180–6. Zamparelli L, Martiniello AR. Right ventricular bifocal DDD pacing as primary choice for cardiac resynchronization in heart failure patients with severe mitral regurgitation (abstr). Heart Rhythm. 2005;2(Suppl):S250. Aonuma K, Yokoyama Y, Seo Y, et al. Tri-ventricular pacing: a novel concept of resynchronization therapy for better left ventricular performance in end-stage heart failure (abstract). Heart Rhythm. 2005;2(Suppl):S131. Yoshida K, Seo Y, Yamasaki H, Tanoue K, Murakoshi N, Ishizu T, Sekiguchi Y, Kawano S, Otsuka S, Watanabe S, Yamaguchi I,
282.
283.
284.
285.
286.
287.
288.
289.
290.
291.
292.
293.
294.
295.
296.
Aonuma K. Effect of triangle ventricular pacing on haemodynamics and dyssynchrony in patients with advanced heart failure: a comparison study with conventional bi-ventricular pacing therapy. Eur Heart J. 2007;28(21):2610–9. Singh JP, Klein HU, Huang DT, Reek S, Kuniss M, Quesada A, Barsheshet A, Cannom D, Goldenberg I, McNitt S, Daubert JP, Zareba W, Moss AJ. Left ventricular lead position and clinical outcome in the multicenter automatic defibrillator implantation trial-cardiac resynchronization therapy (MADIT-CRT) trial. Circulation. 2011;123(11):1159–66. Derval N, Jaïs P. Optimizing hemodynamics in cardiac resynchronization therapy by left ventricular pacing site: you find only what you are looking for. J Am Coll Cardiol. 2010;56(10):782–3. Peichl P, Kautzner J. Variable patterns of septal activation in patients with left bundle branch block and heart failure. J Cardiovasc Electrophysiol. 2003;14(8):900. author reply 900–1. Bordachar P, Labrousse L, Thambo JB, Reant P, Lafitte S, O’Neill MD, Jais P, Haissaguerre M, Clementy J, Dos Santos P. Haemodynamic impact of the left ventricular pacing site during graded ischaemia in an open-chest pig model. Europace. 2008;10(2): 242–8. Murphy RT, Sigurdsson G, Mulamalla S, Agler D, Popovic ZB, Starling RC, Wilkoff BL, Thomas JD, Grimm RA. Tissue synchronization imaging and optimal left ventricular pacing site in cardiac resynchronization therapy. Am J Cardiol. 2006;97(11):1615–21. Ansalone G, Giannantoni P, Ricci R, Trambaiolo P, Fedele F, Santini M. Doppler myocardial imaging to evaluate the effectiveness of pacing sites in patients receiving biventricular pacing. J Am Coll Cardiol. 2002;39(3):489–99. Buck S, Maass AH, van Veldhuisen DJ, Van Gelder IC. Cardiac resynchronisation therapy and the role of optimal device utilisation. Neth Heart J. 2009;17(9):354–7. Bank AJ, Burns KV, Gage RM. Echocardiographic measurement of mechanical dyssynchrony in heart failure and cardiac resynchronization therapy. US Cardiology. 2010;7(1):24–32. Saba S, Schwartzman D, Jain S, et al. A prospective randomized controlled study of echocardiographic-guided lead placement for cardiac resynchronization therapy: Results of the STARTER trial. Heart Rhythm Society 2012 Scientific Sessions, Boston, MA, May 11, 2012, . Abstract LB02-5. Dekker AL, Phelps B, Dijkman B, van der Nagel T, van der Veen FH, Geskes GG, Maessen JG. Epicardial left ventricular lead placement for cardiac resynchronization therapy: optimal pace site selection with pressure-volume loops. J Thorac Cardiovasc Surg. 2004;127(6):1641–7. Helm RH, Byrne M, Helm PA, Daya SK, Osman NF, Tunin R, Halperin HR, Berger RD, Kass DA, Lardo AC. Three-dimensional mapping of optimal left ventricular pacing site for cardiac resynchronization. Circulation. 2007;115(8):953–61. Khan FZ, Virdee MS, Palmer CR, Pugh PJ, O’Halloran D, Elsik M, Read PA, Begley D, Fynn SP, Dutka DP. Targeted left ventricular lead placement to guide cardiac resynchronization therapy: the TARGET study: a randomized, controlled trial. J Am Coll Cardiol. 2012;59(17):1509–18. Wikstrom G, Blomström-Lundqvist C, Andren B, Lönnerholm S, Blomström P, Freemantle N, Remp T, Cleland JG, CARE-HF study investigators. The effects of aetiology on outcome in patients treated with cardiac resynchronization therapy in the CARE-HF trial. Eur Heart J. 2009;30(7):782–8. Ypenburg C, Roes SD, Bleeker GB, Kaandorp TA, de Roos A, Schalij MJ, van der Wall EE, Bax JJ. Effect of total scar burden on contrast-enhanced magnetic resonance imaging on response to cardiac resynchronization therapy. Am J Cardiol. 2007;99(5): 657–60. Bertini M, Delgado V, den Uijl DW, Nucifora G, Ng AC, van Bommel RJ, Borleffs CJ, Boriani G, Schalij MJ, Bax JJ. Prediction
44
297. 298.
299.
300.
301.
302.
303.
304.
Strategies for Restoring Cardiac Synchrony by Cardiac Pacing of cardiac resynchronization therapy response: value of calibrated integrated backscatter imaging. Circ Cardiovasc Imaging. 2010; 3(1):86–93. Germano G, Berman DS. Quantitative gated SPECT. J Nucl Med. 2001;42(3):528–9. Klein C, Nekolla SG, Bengel FM, Momose M, Sammer A, Haas F, Schnackenburg B, Delius W, Mudra H, Wolfram D, Schwaiger M. Assessment of myocardial viability with contrast-enhanced magnetic resonance imaging: comparison with positron emission tomography. Circulation. 2002;105(2):162–7. Nekolla SG, Miethaner C, Nguyen N, Ziegler SI, Schwaiger M. Reproducibility of polar map generation and assessment of defect severity and extent assessment in myocardial perfusion imaging using positron emission tomography. Eur J Nucl Med. 1998;25(9):1313–21. Van de Veire NR, Schuijf JD, De Sutter J, Devos D, Bleeker GB, de Roos A, van der Wall EE, Schalij MJ, Bax JJ. Non-invasive visualization of the cardiac venous system in coronary artery disease patients using 64-slice computed tomography. J Am Coll Cardiol. 2006;48(9):1832–8. Lozano I, Bocchiardo M, Achtelik M, Gaita F, Trappe HJ, Daoud E, Hummel J, Duby C, Yong P, VENTAK CHF/CONTAK CD Investigators Study Group. Impact of biventricular pacing on mortality in a randomized crossover study of patients with heart failure and ventricular arrhythmias. Pacing Clin Electrophysiol. 2000;23(11 Pt 2):1711–2. Derval N, Steendijk P, Gula LJ, Deplagne A, Laborderie J, Sacher F, Knecht S, Wright M, Nault I, Ploux S, Ritter P, Bordachar P, Lafitte S, Réant P, Klein GJ, Narayan SM, Garrigue S, Hocini M, Haissaguerre M, Clementy J, Jaïs P. Optimizing hemodynamics in heart failure patients by systematic screening of left ventricular pacing sites: the lateral left ventricular wall and the coronary sinus are rarely the best sites. J Am Coll Cardiol. 2010;55(6):566–75. Singh JP, Fan D, Heist EK, Alabiad CR, Taub C, Reddy V, Mansour M, Picard MH, Ruskin JN, Mela T. Left ventricular lead electrical delay predicts response to cardiac resynchronization therapy. Heart Rhythm. 2006;3(11):1285–92. Delgado V, van Bommel RJ, Bertini M, Borleffs CJ, Marsan NA, Arnold CT, Nucifora G, van de Veire NR, Ypenburg C, Boersma E, Holman ER, Schalij MJ, Bax JJ. Relative merits of left
589
305.
306.
307.
308.
309.
310.
311.
ventricular dyssynchrony, left ventricular lead position, and myocardial scar to predict long-term survival of ischemic heart failure patients undergoing cardiac resynchronization therapy. Circulation. 2011;123(1):70–8. Becker M, Kramann R, Franke A, Breithardt OA, Heussen N, Knackstedt C, Stellbrink C, Schauerte P, Kelm M, Hoffmann R. Impact of left ventricular lead position in cardiac resynchronization therapy on left ventricular remodelling. A circumferential strain analysis based on 2D echocardiography. Eur Heart J. 2007; 28(10):1211–20. Becker M, Franke A, Breithardt OA, Ocklenburg C, Kaminski T, Kramann R, Knackstedt C, Stellbrink C, Hanrath P, Schauerte P, Hoffmann R. Impact of left ventricular lead position on the efficacy of cardiac resynchronisation therapy: a two-dimensional strain echocardiography study. Heart. 2007;93(10):1197–203. Leyva F, Foley PW, Chalil S, Ratib K, Smith RE, Prinzen F, Auricchio A. Cardiac resynchronization therapy guided by late gadoliniumenhancement cardiovascular magnetic resonance. J Cardiovasc Magn Reson. 2011;13:29. Shetty AK, Duckett SG, Bostock J, Rosenthal E, Rinaldi CA. Use of a quadripolar left ventricular lead to achieve successful implantation in patients with previous failed attempts at cardiac resynchronization therapy. Europace. 2011;13(7):992–6. Hussain MA, Bhamra-Ariza P, Jacques A, Wilkinson P, Odemuyiwa O, Fluck D, Beeton I, Kaba RA. Benefits of a quadripolar left ventricular lead in patients undergoing cardiac resynchronization therapy with underlying myocardial scar. Pacing Clin Electrophysiol. 2013;36(2):e45–7. Sperzel J, Dänschel W, Gutleben KJ, Kranig W, Mortensen P, Connelly D, Trappe HJ, Seidl K, Duray G, Pieske B, Stockinger J, Boriani G, Jung W, Schilling R, Saberi L, Hallier B, Simon M, Rinaldi CA. First prospective, multi-centre clinical experience with a novel left ventricular quadripolar lead. Europace. 2012;14(3):365–72. Forleo GB, Della Rocca DG, Papavasileiou LP, Molfetta AD, Santini L, Romeo F. Left ventricular pacing with a new quadripolar transvenous lead for CRT: early results of a prospective comparison with conventional implant outcomes. Heart Rhythm. 2011;8(1):31–7.
Device Therapy for Bradycardias
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Chung-Wah Siu and Hung-Fat Tse
Abstract
The number of patients who can benefit from implantable cardiac pacemaker for the treatment of bradycardia is steadily increasing due to the ageing population. Over the past 50 years, there have been remarkable technological advances in the pacing technology. Current pacemakers have extended battery longevity and are equipped with complex device features including advanced telemetry monitoring (wireless, home monitoring), auto-programmability, and multiple rate-adaptive sensor technology. Furthermore, new-generation leads have steroid-eluting tips and better surface coating to reduce long-term pacing threshold and increase their lifespan, respectively. These advances should further improve patient care for treatment of bradycardias; nevertheless, the optimal pacing sites for ventricular pacing as well as the clinical benefit of remote monitoring need to be further studied.
Introduction In 1958, Furman et al. described the initial application of an endocardial pacing lead for the treatment of complete heart block [7]. Since then, intracardiac pacing systems have been used for the treatment of symptomatic bradycardia. There have been remarkable technological advances in the pacing technology over the last 50 years. Current pacemakers have extended battery longevity and are equipped with complex device features such as advanced telemetry monitoring (wireless, home monitoring), auto-programmability, and multiple rate-adaptive sensor technology. Furthermore, newgeneration leads have steroid-eluting tips and better surface coating to reduce long-term pacing threshold and increase their lifespan, respectively. Due to the ageing population
C.-W. Siu, MD (*) • H.-F. Tse, MD, PhD (*) Cardiology Division, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong e-mail:
[email protected];
[email protected]
A.S. Kibos et al. (eds.), Cardiac Arrhythmias, DOI 10.1007/978-1-4471-5316-0_45, © Springer-Verlag London 2014
worldwide, pacemaker use has increased exponentially. A recent survey has showed that the implanted rate for pacemakers continues to rise in most of the countries worldwide [14]. The goals of the present chapter are to highlight some of the fundamental aspect of pacing therapy, to provide an update on recent improvement in technology, and to address some of challenges encountered during follow-up.
Pacemaker Classification The five-letter pacemaker code defined by the North American Society of Pacing and Electrophysiology and British Pacing and Electrophysiology Group represented the basic description of the function of cardiac pacemakers (Table 45.1) [1]. The first and the second position of this code refer to the chamber(s) paced and the chamber(s) sensed respectively. The third position refers to the pacemaker response to sensed event, which could be inhibited (I), triggered (T), or dual (T + I). The fourth position refers to the rate modulation capacity of the pacemaker, i.e., the ability to alter its pacing rate according to the patient’s physiological need. The fifth position indicates the presence or absence of multisite pacing.
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Table 45.1 Revised NASPE/BPEG generic code for anti-bradycardia pacing Position I Chamber paced O = None A = Atrium V = Ventricle D = Dual (A + V)
Position II Chamber sensed O = None A = Atrium V = Ventricle D = Dual (A + V)
Position III Response to sensed event O = None I = Inhibited T = Triggered D = Dual (T + I)
Position IV Rate modulation O = None R = Rate modulation
Position V Multisite pacing O = None A = Atrium V = Ventricle D = Dual (A + V)
Modified from Connolly et al. [3] NASPE North American Society of Pacing and Electrophysiology, BPEG British Pacing and Electrophysiology Group
Indications for Permanent Pacing for Bradycardia (Adapted from [4, 20]) In general, permanent pacing is indicated for patients with symptomatic bradycardia without any reversible cause. Recent guidelines [4, 20] also included the use of cardiac resynchronization therapy to improve the quality of life and/ or survival in patients with heart failure. This will not be addressed in this chapter.
Sinus Node Dysfunction (SND) Pacing therapy is indicated in: • Patients with documented symptomatic bradycardia including frequent sinus pauses • Patients with symptomatic chronotropic incompetence • Patients with documented symptomatic sinus bradycardia due to a required drug therapy for another medical condition Pacing therapy is reasonable in: • Patients with symptomatic SND with heart rate less than 40 bpm but without a clear association between symptom and bradycardia • Patients with unexplained syncope and electrophysiological evidences of significant SND
Atrioventricular Nodal Dysfunction Pacing therapy is indicated in: • Patients with third-degree and advanced second-degree atrioventricular (AV) block at any anatomical level associated with (1) bradycardia and symptom; (2) arrhythmia and other medical conditions requiring a drug therapy leading to symptomatic bradycardia; (3) documented asystole ≥3 s, escape rate <40 bpm, or escape rhythm below the AV node despite the lack of symptom; (4) atrial fibrillation with pause(s) ≥5 s; (5) AV nodal ablation; (6) AV block post-cardiac surgery expected not to resolve; (7) neuromuscular disease with AV block regardless of symptom; and (8) exercise-induced AV block in the absence of myocardial ischemia
• Patients with second-degree AV block with symptom regardless of the type and site of block • Patients with asymptomatic third-degree AV block at any anatomical level associated with left ventricular dysfunction or the site of block is below the AV node despite an average awake ventricular rate >40 bpm • Patients with alternating bundle branch block Pacing therapy is reasonable in: • Patients with persistent asymptomatic third-degree AV block at any anatomical level with escape rate >40 bpm without cardiomegaly • Patients with asymptomatic second-degree AV block at intra- or infra-His level documented at electrophysiological study • Patients with first- or second-degree AV block with symptom typical of hemodynamic compromise • Patients with asymptomatic second-degree AV block with narrow QRS
Pacing Mode Selection The concept of physiological pacing was proposed to provide normal cardiovascular physiology by preserving AV synchrony and/or increasing heart rate (rate adaptation) as required by exercise or other physiological demands. In patients with permanent atrial fibrillation, only ventricular pacing mode is feasible. The use of dual-chamber pacemakers with or without rate adaptation has been shown to improve symptoms and to reduce the incidence of atrial fibrillation compared with single-chamber pacing [3, 18]. However, there was no difference in clinical outcomes between patients treated with dual- vs. single-chamber pacemakers for bradycardia in most clinical trials [12, 17]. Furthermore, recent understandings of the adverse consequences of right ventricular apical pacing have led to the changing definition of physiological pacing [10]. In patients with SND without concomitant AV block, atrial-based pacing with an effort to minimize ventricular pacing should be the pacing mode of choice. To minimize ventricular pacing, programming a fixed long AV delay may minimize ventricular pacing, but it is not always feasible. As a result, some
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pacemaker models have incorporated conduction search algorithms that automatically search for intrinsic ventricular events that, if not sensed during an extension of the AV interval, will resume stimulation at the programmed AV delay. In patients with abnormal AV conduction who require permanent ventricular pacing, alternative ventricular pacing sites such as right ventricular septum or even biventricular pacing have been proposed to maintain ventricular synchrony in addition to AV synchrony by dual-chamber pacing. However, routine clinical applications of alternative ventricular pacing site or biventricular pacing for treatment of bradycardia have yet to be proven in future clinical trials. Currently, in patients with impaired left ventricular function who require permanent pacing, it is advisable to use biventricular pacing to avoid further deterioration of left ventricular function after right ventricular apical pacing [2].
Pacemaker Implantation and Follow-Up Preoperative Preparation Prior to the operation, informed consent and standard 12-lead electrocardiogram should be obtained. Other exam results such as chest X-ray and routine blood tests including complete blood count, renal function, and clotting profile should be performed according to hospital protocols. Left- or rightsided pectoral implant is determined according to several factors including the patient’s hand dominance, occupation and recreational activities, previous cardiac and/or thoracic surgery, previous radiotherapy exposure, abnormal venous drainage (persistent left superior vena cava), and venous occlusion or thrombosis. An intravenous catheter for drug administration, as well as for venogram if needed, should be inserted in the proposed pacemaker implantation side. Routine use of prophylactic intravenous antibiotic perioperatively remains a controversial issue. However, if prophylactic antibiotic is used, intravenous agent with antistaphylococcal activity is generally needed. Likewise, anticoagulants are commonly withheld prior to the implantation. Nevertheless,
if the risk of thromboembolism is high, pacemaker implantation has been performed safely with the continuation of the anticoagulants [2]. Ongoing randomized trials of “bridging or no bridging” are underway to address this issue.
Pacemaker Implantation After overnight fasting and skin preparation, venous access can be obtained by cephalic cutdown technique or axillary or subclavian venous puncture (Table 45.2). Then, pacing leads can be positioned under fluoroscopic guidance. Although the right ventricular apex and right atrial appendage are generally the conventional sites for pacing lead placement, alternative pacing sites, such as right atrial and ventricular septum pacing using active fixation leads, have gained some popularity among implanting physicians to achieve more physiological pacing [16]. This is still the object of controversy and many clinical trials are underway. Then, sensing and pacing thresholds are obtained; leads are secured and connected to the generator. The generator is then placed either in a subcutaneous or submuscular pocket, and the incision is closed.
Postoperative Management Postoperatively, patients are to be monitored with continuous ECG or telemetry system. Chest X-ray and ECG should be performed after implantation (Table 45.3). The pacing system should be evaluated before discharge.
Follow-Up [21] It is recommended that patients implanted with a pacemaker be followed up in person at 2 weeks and 3 months post implantation, and then every 3–12 months thereafter (either in person or with remote monitoring). History taking is crucial to ensure that symptoms prompting the original implantation have been relieved and that device therapy
Table 45.2 Comparison of different methods for venous access Axillary
Subclavian
Cephalic
Advantages Simple puncture technique Minimal risk of pleural complication Low risk of vascular complication Low risk of lead fracture Simple puncture technique Large vessel size for multiple leads No risk of pleural complications Minimal risk of vascular complications Low risk of lead fracture
Disadvantage Smaller vessel size
Risk of pneumothorax and hemothorax Risk of vascular complications Subclavian crush Surgical skill for cutdown required Small vessel size
594 Table 45.3 Complications of pacemaker implantation Acute complications Pneumothorax Hemothorax Pacemaker pocket hematoma Perforation of heart (tamponade) and central veins Lead dislodgement and damage Diaphragmatic stimulation Long-term complications Infection (pocket, leads, endovascular) Pacemaker malfunction Central venous thrombosis and obstruction Lead fracture (e.g., subclavian crush) Insulation break Twiddler’s syndrome
has not resulted in pacemaker syndrome caused by loss of optimal AV synchrony in patients with single-chamber ventricular pacing. Symptoms of pacemaker syndrome include neck/abdominal pulsations, palpitation, fatigue, dyspnea, and/or presyncope. During each follow-up, the devices should be interrogated for basic parameters including battery status, sensing and pacing threshold, lead impedance, high rate, and automatic mode-switching episodes. As the battery approaches elective replacement, the follow-up frequency should be increased to every 1–3 months accordingly.
Device Programming Modern pacemakers store real-time information on battery status, impedance, current, amplitude, pulse duration, and other diagnostic information, including trends, event counters and histograms detailing the percentage of time sensed/ paced, automatic mode-switching episodes, and atrial and/or ventricular arrhythmias with stored intracardiac electrograms. Moreover, recent introduction of remote telemetry in some of the devices has eliminated the need to maintain the programmer head over the pulse generator for the duration of interrogation. Furthermore, some parameters are now automatically programmed, such as mode-switching algorithms, adjustment of sensing and pacing thresholds, autocapture management of pacing threshold, and adjustment of rate responsiveness in which the pacemaker will alter the pacemaker parameters based on the pre-programmed criteria and clinical information collected.
Rate Adaptation The limitations of dual-chamber pacing in the setting of chronotropic incompetence dysfunction led to the devel-
C.-W. Siu and H.-F. Tse
opment of rate-adaptive sensors. This development was possible because of the recognition that during exercise an increase in heart rate, rather than the maintenance of AV synchrony, is the main determinant of the increase in cardiac output [11]. Thus, in a single-chamber rate-adaptive pacemaker that varies the pacing rate with exercise according to a non-atrial sensor, near-normal exercise physiology in patients with bradycardia can be achieved. Currently, mainly accelerometers and/or minute ventilation sensors are widely used in modern pacemakers. Dualsensor pacemakers seek to exploit the advantages of each sensor to provide chronotropic modulation that more closely emulates that of the normal sinus node, but no clear clinical benefit has been shown as compared with single sensor [19]. Other sensors such as QT determination, O2 oxymetry, RV pressure were tested but are not currently used.
Future Perspectives for Device Therapy for Bradycardia Magnetic Resonance Imaging (MRI) Compatibility Due to the increasing pacemaker population and the advance in MRI imaging, there has been a growing need for MRI compatibility. It has been estimated that up to 50–75 % of patients with cardiac devices may need MRI scans at some point in life after implantation [10]. The exposure of the pacemaker under the strong electromagnetic fields during MRI may result in shifting of the device, inappropriate heating of the lead tip, asynchronous erratic and rapid pacing, activation of tachyarrhythmia therapies, or inhibition of a demand pacemaker [5, 9]. Although prior studies [15] suggested that MRI can be safely performed in pacemaker patients after appropriate precautions, including close observation of vital signs and electrocardiography during MRI, isolated instances of clinically significant pacemaker-MRI interaction have been reported, including deaths [8]. As a result, specifically designed MRI-compatible pacing systems are now available. For those devices called MRI-conditional pacing systems, the new pacemakers eliminate ferromagnetic substances and incorporate new circuitry and geometry. Furthermore, those devices have MRI-specific programming features during MRI. Some MRI-conditional pacing systems require dedicated leads that are also MRI compatible. It should always be remembered that abandoned leads are a contraindication to MRI and all the implanted material should be MRI compatible and every effort made to cross check all the information about the implanted material.
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Leadless Pacing Other than the generator itself, pacing leads can lead to multiple issues including infections, fractures, failed sensing or pacing, perforation, dislodgment, vascular occlusion, and potential need for extraction, which are major limitations of the current technology. As a result, the concept of leadless pacing has been proposed. Recent studies [13] have shown that transcutaneous ultrasound energy delivery is a feasible method to induce cardiac stimulation. Furthermore, several miniaturized pacing devices which can be directly delivered into the endocardium for leadless pacing have also been under research development. Although numerous technical issues as well as the efficacy of long-term sensing and pacing remain to be addressed, leadless pacing is a potential novel approach that could entirely eliminate problems related to chronic lead implantation.
Home Monitoring More recently, some of the latest pacing systems can also perform remote monitoring via a home transmitter. Information obtained from the devices can be transmitted via phone and/or computer network either manually or automatically with wireless technology [6]. The remote monitoring system can transfer both the device function and patients’ status to the physicians based on selection criteria defined by the physicians. This could reduce the workload in outpatient clinics and provide better patient’s care via a closer monitoring of individual patients. Remote monitoring systems can also detect early any dysfunction as well as a change in patient’s condition [6]. Conclusions
The patient population with implanted pacing systems for the treatment of bradycardia is steadily increasing, as well as the complexity associated with these devices. Recent advances in pacemaker technologies, including automatic programming and remote monitoring, should further improve the care for these patients. Nevertheless, the optimal pacing sites for ventricular pacing as well as the clinical benefit of remote monitoring need to be further studied.
References 1. Bernstein AD, Daubert JC, Fletcher RD, Hayes DL, Lüderitz B, Reynolds DW, Schoenfeld MH, Sutton R. The revised NASPE/ BPEG generic code for antibradycardia, adaptive-rate, and multisite pacing. North American Society of Pacing and Electrophysiology/British Pacing and Electrophysiology Group. Pacing Clin Electrophysiol. 2002;25:260–4.
595 2. Cano O, Muñoz B, Tejada D, Osca J, Sancho-Tello MJ, Olagüe J, Castro JE, Salvador A. Evaluation of a new standardized protocol for the perioperative management of chronically anticoagulated patients receiving implantable cardiac arrhythmia devices. Heart Rhythm. 2012;9:361–7. 3. Connolly SJ, Kerr CR, Gent M, Roberts RS, Yusuf S, Gillis AM, Sami MH, Talajic M, Tang AS, Klein GJ, Lau C, Newman DM. Effects of physiologic pacing versus ventricular pacing on the risk of stroke and death due to cardiovascular causes. Canadian Trial of Physiologic Pacing Investigators. N Engl J Med. 2000;342:1385–91. 4. Epstein AE, DiMarco JP, Ellenbogen KA, Estes NA, Freedman RA, Gettes LS, Gillinov AM, Gregoratos G, Hammill SC, Hayes DL, Hlatky MA, Newby LK, Page RL, Schoenfeld MH, Silka MJ, Stevenson LW, Sweeney MO, Smith Jr SC, Jacobs AK, Adams CD, Anderson JL, Buller CE, Creager MA, Ettinger SM, Faxon DP, Halperin JL, Hiratzka LF, Hunt SA, Krumholz HM, Kushner FG, Lytle BW, Nishimura RA, Ornato JP, Page RL, Riegel B, Tarkington LG, Yancy CW, American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE, American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices), American Association for Thoracic Surgery, Society of Thoracic Surgeons. ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices): developed in collaboration with the American Association for Thoracic Surgery and Society of Thoracic Surgeons. Circulation. 2008;117:e350–408. 5. Erlebacher JA, Cahill PT, Pannizzo F, Knowles RJ. Effect of magnetic resonance imaging on DDD pacemakers. Am J Cardiol. 1986;57:437–40. 6. Folino AF, Chiusso F, Zanotto G, Vaccari D, Gasparini G, Megna A, Marras E, Mantovan R, Vaglio A, Boscolo G, Biancalana G, Leoni L, Iliceto S, Buja G. Management of alert messages in the remote monitoring of implantable cardioverter defibrillators and pacemakers: an Italian single-region study. Europace. 2011;13:1281–91. 7. Furman S, Schwedel JB. An intracardiac pacemaker for StokesAdams seizures. N Engl J Med. 1959;261:943–8. 8. Gimbel JR. Unexpected asystole during 3T magnetic resonance imaging of a pacemaker-dependent patient with a “modern” pacemaker. Europace. 2009;11:1241–2. 9. Hayes DL, Holmes Jr DR, Gray JE. Effect of 1.5 tesla nuclear magnetic resonance imaging scanner on implanted permanent pacemakers. J Am Coll Cardiol. 1987;10:782–6. 10. Kalin R, Stanton MS. Current clinical issues for MRI scanning of pacemaker and defibrillator patients. Pacing Clin Electrophysiol. 2005;28:326–8. 11. Karlof I. Haemodynamic effect of atrial triggered versus fixed rate pacing at rest and during exercise in complete heart block. Acta Med Scand. 1975;197:195–206. 12. Lamas GA, Orav EJ, Stambler BS, Ellenbogen KA, Sgarbossa EG, Huang SKS, Marinchak RA, Estes 3rd NAM, Mitchell GF, Lieberman EH, Mangione CM, Goldman L. Quality of life and clinical outcomes in elderly patients treated with ventricular pacing as compared with dual-chamber pacing. N Engl J Med. 1998;338:1097–104. 13. Lee KL, Lau CP, Tse HF, Echt DS, Heaven D, Smith W, Hood M. First human demonstration of cardiac stimulation with transcutaneous ultrasound energy delivery: implications for wireless pacing with implantable devices. J Am Coll Cardiol. 2007;50:877–83.
596 14. Mond HG, Proclemer A. The 11th world survey of cardiac pacing and implantable cardioverter-defibrillators: calendar year 2009 – a World Society of Arrhythmia’s project. Pacing Clin Electrophysiol. 2011;34:1013–27. 15. Nazarian S, Roguin A, Zviman MM, Lardo AC, Dickfeld TL, Calkins H, Weiss RG, Berger RD, Bluemke DA, Halperin HR. Clinical utility and safety of a protocol for noncardiac and cardiac magnetic resonance imaging of patients with permanent pacemakers and implantable-cardioverter defibrillators at 1.5 tesla. Circulation. 2006;114:1277–84. 16. Siu CW, Wang M, Zhang XH, Lau CP, Tse HF. Analysis of ventricular performance as a function of pacing site and mode. Prog Cardiovasc Dis. 2008;51:171–82. 17. Toff WD, Camm AJ, Skehan JD. Single-chamber versus dualchamber pacing for high-grade atrioventricular block. N Engl J Med. 2005;353:145–55. 18. Tse HF, Lau CP. Clinical trials for cardiac pacing in bradycardia: the end or the beginning? Circulation. 2006;114:3–5. 19. Tse HF, Lau CP. Sensors for implantable devices: ideal characteristics, sensor combination, and automaticity. In: Ellenbogen KA, Wilkoff BL, Kay GN, Lau CP, editors. Clinical cardiac pacing, defibrillation, and resynchronization therapy. 3rd ed. Philadelphia: Saunders/Elsevier; 2007. p. 201–33. 20. Vardas PE, Auricchio A, Blanc JJ, Daubert JC, Drexler H, Ector H, Gasparini M, Linde C, Morgado FB, Oto A, Sutton R, Trusz-Gluza M, European Society of Cardiology, European Heart Rhythm
C.-W. Siu and H.-F. Tse Association. Guidelines for cardiac pacing and cardiac resynchronization therapy: The Task Force for Cardiac Pacing and Cardiac Resynchronization Therapy of the European Society of Cardiology. Developed in collaboration with the European Heart Rhythm Association. Eur Heart J. 2007;28:2256–95. 21. Wilkoff BL, Auricchio A, Brugada J, Cowie M, Ellenbogen KA, Gillis AM, Hayes DL, Howlett JG, Kautzner J, Love CJ, Morgan JM, Priori SG, Reynolds DW, Schoenfeld MH, Vardas PE, Heart Rhythm Society (HRS), European Heart Rhythm Association (EHRA), American College of Cardiology (ACC), American Heart Association (AHA), European Society of Cardiology (ESC), Heart Failure Association of ESC (HFA), Heart Failure Society of America (HFSA), HRS/EHRA Expert Consensus on the Monitoring of Cardiovascular Implantable Electronic Devices (CIEDs): description of techniques, indications, personnel, frequency and ethical considerations: developed in partnership with the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA); and in collaboration with the American College of Cardiology (ACC), the American Heart Association (AHA), the European Society of Cardiology (ESC), the Heart Failure Association of ESC (HFA), and the Heart Failure Society of America (HFSA). Endorsed by the Heart Rhythm Society, the European Heart Rhythm Association (a registered branch of the ESC), the American College of Cardiology, the American Heart Association. Europace. 2008;10:707–25.
Pacemaker Dependence After Atrioventricular Node Ablation
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Joseph Yat-Sun Chan and Cheuk-Man Yu
Abstract
Atrial fibrillation is related to increased risk of stroke and heart failure and is a growing health issue with the aging of the world population. Rate control strategy for atrial fibrillation is not inferior to rhythm control strategy in patients with and without heart failure, however could be difficult to achieve with pharmacological agent alone even with the latest, more lenient target of rate control of below 110 beats per minute. Atrial fibrillation especially with uncontrolled heart rate could be associated with tachycardia-mediated cardiomyopathy which can be reversible. Non-pharmacological method for rate control includes atrioventricular node modification, atrioventricular node ablation with permanent pacing, and selective vagal stimulation. Atrioventricular node ablation with permanent pacing is the most well-established method with evidence showing different degrees of improvement in left ventricular function. However, some of the early beneficial effect was cancelled out by the deleterious effect of dyssynchrony induced by right ventricular pacing. The beneficial effect is more pronounced and sustained in atrial fibrillation patients with heart failure receiving cardiac resynchronization therapy. Atrioventricular node ablation and biventricular pacing could turn out to be the superior non-pharmacological method of atrial fibrillation rate control. Keywords
Atrial fibrillation • Atrioventricular nodal ablation • Pacemaker • Dependence • Cardiac resynchronization therapy
Introduction Atrial fibrillation (AF) is associated with significant morbidity and mortality and is the commonest tachyarrhythmia affecting 5 % of the population over the age of 60 [1]. The management of symptomatic AF includes rhythm control
J.Y.-S. Chan, FRCP C.-M. Yu, MD, MBChB, FRCP, FRACP, FACC (*) Division of Cardiology, Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, 9/F, Clinical Sciences Building, Shatin, N.T., Hong Kong e-mail:
[email protected] A.S. Kibos et al. (eds.), Cardiac Arrhythmias, DOI 10.1007/978-1-4471-5316-0_46, © Springer-Verlag London 2014
strategy by prevention of recurrence of AF or rate control strategy by controlling only the ventricular rate. Randomized controlled trials have shown that rate control strategy is not inferior to rhythm control strategy when symptoms are controlled [2]. Analysis of the data from the AFFIRM study (Atrial Fibrillation Follow-Up Investigation of Rhythm Management) showed better outcome with rhythm control strategy for subgroup of patients able to be maintained in sinus rhythm [3]. The unexpected outcome of rhythm control strategy is likely because of the poor efficacy and the side effects of antiarrhythmic agents including pro-arrhythmia and worsening of heart failure. Even newer antiarrhythmic drugs such as dronedarone, possibly associated with less systemic side effects when compared with amiodarone, was associated with an increase in cardiovascular 597
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mortality when used in patients with permanent AF [4]. However, rate control strategy is not without its problems, as many as one-third of heart failure patients may have rapid rates that are poorly controlled with medications alone [5]. Other limitations include symptoms from fast and irregular heart rate and difficulty in controlling heart rate with drugs alone despite the recent RACE trial advocating a loosen target of 110 beats per minute (lenient control) at rest [6]. A better method of rate control is required especially when medications failed and atrioventricular node (AVN) ablation together with permanent pacing has evolved to become the non-pharmacological method of choice for rate control in permanent AF.
Non-pharmacological Method of Rate Control Apart from AVN ablation there are other non-pharmacological means of AF rate control and one of these is AVN modification without ablation of the AVN or His bundle system. The AVN is known to have anterior and posterior atrial insertions and either of these can be targeted for ablation. Early experience with modification of the anterior AVN insertion or fast pathway modification was associated with high incidence of inadvertent atrioventricular heart block [7]. Subsequently, the technique was modified targeting posterior inputs or the slow pathway region, the end point being ventricular rate slowing to 120–130 beats per minute during isoproterenol infusion [8]. Because of limited success rate and high recurrence rate of 10 % with high probability of high-grade heart block (16 %), it is nowadays only considered when concurrent pacemaker implantation is planned. AVN ablation and pacemaker implantation is now the preferred technique [9]. The other potential benefit of AVN ablation over AVN modification is the regularization of ventricular rate with better symptom control. Studies have shown that irregular RR intervals are associated with negative hemodynamic performance compared to a regular rate at the same mean heart rate [10]. Regularization of heart rate may explain the better quality of life and improvement in LV ejection fraction after AVN ablation in randomized trials comparing AVN modification and AVN ablation [11, 12]. Another non-pharmacological method for rate control is selective stimulation of the vagal nerve supplying the AVN, located around the inferior vena cava and the left atrial fat pad. In animal studies, selective vagal nerve stimulation together with VVI pacing completely regularized the ventricular rate [13]. In a post open heart surgery study, selective stimulation of the right inferior fat pad was able to achieve satisfactory rate control during AF [14]. The application of such method in the human AF population awaits further clinical studies.
J.Y.-S. Chan and C.-M. Yu
AVN Ablation and Pacing Data mainly from uncontrolled nonrandomized trials showed the benefit of AVN ablation and permanent pacing to improve symptoms in AF patients irrespective of congestive heart failure history. Complete heart block can be achieved by interruption of either of the His bundle or compact AVN. The penetrating His bundle is protected by fibrous tissue as it traverses the tricuspid annulus. Hence, ablation is targeted at the atrial side of the annulus. In the multicenter Ablate and Pace Trial, transcatheter AVN ablation achieved acute success in 155 out of 156 patients. Early recurrence of conduction was noted in 6 patients who were all successfully re-ablated in a second procedure. Early procedure related complications were observed in 4.5 % at 30 days and late complications occurred in an additional 5.1 % of patients [15]. A meta-analysis of 21 studies involving 1,181 subjects showed that AVN ablation and pacing improved outcomes including exercise duration and LV ejection fraction and the benefit was sustained over long-term follow-up [16]. The improvement in symptoms was seen across all studies. However, the effect on LV function varies among studies and was most likely due to the small sample size and heterogeneous baseline characteristics of patients such as preexisting LV function and prevalence of tachycardia-mediated cardiomyopathy. Noticeably, the LV ejection fraction improved in patients with preexisting impaired LV function but remained unchanged or deteriorated in patients with normal ejection fraction. Similar observation of LV function deterioration was noted in an observational study by Mayo Clinic involving 286 patients with baseline normal LV ejection fraction [17]. The mean LV ejection fraction was 48 % before and 48 % after AVN ablation and pacing after a mean follow-up of 20 months. Patients with a shorter follow-up had a significant improvement in mean LV ejection fraction (46 % before versus 49 % after), while patients with a longer follow-up have no significant change in mean LV ejection fraction (49 % before and 48 % after). Baseline LV ejection fraction >40 % was found to be an independent risk factor for LV ejection fraction decline. This finding suggested that the benefit from AVN ablation on LV ejection fraction by controlling the heart rate may be undermined by the deleterious effect of long-term right ventricular apical pacing. Improved LV function after ablation may be attributed to enhanced diastolic filling times and reversal of tachycardia-induced cardiomyopathy, while the worsening of LV function is plausibly attributed to dyssynchronous contraction induced by longterm high-percentage right ventricular pacing. In a case control study by Mayo Clinic involving 350 patients who underwent AVN ablation and pacemaker implantation, at a mean follow-up of 36 months, 78 patients died [18]. The expected survival rate was significantly lower than matched controls, and the independent predictors of
46 Pacemaker Dependence After Atrioventricular Node Ablation
mortality were prior myocardial infarction, history of congestive heart failure, and use of cardiac drugs. In the absence of these three risk factors, the survival of the post AVN ablation population was similar to the expected survival in the general population.
Sudden Death Following AVN Ablation In the era of direct current ablation, sudden death was observed in patients undergoing AVN ablation. Barotrauma leading to collateral damage to the surrounding myocardium leading to ventricular tachycardia was incriminated as the cause of sudden death [19]. However, sudden death still occurred after switching to radiofrequency ablation of the AVN [20]. The rate of sudden death was reported to be between 2.7–3.2 %, and independent predictors of sudden death included prior history of ventricular tachycardia, NYHA functional class >2, valvular heart diseases, and pulmonary diseases [15, 21]. Sudden death was thought to be related to polymorphic ventricular tachycardia that was pause dependent and observed early after AVN ablation [15, 22]. It is therefore recommended to monitor patients after ablation and to program a higher-pacing rate in the early period after ablation (usually 80 beats per minute for the first month and reprogrammed to 60–70 beats per minute thereafter).
Pacing While AVN ablation and pacing may reduce symptoms, there is concern that long-term high percentage of right ventricular pacing can have deleterious effects on LV function and even overall mortality. Right ventricular pacing induced interventricular and intraventricular dyssynchrony which redistributed the work and strain enough to cause an increase in myocardial blood flow in late activated regions [23–26]. As a result, structural and histological changes including myocardial disarray and disorganized mitochondria are observed [27, 28]. Magnetic resonance imaging tagging was used to show the loss of contractile function in early activated region with compensatory hyperfunctioning and hypertrophy of the late activated sites [24]. In addition, mechanical dyssynchrony and LV remodelling can result in mitral regurgitation and cause further structural remodelling [29]. Structural alteration of the left ventricle can developed as soon as 1 week after right ventricular apical pacing with reduction of LV ejection fraction persisting after cessation of pacing [30]. All these structural changes are expected to progress with time which may explain the progressive worsening of LV function and remodelling over extended periods of follow-up. In the MOST (Mode Selection Trial), where patients with sinus node dysfunction were randomized to
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VVI or DDD pacing modes, the amount of ventricular pacing but not the pacing mode affected the clinical outcome. Patients with more than 40 % of right ventricular pacing, regardless of pacing mode, had a significantly higher rate of heart failure hospitalization [31]. In the DAVID (Dual Chamber and VVI Implantable Defibrillator) trial, patients without standard indication for bradycardia pacing were randomized to DDDR pacing mode with a lower rate set at 70 beats per minute or VVIR mode with a lower rate of 40 beats per minute. There was a trend towards higher mortality and significant higher rates of death or worsening heart failure in the DDDR group at an average of 8.4 months of follow-up, suggesting a deleterious effect of right ventricular pacing [32]. One of the possible solutions in preventing deleterious effect of right ventricular pacing is the avoidance of high percentage of right ventricular pacing, but this is not possible in the setting of complete heart block after AVN ablation. Prevention of dyssynchrony by cardiac resynchronization therapy (CRT) in principle could prevent deleterious effect on LV function. In the PACE trial (Pacing to Avoid Cardiac Enlargement), 177 patients with conventional pacemaker indications were randomized to biventricular pacing versus right ventricular apical pacing. The deleterious effects of right ventricular pacing were observed in patients without preexisting structural heart disease [33], and the LV dilatation and worsening of ejection fraction continues to deteriorate after 1 year [34]. In a meta-analysis, three randomized trials comparing CRT versus right ventricular pacing after AVN ablation among patients with AF were analyzed [35]. These three trials were as follows: MUSTIC-AF (Multisite Stimulation in Cardiomyopathy Study-Atrial Fibrillation) [36], PAVE (Post AV Nodal Ablation Evaluation) [37], and OPSITE (Optimal Pacing SITE Study) [38], and only the MUSTIC-AF required a paced QRS >200 ms as an inclusion criteria. CRT was associated with a statistical significant improvement in NYHA functional class (OPSITE), 6-min walk distance (PAVE), and quality of life (OPSITE). Only two out of the three trials found improvement in LV ejection fraction among patients randomized to CRT versus right ventricular pacing. The mean absolute LV ejection fraction improvement was 5 % in PAVE and 2 % in OPSITE. All three trials did not report any significant improvement in survival, stroke, hospitalization, or exercise capacity with CRT compared to right ventricular pacing. All trials noted a significant improvement in LV ejection fraction in both CRT and RV pacing arm when compared to baseline. The more recent APAF trial (Ablate and Pace in Atrial Fibrillation) included 186 patients and showed a significant difference in the clinical end point of composite of death from heart failure, hospitalization due to heart failure, or worsening heart failure at a median follow-up of 20 months, in favor of CRT [39]. Another piece of evidence supporting CRT over right
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ventricular pacing is the study by Leon et al who upgraded 20 patients with NYHA class III and IV who had undergone AVN ablation and right ventricular pacing to CRT and noted a 44 % improvement in LV ejection fraction. [40] The ACC/AHA/ESC 2011 AF guidelines recommended when the rate cannot be controlled with pharmacological agents or if tachycardia-mediated cardiomyopathy is suspected to consider AVN ablation (Class IIb and Level of Evidence: C) [41]. The 2010 ESC guidelines on management of AF recommended AVN ablation when heart rate cannot be controlled with pharmacological agents and when AF cannot be prevented by antiarrhythmic therapy without intolerable side effects, and direct catheter-based or surgical ablation of AF is not indicated, has failed, or is rejected (Class IIa and Level of Evidence: B) [42]. The same guidelines also recommended CRT in patients with permanent AF, LV ejection ≤35 %, and NYHA III or IV symptoms on optimal medical therapy after AVN ablation to control heart rate (Class IIa, Level of Evidence: C), and CRT when AVN ablation is chosen for rate control for any type of AF, LV ejection fraction ≤45 %, and mild heart failure symptoms NYHA II (Class IIb and Level of Evidence: C). Current guidelines do not take a strong stand on AVN ablation with concurrent CRT pacing for rate control in atrial fibrillation and normal LV function since large randomized trials with hard clinical end point such as mortality are lacking. To determine whether patients with AF benefit from AVN ablation and what the optimal pacing strategy is, namely, CRT versus conventional right ventricular pacing, a largescale randomized trial, the PACIFIC (Pacing and AV Node Ablation Compared to Drug Therapy in Symptomatic Elderly Patients with Atrial Fibrillation Clinical, NCT00589303) trial, will randomize AF patients to one of three arms: pharmacological therapy, AVN ablation with conventional right ventricular pacing, or AVN ablation with CRT pacing. This trial is completed and results are to be published [35].
Patients with Standard CRT Indication Another area of uncertainty regarding management of patients with LV dysfunction, heart failure, and AF is whether candidate of cardiac resynchronization therapy with wide QRS complex should all receive AVN ablation to promote biventricular pacing. In a recent report, AF was detected in 443 of 1,404 patients (32 %) implanted with cardiac resynchronization therapy defibrillator (CRT-D), and this led to suboptimal CRT delivery defined as less than 95 % of biventricular pacing delivery and was associated with heart failure hospitalization and death [43]. One observational study included 1,285 consecutive patients implanted with CRT devices (1,042 in sinus rhythm, 243 in AF), and AVN ablation was performed in AF patients with biventricular
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pacing in less than 85 % at 2 months [44]. All-cause mortality was similar in patients in sinus rhythm compared to AF patients at a mean follow-up of 34 months. AVN ablation was associated with significant improvement in survival when compared to rate control by drugs alone in AF patients. In another observational study in 470 consecutive patients who underwent CRT devices (344 in sinus rhythm, 126 in AF, and 19 had received AVN ablation), there was no difference in the magnitude of improvement in AF patients compared with those in sinus rhythm with respect to quality of life, 6-min walk distance, and LV reverse remodelling [45]. However, death from refractory heart failure at 12 months was higher in patients with AF than those in sinus rhythm. At present there is no adequately powered randomized study to address whether AVN ablation is necessary in all permanent AF patients receiving CRT devices under current standard indications. Other areas that need future researches include the following: what the minimal percentage of biventricular pacing for optimal CRT response at rest and during exercise is, whether fusion and pseudofusion should be totally avoided, and whether rate smoothing or trigger mode to promote biventricular capture during AF is useful. The 2009 ACCF/AHA Heart Failure Guidelines recommended in patients with LV ejection fraction ≤35 %, QRS width ≥120 ms, and AF: CRT with or without an ICD is reasonable for NYHA III or ambulatory class IV (Class IIa and Level of Evidence: B) patients [46]. The 2010 ESC guidelines on AF recommended AVN ablation for patients with permanent AF and standard CRT indication (Class IIa and Level of Evidence: B) and in CRT nonresponders in whom rapid AF prevents effective biventricular stimulation and amiodarone is ineffective or contraindicated (Class IIa and Level of Evidence: C) [42].
Tachycardia-Induced Cardiomyopathy (Tachycardiomyopathy) In experimental models, rapid pacing for 3–5 weeks causes severe ventricular dilatation and systolic and diastolic dysfunction that normalize in 1–2 weeks after cessation of pacing [47]. In some cases, ventricular dilatation and diastolic dysfunction persist despite recovery of the LV systolic function [48]. The precise mechanisms responsible for contractile dysfunction and structural changes from tachycardia-induced cardiomyopathy are not known [49, 50]. Possible mechanisms are myocardial energy depletion, ischemia, altered intracellular calcium handling, and myocyte and extracellular matrix remodelling. Tachycardia-induced cardiomyopathy has been reported in patients with AF as well as other supraventricular and ventricular arrhythmias. However, defining tachycardia-mediated cardiomyopathy can be difficult in clinical setting because of complex interactions between heart failure and AF. Rapid heart rate as
46 Pacemaker Dependence After Atrioventricular Node Ablation
the cause of the newly diagnosed cardiomyopathy could be difficult to prove at the time of presentation. In acute heart failure, AF can be conducted rapidly with raised sympathetic tone. On the other hand, AF development may cause heart failure decompensation [5]. Rate control strategy does not restore atrial contraction and atrioventricular synchrony. Hence, the benefit from AVN ablation and pacemaker therapy is solely mediated through slowing of heart rate and possibly regularization of ventricular rate. Those patients who have improvement in LV function and positive reverse remodelling after AVN ablation and pacemaker implantation strongly suggest that their LV dysfunction and dilatation were the result of tachycardia-induced cardiomyopathy. In an observational study in 213 consecutive patients admitted with heart failure and AF, 39 % had normal LV ejection fraction, 29 % had rapid normalization of LV function after AF management, and 32 % had persisted LV dysfunction. Those with rapid normalization of LV function had smaller LV size at presentation despite similar degrees of LV dysfunction.
Non-pharmacological Rhythm Control in Heart Failure Patients Intense research effort is striving to look for the best strategy in AF patients with LV dysfunction and heart failure. In a randomized controlled trial including 1,376 patients, rhythm control mainly by amiodarone and electrical cardioversion were compared to rate control strategy in patients with AF, heart failure symptoms, and LV ejection fraction ≤35 %. It showed that 42 % of patients in the rhythm control arm had no recurrence of AF, but there was no significant difference in death from cardiovascular causes and composite end point of death from cardiovascular causes, stroke, or worsening of heart failure between the two strategies [51]. On the other hand, catheter ablation of AF with pulmonary vein isolation and optional linear ablation in a study involving 58 patients with heart failure, LV ejection fraction <45 %, and AF successfully maintained 78 % of patients in sinus rhythm after 12 months. More importantly, there was a 21 % improvement in mean LV ejection fraction at 12 months. The adequacy of rate control before ablation did not affect the improvement in LV function after ablation. Therefore, reversing tachycardia-mediated cardiomyopathy was not the sole mechanism for the LV ejection fraction improvement. Superiority of the rhythm control strategy (pulmonary vein isolation) was also shown in a randomized controlled trial involving 81 patients compared to rate control strategy including AVN ablation and CRT for patients in NYHA class II or III, drug-resistant symptomatic AF, and LV ejection fraction ≤40 % [52]. Greater improvements in composite end point of LV ejection fraction, 6-min walk distance, and
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quality of life score were seen in the pulmonary vein isolation arm where 78 % were still in sinus rhythm at 6 months. This study was designed so that dyssynchronous contraction on LV functions from long-term right ventricular pacing as well as heart rhythm irregularity was minimized for rate control strategy. However, from a recent report, the arrhythmiafree survival after a single catheter ablation procedure was only 40, 37, and 29 % at 1, 2, and 5 years with higher recurrence rate in those with persistent AF and nonischemic cardiomyopathy [53]. Whether AF ablation including pulmonary vein isolation and linear lesions is the best strategy for patients with LV dysfunction and heart failure awaits larger randomized trials with longer follow-up. Conclusion
In the AF population, rate control strategy despite its proven comparable efficacy to the rhythm control strategy can be difficult to achieve with medications alone. Uncontrolled ventricular rate in patient with AF can induce tachycardia-mediated cardiomyopathy and heart failure decompensation in susceptible individuals. AVN ablation together with pacing is the non-pharmacological option of choice for rate control in persistent AF especially when medications failed or are not tolerated. However, there is concern that pacemaker dependency associated with right ventricular pacing after AVN ablation will cause LV dysfunction from dyssynchronous contraction. Biventricular pacing after AVN ablation may be the solution to circumvent the deleterious effect of right ventricular pacing, and latest evidence suggests that CRT after AVN ablation reduces heart failure-related hospitalization and mortality. On the other hand, patients with heart failure and wide QRS complex may receive suboptimal CRT delivery because of rapid AF, and there is additional evidence to suggest that AVN ablation will improve outcome in AF patients with CRT devices. Whether AVN ablation or other treatment options including AF ablation (pulmonary vein isolation) is the best strategy for AF patients with CRT devices implanted for heart failure awaits further trials.
Abbreviations ACC/ESC American College of Cardiology/European Society of Cardiology AF Atrial fibrillation AFFIRM Atrial Fibrillation Follow-Up Investigation of Rhythm Management APAF Ablate and Pace in Atrial Fibrillation AVN Atrioventricular node CRT Cardiac resynchronization therapy CRT-D Cardiac resynchronization therapy defibrillator DAVID Dual Chamber and VVI Implantable Defibrillator
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LV MOST MUSTIC-AF NYHA OPSITE PACIFIC
PAVE
J.Y.-S. Chan and C.-M. Yu
Left ventricle Mode Selection Trial Multisite Stimulation in Cardiomyopathy Study-Atrial Fibrillation New York Heart Association Optimal Pacing SITE Pacing and AV Node Ablation Compared to Drug Therapy in Symptomatic Elderly Patients with Atrial Fibrillation Clinical Post AV Nodal Ablation Evaluation
References 1. Kannel WB, Abbott RD, Savage DD, McNamara PM. Epidemiologic features of chronic atrial fibrillation: the Framingham study. N Engl J Med. 1982;306(17):1018–22. 2. Wyse DG, Waldo AL, DiMarco JP, Domanski MJ, Rosenberg Y, Schron EB, Kellen JC, Greene HL, Mickel MC, Dalquist JE, Corley SD, Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med. 2002;347(23):1825–33. 3. Corley SD, Epstein AE, DiMarco JP, Domanski MJ, Geller N, Greene HL, Josephson RA, Kellen JC, Klein RC, Krahn AD, Mickel M, Mitchell LB, Nelson JD, Rosenberg Y, Schron E, Shemanski L, Waldo AL, Wyse DG, AFFIRM Investigators. Relationships between sinus rhythm, treatment, and survival in the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Study. Circulation. 2004;109(12):1509–13. 4. Connolly SJ, Camm AJ, Halperin JL, Joyner C, Alings M, Amerena J, Atar D, Avezum Á, Blomström P, Borggrefe M, Budaj A, Chen SA, Ching CK, Commerford P, Dans A, Davy JM, Delacrétaz E, Di Pasquale G, Diaz R, Dorian P, Flaker G, Golitsyn S, GonzalezHermosillo A, Granger CB, Heidbüchel H, Kautzner J, Kim JS, Lanas F, Lewis BS, Merino JL, Morillo C, Murin J, Narasimhan C, Paolasso E, Parkhomenko A, Peters NS, Sim KH, Stiles MK, Tanomsup S, Toivonen L, Tomcsányi J, Torp-Pedersen C, Tse HF, Vardas P, Vinereanu D, Xavier D, Zhu J, Zhu JR, Baret-Cormel L, Weinling E, Staiger C, Yusuf S, Chrolavicius S, Afzal R, Hohnloser SH, PALLAS Investigators. Dronedarone in high-risk permanent atrial fibrillation. N Engl J Med. 2011;365(24):2268–76. 5. Fujino T, Yamashita T, Suzuki S, Sugiyma H, Sagara K, Sawada H, Aizawa T, Igarashi M, Yamazaki J. Characteristics of congestive heart failure accompanied by atrial fibrillation with special reference to tachycardia-induced cardiomyopathy. Circ J. 2007;71(6):936–40. 6. Wann LS, Curtis AB, January CT, Ellenbogen KA, Lowe JE, Estes NA 3rd, Page RL, Ezekowitz MD, Slotwiner DJ, Jackman WM, Stevenson WG, Tracy CM; 2011 Writing Group Members, Fuster V, Rydén LE, Cannom DS, Le Heuzey JY, Crijns HJ, Lowe JE, Curtis AB, Olsson SB, Ellenbogen KA, Prystowsky EN, Halperin JL, Tamargo JL, Kay GN, Wann LS; 2006 Writing Committee Members, Jacobs AK, Anderson JL, Albert N, Hochman JS, Buller CE, Kushner FG, Creager MA, Ohman EM, Ettinger SM, Stevenson WG, Guyton RA, Tarkington LG, Halperin JL, Yancy CW; ACCF/ AHA Task Force Members. ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (updating the 2006 guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2011;123(1):104–23. 7. Jazayeri MR, Sra JS, Deshpande SS, Blanck Z, Dhala AA, Krum DP, Avitall B, Akhtar M. Electrophysiologic spectrum of atrioventricular
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
nodal behavior in patients with atrioventricular nodal reentrant tachycardia undergoing selective fast or slow pathway ablation. J Cardiovasc Electrophysiol. 1993;4(2):99–111. Williamson BD, Man KC, Daoud E, Niebauer M, Strickberger SA, Morady F. Radiofrequency catheter modification of atrioventricular conduction to control the ventricular rate during atrial fibrillation. N Engl J Med. 1994;331(14):910–7. Morady F, Hasse C, Strickberger SA, Man KC, Daoud E, Bogun F, Goyal R, Harvey M, Knight BP, Weiss R, Bahu MJ. Long-term follow-up after radiofrequency modification of the atrioventricular node in patients with atrial fibrillation. J Am Coll Cardiol. 1997;29(1): 113–21. Clark DM, Plumb VJ, Epstein AE, Kay GN. Hemodynamic effects of an irregular sequence of ventricular cycle lengths during atrial fibrillation. J Am Coll Cardiol. 1997;30(4):1039–45. Lee SH, Chen SA, Tai CT, Chiang CE, Wen ZC, Cheng JJ, Ding YA, Chang MS. Comparisons of quality of life and cardiac performance after complete atrioventricular junction ablation and atrioventricular junction modification in patients with medically refractory atrial fibrillation. J Am Coll Cardiol. 1998;31(3): 637–44. Twidale N, McDonald T, Nave K, Seal A. Comparison of the effects of AV nodal ablation versus AV nodal modification in patients with congestive heart failure and uncontrolled atrial fibrillation. Pacing Clin Electrophysiol. 1998;21(4 Pt 1):641–51. Zhang Y, Yamada H, Bibevski S, Zhuang S, Mowrey KA, Wallick DW, Oh S, Mazgalev TN. Chronic atrioventricular nodal vagal stimulation: first evidence for long-term ventricular rate control in canine atrial fibrillation model. Circulation. 2005;112(19): 2904–11. Rossi P, Bianchi S, Barretta A, Della Scala A, Kornet L, De Paulis R, Bellisario A, D’Addio V, Pavaci H, Miraldi F. Post-operative atrial fibrillation management by selective epicardial vagal fat pad stimulation. J Interv Card Electrophysiol. 2009;24(1):37–45. Kay GN, Ellenbogen KA, Giudici M, Redfield MM, Jenkins LS, Mianulli M, Wilkoff B. The Ablate and Pace Trial: a prospective study of catheter ablation of the AV conduction system and permanent pacemaker implantation for treatment of atrial fibrillation. APT Investigators. J Interv Card Electrophysiol. 1998;2(2): 121–35. Wood MA, Brown-Mahoney C, Kay GN, Ellenbogen KA. Clinical outcomes after ablation and pacing therapy for atrial fibrillation: a meta-analysis. Circulation. 2000;101(10):1138–44. Chen L, Hodge D, Jahangir A, Ozcan C, Trusty J, Friedman P, Rea R, Bradley D, Brady P, Hammill S, Hayes D, Shen WK. Preserved left ventricular ejection fraction following atrioventricular junction ablation and pacing for atrial fibrillation. J Cardiovasc Electrophysiol. 2008;19(1):19–27. Ozcan C, Jahangir A, Friedman PA, Patel PJ, Munger TM, Rea RF, Lloyd MA, Packer DL, Hodge DO, Gersh BJ, Hammill SC, Shen WK. Long-term survival after ablation of the atrioventricular node and implantation of a permanent pacemaker in patients with atrial fibrillation. N Engl J Med. 2001;344(14):1043–51. Lemery R, Brugada P, Havenith M, Barbour D, Roberts WC, Wellens HJ. Sudden death in hemochromatosis after closed-chest catheter ablation of the atrioventricular junction. Am J Cardiol. 1988;61(11):941–3. Darpö B, Walfridsson H, Aunes M, Bergfeldt L, Edvardsson N, Linde C, Lurje L, van der Linden M, Rosenqvist M. Incidence of sudden death after radiofrequency ablation of the atrioventricular junction for atrial fibrillation. Am J Cardiol. 1997;80(9):1174–7. Ozcan C, Jahangir A, Friedman PA, Hayes DL, Munger TM, Rea RF, Lloyd MA, Packer DL, Hodge DO, Gersh BJ, Hammill SC, Shen WK. Sudden death after radiofrequency ablation of the atrioventricular node in patients with atrial fibrillation. J Am Coll Cardiol. 2002;40(1):105–10.
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Pacemaker Dependence After Atrioventricular Node Ablation
22. Evans Jr GT, Scheinman MM, Bardy G, Borggrefe M, Brugada P, Fisher J, Fontaine G, Huang SK, Huang WH, Josephson M. Predictors of in-hospital mortality after DC catheter ablation of atrioventricular junction. Results of a prospective, international, multicenter study. Circulation. 1991;84(5):1924–37. 23. Tops LF, Schalij MJ, Holman ER, van Erven L, van der Wall EE, Bax JJ. Right ventricular pacing can induce ventricular dyssynchrony in patients with atrial fibrillation after atrioventricular node ablation. J Am Coll Cardiol. 2006;48:1642–8. 24. Prinzen FW, Hunter WC, Wyman BT, McVeigh ER. Mapping of regional myocardial strain and work during ventricular pacing: experimental study using magnetic resonance imaging tagging. J Am Coll Cardiol. 1999;33:1735–42. 25. Nielsen JC, Bøttcher M, Nielsen TT, Pedersen AK, Andersen HR. Regional myocardial blood flow in patients with sick sinus syndrome randomized to long-term single chamber atrial or dual chamber pacing–effect of pacing mode and rate. J Am Coll Cardiol. 2000;35:1453–61. 26. Tse HF, Lau CP. Long-term effect of right ventricular pacing on myocardial perfusion and function. J Am Coll Cardiol. 1997;29(4):744–9. 27. Karpawich PP, Justice CD, Cavitt DL, Chang CH. Developmental sequelae of fixed-rate ventricular pacing in the immature canine heart: an electrophysiologic, hemodynamic, and histopathologic evaluation. Am Heart J. 1990;119:1077–83. 28. Prinzen FW, Cheriex EC, Delhaas T, van Oosterhout MF, Arts T, Wellens HJ, Reneman RS. Asymmetric thickness of the left ventricular wall resulting from asynchronous electric activation: a study in dogs with ventricular pacing and in patients with left bundle branch block. Am Heart J. 1995;130(5):1045–53. 29. Kanzaki H, Bazaz R, Schwartzman D, Dohi K, Sade LE, Gorcsan III J. A mechanism for immediate reduction in mitral regurgitation after cardiac resynchronization therapy: insights from mechanical activation strain mapping. J Am Coll Cardiol. 2004;44:1619–25. 30. Nahlawi M, Waligora M, Spies SM, Bonow RO, Kadish AH, Goldberger JJ. Left ventricular function during and after right ventricular pacing. J Am Coll Cardiol. 2004;44:1883–8. 31. Lamas GA, Lee KL, Sweeney MO, Silverman R, Leon A, Yee R, Marinchak RA, Flaker G, Schron E, Orav EJ, Hellkamp AS, Greer S, McAnulty J, Ellenbogen K, Ehlert F, Freedman RA, Estes 3rd NA, Greenspon A, Goldman L, Mode Selection Trial in SinusNode Dysfunction. Ventricular pacing or dual-chamber pacing for sinus-node dysfunction. N Engl J Med. 2002;346(24):1854–62. 32. Wilkoff BL, Cook JR, Epstein AE, Greene HL, Hallstrom AP, Hsia H, Kutalek SP, Sharma A, Dual Chamber and VVI Implantable Defibrillator Trial Investigators. Dual-chamber pacing or ventricular backup pacing in patients with an implantable defibrillator: the Dual Chamber and VVI Implantable Defibrillator (DAVID) Trial. JAMA. 2002;288(24):3115–23. 33. Yu CM, Chan JY, Zhang Q, Omar R, Yip GW, Hussin A, Fang F, Lam KH, Chan HC, Fung JW. Biventricular pacing in patients with bradycardia and normal ejection fraction. N Engl J Med. 2009;361(22):2123–34. 34. Chan JY, Fang F, Zhang Q, Fung JW, Razali O, Azlan H, Lam KH, Chan HC, Yu CM. Biventricular pacing is superior to right ventricular pacing in bradycardia patients with preserved systolic function: 2-year results of the PACE trial. Eur Heart J. 2011;32(20): 2533–40. 35. Bradley DJ, Shen WK. Atrioventricular junction ablation combined with either right ventricular pacing or cardiac resynchronization therapy for atrial fibrillation: the need for large-scale randomized trials. Heart Rhythm. 2007;4(2):224–32. 36. Leclercq C, Walker S, Linde C, Clementy J, Marshall AJ, Ritter P, Djiane P, Mabo P, Levy T, Gadler F, Bailleul C, Daubert JC. Comparative effects of permanent biventricular and rightuniventricular pacing in heart failure patients with chronic atrial fibrillation. Eur Heart J. 2002;23(22):1780–7.
603 37. Brignole M, Gammage M, Puggioni E, Alboni P, Raviele A, Sutton R, Vardas P, Bongiorni MG, Bergfeldt L, Menozzi C, Musso G, Optimal Pacing SITE (OPSITE) Study Investigators. Comparative assessment of right, left, and biventricular pacing in patients with permanent atrial fibrillation. Eur Heart J. 2005;26(7):712–22. 38. Doshi RN, Daoud EG, Fellows C, Turk K, Duran A, Hamdan MH, Pires LA, PAVE Study Group. Left ventricular-based cardiac stimulation post AV nodal ablation evaluation (the PAVE study). J Cardiovasc Electrophysiol. 2005;16(11):1160–5. 39. Brignole M, Botto G, Mont L, Iacopino S, De Marchi G, Oddone D, Luzi M, Tolosana JM, Navazio A, Menozzi C. Cardiac resynchronization therapy in patients undergoing atrioventricular junction ablation for permanent atrial fibrillation: a randomized trial. Eur Heart J. 2011;32(19):2420–9. 40. Leon AR, Greenberg JM, Kanuru N, Baker CM, Mera FV, Smith AL, Langberg JJ, DeLurgio DB. Cardiac resynchronization in patients with congestive heart failure and chronic atrial fibrillation: effect of upgrading to biventricular pacing after chronic right ventricular pacing. J Am Coll Cardiol. 2002;39(8):1258–63. 41. Fuster V, Rydén LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, Halperin JL, Kay GN, Le Huezey JY, Lowe JE, Olsson SB, Prystowsky EN, Tamargo JL, Wann LS, Smith Jr SC, Priori SG, Estes 3rd NA, Ezekowitz MD, Jackman WM, January CT, Lowe JE, Page RL, Slotwiner DJ, Stevenson WG, Tracy CM, Jacobs AK, Anderson JL, Albert N, Buller CE, Creager MA, Ettinger SM, Guyton RA, Halperin JL, Hochman JS, Kushner FG, Ohman EM, Stevenson WG, Tarkington LG, Yancy CW, American College of Cardiology Foundation/American Heart Association Task Force. 2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2011;123(10):e269–367. 42. European Heart Rhythm Association; European Association for Cardio-Thoracic Surgery, Camm AJ, Kirchhof P, Lip GY, Schotten U, Savelieva I, Ernst S, Van Gelder IC, Al-Attar N, Hindricks G, Prendergast B, Heidbuchel H, Alfieri O, Angelini A, Atar D, Colonna P, De Caterina R, De Sutter J, Goette A, Gorenek B, Heldal M, Hohloser SH, Kolh P, Le Heuzey JY, Ponikowski P, Rutten FH; ESC Committee for Practice Guidelines, Vahanian A, Auricchio A, Bax J, Ceconi C, Dean V, Filippatos G, Funck-Brentano C, Hobbs R, Kearney P, McDonagh T, Popescu BA, Reiner Z, Sechtem U, Sirnes PA, Tendera M, Vardas PE, Widimsky P; Document Reviewers, Vardas PE, Agladze V, Aliot E, Balabanski T, Blomstrom-Lundqvist C, Capucci A, Crijns H, Dahlöf B, Folliguet T, Glikson M, Goethals M, Gulba DC, Ho SY, Klautz RJ, Kose S, McMurray J, Perrone Filardi P, Raatikainen P, Salvador MJ, Schalij MJ, Shpektor A, Sousa J, Stepinska J, Uuetoa H, Zamorano JL, Zupan I. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Europace. 2010;12(10):1360–420. 43. Boriani G, Gasparini M, Landolina M, Lunati M, Proclemer A, Lonardi G, Iacopino S, Rahue W, Biffi M, DiStefano P, Grammatico A, Santini M, ClinicalService cardiac centres. Incidence and clinical relevance of uncontrolled ventricular rate during atrial fibrillation in heart failure patients treated with cardiac resynchronization therapy. Eur J Heart Fail. 2011;13(8):868–76. 44. Gasparini M, Auricchio A, Metra M, Regoli F, Fantoni C, Lamp B, Curnis A, Vogt J, Klersy C, Multicentre Longitudinal Observational Study (MILOS) Group. Long-term survival in patients undergoing cardiac resynchronization therapy: the importance of performing atrio-ventricular junction ablation in patients with permanent atrial fibrillation. Eur Heart J. 2008;29(13):1644–52. 45. Tolosana JM, Hernandez Madrid A, Brugada J, Sitges M, Garcia Bolao I, Fernandez Lozano I, Martinez Ferrer J, Quesada A, Macias A, Marin W, Escudier JM, Gomez AA, Gimenez Alcala M, Tamborero D,
604
46.
47.
48.
49.
J.Y.-S. Chan and C.-M. Yu Berruezo A, Mont L, SPARE Investigators. Comparison of benefits and mortality in cardiac resynchronization therapy in patients with atrial fibrillation versus patients in sinus rhythm (Results of the Spanish Atrial Fibrillation and Resynchronization [SPARE] Study). Am J Cardiol. 2008;102(4):444–9. Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, Jessup M, Konstam MA, Mancini DM, Michl K, Oates JA, Rahko PS, Silver MA, Stevenson LW, Yancy CW, American College of Cardiology Foundation; American Heart Association. 2009 Focused update incorporated into the ACC/AHA 2005 guidelines for the diagnosis and management of heart failure in adults a report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines developed in collaboration with the International Society for Heart and Lung Transplantation. J Am Coll Cardiol. 2009;53(15):e1–90. Wilson JR, Douglas P, Hickey WF, Lanoce V, Ferraro N, Muhammad A, Reichek N. Experimental congestive heart failure produced by rapid ventricular pacing in the dog: cardiac effects. Circulation. 1987;75(4):857–67. Moe GW, Grima EA, Howard RJ, Seth R, Armstrong PW. Left ventricular remodelling and disparate changes in contractility and relaxation during the development of and recovery from experimental heart failure. Cardiovasc Res. 1994;28(1):66–71. Shinbane JS, Wood MA, Jensen DN, Ellenbogen KA, Fitzpatrick AP, Scheinman MM. Tachycardia-induced cardiomyopathy: a review of
50.
51.
52.
53.
animal models and clinical studies. J Am Coll Cardiol. 1997; 29(4):709–15. Khasnis A, Jongnarangsin K, Abela G, Veerareddy S, Reddy V, Thakur R. Tachycardia-induced cardiomyopathy: a review of literature. Pacing Clin Electrophysiol. 2005;28(7):710–21. Roy D, Talajic M, Nattel S, Wyse DG, Dorian P, Lee KL, Bourassa MG, Arnold JM, Buxton AE, Camm AJ, Connolly SJ, Dubuc M, Ducharme A, Guerra PG, Hohnloser SH, Lambert J, Le Heuzey JY, O’Hara G, Pedersen OD, Rouleau JL, Singh BN, Stevenson LW, Stevenson WG, Thibault B, Waldo AL, Atrial Fibrillation and Congestive Heart Failure Investigators. Rhythm control versus rate control for atrial fibrillation and heart failure. N Engl J Med. 2008;358(25):2667–77. Khan MN, Jaïs P, Cummings J, Di Biase L, Sanders P, Martin DO, Kautzner J, Hao S, Themistoclakis S, Fanelli R, Potenza D, Massaro R, Wazni O, Schweikert R, Saliba W, Wang P, Al-Ahmad A, Beheiry S, Santarelli P, Starling RC, Dello Russo A, Pelargonio G, Brachmann J, Schibgilla V, Bonso A, Casella M, Raviele A, Haïssaguerre M, Natale A, PABA-CHF Investigators. Pulmonaryvein isolation for atrial fibrillation in patients with heart failure. N Engl J Med. 2008;359(17):1778–85. Weerasooriya R, Khairy P, Litalien J, Macle L, Hocini M, Sacher F, Lellouche N, Knecht S, Wright M, Nault I, Miyazaki S, Scavee C, Clementy J, Haissaguerre M, Jais P. Catheter ablation for atrial fibrillation: are results maintained at 5 years of follow-up? J Am Coll Cardiol. 2011;57(2):160–6.
Pacing Site: From Theory to Practice
47
Cristian Stătescu and Cătălina Arsenescu Georgescu
Abstract
Initially the cardiac pacing was envisioned to treat the hemodynamic instability as a result of a cardiac output decrease due to a slow ventricular rate. Selective site (non apical) right ventricular (RV) pacing has been suggested as a manner to decrease the incidence of atrial arrhythmias, ventricular dysfunction, and to influence the morbidity resulting from asynchronous left ventricular (LV) activation as a fact due to traditional RV apical pacing. The right atrial appendage and right ventricular apex were used, traditionally, as pacing sites because they allow easily endocardial lead placement while providing stable and reliable chronic pacing parameters. While these sites maintain heart rates and atrioventricular synchrony, right ventricular apical pacing is more associated with increased morbidity and mortality, because it initiates an abnormal asynchronous electrical activation sequence which results in asynchronous LV contraction and relaxation. The width of the paced QRS complex has been suggested that could indicate the most auspicious depolarization conditions during ventricular pacing from different sites. Pacing the His area in its distal part with a screw-in lead and with high outputs will lead to normalization of QRS complex in patients with both right bundle branch block and left bundle branch block. The outcomes from the big trials like DANISH, DAVID, MADIT II, and PAVE recommend to minimize or to avoid the right ventricular apical pacing, especially in patients with depressed LV ejection fraction. The results about the right ventricular selective sites have been disappointing for patients who require permanent ventricular pacing. There is no evidence to change RV apex in these cases. The scientists must identify the best site to stimulate the heart, to determine the location that provides optimal, long-term hemodynamic benefits, and then the industry has to create costeffective tools that require the minimum of advance training to meet the challenge. Keywords
Pacing • Selective site • Activation • Ventricular dysfunction
C. Stătescu, MD, PhD (*) Department of Cardiology and Internal Medicine, “Gr.T. Popa” University of Medicine and Pharmacy, Iaşi, Romania Department of Electrophysiology and Pacing, “George I.M. Georgescu” Cardiovascular Diseases Institute, Iaşi, Romania e-mail:
[email protected] C.A. Georgescu, MD, PhD, FESC Department of Cardiology, “George I.M. Georgescu” Cardiovascular Diseases Institute, Iaşi, Romania Department of Cardiology and Internal Medicine, “Gr.T. Popa” University of Medicine and Pharmacy, Iaşi, Romania A.S. Kibos et al. (eds.), Cardiac Arrhythmias, DOI 10.1007/978-1-4471-5316-0_47, © Springer-Verlag London 2014
Introduction To reestablish a “physiological” heart rhythm is the foremost objective of cardiac pacing. In the last decades, have been developed various tools to achieve this goal, including pacing algorithms, devices, and leads. Selective site (non apical) right ventricular (RV) pacing has been suggested as a manner to decrease the incidence of atrial arrhythmias, ventricular dysfunction, and to influence the morbidity resulting from asynchronous left ventricular (LV) activation as a fact due to 605
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traditional RV apical pacing. The RV apex stimulation during bicameral mode (DDD) allows a stable ventricular rate and permits the restauration of atrioventricular synchrony but does not imitate the physiological activation of the left ventricle. Studies have also proved the diminution of the frequency of symptomatic atrial tachyarrhythmia episodes by the lead placement in nontraditional atrial sites, especially together with the prevention algorithms [1]. The wide assimilation of selective right atrial (RA) and RV site pacing will require confident clinical prospective trials and a confirmation of the ability for safe and efficient implants.
General Considerations Initially the cardiac pacing was envisioned to treat the hemodynamic instability as a result of a cardiac output decrease due to a slow ventricular rate [2]. Reliable developments in the field of cardiac physiology have acknowledged that cardiac output is not merely dependent on rate but on the apposition of the atrial contribution, a physiologic heart rate (HR), and the LV activation sequence, all striking upon the LV function. In an endeavor to convey these physiological parameters, the cardiac pacing using electrical stimulation has evolved accordingly to reestablish the physiological LV function. The electrical stimulation of the heart has four main goals: reestablishing steady heart rate, recovering atrioventricular synchrony, achieving chronotropic competence (rate-response), and gaining normal physiological activation sequence and timing patterns. All four of these aims are based on the expectation that safe and unfailing cardiac pacing is constantly available.
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either pacing the atrium or sensing and tracking its intrinsic activity. Either of these events triggered a programmable atrioventricular delay after which, if intrinsic ventricular activity was not sensed, then the right ventricle was paced. These improvements solved most cases of pacemaker syndrome and offered physiological heart rate variation for those patients with a stable atrial rhythm.
Achieving Chronotropic Competence (Rate Response) Sensors that detect the necessity to change pacing rates enable pacing devices to respond to patient’s metabolic needs and to improve exercise capacity. The benefits in terms of quality of life of these sensor-driven, rate-responsive pacemakers were quickly demonstrated. With the introduction of rate response, the technical issue of delivering an electrical stimulus that depolarizes the atria and ventricles at the appropriate time has been resolved from a practical standpoint. The rate-responsive pacing modality has not resulted in all patients receiving a good level of cardiac function and long-term stability [5]. Proved by UKPACE trial, the difficulty to differentiate the benefits of rate response from those of atrioventricular synchrony keeps to be an issue [6]. Therefore, the attention is concentrated on the reasons for failing to demonstrate the expected benefits of “physiological pacing” and it is detaching from the simple electrical aspects of pacing towards the functional effects of the way in which therapy is delivered [7].
Gaining Normal Physiological Activation Sequence and Timing Patterns Reestablishing the Heart Rate The original goal of pacing was the establishment of a steady ventricular rhythm. The first patient treated with asynchronous, single site ventricular pacing (VOO) had atrioventricular (AV) block. At that time, due to available technology, pacing was limited to a fixed rate, but nowadays the technological progress evolved to enable the demand pacing [3]. Stimulating lead technology initially required an epicardial placement but it developed to allow endovenous, endocardial implants with certain electrical performance and stability at the right ventricular apex [4].
Recovering Atrioventricular Synchrony Amendments in lead design and materials, along with developments in amplifier and sensing technologies, created the first opportunities to restore atrioventricular synchrony by
The examination of long-term effects of pacing from traditional sites has revealed nonphysiological facets of current approaches. So, it is not enough to generate normal heart rates and atrioventricular delays on the electrocardiogram. Now we should take a look at the entire depolarization pattern through all four chambers of the heart as well as the functional effects of sensing and stimulating at different sites within the atria and ventricles [8]. Pacing in the right atrial appendage could generate a significant activation delay to the left atrium, with subsequent effects on timing between left atrial and left ventricular contraction. Pacing the ventricles at the right ventricular apex has deleterious effects. Ventricular contraction patterns compound with pacing at the right ventricular apex can explain significant variations in the ventricular muscle strain as well as left/right discoordination and longer depolarization times [9]. Some clinical data has proved that right ventricular apical pacing alone, independent of pacing mode, can bring left ventricular
47 Pacing Site: From Theory to Practice
dysfunction. In the DAVID trial, it was noted that ICD recipients with prior LV dysfunction, low-rate single chamber ventricular pacing patients (VVI-40) was associated with less deleterious effects than dual chamber pacing patients at a nominal rate (DDDR-70) [10]. The MOST trial showed that single chamber atrial pacing in patients with sick sinus node disease was associated with a lower incidence of hospitalization related to symptoms of congestive heart failure than patients who received dual chamber pacemakers, with all RV leads placed at the apex [11]. Additionally, it was reported in a prospective 3 years follow-up study by Nielsen et al. that patients with sick sinus node randomized to DDDR pacing, no matter of their atrioventricular delay, pointed out an increased left atrial dilation and a higher incidence of atrial fibrillation, compared to those patients randomized to single chamber atrial pacing (AAI) [12]. Since 1925, on mammals, it was demonstrated that ventricular pacing generates asynchronous delayed activation of the myocardium which compromised hemodynamics [13]. Some other studies in dogs showed that right ventricular apical (RVA) pacing results in abnormal contraction patterns, possibly secondary to inappropriate activation of the left ventricle during right ventricular apical pacing compared to normal sinus rhythm. The negative inotropic effect secondary to RVA pacing has been certified by magnetic resonance imaging (MRI) tagging techniques to be secondary to abnormal activation and contraction of the heart [14]. Right ventricular (RV) pacing has also an adverse effect on maximum venous consumption uptake and cardiac efficiency, secondary to histological and structural changes that cause left ventricular function to deteriorate [15]. For humans, short- and longterm studies confirm adverse affects of RV pacing, too [16].
Pacing Sites: Definitions The right atrial appendage and right ventricular apex were used, traditionally, as pacing sites because they allow easily endocardial lead placement while providing stable and reliable chronic pacing parameters. While these sites maintain heart rates and atrioventricular synchrony, RVA pacing is more associated with increased morbidity and mortality [12], because it initiates an abnormal asynchronous electrical activation sequence which results in asynchronous LV contraction and relaxation [17]. Consequently, the right ventricle apical pacing can bring myofibrillar disarray, inhomogeneous left ventricular wall strain, and pathological perfusion defects with increases in CHF and mortality [18–20]. The “alternative site pacing” term refers to sites other than the right atrial appendage or right ventricular apex. The “selective site pacing” term reflects more accurately the physician’s rationale for where he chooses to implant the pacing lead. The physician selects a more specific pacing site for
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some potential benefits. The aim of selection of a specific site in the atrium is to reduce intra-atrial conduction delays and to minimize the dispersion of refractoriness which improves clinical syndromes and their associated disease condition such as paroxysmal atrial fibrillation, as well as the reduction of other adverse effects of traditional pacing [21]. These include improvement of hemodynamics, depolarization patterns, and sensing and efficacy of atrial fibrillation therapy. Selective site pacing also allows minimization of far field detection. The expected improvements from a more physiologic depolarization pattern in the ventricles include less remodeling, decrease of mitral valve regurgitation, and better hemodynamics, as well as reducing or delaying longterm unfavorable changes such as perfusion defects and heart failure [22–24].
Right Ventricular Selective Site Pacing Results of searching, in the early 60s, for alternative ventricular pacing sites were disappointing and discouraged further studies for almost 20 years. The hemodynamics were tested acutely while pacing the right ventricle from different sites within the inflow and outflow tract [25]. Numerous reports have no contribution to the value of searching pacing sites other than the right ventricular apex. Regarding the impact on diastolic left ventricular function that may arise from pacing at different right ventricular sites exists only conflicting data. There is one study (14 patients) with reduced left ventricular ejection fraction (<40 %) which compared diastolic function between apical and RVOT pacing and did not reveal any difference in left ventricular end-diastolic pressure (LVEDP), time constant of diastolic relaxation (Tau), or negative dP/dt [26]. In contrast, atrioventricular (AV) sequential stimulation from RVOT in 20 patients without structural heart disease was superior comparing to pacing from apical sites in terms of negative dP/dt (1,221 ± 294 vs 1,431 ± 435 mmHg/s) and Tau (47.9 ± 14.0 vs 42.5 ± 11.2 ms); it did not even differ from AAI pacing mode [27]. Using radionuclide techniques in a prospective parallel design with ten patients in each group, one study traced the evolution of left ventricular systolic and diastolic function from about 6 to 23 weeks after pacemaker implantation. Other than with apical pacing (141 ± 31 vs 152 ± 30 cm2 ), the left ventricular area decreased in patients with outflow tract stimulation (151 ± 25 vs 143 ± 25 cm2 ) and was considered as functional improvement despite the absence of any changes in the ejection fraction or the wall motion score. There were some insidious changes in diastolic parameters with pacing from either ventricular site, which lengthened the time to peak filling rate (0.13 ± 0.06 vs 0.16 ± 0.03 s; P = 0.04, apical pacing), or decreased the peak filling rate itself (278 ± 64 vs 238 ± 67 mm3/s; P = 0.04, outflow tract).
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Latter efforts to search for right ventricular pacing sites other than the right ventricular apex were stipulated by the purpose of not to impair the left ventricular function if it was already compromised and the patients had to be paced for bradycardia, or if the attempts were made to improve congestive heart failure by pacing with optimal mechanically AV delay. The observation that improvements with alternative site pacing were inversely correlated with the cardiac index at baseline (apical pacing) may also have been incentive [28]. About the beneficial effects of septal or RVOT pacing in impaired left ventricular function patient population, there is only one report. It was used as a very selective lead placement close to the bundle of His and some various values for AV delay to improve the cardiac output from baseline without pacing (4.86 ± 0.79 vs 4.1 ± 0.75 L/min; P = 0.037) while it failed to prove any significant benefit of VDD pacing from the right ventricular apex (4.45 ± 0.74 versus 4.1 ± 0.74 L/min; n = 15) [29]. Another group studied two patient cohorts in an attempt to establish VDD pacing with short or optimal AV delays as a nonpharmacological therapy in advanced heart failure. They were paced VDD with active septal ventricular leads and were compared to AAI or no pacing and/or to VDD pacing with apical leads. As compared to either baseline conditions (n = 13; n = 23) or to apical pacing with different AV delays (n = 21), VDD pacing from the septal site did not improve hemodynamic variables [30]. Additionally, in patients (n = 23) with severe heart failure, in a multiple comparison of different pacing sites, including left and biventricular pacing configurations, the septal ventricular pacing was not superior to the right apical pacing as judged from systolic or diastolic filling pressures. There was VVI pacing mode in patients with persistent atrial fibrillation (n = 6) and VDD with a fixed AV delay in those with sinus rhythm. Both RV configurations did not improve hemodynamic variables, in contrast to techniques that included left ventricular stimulation sites and biventricular pacing. However, it was noted that some patients benefitted also from those, whereas some deteriorated with septal right ventricular stimulation. There is another study that upholds the idea that alternative site pacing within the right ventricle offers little, if any, benefit to patients with severely depressed left ventricular function. They followed, for 12 months, pacemaker recipients with permanent atrial fibrillation, systolic dysfunction (EF ≤ 40 %), and congestive heart failure. What followed up was subdivided in a lead-in phase (3 months), a period randomized to right ventricular apical or RVOT pacing (3 months), a crossover period (3 months), and a last 3-month period with dual-site right ventricular pacing (DDD pacemaker, 31 ms AV delay). There was no consistent superiority of any of the pacing modes. In more details, the left ventricular ejection fraction was higher in those assigned to apical rather than RVOT pacing between months 6 and 9 (P = 0.04). Within-patient comparison revealed a better
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SF-36 quality of life subscale score for mental health with RVOT pacing (P = 0.03). The bifocal right ventricular pacing resulted in worsening of physical function (P = 0.04 versus apical pacing) and mental healthscores (P = 0.02 vs RVOT pacing), and the functional class was better than with RVOT pacing (P = 0.03). No other differences were shown in the left ventricular ejection fraction, the mitral regurgitation, the quality of life scores, the functional class, or the 6-min walk distance [31]. During midterm follow-up, Victor et al. found neither the significant change in functional class nor the hemodynamic benefit during RVOT pacing as compared with RVA pacing. Instead of this, Tse et al. compared both types of stimulation at 18 months and proved that patients with RVA pacing have more often pacing-induced regional wall-motion abnormalities than those with stimulation of the interventricular septum corresponding with the RVOT [17, 32]. There was no significant difference in the prevalence of regional wallmotion abnormalities at 6 months during follow-up. The variability of these studies’ results can be explained by the probability that different investigators were pacing at different sites in the RVOT. Electrophysiological data sustain the idea that when you pace from the higher RVOT, you are further away from the His-Purkinje system. The ideal position seems to be pacing from the mid-septum, where the earliest endocardial signal, often with a potential from the right bundle, can be observed. This is at the level of the His-Purkinje system or lower. On the electrogram, this is reflected by the narrowest QRS complex as compared to the RVA or high RVOT pacing. Similarly, Stambler et al. conducted a randomized, crossover multicenter study of right ventricular apical pacing compared to RVOT pacing [31]. This trial included 103 patients with chronic atrial fibrillation and ejection fraction ≤40 % with 3 months follow-up of pacing at each site and quality of life endpoint. As a result, RVOT pacing shortened the QRS duration in this study, but did not improve the quality of life or other clinical outcomes. The width of the paced QRS complex has been suggested that could indicate the most auspicious depolarization conditions during ventricular pacing from different sites. This evidence seems reasonable if one assumes that, after pacing, the early penetration into the His-Purkinje system may speed up the dispersion of depolarization, consequently shortening the QRS complex duration. The involvement of the specific conduction system is thought to synchronize the electrical and mechanical activation and should eventually follow in optimal systolic and diastolic functions. This concept is upheld by a significant correlation between the native and paced QRS complex duration that has been found with RVOT pacing and it is supposable to reflect the disease state of the specific conduction system once this has been entered by the pacing-induced wave front [33]. Some other similar correlations between electrical and mechanical parameters have
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47 Pacing Site: From Theory to Practice
been found in heart failure patients with cardiac resynchronization therapy (CRT). There is also a growing evidence of dissociating electrical and mechanical dyssynchrony in dilated failing hearts with and without left bundle branch block [34, 35].
Left Ventricular Apex The study of Vanagt et al. has the most direct clinical implication because they prove that epicardial LV apex pacing is the preferred pacing site for short-term backup pacing in children with narrow QRS complex [36]. Epicardial pacing is preferred as a rule over endocardial pacing in little children and mainly in those with contraindications to endocardial pacing. Further clinical application of LV apex pacing requires determining whether the good hemodynamic performance is maintained over time and whether the LV apex is also a good pacing site in adult patients with narrow QRS complex. It would be interesting to find whether the deleterious effects induced by the RV pacing, potentially associated with increased risk for development of heart failure, can be prevented by LV apex pacing [37]. This affirmation seems to be feasible, because Karpawich et al. have already shown in puppies that His-bundle pacing, in the proximal part of the conduction system, preserves hemodynamic performance in conjunction with normal ventricular structure.
His-Bundle Pacing Normal His-Purkinje activation of the myocardium brings rapid sequential synchronous multisite depolarization of myocardial cells and efficient ventricular contraction. Consequently, to prevent dyssynchrony of the ventricles and to maintain a normal activation pattern, the His-bundle would be an ideal pacing site. His-bundle pacing has been of theoretical interest for many years. This idea of sending an electrical impulse directly into the cardiac conduction system is interesting because of the possible hemodynamic benefits that could be acquired by preserving a normal activation sequence. However, the anatomic position and the size of the His-bundle have made this approach very difficult. Direct His-bundle pacing was first described in dogs in 1968 by Scherlag et al. In 1992, Karpawich et al. presented a permanent approach to His-bundle pacing in dogs whereby a specifically designed active fixation lead was delivered through a custom mapping introducer and inserted into the septum over the tricuspid valve. Another work by Scherlag showed that rapid, subthreshold stimulation in the area of the Hisbundle using direct or alternating current at 90 Hz can restore 1:1 AV conduction in animals showing intermittent conduction through a diseased His-bundle [38]. This could be
explained by local stimulation of sympathetic nerves with facilitated conduction due to catecholamine release. It has been acknowledged that the delayed ventricular activation, associated with left bundle branch block or RV pacing, may increase the inducibility of ventricular tachyarrhythmias in an electrophysiological study. This is also associated with higher incidence of defibrillator discharges in patients who were paced in the right ventricle [39]. His-bundle pacing would be associated with a lower incidence of ventricular arrhythmias, because of its property of rapid depolarization of His-Purkinje system. Pacing the His area in its distal part with a screw-in lead and with high outputs will lead to normalization of QRS complex in patients with both right bundle branch block and left bundle branch block. This has been reported by El Sherif et al. in 1978 and it was elucidated by functional longitudinal dissociation between the bundles [40]. Peschar et al. have demonstrated that left ventricular septal pacing is associated with cardiac output similar to sinus rhythm [41]. In 2000, another group, Deshmukh et al. observed a significant improvement of the left ventricular ejection fraction, reduction of left ventricular end-systolic and end-diastolic diameter, and in NYHA class during permanent direct His-bundle pacing in 14 patients with a narrow QRS (≤120 ms), chronic atrial fibrillation, and depressed left ventricular ejection fraction (≤40 %) [42]. The rate control and rhythm regularity could influence substantially hemodynamic improvement, more than the pacing site. We need future studies to demonstrate if patients with chronic heart failure and intraventricular delay will benefit from Hisbundle pacing as much as from cardiac resynchronization therapy. The wide acknowledgement of this pacing site would depend on the development of better devices and specialized leads capable of stimulating not only the His-bundle but the His-Purkinje system on the right and left side of the septum.
From Traditional to Selective Site Pacing Lead Placement The first goal is to define the best pacing sites of the heart. The data from trials must be persuasive to motivate beginning of transition from traditional to selective site pacing lead placement. Placing the leads at the alternative sites seems to be difficult with current lead technology. The industry should provide specific delivery tools to simplify lead implantation. Until then, placing the leads at traditional sites (right ventricular apex and right atrial appendage) will resist any change to selective site pacing. The transition to alternative site pacing will be an arduous process. The efforts to place currently available leads in selective sites are real challenges. For an accurate lead placement, we should define first the locations that provide satisfactory long-term hemodynamic
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and clinical benefit to the patient. On this line, we need clinical trials to establish whether this optimal selective sites for pacing are different through patients with varying degrees of heart failure or distinct states of structural heart impairment. We need, also, new combined technologies like mapping, computer tomography, and magnetic resonance imaging to give us the opportunity to precisely locate these optimal pacing sites in a time- and cost-efficient manner. Fluoroscopic view has limitations because it provides only a bi-dimensional image of a three-dimensional structure. There are a few laboratories and physicians that use a second concomitant fluoroscopic view for more accurately lead position appreciation. In patients with structural heart disease, biplane fluoroscopic imaging cannot appreciate sharp anatomy. The 12-lead electrocardiogram is another limited method currently used because paced P wave or QRS vectors may help to accurate lead placement. Physicians need more training strategies to complete the transition to implant the leads in alternative sites. Only long-term clinically significant benefits for patients following clinical trials could generate motivation for passage to new selective sites [43].
C. Stătescu and C.A. Georgescu
Most studies about selective site pacing in the atria and ventricles have been small and presented conflicting and confusing data. It is certain and accepted that long-term RV apex pacing generates deleterious effects in the left ventricular structure and function. For instance patients with already impaired LV function are at the greatest risk from RV apex pacing. However, for patients with normal LV function, the incidence of harmful effects from RV apex pacing is unknown, due to not complex, carefully designed clinical studies. The results about the right ventricular selective sites have been disappointing for patients who require permanent ventricular pacing [46]. There is no evidence to change RV apex in these cases. There are also problems defining the ideal alternative site as well as reliable, accurate, and stable lead placement. The scientists must identify the best site to stimulate the heart, to determine the location that provides optimal, long-term hemodynamic benefits, and then the industry has to create cost-effective tools that require the minimum of advance training to meet the challenge.
Conclusion
The outcomes from the big trials like DANISH, DAVID, MADIT II, and PAVE recommend to minimize or to avoid the right ventricular apical pacing, especially in patients with depressed LV ejection fraction. In this case, we need extended clinical trials to define long-term effects of RV apex pacing versus other RV selective sites or even biventricular pacing in patients with LV dysfunction or heart failure. The problem will be for patients with the conventional antibradycardia pacemaker indications with the need for permanent ventricular support to find alternative RV pacing sites to prevent deleterious effects of remodeling when ventricular function is only moderately impaired as well as to reduce the progression to congestive heart failure induced by pacing [44]. Larger studies should also evaluate the consequences of selected site pacing. For patients with severe impairment of LV function, the biventricular pacing for cardiac resynchronization therapy is a better option than pacing the right ventricular septum or outflow tract. In the light of actual evidence on the impact of alternative RV pacing sites on long-term LV function, it is premature to leave, at this moment, RV apical pacing site in patients with normal ejection fraction. Pacing of His-bundle is technically challenging and is recommended only in patients without intraventricular conduction delay, but its beneficial role is presently unclear [45]. The transition to the new pacing modalities will have an important impact in children with or without congenital cardiac defects because of throughout life pacing [36].
References 1. Padeletti L, Pürerfellner H, Adler SW, et al. Combined efficacy of atrial septal lead placement and atrial pacing algorithms for prevention of paroxysmal atrial tachyarrhythmia. J Cardiovasc Electrophysiol. 2003;14:1189–96. 2. Stătescu C, Arsenescu Georgescu C. Cardiac pacing – a chance for the patient with atrioventricular conduction disturbances. In: Alexa I, editor. News in geriatrics. Iaşi: “Gr.T.Popa” U.M.F.; 2011. p. 137–42. ISBN 978-606-544-077-7. 3. Abrams LD, Hudson WA, Lightwood R. A surgical approach to the management of heart-block using an inductive coupled artificial cardiac pacemaker. Lancet. 1960;1:1372–4. 4. Furman S, Schwedel JB. An intracardiac pacemaker for StokesAdams seizures. N Engl J Med. 1959;261:943–8. 5. Lamas GA, Orav EJ, Stambler BS, et al. Quality of life and clinical outcomes in elderly patients treated with ventricular pacing as compared with dual chamber pacing – PASE (Pacemaker Selection in the Elderly). N Engl J Med. 1998;338:1097–104. 6. Toff WD, Skehan JD, De Bono DP, Camm AJ. The United Kingdom pacing and cardiovascular events (UKPACE) trial. United Kingdom Pacing and Cardiovascular Events. Heart. 1997;78:221–3. 7. Stătescu C, Sascău RA, Maciuc V, Arsenescu GC. Programming an optimal atrioventricular interval in a dual chamber pacemaker regional population. Maedica (Buchar). 2011;6(4):272–6. 8. Georgescu GIM, Arsenescu Georgescu C. Rational treatment of major cardiovascular diseases. Iasi, Romania, Polirom; 2001. p. 211–38. 9. Prinzen F, Peschar M. Relation between the pacing induced sequence of activation and left ventricular pump function in animals. Pacing Clin Electrophysiol. 2002;25(Pt. I):484–98. 10. Wilkoff BL, Cook JR, Epstein AE, et al. Dual-chamber pacing or ventricular backup pacing in patients with an implantable defibrillator: the Dual Chamber and VVI Implantable Defi brillator (DAVID) Trial. JAMA. 2002;288(24):3115–23. 11. Sweeney MO, Hellkamp AS, Greenspon AJ, et al. Baseline QRS duration ≥ 120 milliseconds and cumulative percent time
47 Pacing Site: From Theory to Practice
12.
13. 14.
15.
16. 17.
18.
19.
20.
21.
22.
23. 24.
25.
26.
27.
28.
29.
ventricular paced predicts increased risk of heart failure, stroke, and death in DDDR-paced patients with sick sinus syndrome in MOST (conference abstract). Pacing Clin Electrophysiol. 2002;25(4, Part II):690. Nielsen JC, Kristensen L, Andersen HR, et al. A randomized comparison of atrial and dual-chamber pacing in 177 consecutive patients with sick sinus syndrome: echocardiographic and clinical outcome. J Am Coll Cardiol. 2003;42(4):614–23. Wiggers C. The muscular reactions of the mammalian ventricles to artificial surface stimuli. Am J Physiol. 1925;73:346–78. Wyman B, Hunter W, Prinzen F, et al. Mapping propagation of mechanical activation in the paced heart with MRI tagging. Am J Physiol. 1999;276:881–91. Lee M, Dae M, Langberg J, et al. Effects of long-term right ventricular apical pacing on left ventricular perfusion, innervation, function and histology. J Am Coll Cardiol. 1994;24:225–32. Tse H, Lau C. Long term effects of right ventricular pacing on myocardial perfusion and function. J Am Coll Cardiol. 1997;29:744–9. Tse HF, Yu C, Wong KK, et al. Functional abnormalities in patients with permanent right ventricular pacing: the effect of sites of electrical stimulation. J Am Coll Cardiol. 2002;40(8):1451–8. Prinzen FW, Augustijn CH, Arts T, et al. Redistribution of myocardial fiber strain and blood flow by asynchronous activation. Am J Physiol. 1990;259(2 Pt 2):H300–8. Karpawich PP, Justice CD, Cavitt DL, Chang CH. Developmental sequelae of fixed-rate ventricular pacing in the immature canine heart: an electrophysiologic, hemodynamic, and histopathologic evaluation. Am Heart J. 1990;119(5):1077–83. Heyndrickx GR, Vilaine JP, Knight DR, Vatner SF. Effects of altered site of electrical activation on myocardial performance during inotropic stimulation. Circulation. 1985;71(5):1010–6. Bailin SJ, Adler S, Giudici M. Prevention of chronic atrial fibrillation by pacing in the region of Bachmann’s bundle: results of a multicenter randomized trial. J Cardiovasc Electrophysiol. 2001;12(8):912–7. de Cock CC, Giudici MC, Twisk JW. Comparison of the haemodynamic effects of right ventricular outflow tract pacing with right ventricular apex pacing: a quantitative review. Europace. 2003;5(3):275–8. Harris ZI, Gammage MD. Alternative right ventricular pacing sites – where are we going? Europace. 2000;2(2):93–8. Karpawich PP, Justice CD, Chang CH, et al. Septal ventricular pacing in the immature canine heart: a new perspective. Am Heart J. 1991;121(3 Pt 1):827–33. Benchimol A, Liggett MS. Cardiac hemodynamics during stimulation of the right atrium, right ventricle, and left ventricle in normal and abnormal hearts. Circulation. 1966;33:933–44. Buckingham TA, Candinas R, Attenhofer C, et al. Systolic and diastolic function with alternate and combined site pacing in the right ventricle. Pacing Clin Electrophysiol. 1998;21:1077–84. Kolettis TM, Kyriakides ZS, Tsiapras D, et al. Improved left ventricular relaxation during short-term right ventricular outflow tract compared to apical pacing. Chest. 2000;117:60–4. Giudici MC, Thornburg GA, Buck DL, et al. Comparison of right ventricular outflow tract and apical lead permanent pacing on cardiac output. Am J Cardiol. 1997;79:209–12. Cowell R, Morris-Thurgood J, Ilsley C, et al. Septal short atrioventricular delay pacing: Additional hemodynamic improvements in heart failure. Pacing Clin Electrophysiol. 1994;17:1980–3.
611 30. Gold MR, Brockman R, Peters RW, et al. Acute hemodynamic effects of right ventricular pacing site and pacing mode in patients with congestive heart failure secondary to either ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol. 2000;85:1106–9. 31. Stambler BS, Ellenbogen K, Zhang X, et al. Right ventricular outflow versus apical pacing in pacemaker patients with congestive heart failure and atrial fibrillation. J Cardiovasc Electrophysiol. 2003;14:1180–6. 32. Victor F, Leclercq C, Mabo P, et al. Optimal right ventricular pacing site in chronically implanted patients: prospective randomized crossover comparison of apical and outflow tract pacing. J Am Coll Cardiol. 1999;33:311–6. 33. Giudici MC, Barold SS, Moeller AL, et al. Influence of native conduction status on clinical results with right ventricular outflow tract pacing. Am J Cardiol. 2003;91:240–2. 34. Toussaint JF, Lavergne T, Kerrou K, et al. Ventricular coupling of electrical and mechanical dyssynchronization in heart failure patients. Pacing Clin Electrophysiol. 2002;25:178–82. 35. Yu CM, Lin H, Zhang Q, et al. High prevalence of left ventricular systolic and diastolic asynchrony in patients with congestive heart failure and normal QRS duration. Heart. 2003;89:54–60. 36. Vanagt WY, Verbeek XA, Delhaas T, Mertens L, Daenen WJ, Prinzen FW. The left ventricular apex is the optimal site for pediatric pacing: correlation with animal experiments. Pacing Clin Electrophysiol. 2004;27:837–43. 37. Tantengco MV, Thomas RL, Karpawich PP. Left ventricular dysfunction after long-term right ventricular apical pacing in the young. J Am Coll Cardiol. 2001;37:2093–100. 38. Scherlag B, inventor. Board of Regents for the University of Oklahoma, assignee. Method for alleviating and diagnosing symptoms of heart block. US patent 5,083,564, June 1994. 39. Himmrich E, Przibille O, Zellerhoff C, et al. Proarrhythmia effect of pacemaker stimulation in patients with implanted cardioverter defibrillators. Circulation. 2002;7:192–7. 40. El Sherif N, Amat-y-Leon F, Schonfield C, et al. Normalization of bundle branch block patterns by distal his-bundle pacing. Circulation. 1978;57:473–9. 41. Peschar M, de Swart H, Michels K, et al. Left ventricular septal and apex pacing for optimal pump function in canine hearts. J Am Coll Cardiol. 2003;41:1218–26. 42. Deshmukh P, Casavant DA, Romanyshyn M, et al. Permanent, direct His-bundle pacing: a novel approach to cardiac pacing in patients with normal His-Purkinje activation. Circulation. 2000;101:869–77. 43. Yee R. Selective site pacing: tools and training. Pacing Clin Electrophysiol. 2004;27:894–6. 44. Sweeney MO, Hellkamp AS, Ellenbogen KA, et al. Adverse effect of ventricular pacing on heart failure and atrial fibrillation among patients with normal baseline QRS duration in a clinical trial of pacemaker therapy for sinus node dysfunction. Circulation. 2003;107:2932–7. 45. Deshmukh PM, Romanyshyn M. Direct His-bundle pacing: present and future. Pacing Clin Electrophysiol. 2004;27:862–70. 46. Stătescu C, Arsenescu Georgescu C. The prognosis after cardiac pacing according to selective sites. In: Alexa I, editor. News in geriatrics. Iaşi: “Gr.T.Popa” U.M.F.; 2011. p. 143–52. ISBN 978-606-544-077-7.
Implantable Cardioverter Defibrillators in the Pediatric and Congenital Heart Population
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Steven B. Fishberger
Abstract
Implantable cardioverter defibrillators (ICDs) have become the treatment of choice for primary and secondary prevention of sudden cardiac death, though pediatric indications often differ from the adult population. Pediatric indications include primary electrical disease, structural congenital heart disease, hypertrophic cardiomyopathy, and dilated cardiomyopathy. The role of ICD implantation for primary prevention of sudden cardiac death in patients with congenital heart disease remains imprecise due to the relatively small population size and the infrequency of events. Technical aspects of ICD implantation can be uniquely challenging in younger pediatric patients and those with congenital heart disease, particularly those with complex anatomy. Issues that must be considered include patient size, venous anatomy, and the presence of residual intracardiac shunts. The limitations encountered when considering ICD implantation for a pediatric or congenital heart patient have led to a number of creative, nontransvenous system implants. However, these various nontransvenous techniques have been associated with a high incidence of early failure. Advances in ICD system construction and function will serve to expand the indications for these populations, particularly as it applies to primary prevention. Keywords
Congenital heart disease • Pediatrics • Implantable defibrillators
Implantable cardioverter defibrillators (ICDs) have become the treatment of choice for primary and secondary prevention of sudden cardiac death [1]. The superiority of ICDs in reducing all-cause mortality compared with antiarrhythmic therapy has been established in high-risk patients with ischemic and nonischemic cardiomyopathy [2, 3]. This strategy has been applied to the pediatric population at risk for sudden cardiac death, though indications often differ from the adult population. Pediatric indications include primary electrical disease, structural congenital heart disease, hypertrophic cardiomyopathy, and dilated cardiomyopathy
S.B. Fishberger, MD Department of Cardiology, Miami Children’s Hospital, Miami, FL, USA e-mail:
[email protected] A.S. Kibos et al. (eds.), Cardiac Arrhythmias, DOI 10.1007/978-1-4471-5316-0_48, © Springer-Verlag London 2014
[4, 5]. Pediatric patients represent <1 % of all patients with ICDs [6].
Historical Perspective Electrical defibrillation was first described by Zoll in 1952 as a method of successful resuscitation during cardiac arrest [7]. The concept of a fully automatic implantable cardioverter defibrillator system for recognition and treatment of ventricular arrhythmias was initially suggested in 1970, though the first human implantation of a device was performed in February 1980 by Mirowski and associates [8]. The early devices were relatively cumbersome, requiring abdominal implantation with pericardial defibrillation patches. This limited the use of these devices, particularly in children. In 1989, Kral and colleagues reported the first use 613
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of ICDs in young children [9]. ICD use in the pediatric population has increased significantly, in part due to technological advancements, including smaller devices and the introduction of transvenous leads. Additionally, indications for ICD implantation have expanded as a result of a number of trials in the adult population that demonstrated superiority compared with antiarrhythmic medications as a strategy for primary and secondary prevention of sudden cardiac death. Increased identification of primary electrical diseases that may result in cardiac arrest in the pediatric population including long QT syndrome (LQT), Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia (CPVT) has further increased the application of ICD implantation. The expanding population of adults with congenital heart disease who have an increased risk of ventricular arrhythmias and sudden death with advancing age identifies another group that benefits from ICD implantation.
Indications for ICD Implantation The ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and prevention of sudden cardiac death included specific recommendations for ICD therapy in pediatric patients and for specific cardiac diseases relevant to children, including congenital heart disease, inherited arrhythmogenic diseases, and cardiomyopathies [10].
Class I There is general agreement that children with aborted sudden cardiac death without reversible cause require ICD implantation, regardless of underlying cardiac disease. In young patients, reversible causes of sudden cardiac death include Wolff-Parkinson-White syndrome, myocarditis, and some cases of drug-induced QT prolongation. For young survivors of aborted sudden cardiac death, a 30 % 1-year risk and 55 % 3-year risk for recurrent event (ICD shock) were reported in the initial large-scale study of the use of ICDs in pediatric patients [11]. Spontaneous sustained ventricular tachycardia in the patient with congenital heart disease may result in hemodynamic consequences. In the absence of a definitive cure such as catheter or surgical ablation, an ICD is indicated.
Class II There are patients without structural heart disease with spontaneous sustained ventricular tachycardia due to geneticbased channelopathies. In the absence of other effective
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treatment alternatives, an ICD is generally indicated when either sustained ventricular tachycardia or unexplained syncope has occurred. This includes patients with long QT syndrome, CPVT, Brugada syndrome, and short QT syndrome. Indications for ICD implantation for primary prevention in the young patient with an increased risk for sudden cardiac death are controversial. Risk stratification for various disease substrates is often not validated by prospective clinical trials or may be limited in their predictive power due to the relatively small population size. This is compounded by the potential challenge of ICD implantation and durability due to patient size, venous and/or intracardiac anatomy. In patients with long QT syndrome, the risk of sudden cardiac death is 2 % per year, though varies based on long QT type, duration of the corrected QT interval, and gender [12]. Risk factors include QTc > 500 ms, family history of sudden cardiac death, T-wave alternans, and long QT type 3. Additionally, those with more than one disease-causing mutation appear to have a longer QTc and increased risk of cardiac arrest. Nevertheless, ICD implantation as primary prevention in high risk, asymptomatic children with long QT syndrome remains controversial and is classified as a class IIB indication. Many experts in the field have recommended “following closely”; however, events are typically sudden, without warning, and may be fatal. Providing a family with an automated external defibrillator (AED) may impart some increased level of protection; though particularly in long QT3, events may occur during sleep. Therefore an AED would be of little use, unless there is a method of cardiac monitoring. In patients with hypertrophic cardiomyopathy, studies have demonstrated that, among other parameters, young age at diagnosis appears to be an important risk factor for sudden cardiac death. Prophylactic ICD implantation should be considered in a child with hypertrophic cardiomyopathy with one or more risk factors such as family history of sudden cardiac death, septal thickness >30 mm, ventricular ectopy, syncope with exercise, or an abnormal blood pressure response during an exercise stress test. Maron and colleagues reported appropriate discharges for ventricular tachycardia in 23 % of patients followed for 3 years, with an average discharge rate of 5 % per year for primary prevention and 11 % per year for secondary prevention [13]. ICD implantation should be considered in children with severe left ventricular dysfunction in the presence of ventricular arrhythmias [14]. However, in contrast to the adult population, there is no data that supports routine use of ICDs in young patients with impaired ventricular function as an isolated risk factor with respect to survival benefit. The role of ICD implantation for primary prevention of sudden cardiac death in patients with congenital heart disease is not clearly defined. In general, the risk is highest in patients with prior repair of tetralogy of Fallot, intra-atrial
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repair of transposition of the great arteries (Mustard or Senning), or aortic stenosis [15]. Risk stratification remains challenging due to the relatively small population size and the infrequency of events. For example, the incidence of sudden death in patients with tetralogy of Fallot is approximately 2 % per decade. In this group, risk factors that have been identified include older age at repair, poor ventricular function, prolonged QRS duration, high-grade ventricular ectopy, and a positive ventricular stimulation study [16]. Overall, in patients with congenital heart disease, risk factors for sudden cardiac death appear to increase with age, degree of ventricular dysfunction, and the presence of spontaneous ventricular arrhythmia.
ICD Implantation Technical aspects of ICD implantation can be uniquely challenging in younger pediatric patients and those with congenital heart disease, particularly those with complex anatomy. Issues that must be considered include patient size, venous anatomy, and the presence of residual intracardiac shunts. For the adolescent patient with a structurally normal heart, standard transvenous ICD lead placement and a prepectoral or subpectoral generator implant is generally performed. While the subpectoral site requires more dissection, it provides a better cosmetic result and may decrease the likelihood of infection or erosion. This is compounded in younger, thinner patients in whom a prepectoral implant of a relatively large ICD generator (compared with a pacemaker pulse generator) would place excessive tension on the overlying tissue. A number of factors must be considered when performing ICD lead implantation in a pediatric patient. Patient size may raise significant concerns with respect to transvenous ICD lead implantation. Transvenous pacemaker lead implantation is generally utilized for patients greater than 10–15 kg; however the diameter of a standard pacemaker lead is 7 French, while a standard ICD lead is 9 French. There is data that indicates that vascular occlusion is related to lead diameter compared with BSA, though others have data that does not support this conclusion [17, 18]. There is no consensus as to what the weight cutoff should be to consider transvenous ICD lead implantation, though at least 25 kg has been recommended [19]. It should be noted that 7 French ICD leads have been available, though the initial offerings by Medtronic and St. Jude were associated with unacceptable long-term complications. This included early lead fracture in the Medtronic Sprint Fidelis lead, particularly in children, and myocardial perforation by the St. Jude Riata lead [20, 21]. Along with concerns of inadequate vascular caliber, somatic growth must be accounted for in the pediatric patient. It is important to provide some redundant lead length within the
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heart to avoid excessive lead tension in the future when leads are place in growing children. In patients with congenital heart disease, venous and intracardiac anatomy may preclude transvenous implantation of an ICD system. The assumption that there is superior venous access to the pulmonary ventricle may not always be accurate. Patients with congenital heart disease may have persistence of the left superior vena cava draining into the coronary sinus or directly into the left atrium, may not have an innominate vein or right superior vena cava, or may have stenosis or occlusion of the superior veins as a result of instrumentation during previous surgery. Those who have had a Glenn anastomosis are left with the superior veins draining directly into the pulmonary arteries and therefore have no superior venous access to the heart. In an earlier era, surgical repair for transposition of the great arteries involved creating an intra-atrial baffle, redirecting venous return to the opposite ventricle (Mustard or Senning operation). Stenosis at the region of the superior vena cava – atrial junction – occurs and may require balloon dilation and stent placement prior to implantation of a transvenous ICD lead (Fig. 48.1). There are a variety of complex congenital heart lesions that anatomically or physiologically have only one functional ventricle. The sole ventricle must serve as the systemic ventricle; therefore there is no pulmonary ventricle available to place an ICD lead. Finally, even if there is superior venous access to a pulmonary ventricle, the presence of
Fig. 48.1 Chest radiograph of a transvenous ICD lead placed through a stent in an adult patient with transposition of the great arteries who had a Mustard operation in infancy. The SVC-atrial baffle was severely stenotic prior to stent implantation
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Fig. 48.2 Chest radiograph of a transvenous 7 French ICD lead place in a 1 year old with long QT syndrome who survived a cardiac arrest
an intracardiac shunt must be excluded prior to lead implantation, as this poses a significant risk for a systemic thromboembolic event. The limitations encountered when considering ICD implantation for a pediatric or congenital heart patient have led to a number of creative, nontransvenous system implants. While the earliest ICD implants utilized a nontransvenous system with epicardial patches, there were reports of restrictive pericarditis [22]. Berul and colleagues evaluated the feasibility and performance of utilizing a subcutaneous array and an abdominally placed active ICD generator as the electrical vector configuration for defibrillation in immature piglets [23]. This technique requires a separate epicardial ventricular pace sense lead, though avoids the need for epicardial patches or transvenous access. They then successfully applied this approach to a 2-year-old child with repaired congenital heart disease. A multicenter study reported on this technique and variations that include the use of a subcutaneous shock coil and the placement of an ICD lead within the pericardial space along the epicardial surface of the heart (Fig. 48.2) [24]. An additional approach that has been reported is to place the ICD defibrillation lead in the pleural space [25]. Initial enthusiasm for these various nontransvenous techniques has been tempered by a recent report describing the high incidence of early failure rate compared with standard transvenous ICD systems [26]. System survival at 24 months was only 55 % for the nontransvenous
Fig. 48.3 Radiograph of a nontransvenous ICD system with an epicardial pace-sense lead, a subcutaneous array around the left thorax and an abdominal ICD generator
group versus 83 % for the transvenous group. This data identifies the need for a more durable system for pediatric patients. This author has attempted an additional approach in an 11-kg, 1-year-old patient with congenital long QT syndrome who survived a cardiac arrest. The availability of a 7 French, St. Jude Durata transvenous ICD lead provided the opportunity for transvenous placement in this size patient. Lead redundancy was provided by creating a loop in the right atrium (Fig. 48.3). An extra long lead was used to allow for tunneling from the subclavicular region to the abdominally placed generator. The system is functioning well at 1 year, though further follow-up is necessary before any conclusions can be made.
Utilization and Outcomes The implications of ICD placement in pediatric and congenital heart disease patients have been determined by a large single-center report and a multicenter retrospective data analysis [4, 27]. The single-center retrospective analysis reported on 76 patients, 42 % with congenital heart disease, 33 % with primary electrical disease, 17 % with hypertrophic cardiomyopathy, and 8 % with idiopathic dilated car-
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Implantable Cardioverter Defibrillators in the Pediatric and Congenital Heart Population
diomyopathy. Indications for ICD implantation included cardiac arrest or sustained ventricular tachycardia (n = 27), combinations of syncope (n = 32), palpitations (n = 17), spontaneous ventricular arrhythmia (n = 40), inducible ventricular tachycardia (n = 36), or severe hypertrophic cardiomyopathy. Subcutaneous arrays or epicardial patches were used in 9 patients. Over a median 2-year follow-up, 28 % of patients received appropriate shocks for ventricular tachycardia, and 25 % experienced inappropriate shocks for multiple causes. Complications occurred in 29 patients, including lead failure in 16, ICD storm with sequential shocks in 5, and infection in 2 patients. The multicenter collaborative data set reported on 443 patients with a median age of 16 years, 69 % with structural heart disease [27]. The most common diagnoses were tetralogy of Fallot (19 %) and hypertrophic cardiomyopathy (14 %). Primary prevention was the indication for ICD implantation in 52 %. Appropriate shocks occurred in 26 %, while 21 % received inappropriate shocks. Inappropriate shocks were mainly attributed to lead failure (14 %), sinus or atrial tachycardia (9 %), and/or oversensing (4 %). Pediatric ICD utilization and trends in the USA between 1997 and 2006 was reported using the Kids’ Inpatient Database, a national, all-payer, hospital administrative database [28]. The number of pediatric ICD implants per year increased threefold from 130 in 1997 to 396 in 2006. There was a trend toward primary prevention over this time period as evidenced by the decrease in diagnosis of life-threatening arrhythmia from 77 to 45 %.
Complications Complications associated with ICDs in the pediatric and congenital heart population mirror those that occur in their adult counterpart’s including infection, lead dislodgement, lead failure/fracture, myocardial perforation, vascular occlusion, device failure/malfunction, and inappropriate therapy. The unique features of the pediatric population including a higher level of activity, diminutive size, and potential for somatic growth put them at increased risk for many of these problems [29]. The pediatric cohort tends to be healthier and more active, resulting in more wear and tear on the ICD leads and a greater risk of lead fracture. Vascular occlusion and the unique problems associated with nontransvenous systems have been discussed previously in this chapter. Inappropriate shocks result from the aforementioned lead fracture, T-wave oversensing, and supraventricular tachycardia. Many pediatric patients who receive an ICD have long QT syndrome or hypertrophic cardiomyopathy, two conditions that increase the risk of T-wave oversensing. Appropriate programming, vigilant remote monitoring, and exercise stress testing may serve to avoid this problem [30]. In con-
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trast to adults with ICDs, atrial fibrillation is extremely uncommon in the pediatric population. However, sinus tachycardia from vigorous activity may result in inappropriate therapy if the patient is not on adequate beta blockade or the detection rate is set too low. Once again, setting a monitoring zone, vigilant remote monitoring, and an exercise stress test can assess this. Conclusion
The use of ICDs for the prevention of sudden cardiac death in the pediatric and congenital heart populations continues to grow. Advances in ICD system construction and function will serve to expand the indications for these populations, particularly as it applies to primary prevention. Future developments may enhance the durability and safety of these life-saving devices in this vulnerable population of patients.
References 1. Goldberger Z, Lampert R. Implantable cardioverter-defibrillators: expanding indications and technologies. JAMA. 2006;295: 809–18. 2. Prystowsky EN, Nisam S. Prophylactic implantable cardioverter defibrillator trials: MUSTT, MADIT, and beyond. Am J Cardiol. 2000;86:1214–5. 3. Grimm W, Alter P, Maisch B. Arrhythmia risk stratification with regard to prophylactic implantable defibrillator therapy in patients with dilated cardiomyopathy. Results of MACAS, DEFINITE, and SCD-HeFT. Herz. 2004;29:348–52. 4. Alexander ME, Cecchin F, Walsh EP, Triedman JK, Bevilacqua LM, Berul CI. Implications of implantable cardioverter defibrillators in congenital heart disease and pediatrics. J Cardiovasc Electrophysiol. 2004;15:72–6. 5. Etheridge SP, Sanatani S, Cohen MI, Albaro CA, Saarel EV, Bradley DJ. Long QT syndrome in children in the era of implantable defibrillators. J Am Coll Cardiol. 2007;50:1335–40. 6. Kozak LJ, Owings MF, Hall MJ. National hospital discharge survey: 2002 annual summary with detailed diagnosis and procedure data. Viral Health Data. 2005;13:1–199. 7. Zoll PM. Resuscitation of the heart in ventricular standstill by external electric stimulation. N Engl J Med. 1952;247:768–71. 8. Mirowski M, Reid PR, Mower MM, Watkins L, Gott VL, Schauble JF, et al. Termination of malignant ventricular arrhythmias with an implanted automatic defibrillator in human beings. N Engl J Med. 1980;303:322–4. 9. Kral MA, Spotnitz HM, Hordof A, Bigger JT, Steinberg JS, Livelli FD. Automatic implantable cardioverter defibrillator implantation for malignant ventricular arrhythmias associated with congenital heart disease. Am J Cardiol. 1989;63:118–9. 10. Zipes DP, Camm AJ, Borggrefe M, Buxton AE, Chaitman B, Fromer M, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Circulation. 2006;114:e385–484. 11. Silka MH, Kron J, Dunnigan A, Dick II M. Sudden cardiac death and the use of implantable cardioverter-defibrillators in pediatric patients. Circulation. 1993;87:800–7. 12. Priori SG, Schwartz PJ, Napolitano C, Bloise R, Ronchetti E, Grillo M, et al. Risk stratification in the long-QT syndrome. N Engl J Med. 2003;348:1866–74.
618 13. Maron BJ, Shen WK, Link MS, Epstein AE, Almquist AK, Daubert JP, et al. Efficacy of implantable cardioverter-defibrillators for the prevention of sudden death in patients with hypertrophic cardiomyopathy. N Engl J Med. 2000;342:365–73. 14. Dubin AM, Berul CI, Bevilacqua LM, Collins KK, Etheridge SP, Fenrich AL, et al. The use of implantable cardioverter-defibrillators in pediatric patients awaiting heart transplantation. J Card Fail. 2003;9:375–9. 15. Pelech AN, Neish SR. Sudden death in congenital heart disease. Pediatr Clin North Am. 2005;51:1257–71. 16. Khairy P, Dore A, Poirier N, Marcotte F, Ibrahim R, Mamgeam FP, et al. Risk stratification in surgically repaired tetralogy of Fallot. Expert Rev Cardiovasc Ther. 2009;7:755–62. 17. Figa FH, McCrindle BW, Bigras JL, Hamilton RM, Gow RM. Risk factors for venous obstruction in children with transvenous pacing leads. Pacing Clin Electrophysiol. 1997;20:1902–9. 18. Bar-Cohen Y, Berul CI, Alexander ME, Fortesue EB, Walsh EP, Triedman JK, et al. Age, size, and lead factors alone do not predict venous obstruction in children and young adults with transvenous lead systems. J Cardiovasc Electrophysiol. 2006;17:754–9. 19. Silka MJ, Bar-Cohen Y. Pacemakers and implantable cardioverterdefibrillators in pediatric patient. Heart Rhythm. 2006;3:1360–6. 20. Rao A, Wright J, Waktare J, Todd D. Sprint Fidelis 6949 highvoltage lead appears to be prone to early failure. Heart Rhythm. 2008;5:167. 21. Morrison TB, Ackerman MJ, Rea RF. Subacute perforation of the St. Jude Riata implantable cardioverter-defibrillator lead: a report of two pediatric cases. Pediatr Cardiol. 2009;30:834–6. 22. Chevalier P, Moncada E, Canu G, Claudel JP, Bellon C, Kirkorian G, et al. Symptomatic pericardial disease associated with patch electrodes of the automatic implantable cardioverter defibrillator:
S.B. Fishberger
23.
24.
25.
26.
27.
28. 29. 30.
an underestimated complication? Pacing Clin Electrophysiol. 1996;19:2150–2. Berul CI, Triedman JK, Forbess J, Bevilacqua LM, Alexander ME, Dahlby D, et al. Minimally invasive cardioverter-defibrillator implantation for children: an animal model and pediatric case report. Pacing Clin Electrophysiol. 2001;24:1789–94. Stephenson EA, Batra AS, Knilans TK, Gow RM, Gradaus R, Balaji S, et al. A multicenter experience with novel implantable cardioverter defibrillator configurations in the pediatric and congenital heart disease population. J Cardiovasc Electrophysiol. 2006;17:41–6. Tomaske M, Pretre R, Rahn M, Bauersfeld U. Epicardial and pleural lead ICD systems in children and adolescents maintain functionality over 5 years. Europace. 2008;10:1152–6. Radbill AE, Triedman JK, Berul CI, Fynn-Thompson F, Atallah J, Alexander ME, et al. System survival of nontransvenous implantable cardioverter-defibrillators compared to transvenous implantable cardioverter-defibrillators in pediatric and congenital heart disease. Heart Rhythm. 2010;7:193–8. Berul CI, Van Hare GF, Kertesz NJ, Dubin AM, Cecchin F, Collins KK, et al. Results of a multicenter retrospective implantable cardioverter-defibrillator registry of pediatric and congenital heart disease patients. J Am Coll Cardiol. 2008;51:1685–91. Burns KM, Evans F, Kaltman J. Pediatric ICD utilization in the United States from 1997–2006. Heart Rhythm. 2011;8:23–8. Shah MJ. Implantable cardioverter defibrillator-related complications in the pediatric population. Pacing Clin Electrophysiol. 2009;32:S71–4. Cohen MI, Shaffer J, Pedersen S, Sims JJ, Papez A. Limited utility of exercise-stress testing to prevent T-wave oversensing in pediatric internal cardioverter defibrillator recipients. Pacing Clin Electrophysiol. 2011;34:436–42.
Sensing Issues in CRT Devices
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Giuseppe Stabile, Assunta Iuliano, and Roberto Ospizio
Abstract
Sensing of cardiac depolarization is the basis of pacemakers and implantable cardioverterdefibrillators (ICDs) function. Appropriate sensing results in one sensed event for each activation wavefront in the corresponding chamber. Failure to sense activation wavefronts results in undersensing, which can cause inappropriate pacing, failure to switch modes, or failure to detect a tachyarrhythmia. Oversensing occurs when nonphysiologic signals or physiologic signals that do not reflect local myocardial depolarization are sensed. Oversensing can cause inappropriate pacing inhibition, pacemaker tracking, or inappropriate ICD therapy. Specific issues arise for biventricular devices delivering cardiac resynchronization therapy (CRT) and are discussed in details, like sensing causes of loss of CRT, atrial undersensing and oversensing, coronary sinus lead oversensing, algorithms interactions. Keywords
cardiac resynchronization therapy • ICD • Sensing
Sensing of cardiac depolarization is the basis of pacemakers and implantable cardioverter-defibrillators (ICDs) function. When a wave front of depolarization passes the tip electrode of an intracardiac lead, a deflection in the continuous electrogram signal travels instantaneously up the lead wire to the pacemaker or ICD, where sensing electronics amplifies, filters, digitizes, and processes the signal. A sensed event occurs when the sensing system determines that an atrial or ventricular depolarization has occurred. Dual-chamber pacemakers and ICDs have separate sensing systems for the atrium and ventricle. Biventricular devices have a third sensing channel for coronary sinus lead. Appropriate sensing results in one sensed event for each activation wave front in the corresponding chamber. Failure G. Stabile, MD (*) • A. Iuliano, MD Laboratorio di Elettrofisiologia - Clinica Mediterranea, Naples, Italy e-mail:
[email protected] R. Ospizio, BS Cardiac Rhythm Managment - Boston Scientific, Naples, Italy A.S. Kibos et al. (eds.), Cardiac Arrhythmias, DOI 10.1007/978-1-4471-5316-0_49, © Springer-Verlag London 2014
to sense activation wave fronts results in undersensing, which can cause inappropriate pacing, failure to switch modes, or failure to detect a tachyarrhythmia. Undersensing occurs if the depolarization signal has insufficient amplitude or frequency content to be recognized as a sensed event or if a blanking period disables the sensing amplifier at the time of the event. Oversensing occurs when nonphysiologic signals or physiologic signals that do not reflect local myocardial depolarization are sensed. Oversensing can cause inappropriate pacing inhibition, pacemaker tracking, or inappropriate ICD therapy [1]. Specific issues arise for biventricular devices delivering cardiac resynchronization therapy (CRT). Left ventricular premature ventricular contractions (PVCs) may activate the left ventricle but may not be sensed in the right ventricle before pacing is delivered. In this case, left ventricle (LV) pacing could be delivered during the vulnerable period of the PVC. Not all companies have a dedicate LV-sensing channel so is not always possible to identify if the PVC activate the LV first. Boston Scientific cardiac resynchronization ICDs also sense in the left ventricle to reduce ventricular 619
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proarrhythmia by preventing pacing into the LV vulnerable period. The left ventricular protection period (LVPP) is a programmable interval (300–500 ms) following an LV event when LV pacing will be inhibited. This prevents inadvertent delivery of an LV pacing pulse during the LV vulnerable period. The LVPP differs from other pacing refractory periods, which are designed to prevent inappropriate inhibition of pacing. In contrast, the left ventricular refractory period (LVRP), after a sensed or paced event on the LV lead, is a conventional refractory period. It prevents sensed events from causing inappropriate loss of cardiac resynchronization pacing following sensed events such as T-wave oversensing on the LV lead. The LVRP provides an interval following either an LV sense or an LV pace event, during which LV-sensed events do not inhibit pacing. Use of a long LVRP shortens the LV-sensing window. LVRP is available whenever LV sensing is enabled. Thus, LVRP minimizes unnecessary inhibition of resynchronization pacing, while the LVPP minimizes the risk of LV pacing during the LV vulnerable periods.
Sensing Causes of Loss of CRT
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Fig. 49.1 Atrial and ventricular activity histogram. Full bars are sensed beat; dashed bars are paced beats. Any sensed atrial event is followed by both right- and left-paced ventricular beats
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The objective during CRT should guarantee biventricular pacing on every cardiac cycle. Therefore, any programmed parameter that might reduce the frequency of ventricular pacing should be avoided. To maintain continuous biventricular pacing, appropriate AV interval must first be determined. The majority of patients who receive CRT have intrinsic AV conduction, and therefore programming choices that permit the emergence of native ventricular activation will interrupt continuous biventricular pacing. Effective biventricular pacing requires that pacing activation replace native ventricular activation. Thus, the paced AV interval should be substantially shorter than the intrinsic AV interval. Therefore, interruption of continuous biventricular pacing due to emergence of native AV conduction should be avoided. However, fusion of native ventricular activation and biventricular-paced activation is more likely to occur when the intrinsic AV interval is relatively short. This should be of concern since short AV interval can compromise diastolic function and LV filling. In this situation, 100 % biventricular pacing may result in continuous but nonphysiological AV delay and suboptimal cardiac resynchronization. The use of automatic AV interval extensions or any parameter that compromises continuous tracking should be avoided. In patients with complete AV block or very long intrinsic PR intervals, physiological AV delays and complete resynchronization are easily achieved. There are several causes that can compromise the delivery of 100 % biventricular pacing, and device histograms are a useful method to identify the cause of low percentage of pacing. Figure 49.1 shows a normal histogram with 100 %
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Fig. 49.2 Atrial and ventricular activity histogram. Full bars are sensed beat; dashed bars are paced beats. At lower atrial rate, atrial events are followed by paced ventricular beats and at higher rates by sensed ventricular beats
biventricular pacing. One of the most common causes of non-CRT delivery is an inappropriate AV delay at higher rates when the intrinsic PR is shorter and native AV conduction emerges. Figure 49.2 shows this behaviour where all beats at higher rates are sensed. Other causes of suboptimal CRT delivery are atrial tachyarrhythmias (atrial fibrillation with rapid ventricular response rate, premature atrial contractions, atrial flutter, or tachycardia) or frequent premature ventricular contractions. In these cases, the loss of resynchronization therapy is due to the onset of spontaneous beats without atrial tracking as shown in Fig. 49.3. On the other hand, Fig. 49.4 shows some atrial beats with BiV tracking and some atrial beats too fast to trigger appropriate CRT. Some algorithms such as Boston Scientific Biventricular Trigger could help to partially
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Fig. 49.4 Response to atrial-paced and atrial-sensed events
recover resynchronization therapy. BiV Trigger is designed to promote synchronized RV and LV pacing in absence of atrial tracking. A LV pacing is triggered immediately after a RV-sensed event. It should be remembered that this pacing mode is not equivalent to full BiV capture since the paced complex is a fusion between intrinsic RV activation and LV pacing. The hemodynamic effect of this mode of pacing compared to full BiV capture is not known (Fig. 49.5).
Atrial Undersensing Atrial undersensing may result in loss of atrial-synchronous biventricular pacing. Atrial undersensing can be divided in true undersensing and functional undersensing. True atrial undersensing results from a mismatch between endocardial
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Fig. 49.5 Atrial and ventricular activity histogram. Full bars are sensed beat; dashed bars are paced beats. Sensed ventricular premature contractions reduce the percentage of ventricular pacing
signal amplitude and programmed sensitivity. This can usually be corrected by reprogramming atrial sensitivity, but in some cases, surgical repositioning of the atrial lead will be required. Functional atrial undersensing (“pseudo-atrial undersensing”) is caused by atrial events falling in refractory periods and is a much more common cause of transient loss of CRT. This is typically registered as a reduction in biventricular pacing caused by loss of atrial tracking at high sinus rates. In this circumstance, fast sinus rates and first-degree AV block, which are common in heart failure patients, displace the oncoming P-wave into the postventricular atrial refractory period (PVARP) initiated by the biventricular stimulus on the preceding cycle, resulting in simultaneous loss of atrial tracking and synchronous ventricular pacing. This situation is usually triggered by automatic PVARP extensions after a ventricular premature depolarization (VPD) or other circumstances intended to prevent pacemaker-mediated tachycardia [2]. Although not required for pseudo-atrial undersensing, double counting of the native ventricular EGM often participates in the initiation and maintenance of the phenomenon in nondedicated (Y adapters) or first-generation dual cathodal CRT systems where pacing and sensing from the right ventricle and left ventricle occurs simultaneously. When spontaneous conduction with LBBB (or any form of ventricular conduction delay) emerges, the LV EGM may be sensed sometime after detection of the RV EGM if the LV signal extends beyond the relatively short ventricular blanking period initiated by RV sensing. The LV signal continuously resets the PVARP resulting in an “implied total atrial refractory period” (iTARP) conflict and maintenance of pseudo-atrial undersensing. Failure to deliver CRT at fast sinus rates can be corrected by reducing the PVARP, increasing the upper tracking limit, and deactivating the VPD response in the DDD mode. Newer CRT systems minimize ventricular double counting by using
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an interventricular ventricular refractory period (IVRP). Ventricular-sensed events (e.g., LV sensing) during the IVRP do not reset the PVARP, eliminating the “implied TARP” conflict. Another method to minimize loss of CRT caused by pseudo-atrial undersensing is Atrial Tracking Recovery (Medtronic; ATR). ATR operates in the DDD/R mode when a mode-switch episode is not in progress. Under certain conditions, ATR temporarily shortens PVARP to reduce the intrinsic TARP. ATR is initiated when eight consecutive pacing cycles satisfy the following conditions: (1) the current ventricular event is sensed, not paced; (2) the last ventricular interval contains exactly one refractory atrial event; (3) the last two atrial intervals vary from each other by less than 50 ms; (4) the last atrial interval is longer than the upper tracking rate (UTR) interval by at least 50 ms; (5) the last atrial interval is greater than current PAV plus current PVARP; and (6) the last VS-AR interval (from previous ventricular event to atrial refractory event) is greater than postventricular atrial blanking (PVAB). To start or continue an ATR intervention, the device sets a temporary truncated PVARP equal to last VS-AR interval minus 50 ms. If this computed value is shorter than the programmed PVAB, the PVAB value is used. On subsequent pacing cycles during ATR intervention, the device recalculates the temporary PVARP. ATR intervention ends when a biventricular-paced event occurs at the scheduled PAV or when the computed temporary PVARP is no longer shorter than the otherwise indicated PVARP. If the pacing pattern is interrupted, as by a ventricular-sensed event, the intervention aborts. Atrial Tracking Preference (ATP) (Fig. 49.6) is a similar approach than ATR used in Boston Scientific (St. Paul, Minn.) pulse generators. ATP is designed to mitigate loss of
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AV resynchronization caused by pseudo-atrial undersensing at high sinus rates. It supports the delivery of CRT by temporarily reducing PVARP to reestablish atrial-tracked ventricular pacing. ATP algorithm identifies atrial events below the MTR that should be tracked but are hidden in PVARP and shortens PVARP resulting in atrial-tracked ventricular pacing restoration. Atrial tracking may also be lost when PVCs, PACs, atrial rates above MTR, or rate-smoothing result in an atrial-sensed beat within PVARP. If the algorithm recognizes two successive cycles in which an RV-sensed event is preceded by an A-sensed event in PVARP, the device shortens PVARP until normal atrial-tracked ventricular pacing is reestablished. By programming ATP on, continuous CRT is delivered at rates below the maximum tracking rate (MTR), rates that otherwise might result in loss of AV resynchronization when the sum of PVARP and intrinsic AV intervals exceed the MTR interval. Figure 49.7 shows the rates where this behavior is more frequently encountered. This phenomenon is amplified when there is a long intrinsic AV interval because the sum of PVARP and the intrinsic AV is longer. Of note, ATP is disabled if the atrial rate interval is equal to or greater than the MTR interval (Fig. 49.8).
Atrial Oversensing Automatic mode switching is intended to prevent undesirable rapid ventricular pacing caused by tracking of atrial tachyarrhythmias during DDD operation. Detection of atrial tachyarrhythmias results in reversion to a nontracking mode (DDI or VDI). Spurious mode switching is a common problem and can result in loss of atrial-synchronous ventricular pacing during CRT. The dominant cause of spurious mode switching is far-field R-wave (FFRW) oversensing [3, 4]. This can be recognized on stored marker channels or EGMs by an alternating pattern of atrial cycle lengths with one signal timed closely to the ventricular EGM (Fig. 49.9). Less common causes of spurious mode switching include “nearfield” or “early” R-wave oversensing (pre ventricular oversensing in the atrial channel within the PAV) and oversensing of the paced atrial depolarization during the PAV. Spurious
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Fig. 49.8 An example of ATP activation
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Fig. 49.9 An EGM showing a far-field of R-wave
Fig. 49.10 Surface ECG lead and EGM showing the delay (80 ms) between the onset of the P-wave (dotted line) and the atrial electrogram sensed by the atrial lead positioned in the inferior lateral wall
mode switching can usually be eliminated by the use of bipolar atrial pacing leads, extending the PVAB or reducing atrial sensitivity to reject far-field signals without compromising atrial sensing. Nonphysiological AV delay in CRT patients can also result from a delay between the intrinsic atrial depolarization and the sensed atrial EGM due to lead positioning or intra-atrial
conduction delay. This can cause inappropriate short AV delay in response to a sensed event. In Fig. 49.10, the atrial lead is positioned in the inferior lateral wall. The sensed intrinsic P-wave is delayed for about 80 ms resulting in too short AV synchronization and loss of biventricular pacing. The problem can be solved by programming a longer AV delay to account for the intra-atrial conduction delay.
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Fig. 49.11 An example of loss of biventricular pacing from El-Chami et al. [5]. See text for explanation
CS Lead Oversensing Pacing of the LV is commonly achieved with specially designed leads positioned in one of the coronary veins, via the coronary sinus and, therefore, relatively close to the left atrium, a situation carrying the risk of oversensing far-field atrial signals by the LV lead. A basal LV lead position may predispose to far-field sensing of atrial signals and, subsequently, may result in inhibition of biventricular pacing when LV sensing is activated. Telemetry strip in Fig. 49.11 [5] demonstrates a change in paced QRS morphology following an AS event. The first few beats demonstrate AV sequential pacing with a relatively narrow QRS complex. The last three beats are atrial-sensed (AS) events with an associated change in the paced QRS morphology (arrows). This change was reproducible and seen only following AS events but not atrial-paced (AP) events. The differential diagnosis for intermittent variations in BiV-paced QRS morphology includes: • Intermittent fusion or intermittent pseudofusion • Intermittent anodal capture with LV pacing • Intermittent loss of right ventricle (RV) or LV pacing The native PR interval was 200 ms, which is longer than the paced and sensed AV delays, making fusion or pseudofusion unlikely. Intermittent anodal capture occurs at specific LV pacing outputs, or when pacing output is very near the anodal
threshold. LV output in this case was constant, and no anodal capture was noted when pacing at very high output at implant while screening for diaphragmatic stimulation. Furthermore, the change in QRS morphology occurred only when atrial events switched from paced to sensed events. Thus, intermittent anodal capture seems unlikely. LV lead dislodgement is relatively common and could lead to intermittent loss of LV capture but would not cause loss of capture only following AS events. Device interrogation showed intermittent inhibition of LV pacing following AS events because of far-field sensing of atrial electrograms from the LV lead. Far-field sensing did not occur following AP events because the far-field electrogram on the LV lead occurred during the ventricular blanking period after atrial pacing (LV-Blank after A-Pace, 37.5 ms). Left ventricular protection period (LVPP) is a specific Boston Scientific algorithm, which allows detection by the left ventricular electrode and inhibits ventricular stimulation in case of an LVPB. In fact, a slow-conduction area in severe cardiomyopathy can be responsible for delayed detection of a left ventricular premature beat (LVPB) by the right ventricular lead. It can cause stimulation in the vulnerable period with a theoretical proarrhythmic effect. A possible adverse effect is oversensing by this electrode, leading to an inhibition of the biventricular stimulation. Reducing the sensitivity on the LV lead minimized far-field sensing but did not eliminate it. Inactivation of the
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LV sensing feature eliminated far-field sensing on the LV lead and intermittent inhibition of biventricular pacing. Figure 49.12 shows how histograms in a CRT system resulting from this type of oversensing. An alternative explanation has been reported by Duparc et al. [6]. In this case report, the oversensing appeared during an atrial arrhythmia. Reprogramming LV detection from standard bipolar (LV tip to LV ring) to extended bipolar (LV tip to right ventricular [RV] coil) stopped the oversensing. So we Atrial activity 50
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Fig. 49.12 Atrial and ventricular activity histogram. Full bars are sensed beat; dashed bars are paced beats. Sensed events only on LV channel due to atrial activity oversensing
can hypothesize that only the ventricular dipole involving the proximal electrode selectively detected atrial activity. This is probably due to its more proximal location. Thus, atrial oversensing by a left ventricular lead is possible but rarely seen. Oversensing on LV lead was not only a source of CRT failure when dedicated CRT systems with separate ventricular ports were not available but, in pacemaker dependency, a cause of asystole or inappropriate shocks (in combined CRT/ ICD systems). In these devices, a “triple chamber” systems consisted of a standard dual chamber device with a right atrial lead conventionally connected to the atrial channel, and RV and LV leads both connected to the RV channel via a Y connector. Then, if the signal amplitude was larger than the biventricular channel-sensing threshold, stimulation was inhibited or double counting started [7]. Since benefits obtained with CRT are directly related to continuous biventricular capture, intermittent loss of biventricular pacing due to any type of ventricular oversensing can prevent effective resynchronization therapy. Figure 49.13 [8] shows a case of intermittent T-wave oversensing during sinus rhythm. T-wave oversensing was seen only after paced QRS complexes with resultant double counting detection (VS–VS) following a biventricular-paced event. The ventricular-sensed event as a result of T-wave oversensing occurred before (250 ms) an atrial-sensed event. The atrial-sensed event was classified as refractory and not tracked since the PVARP was programmed at 310 ms and followed by a VS event. Some options might be useful to correct T-wave oversensing:
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1. To shorten the PVARP, but this carries the risk of inappropriate therapies. 2. To alter the V–V sequence and timing in order to try to modulate repolarization and T-wave morphology until oversensing no longer occurs; that option can eliminate the problem while preserving sensitivity to detect true malignant ventricular tachyarrhythmias, but the potential deleterious effects on ventricular dyssynchrony and functional status limit its general use. 3. To decrease the ventricular sensitivity. This should be valued against the risk of VF undersensing. It is generally recommended to program a sensitivity that was tested during VF induction at implant. If not, testing in the EP lab to insure proper VF detection should be considered. 4. Reprogramming the “decay delay” and the “threshold start” can also prevent T-wave undersensing in the St. Jude devices. The automatic sensing algorithm will then starts at a lower sensitivity value and will lower its sensitivity later in the cardiac cycle to overcome T-wave oversensing [8].
Algorithms Interactions Current biventricular devices use different algorithms to ensure biventricular capture and CRT delivery and to satisfy many other clinical requests. Some of these functions could have potential undesirable effects on resynchronization therapy. An example is rate-smoothing algorithms that are used to regularize the ventricular response in patients with irregular
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heart rhythms such as atrial fibrillation, 2:1 AV block, or Wenckebach-type heart block, and frequent ventricular ectopy. As reported by Darby et al. [9], the algorithm was programmed to allow 3 % upward but no downward rate smoothing. With this programming and the specific ratesmoothing algorithm in this device, the interval of time from the previous right ventricular electrogram during which biventricular pacing is inhibited (upper rate smoothing or URS window) is equal to 97 % of the longest of the following three intervals: the previous R-R interval, the URS window for the previous interval, and the interval corresponding to the maximum tracking rate (375 ms). As shown in the annotated device strip in Fig. 49.14 (boxes show duration of URS window), biventricular pacing does not occur for beats 1, 6, 7, 8, and 11 because ventricular sensing occurs before the URS window has ended for each of these beats. Of note, beats 4 and 9 are premature ventricular contractions followed by atrial-sensed events in the PVARP, followed by ventricularsensed events in beats 5 and 10. As a result, biventricular pacing does not occur for beats 5 and 10 for two reasons: inhibition by rate smoothing and atrial sensing in the PVARP. On beat 12, ventricular sensing has not occurred by the end of the URS window, so biventricular pacing occurs. Interestingly, the URS window ends more than 100 ms after atrial sensing, so the AV interval for this beat is longer than that for the other biventricular-paced beat (no. 3). This would be expected because rate smoothing upward is similar to having an upper rate limit for that one particular cycle. As a result, upper rate behavior such as increased AV delays at slower rates is not uncommon with a very small or tight
Fig. 49.14 Loss of BiV pacing due to rate-smoothing algorithm from Darby and Bilchick [9]
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Fig. 49.15 Marker channels stored by ventricular-sensing episode triggered by PMT algorithm from Richardson et al. [2]
upward rate-smoothing percentage. The rate-smoothing algorithm was subsequently programmed off in this patient. Of note, an alternative would have been to program a downward rate-smoothing percentage of 3 % while leaving upward rate smoothing off to help provide a more consistent ventricular rate in the setting of frequent ventricular ectopy without compromising biventricular pacing. In other instances ([2, 10] and Fig. 49.15), the PMT algorithm extends the PVARP to 400 ms on the ninth beat, so it is not tracked. If this were PMT, it would successfully terminate it. However, in this case, it causes loss of biventricular pacing. Because long intrinsic AV conduction is present, the following atrial beat continues to fall in the PVARP, causing perpetuation of this functional undersensing. It is worth noting that this algorithm can be activated at rates lower than the maximum tracking rate, because the algorithm is based on a fixed VA interval. Understanding this algorithm, one can see that PMT was “detected” initiating a PVARP extension and subsequent loss of atrial sensing resulting in intrinsic conduction and loss of BiV pacing. By turning PMT off, the patient no longer experienced any episodes of loss of tracking. Conclusion
Careful examination of device-programmed parameters with knowledge of the different device and manufacturerspecific algorithms and stored EGMs is helpful to assess and correct troubleshooting in CRT patients.
References 1. Swerdlow CD, Gillberg JM, Khairy P. Sensing and detection. In: Clinical cardiac pacing, defibrillation, and resynchronization therapy. Philadelphia: Saunders; 2011. p. 56–126. 2. Richardson K, Cool K, Wang PJ, Al-Ahmad A. Loss of biventricular pacing: what is the mechanism? Heart Rhythm. 2005; 2:110–1. 3. Brandt J, Fahraeus T, Schuller H. Far-field QRS complex sensing via the atrial pacemaker lead. Mechanism, consequences, differential diagnosis and countermeasures in AAI and VDD/DDD pacing. Pacing Clin Electrophysiol. 1988;11:1432–8. 4. Brandt J, Worzewski W. Far-field QRS complex sensing: prevalence and timing with bipolar atrial leads. Pacing Clin Electrophysiol. 2000;23:315–20. 5. El-Chami M, Yoo D, Hoskins MH. Intermittent variation in paced QRS morphology: what is the mechanism? Pacing Clin Electrophysiol. 2010;33:1267–9. 6. Duparc A, Mondoly P, Detis N, Chilon T, Rolin A, Maury P, Delay M. Atrial oversensing by an LV lead during typical flutter: the interest of electronic repositioning. Pacing Clin Electrophysiol. 2011. doi:10.1111/j.1540-8159.2011.03107.x. 7. Taieb JM, Barnay C, Linde C. Left atrial far-field sensing by left ventricular leads: a potential hazard in cardiac resynchronisation therapy. Europace. 2005;7:611–6. 8. Arias MA, Colchero T, Puchol A. Loss of biventricular pacing due to T-wave oversensing. Europace. 2010;12:890–2. 9. Darby AE, Bilchick KC. Intermittent inhibition of biventricular pacing in a cardiac resynchronization therapy defibrillator. Heart Rhythm. 2010;7:1910–2. 10. Barold SS, Herweg B. Mysterious loss of resynchronization during biventricular pacing. Pacing Clin Electrophysiol. 2005; 28:571–2.
Cardiac Resynchronization Therapy: Do Benefits Justify the Costs and Are They Sustained Over the Long Term?
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Chin-Pang Chan and Cheuk-Man Yu
Abstract
Heart failure is one of the commonest causes for hospitalization nowadays. Numerous trials demonstrated the beneficial effect of medical therapies including beta-blockers, angiotensin-converting enzyme inhibitors, and aldosterone blockers. Despite these major advancements, heart failure-related morbidity and mortality are high. In selected patients, namely, the patients with widened QRS duration and evidence of systolic left ventricular dysfunction, cardiac resynchronization therapy was shown to improve clinical outcome symptoms by decreasing of hospitalization rate and significantly reducing of mortality. All these beneficial results were sustained in long-term clinical follow-up as well. In most of landmark trials, cardiac resynchronization therapy consistently improved clinical outcome in 70 % of study patient. Also, it is clearly showed that QRS duration alone was not enough to anticipate clinical response, and other clinical prognosis factors might have significant impact for prediction of clinical response. Identification of these clinical predictors is important in terms of improved cost-effectiveness and avoiding unnecessary implantation in nonresponsive patients. Several parameters had been shown to predict clinical response such as left ventricular lead position, myocardial scar distribution, etiology of systolic dysfunction, percentage of biventricular pacing, lack of mechanical dyssynchrony, and QRS morphology. By better stratification, we will be able to have most suitable patient selection that might obtain the best benefit from cardiac resynchronization therapy. Keywords
Cardiac resynchronization • Heart failure • Cost-effectiveness • Device • Pacing
Abbreviations AF AV CRT ICD IVCD LBBB
Atrial fibrillation Atrioventricular Cardiac resynchronization therapy Implantable cardioverter defibrillator Interventricular conduction delay Left bundle branch block
LVEF NYHA RBBB TDI VV
Left ventricular ejection fraction New York Heart Right bundle branch block Tissue Doppler imaging Interventricular
Introduction C.-P. Chan, MRCP • C.-M. Yu, MD, MBChB, FRCP, FRACP, FACC (*) Division of Cardiology, Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, 9/F, Clinical Sciences Building, Shatin, N.T., Hong Kong SAR e-mail:
[email protected] A.S. Kibos et al. (eds.), Cardiac Arrhythmias, DOI 10.1007/978-1-4471-5316-0_50, © Springer-Verlag London 2014
Heart failure is one of the commonest causes for hospitalization nowadays. The prevalence of the disease has increased dramatically in both developed and underdeveloped countries as our society is facing an aging population. In the past, there were many important pharmacological developments 629
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that targeted different underlying mechanisms of this complicated disease. Certain landmark trials have already established the beneficial effect of optimal medical therapies. These comprise angiotensin-converting enzyme inhibitors [1], beta-blockers [2], angiotensin receptor blockers [3], and aldosterone blockers [4]. Despite these major advancements, heart failure-related morbidity and mortality were still high and a new breakthrough treatment was urgently needed. With the advent of cardiac resynchronization therapy (CRT), this new form of therapy demonstrated to improve heart failure symptoms, to reduce heart failure-related hospitalization, to improve quality of life – New York Heart Association (NYHA) functional class, to improve left ventricular ejection fraction (LVEF), to reduce LV volume (reverse remodeling), to reduce mitral regurgitation severity, and to reduce mortality [5].
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How Resynchronization Works Coordinated cardiac contraction is essential for normal cardiac function. Dyssynchrony can occur between the atria and ventricles (atrioventricular (AV)), between the ventricles (interventricular (VV)), or within the LV (intraventricular). Electrical dyssynchrony and delayed ventricular depolarization, as manifested as widened QRS duration, are identified as the major causes of asynchronous contraction in the left ventricle. This electrical conduction delay is associated with abnormal cardiac remodeling and scarring. In patients with left bundle branch block (LBBB) pattern on the ECG, there is delayed contraction of the LV lateral wall which diminishes the effective cardiac output [6]. As CRT has been shown to improve dyssynchrony within the LV and restore coordination of LV contraction, it is likely that the patients with LBBB will benefit from therapy. Also, by adjusting relative atrioventricular and interventricular intervals, it can be further coordinated the mechanical activation timing with achieving of a better cardiac resynchronization.
Mechanical Dyssynchrony Although the beneficial effects of CRT on clinical endpoints and cardiac function are significant, nonresponders to CRT therapy have been consistently observed in about one-third of patients [7, 8]. Mechanical dyssynchrony demonstrated to be a better predictor of CRT response. Lack of mechanical dyssynchrony assessed by noninvasive echocardiographic techniques was found to be closely correlated to CRT nonresponders in numerous single-center clinical trials [9, 10]. Several echocardiographic methods have been used to assess dyssynchrony. M-mode was the earliest method proposed to assess mechanical dyssynchrony and showed that septal to
Fig. 50.1 Examples of measures on myocardial velocity curve. Measurement of peak myocardial systolic, early diastolic, and late diastolic velocities, as well as the time to peak systolic velocity in ejection phase at basal septal and basal lateral segments by two-dimensional color-coded tissue Doppler imaging in a normal subject (a) and in a patient with systolic heart failure and wide QRS complex (b). AVo and AVC aortic valve opening and closure
posterior wall delay >130 ms was evidence of significant intraventricular dyssynchrony [11]. Tissue Doppler imaging (TDI) is another echocardiographic method to assess the presence of mechanical dyssynchrony [9, 10] (Fig. 50.1). It is a special form of Doppler echocardiography to detect the direction and velocity of the contracting or relaxing regional myocardium. Commonly used TDI indices for dyssynchrony evaluation include septal to lateral wall delay in peak systolic velocity of 65 ms [9], maximal delay in peak systolic velocity of 12 LV segments of 100 ms, and standard deviation of time to peak systolic velocity of 12 LV segments (Ts-SD) of 33 ms [10]. Although most of single-center trials showed promising results in identifying CRT responders, use of mechanical dyssynchrony was heavily criticized after the PROSPECT trial [12]. PROSPECT trial was a multicenter, prospective, nonrandomized study designed to assess different echocardiographic indices of mechanical dyssynchrony for their capability to predict response to CRT. Overall, there
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Cardiac Resynchronization Therapy: Do Benefits Justify the Costs and Are They Sustained Over the Long Term?
were 12 echocardiographic parameters tested and it showed that no single echocardiographic measure of dyssynchrony may be recommended to improve CRT patient selection beyond current guidelines. Of note, this study had major limitations in its design and execution. There were high interobserver and intraobserver variability in echocardiographic dyssynchrony assessment and in fact, these reflected the general complexity in dyssynchrony assessment by transthoracic echocardiography.
Current Recommendations The CRT benefits have been confirmed by multicenter randomized controlled trials [13–15]. According to current guidelines from The American College Cardiology [16] and The European Society of Cardiology [17], CRT is indicated in patients who have evidence of LV systolic dysfunction (EF ≤ 35 %), QRS duration ≥120 ms, under optimal medical therapy, in sinus rhythm, and with marked heart failure symptoms (NYHA Class III and ambulatory Class IV). Apart from patients with advanced heart failure symptoms, there was also evidence that mildly symptomatic patients (NYHA II) will benefit from CRT as well. Cardiac resynchronization therapy for the Treatment of Heart Failure in Patients with Intraventricular Conduction Delay and Malignant Ventricular Tachyarrhythmias (CONTAK-CD) [18] and Effect of Cardiac Resynchronization on Disease Progression in Patients with Left Ventricular Systolic Dysfunction (MIRACLE ICD-II) [19] were the two pioneer trials that demonstrated benefit in patients with mild heart failure. Both trials shown significant reverse remodeling in patients with NYHA functional class II. Subsequent trials, such as REVERSE [20], MADIT-CRT [14], and RAFT [15], also reproduced similar results. A meta-analysis of these five clinical trials including 4,317 patients with NYHA functional class I or II symptoms showed that CRT decreased all-cause mortality, reduced heart failure hospitalization, and improved LVEF in NYHA functional class I or II heart failure patients [21]. CRT was associated with a 19 % reduction in total mortality and a 32 % reduction in heart failure events or hospitalization in comparison to implantable cardioverter defibrillator (ICD) therapy alone. This compelling evidence was reflected in the latest focused update of The European Society of Cardiology guidelines [22]. CRT is now indicated for patients with LVEF ≤ 35 %, QRS ≥ 150 ms, in sinus rhythm, receiving optimal medical therapy, and in symptomatic NYHA class II. Most of the multicenter trials mainly involved patients in sinus rhythm only. However, around one-third of patients with advanced heart failure had atrial fibrillation (AF). Prior trials demonstrated that “ablate and pace” strategy can significantly improve heart failure symptoms in patients with permanent AF [23]. Only univentricular pacing (RV apical
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pacing) was used in the earliest trials, and it is unknown if CRT could have further incremental benefits to reduce mortality. A meta-analysis of prospective cohort studies included 1,164 patients and compared the impact of CRT for patients in AF and sinus rhythm [24]. Both AF and sinus rhythm patients responded significantly to CRT, and there was no difference in mortality at 1 year follow-up. Both groups showed similar improvement in NYHA functional class and LVEF. This meta-analysis suggested that patients in AF showed significant improvement after CRT, with similar or improved LVEF compared to patients in sinus rhythm. In order to maximize pacing capture in patients with AF, AV nodal ablation was advocated as adjunctive therapy in addition to CRT. A systemic review including 768 CRT-AF patients found that AV nodal ablation in CRT-AF patients was associated with a substantial reduction in all-cause mortality and improvement in NYHA functional class [25]. This study showed that it was important to ensure biventricular (BiV) capture in CRT-AF patients, and AV nodal ablation is definitely a better method to achieve this goal. As a result, both American [16] and European [22] guidelines endorsed this practice and further suggest that it is reasonable to implant CRT with AV nodal ablation in patients with AF. Some studies suggested that univentricular LV pacing might be able to achieve similar beneficial effect than CRT. The reasons for this approach were that isolated LV pacing has similar effect in minimizing regional LV delay, and it could minimize the number of lead implanted and potentially reduce lead-related complications. So that, a meta-analysis of randomized controlled trials included 574 patients who received either BiV or univentricular LV pacing [26]. This study demonstrated that there was a trend toward superiority of BiV over LV pacing in improvement of LV systolic function and reverse remodeling, but there was no significant difference between the two pacing methods in regard to clinical status. As it suggested, pacing in heart failure may be achieved by means of two different pacing modalities. Univentricular pacing can be used in patients with CRT-P indication alone. On the other hand, the risk of LV lead dislodgement without right ventricular lead backup in pacing-dependent patients was another concern, and the necessity of ICD backup in selected patients also favored the usage of BiV CRT.
Long-Term Result Long-term outcomes after CRT have been reported in a nationwide database in Brazil [27]. It consisted of 3,526 patients with a mean follow-up of 2.8 years (maximum 7 years). The overall survival rate was 80.1 % at 1 year and 55.6 % at 5 years. In this series, there was no difference in survival between CRT-P (without ICD) and CRT-D
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(with ICD). They found better outcomes compared to patients treated by medical therapy alone. A meta-analysis of CRT randomized controlled trials was performed and consisted of 7,538 patients [28]. Compared with optimal medical therapy, CRT significantly reduced mortality. CRT-D also significantly reduces mortality when it was compared to ICD alone. The author concluded that the cumulative evidence is conclusive that the addition of CRT significantly reduces mortality among patients with heart failure. Cost-effectiveness analyses were performed for two main CRT trials. In the COMPANION trial [29], hospitalization costs were reduced by 29–37 % over 2 years, and they suggested that clinical benefits of CRT with or without ICD backup can be achieved at a reasonable cost. In the costeffectiveness analyses of the CARE-HF trial [30], they also demonstrated that CRT represented a cost-effective use of health care resources. All these findings indicated an unequivocal benefit of CRT in addition to optimal medical therapy, and this effect was evident among patients with different functional capacity. It clearly demonstrated mortality benefit and it was costeffective in patients receiving CRT with or without ICD backup. All these data justified the use of CRT in patients with mild and advanced heart failure symptoms. One of the remaining challenges is to reduce the nonresponder rate and to improve CRT patient selection.
Nonresponders to CRT First of all, the definition of nonresponder is difficult, and there was no universal definition of responder in many different trials. Different markers of response have been used. Clinical markers include heart failure symptoms, improvement in NYHA functional class, improvement in 6 min hallwalk distance, rate of hospitalization, and reverse remodeling markers such as changes in echocardiographic parameters. Assessment of NYHA class showed inconsistent results, and self-reported walking distance did not correlated well with formally measured exercise capacity [31]. Also, it is unknown if improvement of these markers translate into a better long-term prognosis. Reverse remodeling has been advocated as a better marker to assess CRT response. A study including 141 patients from two centers assessed whether changes in clinical status or echocardiographic evidence of reverse remodeling can predict long-term clinical outcome in CRT recipients [32]. Clinical parameters that included NYHA functional class, 6-min hall-walk distance, and quality of life score were not predictive of long-term survival. On the other hand, a 10 % reduction in LV end-systolic volume was clinically relevant reverse remodeling, and it was also a predictor of lower heart failure events and long-term mortality. This study suggested
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that there was an important link between LV reverse remodeling and long-term clinical outcome. Reverse remodeling has now been the standard marker to assess CRT response. Regardless of the compelling evidence for CRT benefits, about one-third of patients do not respond to this therapy. Identification of predictors of nonresponse is important to improve the cost-effectiveness and to reduce unnecessary implantation.
Non-LBBB Pattern Widened QRS complex alone was not specific enough to predict positive response since the QRS pattern may be LBBB, right bundle branch block (RBBB), or interventricular conduction delay (IVCD). In patients with non-LBBB pattern, it is not known if CRT will result in the same magnitude of benefit as those with LBBB. A study using 3D noncontact mapping revealed that there was evidence of significant LV delay in RBBB patients, and this suggested that RBBB patients with concomitant intraventricular dyssynchrony might also receive benefit from CRT [33]. However, this hypothesis was not confirmed in most clinical trials. A subgroup analysis of MADIT-CRT assessed the effectiveness of CRT by different QRS morphology [34]. Echocardiographic parameters showed significantly greater reduction in LV volume and increase in LVEF in LBBB than in non-LBBB patients. Also, there was no clinical benefit observed in patients with non-LBBB pattern. A systemic review also demonstrated that none of the available data showed more favorable outcomes with CRT in patients with RBBB, and it confirmed that electrical dyssynchrony alone is not enough to explain the beneficial effects of CRT [35]. As mentioned before, the activation pattern was different between LBBB and non-LBBB groups, and LV pacing actually increased conduction delay in the right ventricle. At the same time, pulmonary hypertension was more prevalent in patients with RBBB QRS pattern, and it might identify a sicker patient population with less response to CRT. All these factors might explain the lack of similar efficacy of CRT in these groups of patients. In conclusion, currently there is no definite benefit shown in non-LBBB patients, and implantation of CRT in this group of patient should be limited. Further studies are necessary to see if other leads configurations could improve the clinical response rate.
LBBB Pattern and Mechanical Dyssynchrony In the MADIT-CRT trial, though patients with LBBB QRS pattern received better clinical response with CRT, there was still a significant proportion of patient who did not respond to CRT. The proposed mechanism of benefit from CRT is the
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Fig. 50.2 Noncontact left ventricular mapping showing the two types of endocardial activation patterns. (a) (from left to right) Sequence of isopotential maps in a patient with type I LV endocardial activation pattern starting from the onset of QRS complex. There was no acute change in propagation direction and no line of block detected throughout the whole LV activation process. Note the propagation of depolarization wave front across the anterior wall, which was different from that of type II. (b) (From left to right) Sequence of isopotential maps in
a patient with type II LV endocardial activation pattern starting from the onset of QRS complex. Area of conduction block was noted over the anterior wall of LV. Propagation wave front splits when encountering the area of block and merges over the lateral wall. (c) (Right) The conduction block was confirmed by the characteristic virtual electrograms, defined as split potentials, gradual emergence of R wave, and steep downstroke, which were different from the (left) virtual electrogram over the similar area in the patients with type I activation
correction of the electromechanical delay. In order to improve the CRT response rate, better understanding of the relationship between electrical activation and mechanical activation should be sought. A study found that electrical conduction delay can be absent in patients with LBBB [36]. This study identified two different types of LV endocardial activation. By using a noncontact mapping system (Fig. 50.2), presence of conduction block patterns (type II) were found in two-third of patients, and the remaining group showed homogenous activation (type I) without conduction block. For type II pattern, there was significant correlation between mechanical dyssynchrony as assessed by echocardiographic methods, and they showed better functional improvement and significant LV reverse remodeling. The authors hypothesized that the absence of conduction block suggests that the electromechanical coupling might be disrupted. The absence of conduction block in wide QRS pattern might explain the lack of response to CRT. Though advanced 3D mapping can help to better stratify patient’s selection in CRT implantation, it will be more
practical to use noninvasive imaging to identify responders. Identification of mechanical dyssynchrony by echocardiographic parameters has been advocated. After the publication of the PROSPECT trial, the enthusiasm to use mechanical dyssynchrony to predict CRT response diminished. However, this study reported a large variability in the analysis of mechanical dyssynchrony, and it reflected the steep learning curve for mechanical dyssynchrony assessment, and consistent results were not easily reproducible in different centers. As a result, newer methods for dyssynchrony assessment are necessary, and they have to be user friendly and results should be easily reproducible in different clinical settings. Speckle tracking echocardiography (STE) is one notable advance that is based on the evaluation of LV mechanics (myocardial deformation) measured as strain and strain rate. Overall, STE is often obtained by 2D echocardiography, by TDI or by 3D echocardiography by using offline analysis [37] (Fig. 50.3). It can assess longitudinal strain, circumferential strain, and radial strain from apical 4 chambers, apical 2 chambers, and parasternal short-axis views. Speckle-tracking
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Fig. 50.3 An echocardiographic mid-ventricular short-axis view used for speckle-tracking radial strain. The right panel shows time-strain curves from six representative segments in a patient with left bundle branch block before cardiac resynchronization therapy. The yellow line is the anteroseptal wall, which demonstrates early peak strain (arrow), and the purple line is the posterior wall, which demonstrates delayed peak strain (arrow), consistent with significant dyssynchrony
Fig. 50.4 An echocardiographic image from a patient with left bundle branch block of threedimensional speckle-tracking strain acquired from a pyramid of data with color coding of peak strain as orange-yellow. The right panel shows 16 corresponding time-strain curves from standard left ventricular segments demonstrating septal curves with early activation and free-wall curves with late activation, consistent with significant mechanical dyssynchrony
strain for dyssynchrony assessment has advantages and disadvantages in the evaluation of AV, VV, and IV optimization and mechanical dyssynchrony assessment and radial strain from short-axis views and transverse strain from apical views were both significantly associated with EF response and longterm survival following CRT [European Heart Journal (2010) 31, 1690–1700]. Though this technology showed promising result in dyssynchrony assessment, this technology is dependent on the quality of two-dimensional images in short-axis
views, and it is technically more demanding to perform offline analysis. Another recent advancement is 3D speckle-tracking strain assessment [38]. All cardiac segments can be assessed simultaneously at the same cardiac cycle (Fig. 50.4). Radial strain is determined using a 16-segment model from a pyramidal data set. The latest mechanical activation of the whole LV can be assessed easily. Apart from off-line 3D dyssynchrony analysis, 3D LV volume,
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EF, and dyssynchrony index by real-time 3D echocardiography can be assessed [39]. Dyssynchrony index can be measured from the scattering of the time to minimal regional volume of the LV segment. Dedicated training is necessary for good imaging acquisition. All these new technologies demonstrated potential advantages in dyssynchrony assessment, but further clinical trials are necessary to assess the application of these novel tools. Extensive clinical studies suggested mechanical dyssynchrony to be the major mechanism for CRT response, and assessment of mechanical dyssynchrony should be useful to discriminate between responders and nonresponders. While echocardiographic technologies are rapidly evolving, it is not easy for everyone to master these technologies without intensive training. Currently, there is no single parameter that is able to accurately identify responders. Knowledge transfer from different centers is not an easy task, and it takes time to overcome the learning curve. In the future, we have to find out the echocardiographic parameters that can be reproducibly assessed by different operators. With more accurate dyssynchrony assessment, we hope to precisely find out who will be a responder and to further improve the costeffectiveness of CRT.
LV Lead Position Theoretically, the mechanism of CRT is to reduce LV electromechanical delay, and it should be better to deliver pacing at the site with the latest electromechanical activation. In reality, it is not an easy task and it is not practical to undergo noncontact mapping during CRT implantation. In view of limited tool for real-time dyssynchrony assessment, most of us implanted LV lead empirically at the posterolateral branch of coronary sinus and presumed that this was the site corresponding to the latest activation in the LV. Sometimes, we have to choose other branches due to limited choice of veins and small size of particular target veins. Lead position has been suggested as one of the major factor to predict CRT response as it was shown in the MADIT-CRT substudy [40]. The location of the LV lead was assessed by coronary venogram, and the lead position was classified into different LV segments. Among all different lead positions, apical lead location was associated with worse composite outcome when compared to other non-apical lead position. The message from this trial was clear that we should try our best to avoid of implanting the LV lead toward an apical position. However, this study did not tell us about the optimal site for CRT pacing. In order to identify the segment with maximal electrical and mechanical delay, pre-procedural evaluation of mechanical dyssynchrony and integration with venous mapping could be a viable option [41]. Also, studies suggested pacing over the site with maximal concordance between the electro-
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mechanical dyssynchrony and target vein achieved better response rate [42]. However, the choice of vein may be limited by the anatomy or the size of the vein. A study also demonstrated the feasibility of endocardial LV pacing using a transseptal approach [43]. By this method, it is theoretically possible to target the site with the latest electromechanical activation. However, one limitation for this approach is that it is technically more difficult, and lifelong anticoagulation is mandatory after implantation.
Scar Location Myocardial viability and the distribution of myocardial scar quantified by cardiac MRI have been proposed to be predictor of CRT response. A study suggested that the presence of LV posterolateral scar tissue diminished the CRT response, and it was due to ineffective LV pacing at scar tissue [44]. In this study, contrast-enhanced cardiac MRI was performed before CRT implantation. The localization and transmurality of scar tissue were characterized. Posterolateral scar could be identified in 35 % of studied patients, and they showed a lower response rate and there was absence of improvement in clinical or echocardiographic parameter. Also, they demonstrated that LV dyssynchrony remained unchanged in patients with posterolateral scar. According to the study findings, it was evident that preimplantation scar location identification helped to better stratify patients and improve the response rate.
Clinical Predictor of CRT Response Early identification of predictor for poor CRT response is essential to improve CRT response. Besides these poor response predictors, there were several factors that can predict better clinical response in CRT. In the substudy of MADIT-CRT trial [45], a response score was validated and consisted of seven factors. They included female sex, nonischemic origin, LBBB, QRS ≥ 150 ms, prior hospitalization for heart failure, left ventricular end-diastolic volume ≥125 mL/m2, and left atrial volume <40 mL/m2. Every single-point increment in the response score was associated with 13 % increase in the clinical benefit from CRT-D. By using this scoring system, it is hoped that it can improve patient selection for CRT implantation.
AV and VV Timing Optimization Besides correction of intraventricular dyssynchrony, AV and VV optimization could improve CRT response in patients who were nonresponders before. However, clinical trials have not demonstrated any clinical benefit so far from these
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approaches. In SMART-AV study [46], both device algorithm-mediated AV optimization and echocardiographicguided AV optimization failed to demonstrate meaningful benefit over the fixed AV delay of 120 ms It seemed that routine AV optimization might not be helpful to increase the responder rate. Effect of VV optimization was assessed in 306 patients, and study found little difference between simultaneous BiV pacing and sequential BiV pacing [47]. In summary, these trials suggest that routine AV and VV optimization was not able to further improve responder rate after CRT, and the postulated beneficial effect of these device programming should not be overstated.
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Conclusion
The beneficial effect of CRT has been clearly shown in multicenter trials, and it is also a cost-effective therapy for patients with advanced heart failure. In order to achieve better response rate and long-term sustained effect, it is utmost important to identify which predictors could improve the response rate. Factors that determined CRT response included LV lead position, myocardial scar distribution, etiology of systolic dysfunction, percentage of BiV pacing, lack of mechanical dyssynchrony, and QRS morphology. Clinical score derived from clinical trial was also helpful to identify responders. Future studies are necessary to reassess the importance of mechanical dyssynchrony assessment so that we can have better patient selection who can gain the most benefit from CRT therapy.
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References 1. Jong P, Yusuf S, Rousseau MF, Ahn SA, Bangdiwala SI. Effect of enalapril on 12-year survival and life expectancy in patients with left ventricular systolic dysfunction: a follow-up study. Lancet. 2003;361(9372):1843–8. 2. Dargie HJ. Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomised trial. Lancet. 2001;357(9266):1385–90. 3. Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, Michelson EL, Olofsson B, Ostergren J, Yusuf S, Pocock S, CHARM Investigators and Committees. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet. 2003;362(9386):759–66. 4. Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, Vincent J, Pocock SJ, Pitt B, EMPHASIS-HF Study Group. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011;364(1):11–21. 5. Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, Tavazzi L, Cardiac Resynchronization-Heart Failure (CARE-HF) Study Investigators. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med. 2005;352(15):1539–49. 6. Nelson GS, Berger RD, Fetics BJ, Talbot M, Spinelli JC, Hare JM, Kass DA. Left ventricular or biventricular pacing improves cardiac
15.
16.
function at diminished energy cost in patients with dilated cardiomyopathy and left bundle-branch block. Circulation. 2000; 102(25):3053–9. Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E, Kocovic DZ, Packer M, Clavell AL, Hayes DL, Ellestad M, Trupp RJ, Underwood J, Pickering F, Truex C, McAtee P, Messenger J, MIRACLE Study Group. Multicenter InSync Randomized Clinical Evaluation. Cardiac resynchronization in chronic heart failure. N Engl J Med. 2002;346(24):1845–53. Yu CM, Fung JW, Zhang Q, Chan CK, Chan YS, Lin H, Kum LC, Kong SL, Zhang Y, Sanderson JE. Tissue Doppler imaging is superior to strain rate imaging and postsystolic shortening on the prediction of reverse remodeling in both ischemic and nonischemic heart failure after cardiac resynchronization therapy. Circulation. 2004;110(1):66–73. Bax JJ, Bleeker GB, Marwick TH, Molhoek SG, Boersma E, Steendijk P, van der Wall EE, Schalij MJ. Left ventricular dyssynchrony predicts response and prognosis after cardiac resynchronization therapy. J Am Coll Cardiol. 2004;44:1834–40. Yu CM, Fung WH, Lin H, Zhang Q, Sanderson JE, Lau CP. Predictor of left ventricular reverse remodeling after cardiac resynchronization. Am J Cardiol. 2003;91:684–8. Pitzalis MV, Iacoviello M, Romito R, Massari F, Rizzon B, Luzzi G, Guida P, Andriani A, Mastropasqua F, Rizzon P. Cardiac resynchronization therapy tailored by echocardiographic evaluation of ventricular asynchrony. J Am Coll Cardiol. 2002;40(9):1615–22. Chung ES, Leon AR, Tavazzi L, Sun JP, Nihoyannopoulos P, Merlino J, Abraham WT, Ghio S, Leclercq C, Bax JJ, Yu CM, Gorcsan 3rd J, St John Sutton M, De Sutter J, Murillo J. Results of the predictors of response to CRT (PROSPECT) trial. Circulation. 2008;117(20):2608–16. Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De Marco T, Carson P, DiCarlo L, DeMets D, White BG, DeVries DW, Feldman AM, Comparison of Medical Therapy Pacing, and Defibrillation in Heart Failure (COMPANION) Investigators. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med. 2004;350:2140–50. Moss AJ, Hall WJ, Cannom DS, Klein H, Brown MW, Daubert JP, Estes 3rd NA, Foster E, Greenberg H, Higgins SL, Pfeffer MA, Solomon SD, Wilber D, Zareba W, MADIT-CRT Trial Investigators. Cardiac-resynchronization therapy for the prevention of heartfailure events. N Engl J Med. 2009;361(14):1329–38. Tang AS, Wells GA, Talajic M, Arnold MO, Sheldon R, Connolly S, Hohnloser SH, Nichol G, Birnie DH, Sapp JL, Yee R, Healey JS, Rouleau JL, Resynchronization-Defibrillation for Ambulatory Heart Failure Trial Investigators. Cardiac-resynchronization therapy for mild-to-moderate heart failure. N Engl J Med. 2010;363(25):2385–95. Epstein AE, DiMarco JP, Ellenbogen KA, Estes 3rd NA, Freedman RA, Gettes LS, Gillinov AM, Gregoratos G, Hammill SC, Hayes DL, Hlatky MA, Newby LK, Page RL, Schoenfeld MH, Silka MJ, Stevenson LW, Sweeney MO, Smith Jr SC, Jacobs AK, Adams CD, Anderson JL, Buller CE, Creager MA, Ettinger SM, Faxon DP, Halperin JL, Hiratzka LF, Hunt SA, Krumholz HM, Kushner FG, Lytle BW, Nishimura RA, Ornato JP, Page RL, Riegel B, Tarkington LG, Yancy CW. American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices); American Association for Thoracic Surgery; Society of Thoracic Surgeons. ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2008;51(21): e1–62.
50
Cardiac Resynchronization Therapy: Do Benefits Justify the Costs and Are They Sustained Over the Long Term?
17. Vardas PE, Auricchio A, Blanc JJ, Daubert JC, Drexler H, Ector H, Gasparini M, Linde C, Morgado FB, Oto A, Sutton R, Trusz-Gluza M, European Society of Cardiology; European Heart Rhythm Association. Guidelines for cardiac pacing and cardiac resynchronization therapy: The Task Force for Cardiac Pacing and Cardiac Resynchronization Therapy of the European Society of Cardiology. Developed in collaboration with the European Heart Rhythm Association. Eur Heart J. 2007;28(18):2256–95. 18. Higgins SL, Hummel JD, Niazi IK, Giudici MC, Worley SJ, Saxon LA, Boehmer JP, Higginbotham MB, De Marco T, Foster E, Yong PG. Cardiac resynchronization therapy for the treatment of heart failure in patients with intraventricular conduction delay and malignant ventricular tachyarrhythmias. J Am Coll Cardiol. 2003;42(8):1454–9. 19. Abraham WT, Young JB, León AR, Adler S, Bank AJ, Hall SA, Lieberman R, Liem LB, O’Connell JB, Schroeder JS, Wheelan KR, Multicenter InSync ICD II Study Group. Effects of cardiac resynchronization on disease progression in patients with left ventricular systolic dysfunction, an indication for an implantable cardioverterdefibrillator, and mildly symptomatic chronic heart failure. Circulation. 2004;110(18):2864–8. 20. Linde C, Abraham WT, Gold MR, St John Sutton M, Ghio S, Daubert C, REVERSE (REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction) Study Group. Randomized trial of cardiac resynchronization in mildly symptomatic heart failure patients and in asymptomatic patients with left ventricular dysfunction and previous heart failure symptoms. J Am Coll Cardiol. 2008;52(23):1834–43. 21. Adabag S, Roukoz H, Anand IS, Moss AJ. Cardiac resynchronization therapy in patients with minimal heart failure: a systematic review and meta-analysis. J Am Coll Cardiol. 2011;58(9):935–41. 22. Dickstein K, Vardas PE, Auricchio A, Daubert JC, Linde C, McMurray J, Ponikowski P, Priori SG, Sutton R, van Veldhuisen DJ; ESC Committee for Practice Guidelines (CPG), Vahanian A, Auricchio A, Bax J, Ceconi C, Dean V, Filippatos G, FunckBrentano C, Hobbs R, Kearney P, McDonagh T, Popescu BA, Reiner Z, Sechtem U, Sirnes PA, Tendera M, Vardas P, Widimsky P; Document Reviewers, Tendera M, Anker SD, Blanc JJ, Gasparini M, Hoes AW, Israel CW, Kalarus Z, Merkely B, Swedberg K, Camm AJ. 2010 Focused Update of ESC Guidelines on device therapy in heart failure: an update of the 2008 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure and the 2007 ESC guidelines for cardiac and resynchronization therapy. Eur Heart J. 2010;31(21):2677–87. 23. Ozcan C, Jahangir A, Friedman PA, Patel PJ, Munger TM, Rea RF, Lloyd MA, Packer DL, Hodge DO, Gersh BJ, Hammill SC, Shen WK. Long-term survival after ablation of the atrioventricular node and implantation of a permanent pacemaker in patients with atrial fibrillation. N Engl J Med. 2001;344(14):1043–51. 24. Upadhyay GA, Choudhry NK, Auricchio A, Ruskin J, Singh JP. Cardiac resynchronization in patients with atrial fibrillation: a meta-analysis of prospective cohort studies. J Am Coll Cardiol. 2008;52(15):1239–46. 25. Ganesan AN, Brooks AG, Roberts-Thomson KC, Lau DH, Kalman JM, Sanders P. Role of AV nodal ablation in cardiac resynchronization in patients with coexistent atrial fibrillation and heart failure a systematic review. J Am Coll Cardiol. 2012;59(8):719–26. 26. Liang Y, Pan W, Su Y, Ge J. Meta-analysis of randomized controlled trials comparing isolated left ventricular and biventricular pacing in patients with chronic heart failure. Am J Cardiol. 2011;108(8):1160–5. 27. Abreu CD, Xavier RM, Nascimento JS, Ribeiro AL. Long-term outcome after cardiac resynchronization therapy: a nationwide database. Int J Cardiol. 2012;155(3):492–3. 28. Wells G, Parkash R, Healey JS, Talajic M, Arnold JM, Sullivan S, Peterson J, Yetisir E, Theoret-Patrick P, Luce M, Tang AS. Cardiac
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
637
resynchronization therapy: a meta-analysis of randomized controlled trials. CMAJ. 2011;183(4):421–9. Feldman AM, de Lissovoy G, Bristow MR, Saxon LA, De Marco T, Kass DA, Boehmer J, Singh S, Whellan DJ, Carson P, Boscoe A, Baker TM, Gunderman MR. Cost effectiveness of cardiac resynchronization therapy in the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) trial. J Am Coll Cardiol. 2005;46(12):2311–21. Calvert MJ, Freemantle N, Yao G, Cleland JG, Billingham L, Daubert JC, Bryan S, CARE-HF investigators. Cost-effectiveness of cardiac resynchronization therapy: results from the CARE-HF trial. Eur Heart J. 2005;26(24):2681–8. Raphael C, Briscoe C, Davies J, Ian Whinnett Z, Manisty C, Sutton R, Mayet J, Francis DP. Limitations of the New York Heart Association functional classification system and self-reported walking distances in chronic heart failure. Heart. 2007;93(4):476–82. Yu CM, Bleeker GB, Fung JW, Schalij MJ, Zhang Q, van der Wall EE, Chan YS, Kong SL, Bax JJ. Left ventricular reverse remodeling but not clinical improvement predicts long-term survival after cardiac resynchronization therapy. Circulation. 2005;112(11):1580–6. Fantoni C, Kawabata M, Massaro R, Regoli F, Raffa S, Arora V, Salerno-Uriarte JA, Klein HU, Auricchio A. Right and left ventricular activation sequence in patients with heart failure and right bundle branch block. J Cardiovasc Electrophysiol. 2005;16:112–9. Zareba W, Klein H, Cygankiewicz I, Hall WJ, McNitt S, Brown M, Cannom D, Daubert JP, Eldar M, Gold MR, Goldberger JJ, Goldenberg I, Lichstein E, Pitschner H, Rashtian M, Solomon S, Viskin S, Wang P, Moss AJ, MADIT-CRT Investigators. Effectiveness of cardiac resynchronization therapy by QRS morphology in the multicenter automatic defibrillator implantation trial-cardiac resynchronization therapy (MADIT-CRT). Circulation. 2011;123(10):1061–72. Nery PB, Ha AC, Keren A, Birnie DH. Cardiac resynchronization therapy in patients with left ventricular systolic dysfunction and right bundle branch block: a systematic review. Heart Rhythm. 2011;8(7):1083–7. Fung JW, Chan JY, Yip GW, Chan HC, Chan WW, Zhang Q, Yu CM. Effect of left ventricular endocardial activation pattern on echocardiographic and clinical response to cardiac resynchronization therapy. Heart. 2007;93(4):432–7. Gorcsan III J, Tanabe M, Bleeker GB, Suffoletto MS, Thomas NC, Saba S, Tops LF, Schalij MJ, Bax JJ. Combined longitudinal and radial dyssynchrony predicts ventricular response after resynchronization therapy. J Am Coll Cardiol. 2007;50:1476–83. Tanaka H, Hara H, Adelstein EC, Schwartzman D, Saba S, Gorcsan III J. Comparative mechanical activation mapping of RV pacing to LBBB by 2D and 3D speckle tracking and association with response to resynchronization therapy. JACC Cardiovasc Imaging. 2010;3:461–71. Zhang Q, Yu CM, Fung JW, Zhang Y, Chan YS, Chan HC, Yip GW, Sanderson JE. Assessment of the effect of cardiac resynchronization therapy on intraventricular mechanical synchronicity by regional volumetric changes. Am J Cardiol. 2005;95:126–9. Singh JP, Klein HU, Huang DT, Reek S, Kuniss M, Quesada A, Barsheshet A, Cannom D, Goldenberg I, McNitt S, Daubert JP, Zareba W, Moss AJ. Left ventricular lead position and clinical outcome in the multicenter automatic defibrillator implantation trialcardiac resynchronization therapy (MADIT-CRT) trial. Circulation. 2011;123(11):1159–66. Tournoux FB, Manzke R, Chan RC, Solis J, Chen-Tournoux AA, Gerard O, Nandigam V, Allain P, Reddy V, Ruskin JN, Weyman AE, Picard MH, Singh JP. Integrating functional and anatomical information to facilitate cardiac resynchronization therapy. Pacing Clin Electrophysiol. 2007;30:1021–2. Ypenburg C, van Bommel RJ, Delgado V, Mollema SA, Bleeker GB, Boersma E, Schalij MJ, Bax JJ. Optimal left ventricular lead position
638 predicts reverse remodeling and survival after cardiac resynchronization therapy. J Am Coll Cardiol. 2008;52(17):1402–9. 43. Morgan JM, Scott PA, Turner NG, Yue AM, Roberts PR. Targeted left ventricular endocardial pacing using a steerable introducing guide catheter and active fixation pacing lead. Europace. 2009;11(4):502–6. 44. Bleeker GB, Kaandorp TA, Lamb HJ, Boersma E, Steendijk P, de Roos A, van der Wall EE, Schalij MJ, Bax JJ. Effect of posterolateral scar tissue on clinical and echocardiographic improvement after cardiac resynchronization therapy. Circulation. 2006;113(7): 969–76. 45. Goldenberg I, Moss AJ, Hall WJ, Foster E, Goldberger JJ, Santucci P, Shinn T, Solomon S, Steinberg JS, Wilber D, Barsheshet A, McNitt S, Zareba W, Klein H. Predictors of response to cardiac resynchronization therapy in the multicenter automatic defibrillator implantation trial with cardiac resynchronization therapy (MADITCRT). Circulation. 2011;124(14):1527–36.
C.-P. Chan and C.-M. Yu 46. Ellenbogen KA, Gold MR, Meyer TE, Fernndez Lozano I, Mittal S, Waggoner AD, Lemke B, Singh JP, Spinale FG, Van Eyk JE, Whitehill J, Weiner S, Bedi M, Rapkin J, Stein KM. Primary results from the SmartDelay determined AV optimization: a comparison to other AV delay methods used in cardiac resynchronization therapy (SMART-AV) trial: a randomized trial comparing empirical, echocardiography-guided, and algorithmic atrioventricular delay programming in cardiac resynchronization therapy. Circulation. 2010;122(25):2660–8. 47. Rao RK, Kumar UN, Schafer J, Viloria E, De Lurgio D, Foster E. Reduced ventricular volumes and improved systolic function with cardiac resynchronization therapy: a randomized trial comparing simultaneous biventricular pacing, sequential biventricular pacing, and left ventricular pacing. Circulation. 2007;115(16): 2136–44.
Complications of Cardiac Implantable Electronic Devices (CIED)
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Sorin Pescariu and Raluca Sosdean
Abstract
Complications of cardiac implantable electronic devices (CIED) are defined as any adverse event that requires either reintervention or additional diagnosis and therapeutic procedures. The complication rate of CIED devices ranges from 4 to 10 %, with a mortality under 0.1 %. Acute phase and late complications can be related to venous access, lead positioning, and device pocket. There are common and specific complications depending on the electronic device type and the number and localization of the leads. These complications are still a common problem, and the prevalence of some is increasing, since the implantation rate is increasing and also the complexity of the devices. Their economic impact is important as well as the consequences for the patients, that is why monitoring and treatment of these complications, insuring adequate training, and maintenance of competence should be part of the good clinical practice. Keywords
Cardiac implantable electronic device • Complication • Acute • Late • Specific
General Data The term CIED comprises all categories of pacemakers (PMs) and implantable cardioverter defibrillators (ICDs), either single, dual, or triple (resynchronization, biventricular, or CRT) chamber. Complications are defined as any adverse event that occurs either during the implant procedure, in the immediate perioperative period (acute, periprocedural complications), or during a period of time ranging from several days to several years after implantation (late complications) that require either reintervention or additional diagnosis and therapeutic procedures, with subsequent need for prolonged hospitalization or rehospitalization [1–3]. The incidence of complications is related to the operator’s experience, surgical technique, implanted device category, S. Pescariu, MD, PhD (*) • R. Sosdean, MD Department of Cardiology, “Victor Babeş” University of Medicine and Pharmacy, Timişoara, Romania e-mail:
[email protected] A.S. Kibos et al. (eds.), Cardiac Arrhythmias, DOI 10.1007/978-1-4471-5316-0_51, © Springer-Verlag London 2014
patient’s anatomy and comorbidities, patient’s gender, and concurrent medications such as anticoagulants [1–4]. There are common complications for all types of devices and specific complications for ICDs and CRT devices, especially related to the coronary sinus lead implantation [2]. A study including 1,300 patients implanted with PMs reported an acute complication rate of 4.2 % with a mortality of 0.08 % [2, 5]. In the PASE study (Pacemaker Selection in the Elderly), 4.2 % of patients wearing a dual chamber pacemaker had complications [6]. One retrospective study including 5,593 patients from Denmark (Moller et al.) reported lead dysfunction in 4.8 %, pneumothorax in 1 %, bleeding in 0.4 %, and infection in 0.3 % of cases [7]. Nowak et al. reported in their study of 17,826 patients, 1.4 % lead dysfunction, 0.5 % pneumothorax, 0.1 % infections, and 0.7 % bleeding cases [8]. The complication rate of CRT devices ranges from 4 to 10 % [1, 2]. The most frequently described complications are local skin infection, systemic infection secondary to pocket or lead infection, pocket hematoma, lead displacement, pneumothorax, coronary sinus dissection, failure of left ventricular lead placement, or diaphragmatic stimulation [9]. 639
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One study performed on a population of 30,984 ICD patients reported a complication rate of 10.8 % and a mortality of 0.9 % [10]. In the CONTAK CD study 1.8 % coronary sinus perforations or dissections and 1.6 % extracardiac stimulation cases were described, while in the MIRACLE study, 2.1 % coronary sinus dissections or perforations were reported [7, 11, 12]. For both PMs and ICDs, one retrospective study including 6,319 patients reported 1.4 % infections and 5.2 % bleeding cases [13]. Pakarinen et al. in 2010 reported for all cardiac rhythm management devices, at 1-year survey, a 12.2 % complication rate [14]. We propose a list of CIEDs complications below: Acute common complications (during and/or close to the procedure) Due to venous access Cutdown approach Laceration, rupture of the cephalic vein Percutaneous approach Pneumothorax Hemothorax Hemomediastinum Chylothorax (injury to the thoracic duct) Injury to the nerves Air or foreign body embolism Inadvertent entry into the artery Arterial-venous fistula Perforation of a central vein Due to lead placement Rhythm disorders Lead dislodgement Extracardiac stimulation Perforation of the heart Cardiac tamponade Heart valve damage Lead damage Intravascular thrombosis Thromboembolism Improper connection of the lead(s) Diaphragmatic stimulation Pocket Pocket hematoma Pocket infection Specific complications of CRT device implantation Coronary sinus dissection Coronary sinus perforation Perforation of a collateral vein Cardiac tamponade consecutive to coronary sinus perforation Complete heart block Air emboli in the coronary sinus Inappropriate left ventricular lead placement
S. Pescariu and R. Sosdean
Extracardiac stimulation from the left ventricular lead (phrenic stimulation) Arrhythmia such as far-field atrial sensing Contrast nephropathy Late common complications Pocket and generator Pain Migration Erosion Infection: acute, occult Premature failure of the device Twiddler’s syndrome Implanted leads Dislodgment Intravascular thrombosis Venous stenosis Infection, endocarditis Lead failure: insulation failure, conductor fracture Retention wire fracture Chronic perforation Modification of capture/sense threshold Pericarditis
Acute Complications Complications that might occur in the acute phase (close to the intervention) are represented by venous access-related complications such as pneumothorax, hemothorax, hemopneumothorax, and chylothorax; lead positioning-related complications such as rhythm disturbances, lead displacement, myocardial penetration and perforation, and lead injury; device pocket-related complications such as bleeding and hematoma formation, pocket infections, and suture dehiscence [15, 16].
Venous Access-Related Complications Cutdown Approach Laceration, rupture of the cephalic vein, is more frequently seen at inexperienced operators and may be due to multiple causes: lack of adequate exposure of the deltopectoral groove or of the vein itself or forceful dissection of the subcutaneous tissue. Usually, the proximal part can be recovered, but sometimes vein ligation is the only option with other venous access (axillary or subclavian) obtained. Percutaneous Approach Direct puncture of the subclavian or axillary vein, although frequently used, can produce multiple and sometimes serious complications. The subclavian or axillary vein is in close proximity to the pleura, nerves, arteries, and the thoracic duct (on the left). Operator’s experience and
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knowledge of the anatomy are of prime importance to prevent such complications [2]. Venography to visualize the venous access should be taking in consideration in many circumstances such as upgrade of a device with previously implanted leads, small or obese patients, congenital patients, and difficult puncture. This can easily be performed from the IV line inserted in the homolateral arm with 10–20 cc of contrast either before or during the implant procedure.
of the artery is usually managed by direct pressure: light-red arterial blood with high pressure on the exploring needle is certainly the main clue. However, in case of laceration of the artery by inadequate needle movements, or even more dramatically, if the arterial puncture is not detected and the peel away sheath dilator system is inserted in the artery, a very difficult to control arterial hemorrhage can occur. Removal of the system can induce a significant hemorrhage. A quick decision must be taken after consulting the interventional cardiologist and vascular surgeon. An emergency arteriography can localize the artery and the affected area and also establish the dimensions of the lesion. Keeping the system into the lesion has a potential risk of thrombosis and embolization into the cerebrovascular system. Treatment of this complication, if extraction and local compression are not efficient, consists either in stent-graft implantation or in surgical closure of the lesion [2, 17]. Vascular closure has also been tried. Successful use of collagen-based or suture-based devices for treating accidental iatrogenic subclavian artery injury has been described [18, 19].
Pneumothorax Pneumothorax can manifest until 48 hours after the device implantation, and it represents the one of the most frequent complication. Suggestive clinical signs include air aspiration during introduction or withdrawal of the exploring needle, cough, dyspnea, and thoracic pain, especially in the superior part of the back, sudden onset of severe hypotension, without any explanation, respiratory distress, and subcutaneous emphysema. Symptomatology can also occur after the implant procedure itself. During ICD implantation, high defibrillation thresholds and high shock impedance are described in case of massive pneumothorax. Confirmation of pneumothorax is made by fluoroscopic examination during the implant procedure or by the chest X-ray made after the intervention, which should be repeated even at the most insignificant suspicion of pneumothorax (Fig. 51.1). If a small quantity of air is present in the pleural space, a careful follow-up is recommended with the patient breathing 100 % oxygen by mask. In case of a greater than 10 % air in the pleural space, drainage should be considered. Respiratory distress imposes urgent pleural drainage by insertion of a thoracic drainage tube with active suction [1, 2]. Hemothorax Hemothorax usually appears after puncturing the subclavian vein, artery, or other intrathoracic vessels. Simple puncture
Fig. 51.1 Important left pneumothorax by using subclavian vein puncture technique
Hemopneumothorax Hemopneumothorax is produced by puncturing both the pleural space and the subclavian artery. This unusual complication can be associated with thoracic wall or clavicular abnormalities. The treatment is more complex and usually requires surgical and vascular consultations [15]. Chylothorax Chylothorax is produced by trauma to the thoracic duct, but this is a very rare complication. Treatment includes surveillance, monitoring, and even surgical intervention when symptoms worsen [15–17]. Hemomediastinum Hemomediastinum is an even more unusual complication. Treatment depends on the gravity of the manifestations, and a thorough monitoring is necessary [15]. Air Embolism Air embolism can be seen during sheath manipulation and lead insertion mostly when no valve introducers are used. It can also be seen during lead manipulations and insertion when the patient is snoring or even when the cephalic vein is cut down. If after removal of the dilator from the sheath, the patient takes a deep breath and the sheath’s orifice is not closed until the lead is inserted, there is a possibility of air aspiration with consecutive pulmonary air embolism. Minor embolism might not be clinically significant, but massive embolism induces thoracic pain, hypotension, and respiratory distress. Emergency treatment, until air is absorbed includes oxygen on mask, inotropic support, catheter aspiration or mobilization of the air bubble by chest
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compressions. Prevention of air embolism is made primary by hemostatic valved sheaths utilization, and proper manipulation. In the absence of these tools, a sheath with the smallest diameter possible should be used; the patient must be well hydrated, in Trendelenburg position, and advised not to breathe in deeply and to perform the Valsalva maneuver [2, 17].
Brachial Plexus Injury Brachial plexus injury is a rare but possible complication, which can be manifested by neuro-sensitive deficit on the ipsilateral part. Accidental Creation of an Arterial-Venous Fistula Accidental creation of an arterial-venous fistula is another rare complication that needs interventional or surgical management. All these complications can be minimized by proper surgical techniques and advocacy of the use of cephalic and axillary (extrathoracic) approach [3, 17]. It is also possible to accidentally puncture the subclavian artery and enter the lead through the aorta in the left ventricle. Also the lead can go into the left ventricle through an undiagnosed atrial septal defect or ventricular septal defect, or a patent foramen ovale. Placing the lead in the left ventricle can be demonstrated by the posterior position of the lead, visualized in oblique fluoroscopic views, and by a right bundle branch block morphology on the ECG during ventricular stimulation [20].
Lead-Related Complications Atrial Arrhythmias Arrhythmias can occur due to the contact between the tip of the lead and the endocardium. By manipulating the atrial leads and by atrial stimulation, supraventricular tachyarrhythmias like atrial tachycardia, atrial fibrillation, and flutter can occur [21]. They can be converted to sinus rhythm by changing the position of the lead or by simply tapering the atrial wall with the lead and/or by stimulating the atrium with a higher frequency than that of the tachyarrhythmia. In case of atrial fibrillation/flutter, conversion can be sometimes difficult, requiring intravenous antiarrhythmic treatment and/or direct current cardioversion. If this is not done, and the patient remains in atrial fibrillation, a good position of the atrial lead is indicated by a greater than 1 mV signal (after an adequate positioning of the lead under radiologic control) and fluoroscopic stability [15]. Ventricular Arrhythmias Ventricular arrhythmias like ventricular premature beats and ventricular tachycardia can also be encountered. These can
S. Pescariu and R. Sosdean
solve spontaneously, without any intervention, or repositioning of the lead might be required. In extreme cases, direct current cardioversion is necessary [15]. It is also possible to provoke bradyarrhythmias such as asystole in case of vagal hypertony, after administration of anesthetic and/or after determination of the ventricular or atrial stimulation thresholds. In addition, a complete atrioventricular block can be seen after mechanical or electrical injury to the right bundle branch associated with intermittent atrioventricular block and/or permanent left bundle branch block. This is encountered in about 5 % of implant procedures [6].
Lead Displacement Lead displacement has become less frequent nowadays, due to passive and active fixation leads utilization, but still remains one of the most frequent complications. The “acceptable” displacement rate (seen in high-volume centers) is considered to be 1 % for ventricular leads and 2–3 % for atrial leads, respectively. Active fixation leads have a lower rate of displacement than passive fixation ones, but they have a higher rate of myocardial penetration and perforation (especially the atrial leads, the atrial wall being much thinner, around 2 mm). As for ventricular leads, it has been observed in a higher rate in patients with a dilated right ventricle [3, 20, 22]. Displacement can be suspected when stimulationdetection abnormalities are observed on telemetry or postimplantation ECG, manifested by a sudden raise in stimulation or detection thresholds. It is generally confirmed also by radiologic examination (for macro but not for micro displacements). Treatment consists usually in lead repositioning. Other manifestations include oversensing which can cause prolonged asystole in pacemaker-dependent patients. In case of implantable defibrillators, it can cause inappropriate shocks or lack of shock delivery. Stimulation-related arrhythmias can be encountered, most frequently ventricular premature beats, with similar aspect to the stimulated beats. They usually solve spontaneously. Extracardiac stimulation, generally the diaphragm, pectoral muscles, and intercostal muscles, can also be seen [15, 20, 23, 24]. Myocardial Penetration and Perforation Myocardial penetration and perforation is a rare complication, more frequently seen in the right ventricle but also in the right atrium, that manifests with a large spectrum of symptoms, depending on the penetrated area. The perforation can be internal, into another cardiac chamber, or external, into the pericardial space. Elderly patients, women, and patients with recent right ventricle myocardial infarction are more susceptible to this complication. In addition, the use of thinner leads, like “screw-in” type, and steroid therapy are risk factors for myocardial perforation.
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As it was mentioned before, clinical signs are different depending on the perforated cardiac area. Passing through a patent foramen ovale or atrial or ventricular septal defect, with placement of the lead in the left ventricle, initially manifests as right bundle branch block morphology on the surface ECG and a posterior position of the lead tip in oblique fluoroscopic views. The treatment is to remove the lead (if recently implanted) to prevent the risk of thrombosis with systemic embolism, particularly in absence of permanent anticoagulation [2]. External perforation can manifest by several clinical and paraclinical features, which are in ascending order of gravity: a higher stimulation threshold, exit block with capture loss, diaphragm stimulation, precordial thoracic muscular contractions, pericarditis, right bundle branch block morphology during ventricular stimulation by a lead which was initially placed in the right ventricle, or cardiac tamponade. Diagnosis can be confirmed electrocardiographically, radiologically, and echocardiographically, and treatment will depend on the gravity of the clinical situation [14]. Cardiac tamponade can require pericardiocentesis under echocardiographic control. If fluid accumulation persists and if serious hemodynamic compromise is seen, the approach could include an open surgery. Sometimes a drainage tube must be left in the pericardial space, for monitoring a possible subsequent hemorrhage. Withdrawal of the penetrating lead must be done very carefully, with hemodynamic monitoring, because blood extravasation can worsen. Anticoagulation should not be performed in the first 12–24 h, especially if a minimal suspicion of perforation exists [2, 25]. These complications can be seen both in the acute phase and several days after the intervention. Sometimes perforation and penetration of the myocardium can be asymptomatic and so easily misdiagnosed, especially the ones seen in the right ventricle. In such cases, they can be revealed by radiological examination in multiple incidences, and especially by computed tomography, but this technique cannot be routinely used for screening purposes. In published data, there are cases of atrial perforation in which pericardial complications appeared far from the moment of perforation. One potential explanation for these situations is the partial protrusion of the lead tip in the pericardium, with subsequent local inflammation. Also, the lead can perforate the visceral pericardium only during cardiac contraction with intermittent extravasation of blood, or the pericardium can be completely perforated with the possibility for the lead to affect other organs (e.g., the lung). As well, the perforation site could be sealed by a combination of lead, cardiac contraction, and local fibrosis and right atrium’s low pressure [22].
structures if a passive fixation lead is caught in the chordae and brutally removed [2].
Tricuspid Valve Injury Tricuspid valve injury, especially of the chordae tendineae, is also possible. Rarely, this can lead to rupture of these
Lead Injuries Lead injuries can be produced during the implant procedure by their manipulation (introduction into the sheath and/or fixation of the lead), with damage to the silicon or polyurethane (more frequently) insulating layer. Confirmation of these complications is made by device interrogation, when higher lead impedance is detected, in case of interruption of the conductor, or lower impedance, in case of interruption of the lead’s insulating layer. The fracture site can be radiologically visualized. Treatment consists in lead replacement [15]. Venous Thrombosis Venous thrombosis occurs at cephalic and/or subclavian vein level and it is usually asymptomatic. The risk of thrombosis increases with the number of leads introduced in the vein and with vein trauma during lead manipulations. Patients can also present with clinical symptoms of thrombophlebitis, with painful arm edema, tachycardia, and fever. Even more unusual, the thrombus may sometimes progress or migrate into the central venous system into the superior vena cava, and rarely, a superior vena cava syndrome may occur, with massive head and trunk edema. Pulmonary embolism is also a possible complication. Subclavian or axillary vein thrombosis is treated by upper elevation of the arm and intravenous heparin, followed by oral anticoagulation therapy for 3–6 months. Thrombosis that extends proximally may sometimes require thrombolytic therapy. A venography can be used to appreciate the contralateral venous system status if required [26]. The incidence of subclavian and axillary venous thrombosis is relatively high. A frequency between 24 and 44 % was reported, but, fortunately in the majority of cases, it is silent, without clinical signs, being discovered when a venogram was obtained, for generator replacement or upgrade of the pacemaker. Multiple leads and systemic infections are risk factors for venous thrombosis [12]. Acute Venous Thrombosis Acute venous thrombosis occurs more frequently in subclavian and brachiocephalic veins, and it is evidenced by edema, cyanosis, and swollen veins in the affected upper extremity. Generally, the evolution is favorable, under anticoagulant treatment (intravenous heparin followed by oral anticoagulation for at least 3 months). The leads should not be removed because of further trauma to the veins. This intervention is considered in case of lack of treatment response and/or subsequent pulmonary embolism [17]. In case of traumatizing factors, like old leads abandoned in the vein, or a thrombosed lead extraction, superior vena
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cava acute thrombosis can occur. Thrombolytic and anticoagulant agents are generally used in this case. If this fails, balloon vein dilation and/or surgical intervention that targets thrombus extraction and venous reconstruction could be tried [22, 25].
Chronic Venous Thrombosis Chronic venous thrombosis is due generally to trauma and mechanical stress created by the leads on the venous wall, with local generation of proliferative fibrous tissue that favors thrombus formation. It is strongly related to the lead’s dimensions and rigidity, as well as to the time of their implantation [15]. The venous lumen gradually obliterates, or, less frequently, an acute thrombosis occurs, as described before. In most cases, chronic thrombosis is asymptomatic. Thrombosis must be considered in these situations, if for different reasons, the lead has to be removed. The extraction could be difficult because of thrombotic adherences between the lead and the vein’s wall, and vein trauma increases the risk of subsequent thrombosis. The fine thin leads markedly decreased the frequency of symptomatic thrombosis. Chronic thrombosis of the superior vena cava can represent a serious problem. If it is completely occluded, it hardly responds to medical treatment. Lead extraction and subsequent vein dilation and stenting are necessary. Failure of these procedures imposes surgical vein reconstruction with a patch graft, a difficult procedure [24]. Diaphragmatic Stimulation Diaphragmatic stimulation can occur in case of dislodgement of the atrial or ventricular lead or in case of lead perforation. Phrenic nerve stimulation by the atrial or left ventricular lead can also be seen, with consecutive contraction of the diaphragm. Verification and prevention of this complication are made during the implant procedure by stimulating the myocardium at 10 V. If the lead has an appropriate position, diaphragmatic stimulation should not occur. Lead repositioning should be advocated acutely [20].
Pocket-Related Complications Hematomas Hematomas are more frequent in patients already at higher risk of bleeding, for example, those with recent thrombolytic therapy, chronic anticoagulant, or antiagregant treatment before the implant procedure, as in those with early reinterventions. Generally, in low-embolic-risk patients, anticoagulant treatment is stopped 3–4 days prior to the intervention, in order to obtain a low INR value (<1.7). In higher risk patients, a strategy of bridging with heparin or lowmolecular-weight heparin is advocated. Studies have demonstrated a much lower incidence of hematomas in patients
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which resumed oral anticoagulant therapy while bridging with low-dose heparin therapy, compared to those who received standard heparin infusion. Patients at higher risk (prosthetic mechanical valves, especially in mitral position and chronic atrial fibrillation, high CHADS score) must be managed either by bridging therapy or by maintenance of warfarin. Recently many clinical studies have suggested the safety of implanting devices, while patients are maintained on warfarin with therapeutic INR (2–3). Most implanters will not stop aspirin or clopidogrel (or other antiagregant) before implantation. Careful hemostasis should be done, and sometimes hemostatic powders or tissues can be applied into the pocket to prevent recurrent bleeding (Surgicel™, Fibrillar™, Hemostase Cryolife™, Tisseel™) [20, 27, 28]. In patients considered to be at high risk of bleeding, a drainage tube can be left in the pacemaker pocket, or a local suspension of collagen/thrombin can be applied, in order to lower the incidence of these complications [14, 15]. Small hematomas should be treated conservatively with local pressure and stopping anticoagulation. If progression of the hematoma is observed, anticoagulation reversal should be considered. Surgical open drainage should be done if pocket tension is important, when compromission of cutaneous vascularization, important pain or rapid progression is observed. It is usually not recommended to attempt percutaneous drainage, since clot formation will prevent complete drainage and a higher risk of infection could result compared to surgical drainage [27].
Early Pacemaker Pocket Infection Early pacemaker pocket infection after first implant procedures is observed in 1.2–2.0 %, and the most frequent pathogens are the staphylococci (mostly Staphylococcus aureus, but also Staphylococcus epidermidis). Presence of a local hematoma and diabetes mellitus and renal insufficiency are predisposing factors. Strict aseptic methods should be applied with adequate skin preparation: shaving as close to the time of surgery as possible, skin preparation with 2 % chlorhexidine instead of proviodine solutions [2, 29–31]. Pocket infection is more frequently encountered after generator replacement, especially in patients with post-procedural pocket hematoma. A recent study found that antibiotic use before the intervention significantly decreases major infections’ percentage after generator replacement [30]. Pocket Suture Dehiscence Pocket suture dehiscence rarely occurs, usually during first days or weeks after the intervention, when an excessive tension is present at the site of closure (hematoma, hemorrhagic effusion, local trauma). If the suture is not immediately redone, this complication should be treated as pocket infection [15].
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CRT Devices-Specific Complications CRT devices require cannulation of the coronary sinus and lead placement in a tributary of the main coronary veins. Specific complications can be seen, such as coronary sinus dissection or perforation, inability to engage the coronary sinus, diaphragmatic stimulation, higher incidence of lead dislodgments, and higher risk of infection.
Inability of Locating and Cannulating the Coronary Sinus Inability of locating and cannulating the coronary sinus is hard to estimate in percents, and it is clearly influenced by operator’s experience. Some authors describe a percentage range of 1–5 % [32], others 4–10 % [7], respectively. In MUSTIC [33] study, left ventricle stimulation was achieved in 92 % of patients, in MIRACLE [11, 12] study in 93 %, and in CONTAK CD in 91 % of patients [7]. This happens because of multiple reasons. Besides operator inexperience, there are several anatomical situations, like unusually high or low position of the coronary sinus ostium and other abnormal localizations. Very rarely, absence of the coronary sinus orifice can be encountered [3]. The Thebesian valve that bounds the coronary sinus ostium in its inferior part is usually of small dimensions, thin, with crescent shaped, but larger membranous valves, that can occlude the coronary sinus ostium, were also described (25 % of cases in one autopsy study) [34]. For making the approach easier, different techniques can be used, like approaching the coronary sinus from the right ventricle, introducing contrast dye in order to visualize the ostium, and performing a retrograde coronary venogram and intracardiac ultrasonography. After detection of the coronary ostium, difficulties in advancing the guidewire or the sheath can be encountered, due to presence of a “kinking” at the coronary sinus neck level (“goose neck” encountered mostly in patients with massive cardiomegaly). In order to reduce this disadvantage, special lead designs can be used, or, less frequently, a special approach using deflectable electrophysiology catheters is necessary (in order to modify the coronary sinus trajectory during the procedure) [32]. Failure to Obtain an Optimal Lead Position Also strictures and stenoses, tortuosity along the coronary sinus and its branches, and an insufficient caliber that can incommode catheter advancement or favor the failure to obtain an optimal lead position (lateral or posterolateral vein) in order to achieve cardiac resynchronization therapy can be encountered. There are also cases in which those coronary sinus branches are absent [35, 36]. This technical problem is met in about 20 % of cases (optimal lead position was achieved in 80 % of patients in MUSTIC study) [33]. Strictures can spontaneously appear, or they can be caused
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by fibrous bands, usually after pericardiotomy and less frequently after mitral valve surgery, radiations, etc. Solving these problems is tempted by adapting the catheter design, using new cannulation techniques or by using coronary venoplasty methods, with balloon and stents (one study reported growth of success rate from 88 to 98 %) [37].
Phrenic Nerve Stimulation and Diaphragmatic Pacing Phrenic nerve stimulation and diaphragmatic pacing can be observed, given that the phrenic nerve trajectory crosses the lateral vein in about 80 % of cases and the interventricular vein in the remaining 20 % of cases (as it was demonstrated in autopsy studies). This complication is hard to demonstrate during the implant procedure, when the patient is sedated and supine, but becomes obvious later, when he modifies his position and becomes active. Sometimes the problem can be solved by modifying the voltage, but usually lead repositioning is necessary (withdrawal in more proximal position) [15, 32]. Acute Lead Displacement Acute lead displacement from the atrium and the ventricle is less frequent, while the incidence of coronary sinus lead displacement was reported by the large studies as being around 5 %. This is closely related to operator’s experience and also to technical details like the lack of fixation mechanism and the mechanical stress applied on the proximal part of the lead at the right atrium and coronary sinus ostium junction. This complication is suggested by the ECG aspect (morphology and QRS length changing) and X-ray aspect, decreasing amplitude of the local signal and/or increasing stimulation threshold, detected when interrogating the device. Generally, the right atrium lead is displaced on the right atrium floor, right ventricle lead in its inward tract, and left ventricle lead in the coronary sinus main body and less frequent in the right atrium [32]. In order to decrease the rate of this complication, adapting the lead to the target vein caliber, increasing the stability of the lead by stenting the vein, and use of active fixation lead in the coronary veins can be attempted [2, 32]. Coronary Sinus Dissection The most frequent acute complications of coronary sinus cannulation are endothelial flaps and coronary sinus dissection (Fig. 51.2), which are described according to the literature data, in 6–8 % of cases. These complications are closely related to operator’s inexperience, aggressive manipulation, the type of the catheter used, rigid guidewires used for sustaining the coronary sinus sheath, deflectable electrophysiology catheters for cannulations of the coronary sinus, and balloon catheter used for retrograde coronary venogram, which can damage the coronary sinus endothelial surface. Cardiac tamponade was not observed after coronary sinus
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venous pressures, there is no elastic recoil as in arteries. This is why surgical intervention is required for final evacuation and perforated vein’s suture [32]. Any perforation suspicion must be carefully clinical and echocardiographically monitored.
Contrast Nephropathy Contrast nephropathy is possible when a large amount of contrast dye is used for locating an appropriate venous branch for left ventricular stimulation. This is a possible complication especially in patients with advanced heart failure and associated renal function deterioration [23].
Acute ICD Lead-Specific Complications
Fig. 51.2 Coronary sinus dissection due to a deflectable electrophysiology catheter use for cannulation of the coronary sinus
dissection. If after coronary sinus dissection, the operator cannot be sure of the lead’s position, in the true or false lumen, the procedure must be stopped. These lesions generally heal in 2–3 months, without sequelae, and this way the procedure can be resumed after 60 days. If the dissection is proximal to the lead tip and the target vein’s ostium, the procedure can be continued [38]. Target veins endothelial dissection and also acute thrombotic occlusions can be produced. Hematoma in the target vein’s wall is another complication, which does not clinically manifest, and it is usually observed during epicardial placement of the left ventricle lead after failure of endovenous placing [7, 32].
Coronary Sinus Perforation Coronary venous laceration or perforation is a rare but serious complication. Most frequently, it occurs in the distal end of the target veins where their caliber is much diminuted, being equal or even exceeded by the lead tip diameter. Thus, perforation is facilitated by pressure on the venous wall and venous wall distention. Bleeding is generally stopped by the formation of a pericardial blood clot, which compresses the vein. By evacuating the blood from the pericardium, this process is impeded. Even if venous and pericardial pressure values are low and almost equal, there can be a pressure gradient that determines blood to accumulate in the pericardial space. If cardiac tamponade occurs, pericardiocentesis is necessary. Sometimes though, pericardiocentesis can control cardiac tamponade but cannot stop the bleeding, because despite low
The majority of ICD leads are now endovenously placed; thus most of the related complications are similar to those encountered with pacemaker leads. However, there are some specific aspects. Early lead displacement manifests with high stimulation thresholds, oversensing or undersensing, ineffective defibrillation, or inadequate electrical discharges. Myocardial perforation manifests with pain, usually pleuritic pain, diaphragmatic stimulation, undersensing, high stimulation thresholds, and, rarely, cardiac tamponade. Perforation is more frequent with “screw in” type of leads, when the fixation helix is overtorqued in order to fixate it better. Reintervention with lead extraction, or surgical tamponade treatment, could be necessary [39]. Until perforation occurs, overtorquing the lead can produce tissular laceration along with electrical parameters distortion. Stimulation and shock impedance must be checked with a stimulation value of 5V, to verify this type of complications [23].
Late Complications Device Pocket-Related Complications Local Pain Local pain can be seen if the subcutaneous pocket is too tight, resulting in pressure on the adjacent tissue. Surgical revision is sometimes required to prevent erosion, infection, or further pain. An occult or “low-grade” infection should always be suspected in a patient presenting with pocket pain. Migration Migration consists in movement of the pulse generator in the subcutaneous tissue to inferolateral direction. It happens especially in the elderly, and usually it is gradual overtime. Incriminated factors are a large subcutaneous pocket, generator’s weight and shape, laxity of the surrounding
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Fig. 51.3 Pre-erosion that occurred after 3 months from reintervention for device replacement, due to a too superficial pacemaker implantation
subcutaneous tissue, local muscular activity, local fibrous tissue formation, and important weight loss [2, 15]. Surgical revision is sometimes required either to fix the device with suture on the pectoral muscle to prevent migration or even implanting the generator under the pectoral muscle (subpectoral implant) [2].
Erosion Erosion is represented by generator exteriorization consecutive to loss of integrity of the protecting wall, represented by the skin. This occurs more frequently when the pocket is too tight, or too superficial, especially in kids and adults with poor subcutaneous tissue, or when the position is too lateral, in the anterior part of the axilla. It is also favorized by adjacent skin irritation as articles of clothing (e.g., bra braces in the case of women), presence of multiple leads (e.g., three leads in triplechamber devices), or of an adaptor and local infection. Initially, the device adjacent skin is mobile, than it becomes adherent, discolored in the area of contact with the device, with more or less intense inflammation signs. This is the socalled pre-erosion phase (Fig. 51.3). After that, true erosion occurs, when a device ridge or the connector becomes exteriorized (Fig. 51.4). One consequence is bacterial contamination of the pocket and of the entire implanted system. If infection was the underlying cause, than, usually the inflammatory signs are present from the beginning [2, 15, 17, 20]. In the local adherence phase, treatment consists in pocket debridement and creation of a deeper one (possible and efficient method only if infection was excluded). If the erosion is very recent and there are no signs of local infection, a proposed treatment solution was to remove the generator and keep the leads in situ (if they cannot be removed and there are no signs of infection at this site), with creation of a new
Fig. 51.4 Erosion due to a too lateral pacemaker implantation, in the anterior part of the axilla
pocket separately from the old one. The results are rather disappointing. If infection cannot be excluded or it is even confirmed, treatment is the same as that for an infected pocket [15]. It should not be forgotten that even a pre-erosion can be an early sign of pocket infection!
Late Pocket Infection Late pocket infection is a consequence of either bacterial contamination during the implant procedure with late manifestations or dissemination of infection from a distant infection (bacteremia or septicemia). The risk of infection is higher in device replacements, reinterventions, and CRT implants. The most dangerous bacterium that manifests in the first weeks after implantation or reimplantation is Staphylococcus aureus. Unlike this pathogen, Staphylococcus epidermidis, a saprophyte bacterium of the skin, produces pocket infection after months or even years from intervention. Fungus infections or less aggressive bacteria are included in the same category. Infection can manifest in various forms. An acute infection of a chronic pocket is generally encountered when replacing a device with end life battery. This is because some chronic pockets do not tolerate a minimal contamination even with saprophyte pathogens of the skin. Occult infection has a prolonged evolution being minimally symptomatic or even asymptomatic, with proliferative fibrous tissue formation above the generator and even with a minimum exudative reaction. Chronic fistulas appear consecutively to a pocket abscess drainage, treated with antibiotics, or due to a suture
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Fig. 51.5 Chronic fistula consecutive to a pocket abscess drainage, treated with antibiotics, with concomitant erosion, and with device exteriorization
thread abscess. Another frequently seen manifestation is erosion with device exteriorization (Fig. 51.5). Beyond the local inflammatory signs, patients can also present general signs of infection, of septicemia, or of endocarditis (usually subacute). Echocardiographic examination, mostly transesophageal, can detect in these situations vegetations on the mitral and/or tricuspid valve [2, 25, 29]. Treatment of pocket infection most of the time will require complete removal of all leads and generator. Strategies including cutting leads, pocket wash, and revisions or subpectoral placement usually will result in reinfection. Unless comorbidities are so important and preclude a complete extraction, complete removal is recommended. In some chronic, indolent infections associated with severe comorbidities and short life expectancy, pocket revision and chronic antibiotics have been used [2, 15, 29].
Device Allergy Device allergy is a very rare complication, the majority of cases being in fact occult Staphylococcus epidermitis infections (which are generally indolent, without systemic manifestations). To establish this diagnosis, exclusion of infection is necessary as well as skin testing (a panel of test is available from industry). A possible treatment is replacement with another device model or covering the device with nonallergic materials (gold plated, silicone covering, etc.) [15, 17].
Lead-Related Complications Lead Dislodgements Lead dislodgements can manifest by pacing or sensing defects, with more or less serious clinical implication, depending on the patient’s condition (pacemaker
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Fig. 51.6 X-ray revealing a complete fracture of a unipolar lead in the generator pocket
dependency). This could be the result of loose set screw, failure to suture securely the leads, device migration with lead tension, perforation, etc. [2].
Twiddler’s Syndrome “Twiddler’s syndrome” is seen when the patient rotates the device in the pocket and the leads encircle around the generator. Treatment consists in pocket revision and suturing the device to the pectoral muscle or placing the generator subpectorally. Sometimes the leads will have to be replaced if damaged [40].
Lead Injury Lead injury can occur on the insulation or conductor. Most frequently it occurs in the following areas: (1) in the area of suture to the surrounding tissue (Fig. 51.6); (2) in the area of lead folding; (3) in the space between the clavicle and the first rib, if the lead was placed by medial subclavian vein puncture; and (4) at the level of friction with other leads [17]. Lead Infection and Lead Endocarditis There are multiple factors that favor infection. Patient’s background is very important, including advanced age, diabetes mellitus, and immunodepression (AIDS, corticotherapy, cytotoxic and immunosuppressive substances, organ transplantation, irradiations). Jugular vein approach, rarely used, is much more laborious than other approaches, and thus, time consuming with increased exposure time that favors infection. The longer operation time (because of difficult venous approach or endocavitary placement, multiple leads), increases the germ contamination risk. Reintervention in the device’s pocket for device replacement, or for other reasons, also increases the infection risk. Pocket hematoma that is not evacuated in time represents an excellent culture
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Fig. 51.7 Large-dimensioned vegetation on the atrial part of a VDD lead
environment, even if it is of small dimensions. Mechanical complications related to lead introduction and placement can induce local lesions, which represent in turn a propitious ground for suprainfection. Transitory stimulation before the implant, especially if for a prolonged period or if performed in emergency conditions, with inappropriate aseptic conditions, represents an additional germ contamination cause. Antibiotic prophylaxis has a demonstrated beneficial effect in preventing infection [41]. Infection usually progresses from the device’s pocket, thus from an extravascular site to the intravascular part of the lead through an insulation defect or by venous/lymphatic ways. Metastatic infection from other infectious foci (pneumonia, pyelonephritis) is also possible [15, 42]. Clinical manifestations are different, such as classical septicemia, which can progress to septic shock, subacute endocarditis, with prolonged feverish evolution, prostration, and heart failure, liver failure, and renal failure, and pulmonary disorders with recurrent pneumonias, respiratory distress, or pulmonary embolism. Right or congestive heart failure refractory to standard therapy, could be the most important manifestation. Laboratory tests may show characteristic changes for infectious endocarditis. These include inflammatory syndrome, anemia, and positive blood cultures. On echocardiographic examination, especially transesophageal, thickening and/or vegetations (Fig. 51.7) are observed on the lead(s) and/or on the tricuspid valve (Duke criteria) [41, 42]. Vegetations can involve one or more leads. Cardiac device-associated endocarditis represents 4–5 % from endocarditis cases, and it has an incidence bellow 1 % in cardiac implantable device population [2, 41].
Once lead infection is diagnosed, treatment consists in removal of the entire implanted system, including generator and leads. A preliminary antibiotic treatment is necessary. This treatment comprises parenteral antibiotics in dual or triple association for about 4–6 weeks, depending on the antibiogram results, with device and lead extraction after negative blood cultures are obtained. According to the current guidelines, percutaneous extraction is recommended for the majority of patients with device-related endocarditis, even in case of large vegetations (>10 mm), while surgical extraction should be considered if a complete percutaneous extraction is not possible. After cardiac device removal, it is recommended to reevaluate the necessity of reimplantation, and when this is indicated, it should be postponed if possible, to allow antibiotic therapy for at least several days, without transitory stimulation [42–45]. A single bacteremia episode in a patient with implantable cardiac device, in absence of echocardiographical signs of lead infection, or generator pocket infection, must be treated with antibiotics. If recurrence of the infectious episode occurs, the entire implanted system must be removed, even in the absence of evident clinical manifestations and laboratory tests of device infection [2].
Long-Term Complications Related to CRT Devices Long-term complications are related to cardiac resynchronization loss because of ventricular capture loss. This happened to 10 % of patients in VENTAK CHF/CONTAK CD study. Three quarters of them had lead displacement and
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23 % had chronic stimulation threshold increase that could be solved by voltage increase [46]. There are studies that demonstrated that there is no statistically significant difference in CRT loss between thoracotomy leads and endovenous ones. An analysis on 2,078 patients enrolled in the MIRACLE, MIRACLE ICD, and InSync III Study revealed complete left ventricle capture loss in 1.01 % of cases (21 from 2,078 patients) [47]. In epicardial leads, a particularly difficult and important problem is exit block. This complication is strongly related to lead type and surgical technique [32]. Conclusions
Complications related to CIEDs are still a common problem, and the prevalence of some is increasing (infections, leads, and generator recalls) since the implant rates are also increasing. Despite the progress in technology, the incidence of complications varies between 4 and 12 %. A possible explanation could be that the indications for CIEDs have rapidly increased (particularly for ICDs), and comorbidities are more frequent in this aging population. The economical impact of these complications is also important as well as the consequences for the patients. Monitoring and treatment of these complications, insuring adequate training, and maintenance of competence should be part of the good clinical practice.
References 1. Haug B, Kjelsberg K, Lappegård KT. Pacemaker implantation in small hospitals: complication rates comparable to larger centres. Europace. 2011;13:1580–6. 2. Ellenbogen KA, Wood MA. Cardiac pacing and ICDs. 5th ed. Hoboken: Wiley-Blackwell; 2008. p. 245–62. 3. Eberhardt F, Bode F, Bonnemeier H, et al. Long term complications in single and dual chamber pacing are influenced by surgical experience and patient morbidity. Heart. 2005;91:500–6. 4. Peterson PN, Daugherty SL, Wang Y, et al. The National Data Registry. Gender differences in procedure-related adverse events in patients receiving implantable cardioverter-defibrillator therapy. Circulation. 2009;119:1078–84. 5. Tobin K, Stewart J, Westveer D, et al. Acute complications of permanent pacemaker implantation: their financial implications and relation to volume and operator experience. Am J Cardiol. 2000;85:774–7. 6. Link MS, Estes 3rd NA, Griffin JJ, et al. Complications of dual chamber pacemaker implantation in the elderly. Pacemaker Selection in the Elderly (PASE) Investigators. J Interv Card Electrophysiol. 1998;2:175–9. 7. Møller M, Arnsbo P, Asklund M, Christensen PD, Gadsbøll N, Svendsen JH, et al. Quality assessment of pacemaker implantations in Denmark. Europace. 2002;4:107–12. 8. Nowak B, Misselwitz B, Erdogan A, Funck R, Irnich W, Israel C, et al. Do gender differences exist in pacemaker implantation? Results of an obligatory external quality control program. Europace. 2010;12:152–3. 9. Ellery SM, Paul VE. Complications of biventricular pacing. Eur Heart J Suppl. 2004;6(Suppl D):D117–21.
S. Pescariu and R. Sosdean 10. Reinolds MR, Cohen DJ, Kugelmass AD, et al. The frequency and incremental cost of major complications among Medicare beneficiaries receiving implantable cardioverter-defibrillators. J Am Coll Cardiol. 2006;47:2493–7. 11. Abraham WT. Rationale and design of a randomized clinical trial to assess the safety and efficacy of cardiac resynchronization therapy in patients with advanced heart failure: the Multicenter InSync Randomized Clinical Evaluation (MIRACLE). J Card Fail. 2000;6(4):369–80. 12. Luck JC, Wolbrette DL, Boehmer JP, et al. Biventricular pacing in congestive heart failure: a boost toward finer living. Curr Opin Cardiol. 2002;17(1):96–101. 13. Klug D, Balde M, Pavin D, Hidden-Lucet F, Clementy J, Sadoul N, et al. Risk factors related to infections of implanted pacemakers and cardioverter- defibrillators: results of a large prospective study. Circulation. 2007;116:1349–55. 14. Pakarinen S, Oikarinen L, Toivonen L. Short-term implantationrelated complications of cardiac rhythm management device therapy: a retrospective single-centre 1-year survey. Europace. 2010;12:103–8. 15. Pescariu S. Implantul de stimulator cardiac. Timisoara: Brumar; 1996. p. 136–51. 16. Pescariu S. Aritmii. Ghid clinic. Timisoara: Brumar; 2004. p. 170–2. 17. Timperley J, Leeson P, Mitchell ARJ, et al. Pacemakers and ICDs. Oxford: Oxford University Press; 2008. p. 84–93. 18. Molnár L, Szucs G, Zima E, et al. Successful management and long term outcome of an accidental subclavian artery injury with a 9 French dilator during pacemaker implantation with collagen-based closure device. J Interv Card Electrophysiol. 2009;25(3):217–8. 19. Meyhoefer J, Lehmann H, Minden HH, et al. Closure of the subclavian artery puncture site with a percutaneous suture device after removal of an arterial pacemaker lead. Europace. 2006;8(12):1070–2. 20. Libby P, Bonow RO, Zipes DP, Mann DL. Pacemakers and implantable cardioverter-defibrillators. In: Braunwald’s heart disease, A textbook of cardiovascular medicine. 9th ed. Philadelphia: Elsevier Saunders; 2012. p. 162. 21. Villalba S, Roda J, Quesada A, et al. Retrospective study of patients who undergo pacemaker implantation in short-stay ambulatory surgery. Long-term follow-up and cost analysis. Rev Esp Cardiol. 2004;57(3):234–40. 22. Sadamatsu K. Complication of pacemaker implantation: an atrial lead perforation. In: Das MR, editor. Modern pacemakers – present and future. Rijeka: InTech; 2011. doi: 10.5772/13854. ISBN: 978-953-307-214-2. 23. Al Ahmad A, Ellenbogen KA, Natale A, et al. Pacemakers and implantable cardioverter defibrillators. An expert’s manual. Minneapolis: Cardiotext Publishing; 2010. p. 39–43. 24. Ellenbogen KA, Wood MA, Shepard RK, et al. Detection and management of an implantable cardioverter lead failure: incidence and clinical implications. J Am Coll Cardiol. 2003;41:73–80. 25. Ritter F, Fischer W. Pratique de la Stimulation Cardiaque. Paris: Springer; 1997. p. 225–50. 26. Rozmus G, Daubert JP, Huang DT, et al. Venous thrombosis and stenosis after implantation of pacemakers and defibrillators. J Interv Card Electrophysiol. 2005;13:9–19. 27. Wiegand UKH, LeJeune D, Boguschewski F, et al. Pocket hematoma after pacemaker or implantable cardioverter defibrillator surgery influence of patient morbidity, operation strategy, and perioperative antiplatelet/anticoagulation therapy. Chest. 2004;126: 1177–86. 28. Van Eck JWM, Van Hemel NM, Zuithof P, et al. Incidence and predictors of in-hospital events after first implantation of pacemakers. Europace. 2007;9:884–9. 29. Dhua JD, Wilkoff BL, Lee I, et al. Diagnosis and management of infections involving implantable electrophysiologic cardiac devices. Ann Intern Med. 2000;133:604–8.
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Complications of Cardiac Implantable Electronic Devices (CIED)
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30. Uslan DZ, Gleva MJ, Warren DK, et al. Cardiovascular implantable electronic device replacement infections and prevention: results from the REPLACE Registry. Pacing Clin Electrophysiol. 2012;35:81–7. 31. Greenspon AJ, Patel JD, Lau E, et al. 16 year trends in the infection burden for pacemakers and implantable cardioverter-defibrillators in the United States 1993 to 2008. J Am Coli Cardiol. 2011;58:1001–6. 32. Yu CM, Hayes DL, Auricchio A. Cardiac resynchronization therapy. London: Blackwell Futura; 2008. p. 214–31. 33. Cazeau S, Leclercq C, Lavergne T, et al. Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay. N Engl J Med. 2001;344(12):873–80. 34. Hellerstein HK, Orbison JL. Anatomic variations of the orifice of the human coronary sinus. Circulation. 1951;3:514–23. 35. Alonso C, Leclercq C, Revault d’Allonnes F, et al. Six year experience of transvenous left ventricular lead implantation for permanent biventricular pacing in patients with advanced heart failure: technical aspects. Heart. 2001;86:405–10. 36. Lenarczyk R, Kowalski O, Kukulski T, et al. Triple-site biventricular pacing in patients undergoing cardiac resynchronization therapy: a feasibility study. Europace. 2007;9:762–7. 37. Kowalski O, Lanarczyk R, Prokopczuk J, et al. Effect of percutaneous interventions within the coronary sinus on the success rate of the implantations of resynchronization pacemakers. Pacing Clin Electrophysiol. 2006;29:1075–80. 38. De Cock CC, van Campen CM, Visser CA. Major dissection of the coronary sinus and its tributaries during lead implantation for biventricular stimulation: angiographic follow up. Europace. 2004;6:43–7. 39. Mela T, Ngarmukos T, Rosenthal L, et al. Inappropriate ICD therapy due to lead- related noise in an active fixation ICD lead. J Invasive Cardiol. 2001;13(5):406–8.
40. Bayliss CE, Beanlands DS, Baird RJ. The pacemaker-twiddler’s syndrome: a new complication of implantable transvenous pacemakers. Can Med Assoc J. 1968;99(8):371. 41. Nery PB, Fernandes R, Nair GM, et al. Device-related infection among patients with pacemakers and implantable defibrillators: incidence, risk factors, and consequences. J Cardiovasc Electrophysiol. 2010;21:786–90. 42. Habib G, Hoen B, Tornos P, et al. Guidelines on the prevention, diagnosis, and treatment of infective endocarditis (new version 2009). The Task Force on the Prevention, Diagnosis, and Treatment of Infective Endocarditis of the European Society of Cardiology (ESC). Eur Heart J. 2009;30:2369–413. 43. Chua JD, Wilkoff BL, et al. Diagnosis and management of infections involving implantable electrophysiologic cardiac devices. Ann Intern Med. 2000;133:604–8. 44. Sohail MR, Uslan DZ, et al. Infective endocarditis complicating permanent pacemaker and implantable cardioverter-defibrillator infection. Mayo Clin Proc. 2008;83(1):46–53. 45. Ruttman E, Hangler HB, et al. Transvenous pacemaker lead removal is safe and effective even in large vegetations: an analysis of 53 cases of pacemaker lead endocarditis. Pacing Clin Electrophysiol. 2006;29(3):231–6. 46. Knight BP, Desai A, Coman J, et al. Long- term retention of cardiac resynchronization therapy. J Am Coll Cardiol. 2004;44:72–7. 47. Leon AR, Abraham WT, Curtis AB et al. Safety of transvenous cardiac resynchronization system implantation in patients with chronic heart failure: combined results of over 2000 patients from a multicenter study program (MIRACLE study program). J Am Coll Cardiol. 2005;46:2348–56.
Peri-device Implantation Anticoagulation Management: Evidence and Clinical Implications
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Alexander Omelchenko, Martin Bernier, David Birnie, and Vidal Essebag
Abstract
Implantation rates of cardiovascular implantable electronic devices (CIED) have increased over the past decade. A significant number of patients undergoing CIED implantation are treated with oral anticoagulants (OAC). The perioperative management of anticoagulant therapy is often challenging. Selecting a management strategy for anticoagulation therapy depends on a balance between the risk of hemorrhagic complications in the perioperative period and the risk of thrombotic complications. For patients with a low thrombotic risk, short-term interruption of OAC is recommended. For patients with moderate and higher risk of thrombotic complications, interruption of OAC could be unsafe, and bridging anticoagulation with parenteral agents is suggested. This approach, unfortunately, has serious limitations. For this reason, some physicians perform CIED implantation with OAC. However, the relative effectiveness and safety of both approaches remains to be determined by further randomized controlled trials. In this chapter, we provide the rationale for deciding on appropriate antithrombotic management strategy in the perioperative period, discuss advantages and disadvantages of each approach, underline existing evidence, and compare current guidelines for perioperative anticoagulant management. We also review the new oral anticoagulants such as direct thrombin inhibitors and factor Xa inhibitors and discuss implications regarding anticoagulation management during CIED implantation. Keywords
Oral anticoagulants • Perioperative management • Device implantation
Abbreviations CIED CRT ICD
Cardiovascular implantable electronic devices Cardiac resynchronization therapy Implantable cardiac defibrillator
A. Omelchenko, MD • M. Bernier, MD • V. Essebag, MD, PhD, FRCPC, FACC (*) Division of Cardiology, McGill University Health Center, 1650 Cedar Ave., Room E5.200, Montreal, QC H3G 1A4, Canada e-mail:
[email protected];
[email protected];
[email protected] D. Birnie, MB, ChB, MD Division of Cardiology, University of Ottawa, Heart Institute, 40 Ruskin Road, Ottawa, ON K1Y 4W7, Canada e-mail:
[email protected] A.S. Kibos et al. (eds.), Cardiac Arrhythmias, DOI 10.1007/978-1-4471-5316-0_52, © Springer-Verlag London 2014
LMWH OAC TIA UFH VTE
Low-molecular-weight heparin Oral anticoagulant Transient ischemic attack Unfractionated heparin Venous thromboembolism
Introduction Implantation rates of cardiovascular implantable electronic devices (CIED), including pacemakers, implantable cardiac defibrillators (ICD), or cardiac resynchronization therapy (CRT), are steadily increasing by an estimated 10 %/year [1–3]. The rise is related to changes and widening of indications for device implantation and, on the other hand, aging of 653
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the population which leads to increasing number of patients in need of device implantation. A significant proportion of patients undergoing implantation are treated with concomitant anticoagulant therapy (23–24 % in a recent pacemaker trial and 32–37 % in a recent ICD trial) [4, 5]. The management of these patients is challenging because the risk of thromboembolic events during interruption of anticoagulant therapy needs to be balanced against the risk of bleeding associated with perioperative anticoagulation. In this chapter, we will summarize available evidence concerning management of oral anticoagulant (OAC) therapy during CIED implantation and highlight controversial areas as well as provide insight on future practice.
Risks Associated with Perioperative Anticoagulant Therapy When dealing with patients in need of CIED surgery who are treated with anticoagulants, the physician has to consider several important questions. Should the OAC be interrupted? What is the risk-benefit of anticoagulant therapy interruption? How long can anticoagulant therapy safely be interrupted? Is bridging anticoagulation needed during interruption of OAC? When bridging is indicated, what is the best choice of bridging therapy? The answers to these questions must be determined by balancing the thromboembolic risk and perioperative hemorrhagic complications in individual patients.
Hemorrhagic Risk The hemorrhagic risk of the surgical procedure cannot always easily be evaluated. Some authors have classified operations into minor and major surgery and, similarly, the risk of the bleeding [6]. Procedures less than 1 h in duration are considered as minor surgeries. Clearly, this simple scheme cannot take into account all features of the operation. With regard to CIED surgery, most procedures are relatively short and can be performed in less than one hour. Nevertheless, some features make CIED surgery potentially dangerous in terms of bleeding risk. Separation of the infraclavicular fascial layers and lack of cautery or suturing of unopposed tissues within the pacemaker or defibrillator pocket may predispose to pocket hematoma development [7]. The reported incidence of hematoma complicating CIED surgery varies between studies, mainly because of differences in patient populations and no universal hematoma definition. A large prospective study reported a 3.1 % hematoma rate in patients treated with acetylsalicylic acid (ASA) without additional anticoagulation therapy [7]. Another study reported a hematoma rate of 5.5 % in patients with no
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antithrombotic or anticoagulant therapy, compared to a rate of 11.1 % in patients treated with ticlopidine (an antithrombotic agent) [8]. Lower hematoma rates of 1.1 and 1.9 % were reported in other studies of the patients without any antithrombotic agents [9, 10]. Finally, the large multicenter REPLACE registry of Implantable Cardiac Pulse Generator Replacement, two groups were compared: those without (cohort 1) and those with (cohort 2) a planned transvenous lead addition for replacement or upgrade to a device capable of additional therapies. Among 1,750 patients in the REPLACE registry, hematoma rate requiring evacuation, hospitalization, or transfusion was 0.7 and 3.5 % in groups 1 and 2, respectively [11]. There are many factors which increase the risk of hematoma formation [7] including size of the implanted device, number of implanted leads [11, 12], venous access [8, 13–15], concomitant use of antiplatelet agents (especially the combination of ASA and thienopyridine) and the use of anticoagulants, associated disease (renal failure, liver failure, thrombocytopenia, etc.), and operator experience. The risk of pocket hematoma may have serious consequences including (1) hospitalization prolongation and increased cost of treatment (by a mean of 3.1 days and US$6,995 in one study) [16], (2) early reoperation (pocket hematoma accounts for 14–17 % of early reoperations) [13, 17], (3) prolonged cessation of OAC with the attendant risk of thromboembolic events [18], and (4) increased risk of the device-related infection, most probably because of reoperation [19]. The role of the hematoma itself (i.e., independent of reoperation) in triggering infection development is controversial [7] but is supported by the recently published REPLACE registry [20]. Pocket infection can increase morbidity and mortality, especially if followed by system infection requiring lead extraction and/or infective endocarditis. The precise risk of infection associated with an hematoma is not clear and differs between studies [7, 19, 21]. CIED procedures involving insertion of new leads, as opposed to CIED generator change procedures, may be associated with hemorrhagic complications other than pocket hematoma. Hemothorax may occur as a result of inadvertent arterial puncture during venous access or as a complication of chest tube insertion for pneumothorax caused by lung puncture during venous access. Cardiac perforation (with pericardial effusion or cardiac tamponade) may also occur during lead insertion. ICD lead implantation carries greater risk of myocardial perforation. Also, atrial lead insertion and active fixation mechanism may be related to greater risk of perforation [22, 23]. Fortunately, these complications are relatively rare. Different studies reported about 0.7–1.5 % of cases complicated by pneumothorax and 0.3–1 % of perforation during device implantation procedures [9, 13, 16, 17, 24–27]. Nevertheless, the clinical course of these complications may be potentially worse with concomitant anticoagulant treatment.
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Thromboembolic Risk Among the many conditions requiring anticoagulant treatment, three groups of patients form more than 90 % of those requiring prolonged anticoagulant treatment [28 , 29 ]: 1. Patients with mechanical valves 2. Patients with atrial fibrillation and/or atrial flutter with additional risk factors for thromboembolic events 3. Patients with history of venous thromboembolism (VTE) The specific thromboembolic risk in any given patient depends upon the presence of other risk factors which have been evaluated in each of these conditions.
Mechanical Valves The risk of thromboembolic complications is related to: (a) The implanted prosthetic valve position. Valves in the mitral position are more thrombogenic than valves in the aortic position. (b) The type of implanted prosthetic valve. Generally, older generation mechanical valves (e.g., cage ball, tiltingdisc) have higher risk of thromboembolic complications. The newer generation of prosthetic valves (e.g., bileaflet) may be associated with reduced thromboembolic risk, especially when implanted in aortic position. (c) Additional risk factors, such as atrial fibrillation or congestive heart failure.
Atrial Fibrillation Atrial fibrillation combined with additional risk factors for thromboembolic complications represents the largest group
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of patients requiring long-term anticoagulation. The thromboembolic risk rises with increasing number of concomitant risk factors. There are several algorithms for risk assessment in this group of the patient [30]. Two schemes were developed from multivariable analyses of pooled data from randomized trial studies: the Atrial Fibrillation Investigators (AFI) and the Stroke Prevention in Atrial Fibrillation (SPAF) risk schemes [31, 32]. The third one is a risk score system, based on the Framingham Heart Study that was developed to predict 5-year risk of stroke [33]. The most widely used risk stratification algorithm is the CHADS2 (congestive heart failure, hypertension, age 75 years, diabetes mellitus, and prior stroke or transient ischemic attack) index, developed from an amalgamation of the AFI and SPAF schemes and validated using data from a registry of hospitalized Medicare beneficiaries with AF [34, 35]. More recently, the CHADS2-VAS risk stratification algorithm was developed to expand on the CHADS2 score and has been included in the latest European guidelines for treatment of the patients with AF [36].
VTE The strongest risk factor for recurrent thromboembolism is the time from the previous VTE episode. The risk level is also influenced significantly by underlying pathology and etiology of VTE (e.g., oncologic disease, inherited and acquired thrombophilia, immobilization). According to the estimated annual thrombotic risk level, the patients are divided on three groups: (1) high-risk group with annual risk more than 10 %, (2) moderaterisk group with annual risk between 4 and 10 %, and (3) lowrisk group with annual risk below 4 % (Table 52.1).
Table 52.1 Thrombotic risk level Risk level High (>10 %/year) Patient with mechanical valve
Moderate (4–10 %/year)
1. In mitral position
1. Atrial fibrillation
2. Old generation aortic valves 3. History of recent stroke/TIA Patients with history of atrial fibrillation/atrial flutter and 1. CHADS score >4 2. Recent stroke/TIA 3. Rheumatic heart disease
2. Prior stroke/TIA 3. Hypertension 4. Diabetes mellitus
Patients with history of VTE 1. Within 3 months 2. History of severe thrombophilia
Patients with bileaflet aortic valve prosthesis and one of the risk factor for thrombotic event
5. CHF 6. Age >75 Patients with history of atrial fibrillation/flutter and CHADS score 3–4 Patients with VTE 1. Within the past 3–12 months 2. History of non-severe thrombophilia conditions 3. History of active cancer
Low (<4 %/year) Patients with mechanical valve in the aortic position without risk factors for thrombotic event Patients with history of atrial fibrillation and flutter with CHADS score 0–2 Patients with history of remote VTE and no other risk factors
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Recommended choice of antithrombotic or anticoagulant therapy [37–39] is based on these risk levels.
Anticoagulation Management According to Thrombotic Risk Low Thrombotic Risk Patients For patients falling in the category of the low risk, most authors and guidelines recommend withholding oral anticoagulants for several days, providing complete termination of anticoagulant action, and resumption of this treatment after surgery. Indeed, with annual risk less than 5 %, short-term interruption of anticoagulants for 6–8 days should carry low risk (less than 0.1 %). Even taking into account the potential for a nonlinear relationship between duration of interruption of anticoagulants and thromboembolic risk (i.e., due to a possible prothrombotic state after surgery), the level of risk remains relatively low (approximately 0.4 %) [38, 40]. The precise definition of the thromboembolic risk is problematic due to the presence of many possible combinations of risk factors and lack of appropriate studies. Considering the relatively low risk of thromboembolic complications and the potentially increased risk of pocket hematoma, it seems reasonable to stop anticoagulants prior to device implantation in low-risk patients [39].
Moderate to High Thrombotic Risk Patients When the thrombotic risk of patients is higher, simple interruption of OAC before surgery becomes less safe. The riskbenefit ratio in patients at higher thromboembolic risk favors continuation of anticoagulation during the perioperative period [39]. For patients with moderate and higher thromboembolic risk, there are two strategies for maintaining anticoagulation during the perioperative period: (1) bridging anticoagulation during OAC interruption or (2) continuation of OAC during surgery. While the standard approach has been that of bridging, more recent experience has been published regarding CIED surgery performed on therapeutic anticoagulation. Risk and benefits of both approaches will be reviewed, when having available evidence and recommendations.
Approaches to Maintaining Perioperative Anticoagulation Bridging Therapy Bridging anticoagulation implies discontinuation of warfarin 5 days before device surgery and bridging with iv unfractionated heparin (IV UFH) or low-molecular-weight heparin
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(LMWH) until the day before surgery, performing surgery during normal coagulation state, followed by resumption of OAC and UFH/LMWH until INR returns to therapeutic range. This approach aims to minimize the time in which patients are not therapeutically anticoagulated and the risk of thromboembolism. Bridging therapy is used widely and recommended in most of the guidelines for patients with moderate to high thrombotic risk. It should be noted that although the use of parenteral anticoagulants, especially LMWH, is common practice in many centers, its use being entirely empirical, based on clinical sense and experience. Currently, there have been no completed randomized studies on this practice. Although bridging therapy is theoretically most suitable in terms of safety for the patient (i.e., no anticoagulation at the time of the procedure and minimal duration of the period without anticoagulation), this approach has caveats and is associated with several potential disadvantages that will be discussed below. There are two ongoing clinical trials comparing LMWH bridging versus placebo during perioperative interruption of OAC: (1) Effectiveness of Bridging Anticoagulation for Surgery (The BRIDGE Study), ClinicalTrials.gov Identifier NCT00786474, accessed 2012-02-28, and (2) PERIOP 2 – A Safety and Effectiveness Study of LMWH Bridging Therapy Versus Placebo Bridging Therapy for Patients on Long Term Warfarin and Require Temporary Interruption of Their Warfarin, ClinicalTrials.gov Identifier NCT00432796, accessed 2012-02-28). These trials will hopefully answer to the question whether bridging is better than no bridging at all during OAC interruption in a wide range of surgical procedures. The BRUISE CONTROL study, discussed later, will specifically answer whether CIED surgery performed without OAC interruption is better than perioperative bridging [41].
Thromboembolic Risk Associated with Bridging Therapy Little is known about thrombotic risk associated with bridging therapy. There are no large trials addressing the thromboembolic risk related to this approach. This is true not just for bridging therapy during CIED implantation but also bridging therapy for all kinds of surgery in general. Rough estimates of the thrombotic risk can be obtained from the results of studies comparing different regimens of bridging therapy or comparing bridging therapy with non-interruption of OAC. Unfractionated heparin is the first medication that was used for bridging during interruption of OAC. However, there is not any published study comparing bridging with IV UFH versus complete interruption of OAC. Recommendations to use IV UFH as parenteral anticoagulant for bridging are based on results of studies that showed increased risk of thromboembolic complications related to discontinuation of OAC and the assumption that hemorrhagic complications can be reduced using a short-acting reversible anticoagulant in the perioperative period.
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The prospective multicenter REGIMEN registry, comparing bridging therapy with UFH or LMWH in 901 patients, revealed a 2.4 % risk of thrombotic complications in the group of IV UFH (164 patients) [42]. Another relatively small (101 patients) randomized study comparing bridging with IV UFH to non-interruption of OAC during pacemaker device implantation did not find any thromboembolic events in either group during the trial [43]. A recently published retrospective study reported 1 case of cerebrovascular accident (CVA) in the mostly IV UFH-bridged group of 199 patients [44]. Other studies were very small or had no clear data about usage of UFH as anticoagulant for bridging [45–47]. Thromboembolic risk related to usage of LMWH as bridging therapy is apparently similar to UFH with a slight tendency to be lower. LMWH bridging in the previously noted REGIMEN registry was associated with 0.9 % rate of thrombotic complications [42]. Other available data give us a risk ranging between 0 and 0.5 % in different studies; however, it should be noted that there are no adequately powered studies to provide accurate estimates. Most of the available data is based on small retrospective and observational studies [48–51].
Hemorrhagic Complications Associated with Bridging Therapy According to current guidelines, it is recommended to resume parenteral anticoagulation 12–24 h after the invasive procedure. This is a compromise between the desire to prevent thrombotic complications and concerns regarding risk of hemorrhagic complications. The same recommendation applies for CIED device implantation. Nevertheless, the best time for resuming parenteral anticoagulation is not known. Current recommendations are based on results of pooled analyses of the studies that compared early (6 h) versus delayed (12–24 h) administration of low-dose LMWH after orthopedic surgery. The risk of bleeding was higher in the group who received LMWH closer to surgery (6.3 % vs. 2.5 %) [52]. For CIED surgery, a similar trend was obtained in a small (49 patient) randomized trial reporting an excess of pocket hematoma among patients receiving early (within 6 h) versus delayed (24 h) postoperative IV UFH (22 % vs. 17 %, P = 0.7) [53]. Some authors suggest restarting parenteral anticoagulants even later, 48–72 h after procedure, when adequate hemostasis is more likely to have been achieved [38]. Despite the common recommendation regarding usage of bridging therapy, there is evidence that this treatment may lead to increased risk of hemorrhagic complications. A retrospective study from France reported increased hemorrhagic adverse events when IV UFH heparin was used for bridging therapy with a relative risk of 14 (CI 1.88–104, P = 0.0006) [14]. Moreover, an Australian retrospective
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study revealed increased risk of pocket hematoma when bridging anticoagulation was administrated post-pacemaker implantation (26.9 % vs. 0.9 %, P < 0.001) [54]. In a prospective study, IV UFH as well as clopidogrel treatment were predictors of hematoma formation [8]. Another Canadian single-center prospective observational study evaluating different LMWH bridging regimens revealed that omission of postoperative LMWH dramatically reduced hematoma rates (8 % vs. 23 %, P = 0.01) [55].
Increased Cost Associated with Bridging Therapy Bridging therapy, besides the potential inconvenience for patients associated with heparin administration and monitoring, may also increase the perioperative costs. For bridging with IV UFH, the main driver of increased cost is prolonged hospitalization. For LMWH which can often be administered in outpatient setting, costs are driven by the more expensive medication and nursing as well as physician resources to ensure administration of LMWH and monitoring of blood tests to determine duration of therapy. In one study, the mean total health-care costs were 31,625 USD in the IV UFH group (95 % confidence interval [CI], $22,966– $40,285) and 18,511 USD in the LMWH group (95 % CI, $8,355–$28,668) [47].
Non-interruption of OAC The disadvantages of bridging therapy led to increasing interest in the option of performing CIED surgery without cessation of oral VKA. This strategy is convenient for patients and medical personnel, is unlikely to increase the risk thromboembolic complications (and in fact avoids the period of interrupted anticoagulation associated with bridging therapy), and avoids the additional costs associated with bridging therapy.
Risk of Pocket Hematoma The main concern about this strategy is the concern regarding potential increased risk of hemorrhagic complications resulting from operating under therapeutic anticoagulation. Paradoxically, there is some nonrandomized evidence that continuation of OAC without stopping might be safer than bridging therapy. The initial studies suggesting that device surgery without interrupting OAC might be safe were published in the late 1990s. Goldstein et al. were among the first, implanting devices in 37 patients on warfarin at the time of device implantation. They found no difference in wound-related or woundunrelated complications between patients receiving warfarin (mean INR 2.5) and controls (mean INR 1.1) [56]. Al-Khadra reported similar findings in 47 patients with a mean INR 2.3 (range 1.5–3.1) at device implantation [57]. Giudici et al.
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published a large retrospective cohort consisting of 1,025 patients referred for device implantation, comparing 470 anticoagulated patients against 555 non-anticoagulated patients. The rates of bleeding complications were similar between the anticoagulated (mean INR 2.6 ± 1.0) and non-anticoagulated groups (INR <1.5). Hematomas occurred in 2.6 % of the anticoagulated patients and 2.2 % in the non-anticoagulated patients [10]. Imdad Ahmed et al. revealed a higher pocket hematoma rate among 123 patients with bridging versus 222 patients with CIED surgery on continued warfarin (odds ratio 16.2, 95 % confidence interval 4.38–59.9). Interestingly, the hematoma rate in this study was similar between the noninterruption of OAC group and a third group of 114 patients in whom OAC was withheld without bridging [58]. The safety of non-interruption of VKA was also assessed in cardiac resynchronization therapy (CRT) device implantation. This kind of procedure may carry potentially higher risk for hemorrhagic complications due to a generally longer procedure, the necessity to implant an additional lead, and risk of coronary sinus perforation. A retrospective study evaluated 123 consecutive patients who underwent CRT device implantation. Patients were distributed in three groups according to treatment protocol: warfarin group (continuation of warfarin in perioperative period), bridging group (discontinuation of warfarin and bridging therapy), and control group (patients with non-high thromboembolic risk, discontinued anticoagulant treatment 4 days before procedure). Patients in the bridging group had a significant increase in the rate of pocket hematoma (4.1 % [control] vs. 5.0 % [warfarin] vs. 20.7 % [bridging], P = 0.03) and subsequent longer length of stay (1.6 ± 1.6 days [control] vs. 2.9 ± 2.7 days [warfarin] vs. 3.7 ± 3.2 days [bridging], P < 0.001) [59]. A single-center Canadian cohort study prospectively assessed hemorrhagic and thromboembolic complications in 117 patients after CIED surgery without cessation of OAC. This group was compared with 38 patients treated with bridging and with retrospective age-, sex-, and procedurematched control group not taking warfarin. Significant hematoma was noted in 7.7 % of patients on uninterrupted OAC compared to 23.7 % (P = 0.012) in patients on bridging and 4.3 % of control patients [12]. Despite the observational data presented, there is very little randomized data to support the hypothesis that non-interruption of OAC may be superior to bridging therapy. A randomized single-center trial including 101 patients found no difference between groups in the rate of pocket hematoma formation (7.8 % vs. 8 %, p = ns) and other hemorrhagic complications [43]. Another recently published randomized trial of 100 patients undergoing CIED surgery compared discontinuation of OAC versus continuation of OAC and bridging therapy. Fifty patients were assigned to continue warfarin. Among patients randomized to warfarin interruption, only seven received bridging therapy.
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The study was underpowered to detect a difference between bridging versus continued warfarin in patients at high risk of thromboembolic events [60].
Other Hemorrhagic Complications As noted previously, myocardial perforation and pneumothorax are relatively rare, but potentially dangerous complications, related to CIED implantation. Bridging therapy with IV UFH or LMWH is unlikely to influence the incidence or course of pericardial perforation or pneumothorax (if detected and managed prior to resumption of anticoagulation). The frequency of these complications was not increased in the trials assessing the safety and effectiveness of bridging therapy [7, 50, 54]. The most intriguing issue is the potential risk associated with continuation of OAC. Despite concerns regarding consequences of major complications occurring on therapeutic anticoagulation, continuation of OAC during CIED surgery seems to be at least as safe as bridging therapy. Interestingly, in the analysis of the available retrospective and observational studies, there are no described cases of pneumothorax and perforation in more than 1,400 patients continuing OAC during device surgery. The explanation for the apparently lower risk for bleeding with perioperative continuation of a VKA is not clear. The acute administration of intravenous heparin or LMWH in close proximity after surgery may precipitate new bleeding that was not observed during surgery and therefore not managed with local hemostatic measures such as cautery or blood vessel ligation. On the other hand, if patients undergo surgery while anticoagulated, any excessive bleeding may be detectable intraoperatively and would prompt hemostatic measures [61].
Current Guidelines Several recent guidelines discuss perioperative anticoagulant management [36, 38, 39, 62]. These guidelines address surgery in general and have no specific recommendation about CIED surgery. It is important to note that most of the recommendations have level of evidence C. This is related mostly to scant evidence on this particular subject. Table 52.2 summarizes the recommendations from guidelines published in the last few years.
Current Practice The disadvantages of bridging therapy and lack of the strong evidence in this field lead to differences in current practice of anticoagulant management during the periprocedural
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Peri-device Implantation Anticoagulation Management: Evidence and Clinical Implications
Table 52.2 Guidelines for anticoagulant treatment during surgery
Guidelines Low-risk patients Moderate risk
European guidelines for the management of atrial fibrillation (2010) Subtherapeutic anticoagulation up to 48 h, no bridging (class IIa, C) –
High risk
“Bridging” anticoagulation with therapeutic doses of either LMWH or IV UFH (class IIa, C)
Preference for bridging therapy Bridging for CIED surgery
Same level of recommendation for iv UFH and LMWH No specific recommendation
The perioperative management of antithrombotic therapy: American European guidelines on the college of chest physicians evidencemanagement of valvular heart disease based clinical practice guidelines (2007) (2012) – No bridging (grade 2C) –
Approach based on an assessment of individual patient- and surgeryrelated factors (bridging is considered for low bleeding risk procedures and no bridging is considered for high bleeding risk procedures) Bridging anticoagulation with For major surgery – bridging with therapeutic-dose SC LMWH or IV IV UFH (class IIa, C) LMWH – alternative for UFH (class UFH (grade 1C) IIb, C) For minor surgery – avoid interruption of OAC Favor IV UFH Favor LMWH (grade 2C) No specific recommendation
Table 52.3 Preferred strategy for anticoagulant treatment in different countries Moderate to high risk of thromboembolic complication Study UK survey [63] (% of physicians) Canadian survey [6] (% of physicians) France survey [39] (% of physicians)
Stop OAC + bridging Continue OAC 89 11 32–72
23–36
67
11
period. Three studies reporting current practice [63–65] are summarized in Table 52.3. Most physicians treat their patients according to guideline recommendations, namely, stop the OAC without bridging in the case of low thromboembolic risk and stop OAC with bridging therapy in the case of moderate to high risk. On the other hand, a minority of physicians perform CIED surgery without interruption of OAC.
Current Randomized Trial: The Bruise Control Study Despite the disadvantages of bridging therapy and growing nonrandomized evidence of the safety of non-interruption of OAC during CIED surgery, most physicians are reluctant to
No specific recommendation
change the strategy of anticoagulant treatment in the absence of confirmatory data from randomized trials. Furthermore, current guidelines do not recommend operating on continued warfarin. This fact dictates the necessity of a large multicenter international randomized trial comparing the two strategies. The ongoing Bridge or Continue Coumadin for Device Surgery Randomized Controlled Trial (BRUISE CONTROL) is a prospective, single-blind multicenter randomized controlled trial comparing conventional bridging with uninterrupted oral anticoagulation for patients with moderate to high risk for thromboembolic complications (more than 5 %/year). Eligibility criteria are shown in Table 52.4. The hypothesis is that non-interruption of OAC will lead to a reduction in the incidence of clinically significant hematoma with neutral effect on the thrombotic complications comparing with bridging anticoagulation. The primary outcome is “clinically significant hematoma” defined as “hematoma requiring reoperation and/or transfusion and/or unplanned or prolonged hospitalization and/or interruption of LMWH or IV UFH or oral anticoagulation.” Secondary outcomes include (1) each of the components of the primary outcome, (2) composite of all other major perioperative bleeding events (hemothorax and cardiac tamponade and significant pericardial effusion), and (3) thromboembolic events. The study will also include a cost utilization analysis. The target sample size of the study is 984 patients. The trial is expected to complete enrolment by the end of 2013 [41].
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Table 52.4 Eligibility criteria for BRUISE CONTROL study Procedure
Any elective device surgery, include de novo device implantation or pulse generator change or lead replacement or pocket revision Patients Moderate or high risk of arterial thromboembolic events Prosthetic mitral valve replacement Caged ball of tilting disk aortic valve prosthesis Bileaflet aortic valve prosthesis and one or more of atrial fibrillation, prior stoke or TIA, hypertension, DM CHF, age >75 Atrial fibrillation associated with rheumatic valvular heart disease Nonrheumatic atrial fibrillation and CHADS2 score >2 High risk of VTE Recent (within 3 months) VTE Severe thrombophilia (protein C or S deficiency or antithrombin or antiphospholipid antibodies or multiple abnormalities) Exclusion criteria Renal failure with Cr >180 mmol/l Prior heparin-induced thrombocytopenia Active device infection
Perioperative Vitamin K Antagonist Management Algorithm Several treatment algorithms for management of anticoagulant therapy during CIED implantation have been proposed in recent years [61, 66, 67]. Most of them reflect results of observational studies suggesting disadvantages of bridging therapy and relative safety of continuation of VKA during CIED implantation. In the absence of randomized trial evidence of safety and/or superiority of continued OAC, current guidelines recommend bridging for patients at moderate to high thrombotic risk. In fact, current guidelines do not include operating on continued OAC as an option for CIED or other relatively high-risk bleeding procedures. These recommendations may change in the future as new data from randomized trials become available.
New Oral Anticoagulants Both VKA and heparins are not ideal anticoagulants and have several disadvantages. For VKA, disadvantages include slow onset and offset action, unpredictable response to treatment, narrow therapeutic window, multiple food and drug interactions, and the requirement of coagulation monitoring. Disadvantages of IV UFH include parenteral administration, unpredictable response to treatment, and requirement of coagulation monitoring. For LMWH, limitations include parenteral administration and requirement of dose adjusting (or contraindication) depending on the degree of renal dysfunction. Both IV UFH and LMWH are also associated with a risk of heparininduced thrombocytopenia. Some of these disadvantages are overcome by new oral anticoagulants: direct thrombin inhibitors (DTI) and factor Xa inhibitors.
Direct Thrombin Inhibitors Thrombin, one of the main players in clot formation, acts in the blood coagulation pathway for clot formation and stabilization by activating factors XI, VIII, and V and by converting fibrinogen to fibrin. Given its central role in clot formation, thrombin is an attractive target for the development of agents that effectively interfere with thrombogenesis. The oral direct thrombin inhibitor dabigatran is a drug with a rapid onset action. The half-life of the drug is 14–17 h. It is excreted mostly by the kidneys, thus needs dose adjustment in the case of renal failure. Based on results of the meta-analysis of the four trials, dabigatran proved to be equivalent to enoxaparin for the prevention of total VTE and all-cause mortality (risk ratio, 1.03; 95 % confidence interval, 0.93–1.15) with no increased risk of major bleeding (risk ratio, 1.09; 95 % confidence interval, 0.74–1.61) [68]. Dabigatran seems as safe and effective as warfarin for the treatment of acute VTE [69]. Based on results of the RE-LY study, dabigatran was approved in 2010 in both Canada and the United States for anticoagulation in atrial fibrillation [70]. Recent guidelines from the American College of Cardiology and American Heart Association also endorse dabigatran as an alternative to warfarin for chronic anticoagulation in atrial fibrillation in patients without a prosthetic heart valve, significant valvular disease, or severe renal failure (defined as a creatinine clearance – 15 mL/min) (class I recommendation, level of evidence B) [71]. Little is known about administration of the dabigatran in the patients with mechanical heart valves. A few reports published recently showed in vitro and animal model safety of dabigatran for thromboprophylaxis in the setting of mechanical valves [72, 73]. Currently, there is no reversal agent for dabigatran. This is, probably, the main limitation of dabigatran treatment. In life-threatening circumstances, hemodialysis can facilitate its rapid removal [73]. The management of
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Peri-device Implantation Anticoagulation Management: Evidence and Clinical Implications
Table 52.5 Main pharmacological characteristics of new oral anticoagulants Agent Half-life (hours) Tmax (after oral ingestion) (hours) Dosage Renal elimination (%)
Rivaroxaban 7–11 2–4
Apixaban Edoxaban 8–15 6–11 1.5–3.5 1.5
OD 33 (unchanged) 33 (inactive metabolites)
BID ~22
OD ~40
bid twice daily, od once daily, Tmax time to peak plasma concentration
severe bleeding associated with dabigatran may also include the administration of a procoagulant, such as recombinant activated factor VII. Use of a humanized monoclonal antibody specific to dabigatran has also recently proposed as a specific antagonist [74].
Oral Factor Xa Inhibitors Factor Xa is a serine protease that plays a key role in the coagulation pathways and binds to factor Va on the surface of activated platelets to form the prothrombinase complex, which in turn converts prothrombin to thrombin. Inhibitors of factor Xa attenuate thrombin generation and prevent conversion of fibrinogen to fibrin in the final stage of the coagulation cascade and may block factor Xa either directly or indirectly. The oral factor Xa inhibitors bind directly to the active site of factor Xa and block the interaction with its substrate [75]. There are three actively studied oral Xa inhibitors that have reached phase III clinical trials [76]: rivaroxaban, apixaban, and edoxaban. The main characteristic of the oral Xa inhibitors is given in Table 52.5. Oral factor Xa inhibitors have been investigated for the following indications: (1) prophylaxis of venous thromboembolism in major orthopedic surgery, (2) treatment of venous thromboembolism, (3) stroke prophylaxis in patients with atrial fibrillation, and (4) treatment of ACS. Most trials have demonstrated at least non-inferiority of the Xa inhibitors as anticoagulant treatment with a reasonable level of safety. Rivaroxaban has been approved by the FDA for VTE prophylaxis and for stroke prevention in patients with nonvalvular atrial fibrillation. Factor Xa inhibitors have not yet been tested in patients with mechanic valves. There is only in vitro data about usage of rivaroxaban for thrombosis prophylaxis in the setting of the mechanical valves. In this report, high-dose rivaroxaban was effective in prevention of clot formation similar to enoxaparin or UFH [77]. Similar to dabigatran, oral Xa inhibitors do not have a rapidly acting antidote. A recently published small randomized study evaluated reversal of riva-
661
roxaban action with prothrombin complex concentrate; however, it is not known if that result could be extrapolated to other agents from this group [78]. The use of new oral anticoagulants (as opposed to VKA) in patients undergoing CIED surgery who would otherwise require postoperative bridging therapy may reduce the length of hospitalization, particularly in patients for which outpatient subcutaneous LMWH injection is not possible. Because the new oral agents have a short half-life and do not require routine coagulation monitoring, they can be initiated postoperatively without bridging, coagulation testing, or dose adjustment. Therefore, use of new oral agents postoperatively may be more cost-effective than traditional heparin bridging until therapeutic anticoagulation is achieved with VKA. Several reasons prevent full replacement of VKA by new oral anticoagulants: (1) lack of studies about effectiveness of Xa inhibitors in the setting of mechanical valves, (2) inability to use these drugs in the case of severe renal failure, and possibly (3) lack of effective antidote for this group of drugs. The lack on an antidote raises concern about the use of DTI and Xa inhibitors in perioperative period, especially in the case of high hemorrhagic risk. Little is known about the safety of this agent in the early postoperative period. Until more data become available, recommendations about usage of “new” anticoagulants before and after surgery are likely to remain relatively conservative. In one publication regarding therapy with DTI, it has been recommended that dabigatran should be discontinued 24 h before invasive procedures and at least 48 h before procedures with a high risk of bleeding or procedures in which bleeding is catastrophic. For patients with impaired renal function, this time should be longer [73]. Recent recommendations from the French Working Group on perioperative hemostasis are even more careful in terms of bleeding risk [79]. As noted previously, given the lack of specific antidote and variation in the pharmacokinetics of the drugs depending on patient factors, the authors propose an approach for management of new oral anticoagulants considering the ability to mechanically control bleeding associated with the specific surgery, the bleeding risk, the thromboembolic risk, and the urgency of the surgery. For low bleeding risk surgery, the authors propose discontinuation of the new oral anticoagulants 24 h before surgery and resuming anticoagulation 24 h after surgery. For moderate to high bleeding risk, they suggest discontinuation of the new oral anticoagulants 5 days before surgery. The recommendation to discontinue 5 days before the surgery was made empirically in order to guarantee complete elimination of anticoagulant effect for most of the patients. There are no clear recommendations for the resumption of the new oral anticoagulants. The authors suggest resuming of the new oral anticoagulants when the risk of bleeding has
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been controlled with certainty. Extrapolating data regarding current recommendations for initiation of heparin treatment in high thrombotic risk patients, it could be recommended to resume new oral anticoagulants therapy 24 h after CIED surgery. As mentioned before, all recommendations about management of new oral anticoagulants in the perioperative period are based entirely on expert opinion. There are no studies specifically assessing the optimal perioperative management of new oral anticoagulants in patients undergoing CIED surgery. Given the promising results of the observational studies of CIED surgery performed without interruption of VKA and increased hematoma rates when heparins are used for bridging, a study similar to BRUISE CONTROL is needed to evaluate the safety and efficacy of noninterruption of new oral anticoagulant therapy versus temporary interruption with resumption postoperatively. Given the relatively short half-life of these agents, postoperative bridging with heparin would not be required. Conclusion
In 2006, there was a total of 27,286 device implants in Canada and the implant rate is increasing by an estimated 10 %/year. Many patients (23–37 %) requiring device surgery are on chronic OAC, usually with warfarin. The periprocedural management of OAC presents a dilemma to physicians. This is particularly true in the subset of patients with moderate to high (e.g., >4 %/year) risk of thrombotic events. Physicians have responded to concerns about periprocedural thrombotic risk by treating moderate- to high-risk patients with bridging anticoagulation. OAC are discontinued for a few days before the surgery, and the patient is bridged with therapeutic doses of either IV UFH or LMWH. After surgery the patient is restarted on LMWH or IV UFH for a few days while OAC effect is building up to therapeutic levels. However, there are a number of downsides to bridging anticoagulation around device surgery, in particular there is a substantial risk of significant device pocket hematoma with important clinical sequels, and bridging is expensive. Recently, in response to these issues, a number of centers have explored the option of performing device surgery without cessation of OAC. The observational data would suggest a greatly reduced hematoma rate with this strategy. Despite these encouraging results, most physicians are reluctant to move to operating on continued warfarin in the absence of confirmatory data from a randomized trial. Such a trial (BRUISE CONTOL) is ongoing and results are expected in 2013. A final issue is the recent development and approval in 2011 of new OAC agents. They have a much shorter half-life than warfarin, and studies are just beginning to explore perioperative management strategies.
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References 1. John Crysler Inc. Market statistics. Cardiac arrhythmia device implant market. 2008. 2. Birnie D, Williams K, Guo A, Mielniczuk L, Davis D, Lemery R, et al. Reasons for escalating pacemaker implants. Am J Cardiol. 2006;98(1):93–7. 3. Mond HG, Irwin M, Morillo C, Ector H. The world survey of cardiac pacing and cardioverter-defibrillators: calendar year 2001. Pacing Clin Electrophysiol. 2004;27(7):955–64. 4. Greenspon AJ, Hart RG, Dawson D, Hellkamp AS, Silver M, Flaker GC, et al. Predictors of stroke in patient spaced for sick sinus syndrome. J Am Coll Cardiol. 2004;43:1617–22. 5. Bardy GH, Lee KL, Mark DB, Poole JE, Packer DL, Boineau R, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med. 2005;352:225–37. 6. Dunn AS, Spyropoulos A, Turpie AG. Bridging therapy in patients on long-term oral anticoagulants who require surgery: the Prospective Peri-operative Enoxaparin Cohort Trial (PROSPECT). J Thromb Haemost. 2007;5:2211–8. 7. Wiegand UK, LeJeune D, Boguschewski F, Bonnemeier H, Eberhardt F, Schunkert H, et al. Pocket hematoma after pacemaker or implantable cardioverter defibrillator surgery: influence of patient morbidity, operation strategy, and perioperative antiplatelet/ anticoagulation therapy. Chest. 2004;126:1177–86. 8. Kutinsky IB, Jarandilla R, Jewett M, Haines DE. Risk of hematoma complications after device implant in the clopidogrel era. Circ Arrhythm Electrophysiol. 2010;3:312–8. 9. Kiviniemi MS, Pirnes MA, Eranen JK, Kettunen RVJ, Hartikainen JEK. Complications related to permanent pacemaker therapy. Pacing Clin Electrophysiol. 1999;22:711–20. 10. Giudici MC, Barold SS, Paul DL, Bontu P. Pacemaker and implantable cardioverter defibrillator implantation without reversal of warfarin therapy. Pacing Clin Electrophysiol. 2004;27:358–60. 11. Poole JE, Gleva MJ, Mela T, Chung MK, Uslan DZ, Borge R, et al. Complication rates associated with pacemaker or implantable cardioverter-defibrillator generator replacements and upgrade procedures. Circulation. 2010;122:1553–61. 12. Tischenko A, Gula LJ, Yee R, Klein GJ, Skanes AC, Krahn AD. Implantation of cardiac rhythm devices without interruption of oral anticoagulation compared with perioperative bridging with low – molecular weight heparin. Am Heart J. 2009;158:252–6. 13. Chauhan A, Grace AA, Newell SA, Stone DL, Shapiro LM, Schofield PM, Petch MC. Early complications after dual chamber versus single chamber pacemaker implantation. Pacing Clin Electrophysiol. 1994;17:2012–5. 14. Marquie C, De Geeter G, Klug D, Kouakam C, Brigadeau F, Jabourek O. Post-operative use of heparin increases morbidity of pacemaker implantation. Europace. 2006;8:283–7. 15. Przybylski A, Derejko P, Kwaśniewski W, Urbańczyk-Swić D, Zakrzewska J, Orszulak W. Bleeding complications after pacemaker or cardioverter-defibrillator implantation in patients receiving dual antiplatelet therapy: results of a prospective, two-centre registry. Neth Heart J. 2010;18:230–5. 16. Reynolds MR, Cohen DJ, Kugelmass AD, Brown PP, Becker ER, Culler SD, et al. The frequency and incremental cost of major complications among Medicare beneficiaries receiving implantable cardioverter-defibrillators. J Am Coll Cardiol. 2006;47:2493–7. 17. Aggarwal RK, Connelly DT, Ray SG, Ball J, Charles RG. Early complications of permanent pacemaker implantation: no difference between dual and single chamber systems. Br Heart J. 1995;73:571–5. 18. Kovacs MJ, Kearon C, Rodger M, Anderson DR, Turpie AG, Bates SM, et al. Single-arm study of bridging therapy with low-molecularweight heparin for patients at risk of arterial embolism who require temporary interruption of warfarin. Circulation. 2004;110:1658–63.
52
Peri-device Implantation Anticoagulation Management: Evidence and Clinical Implications
19. Klug D, Balde M, Pavin D, Hidden-Lucet F, Clementy J, Sadoul N, et al. Risk factors related to infections of implanted pacemakers and cardioverter-defibrillators: results of a large prospective study. Circulation. 2007;116:1349–55. 20. Uslan DZ, Gleva MJ, Warren DK, Mela T, Chung MK, Gottipaty V, et al. Cardiovascular implantable electronic device replacement infections and prevention: results from the REPLACE registry. Pacing Clin Electrophysiol. 2012;35(1):81–7. 21. de Oliveira JC, Martinelli M, Nishioka SA, Varejão T, Uipe D, Pedrosa AA, et al. Efficacy of antibiotic prophylaxis before the implantation of pacemakers and cardioverter-defibrillators: results of a large, prospective, randomized, double-blinded, placebocontrolled trial. Circ Arrhythm Electrophysiol. 2009;2(1):29–34. 22. Mahapatra S, Bybee KA, Bunch TJ, Espinosa RE, Sinak LJ, McGoon MD, et al. Incidence and predictors of cardiac perforation after permanent pacemaker placement. Heart Rhythm. 2005;2:907–11. 23. Hirschl DA, Jain VR, Spindola-Franco H, Gross JN, Haramati LB. Prevalence and characterization of asymptomatic pacemaker and ICD lead perforation on CT. Pacing Clin Electrophysiol. 2007;30:28–32. 24. Lamas GA, Lee KL, Sweeney MO, Silverman R, Leon A, Yee R, et al. Ventricular pacing or dual-chamber pacing for sinus-node dysfunction. N Engl J Med. 2002;346:1854–62. 25. Link MS, Estes 3rd NA, Griffin JJ, Wang PJ, Maloney JD, Kirchhoffer JB, et al. Complications of dual chamber pacemaker implantation in the elderly. Pacemaker Selection in the Elderly (PASE) Investigators. J Interv Card Electrophysiol. 1998;2:175–9. 26. Gras D, Böcker D, Lunati M, Wellens HJ, Calvert M, Freemantle N, et al.; on behalf of The CARE-HF Study Steering Committee and Investigators. Implantation of cardiac resynchronization therapy systems in the CARE-HF trial: procedural success rate and safety. Europace. 2007;9:516–22. 27. Khan MN, Joseph G, Khaykin Y, Ziada KM, Wilkoff BL. Delayed lead perforation, a disturbing trend. Pacing Clin Electrophysiol. 2005;28:251–3. 28. Hirsh J, Dalen JE, Deykin D, Poller L, Bussey H. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest. 1995;108(Suppl):S231–46. 29. Becker RC, Ansell J. Antithrombotic therapy: an abbreviated reference for clinicians. Arch Intern Med. 1995;155:149–61. 30. Fang MC, Go AS, Chang Y, Borowsky L, Pomernacki NK, Singer DE, ATRIA Study Group. Comparison of risk stratification schemes to predict thromboembolism in people with nonvalvular atrial fibrillation. J Am Coll Cardiol. 2008;51(8):810–5. 31. Atrial Fibrillation Investigators. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation: analysis of pooled data from 5 randomized controlled trials. Arch Intern Med. 1994;154:1449–57. 32. Hart R, Pearce L, McBride R, Rothbart R, Asinger R. Factors associated with ischemic stroke during aspirin therapy in atrial fibrillation: analysis of 2012 participants in the SPAF I-III clinical trials. Stroke. 1999;30:1223–9. 33. Wang TJ, Massaro JM, Levy D, Vasan RS, Wolf PA, D’Agostino RB, et al. A risk score for predicting stroke or death in individuals with new-onset atrial fibrillation in the community: the Framingham Heart Study. JAMA. 2003;290:1049–56. 34. Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classification schemes for predicting stroke: results from the national registry of atrial fibrillation. JAMA. 2001;285:2864–70. 35. Singer DE, Albers GW, Dalen JE, Go AS, Halperin JL, Manning WJ. Antithrombotic therapy in atrial fibrillation: the seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest. 2004;126:S429–56. 36. Camm AJ, Kirchhof P, Lip GY, Schotten U, Savelieva I, Ernst S, et al. Guidelines for the management of atrial fibrillation: the Task
37. 38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
663
Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). European Heart Rhythm Association; European Association for Cardio-Thoracic Surgery. Eur Heart J. 2010;31(19):2369–429. Kearon C, Hirsh J. Management of anticoagulation before and after elective surgery. N Engl J Med. 1997;336(21):1506–11. Douketis JD, Berger PB, Dunn AS, Jaffer AK, Spyropoulos AC, Becker RC, et al. The perioperative management of antithrombotic therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th ed). American College of Chest Physicians. Chest. 2008;133(6 Suppl):299S–339S. Douketis JD, Spyropoulos AC, Spencer FA, Mayr M, Jaffer AK, Eckman MH, et al. Perioperative management of antithrombotic therapy: Antithrombotic Therapy and Prevention of Thrombosis (9th ed). American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. American College of Chest Physicians. Chest. 2012;141(2 Suppl):e326S–50S. Garcia DA, Regan S, Henault LE, Upadhyay A, Baker J, Othman M, et al. Risk of thromboembolism with short-term interruption of warfarin therapy. Arch Intern Med. 2008;168:63–9. Birnie D, Healey JS, Krahn A, Essebag V, Sivakumaran S, Tang A, et al. Bridge or continue Coumadin for device surgery: a randomized controlled trial rationale and design. Curr Opin Cardiol. 2008;24:82–7. Spyropoulos AC, Turpie AG, Dunn AS, Spandorfer J, Douketis J, Jacobson A, et al. Clinical outcomes with unfractionated heparin or low-molecular-weight heparin as bridging therapy in patients on long-term oral anticoagulants: the REGIMEN registry. J Thromb Haemost. 2006;4:1246–52. Tolosana JM, Berne P, Mont L, Heras M, Berruezo A, Monteagudo J, et al. Preparation for pacemaker or implantable cardiac defibrillator implants in patients with high risk of thromboembolic events: oral anticoagulation or bridging with intravenous heparin? A prospective randomized trial. Eur Heart J. 2009;30:1880–4. Li HK, Chen FC, Rea RF, Asirvatham SJ, Powell BD, Friedman PA, et al. No increased bleeding events with continuation of oral anticoagulation therapy for patients undergoing cardiac device procedure. Pacing Clin Electrophysiol. 2011;34:868–74. Fanikos J, Tsilimingras K, Kucher N, Rosen AB, Hieblinger MD, Goldhaber SZ. Comparison of efficacy, safety, and cost of lowmolecular-weight heparin with continuous-infusion unfractionated heparin for initiation of anticoagulation after mechanical prosthetic valve implantation. Am J Cardiol. 2004;93:247–50. Jamula E, Woods K, Verhovsek M, Douketis JD, McDonald E. Comparison of pain and ecchymosis with low-molecular-weight heparin vs. unfractionated heparin in patients requiring bridging anticoagulation after warfarin interruption: a randomized trial. J Thromb Thrombolysis. 2009;28:266–8. Spyropoulos AC, Frost FJ, Hurley JS, Roberts M. Costs and clinical outcomes associated with low-molecular-weight heparin vs unfractionated heparin for perioperative bridging in patients receiving long-term oral anticoagulant therapy. Chest. 2004;125:1642–50. Douketis JD, Johnson JA, Turpie AG. Low-molecular-weight heparin as bridging anticoagulation during interruption of warfarin: assessment of a standardized periprocedural anticoagulation regimen. Arch Intern Med. 2004;164(12):1319–26. Pengo V, Cucchini U, Denas G, Erba N, Guazzaloca G, La Rosa L, et al. Italian federation of centers for the diagnosis of thrombosis and management of antithrombotic therapies (FCSA). standardized low-molecular-weight heparin bridging regimen in outpatients on oral anticoagulants undergoing invasive procedure or surgery: an inception cohort management study. Circulation. 2009;119(22): 2920–7. Hammerstingl C, Omran H. Perioperative bridging of chronic oral anticoagulation in patients undergoing pacemaker implantation – a study in 200 patients. Europace. 2011;13(9):1304–10.
664 51. Omran H, Hammerstingl C, Paar WD. Perioperative bridging with enoxaparin. Results of the prospective BRAVE registry with 779 patients. Med Klin (Munich). 2007;102(10):809–15. German. 52. Strebel N, Prins M, Agnelli G, Büller HR. Preoperative or postoperative start of prophylaxis for VTE with low-molecular-weight heparin in elective hip surgery? Arch Intern Med. 2002;162:1451–6. 53. Michaud GF, Pelosi Jr F, Noble MD, Knight BP, Morady F, Strickberger SA. A randomized trial comparing heparin initiation 6 hours or 24 hours after pacemaker of defibrillator implantation. J Am Coll Cardiol. 2000;35:1918. 54. Chow V, Ranasinghe I, Lau J, Stowe H, Bannon P, Hendel N, et al. Peri-procedural anticoagulation and the incidence of haematoma formation after permanent pacemaker implantation in the elderly. Heart Lung Circ. 2010;19(12):706–12. 55. Robinson M, Healey JS, Eikelboom J, Schulman S, Morillo CA, Nair GM, et al. Postoperative low-molecular-weight heparin bridging is associated with an increase in wound hematoma following surgery for pacemakers and implantable defibrillators. Pacing Clin Electrophysiol. 2009;32:378–82. 56. Goldstein DJ, Losquadro W, Spotnitz HM. Outpatient pacemaker procedures in orally anticoagulated patients. Pacing Clin Electrophysiol. 1998;21:1730–4. 57. Al-Khadra AS. Implantation of pacemakers and implantable cardioverter defibrillators in orally anticoagulated patients. Pacing Clin Electrophysiol. 2003;26:511–4. 58. Ahmed I, Gertner E, Nelson WB, House CM, Dahiya R, Anderson CP, et al. Continuing warfarin therapy is superior to interrupting warfarin with or without bridging anticoagulation therapy in patients undergoing pacemaker and defibrillator implantation. Heart Rhythm. 2010;7:745–9. 59. Ghanbari H, Feldman D, Schmidt M, Ottino J, Machado C, Akoum N, et al. Cardiac resynchronization therapy device implantation in patients with therapeutic international normalized ratios. Pacing Clin Electrophysiol. 2010;33:400–6. 60. Cheng A, Nazarian S, Brinker JA, Tompkins C, Spragg DD, Leng CT, et al. Continuation of warfarin during pacemaker or implantable cardioverter-defibrillator implantation: a randomized clinical trial. Heart Rhythm. 2011;8(4):536–40. 61. Jamula E, Douketis JD, Schulman S. Perioperative anticoagulation in patients having implantation of a cardiac pacemaker or defibrillator: a systematic review and practical management guide. J Thromb Haemost. 2008;6:1615–21. 62. Vahanian A, Baumgartner H, Bax J, Butchart E, Dion R, Filippatos G, et al. Guidelines on the management of valvular heart disease: The Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology. Task Force on the Management of Valvular Hearth Disease of the European Society of Cardiology; ESC Committee for Practice Guidelines. Eur Heart J. 2007;28(2):230–68. 63. Taieb J, Guenoun M, Hero M, et al. Pacemaker implantation and vitamin K antagonist management in real life. The French National Electra Survey. Europace. 2008;10 Suppl 1:i49. 64. Krahn AD, Healey JS, Simpson CS, Essebag V, Sivakumaran S, Birnie DH. Anticoagulation of patients on chronic warfarin undergoing arrhythmia device surgery: wide variability of perioperative bridging in Canada. Heart Rhythm. 2009;6(9):1276–9. 65. de Bono J, Nazir S, Ruperalia N, Bashir Y, Betts T, Rajappan K. Perioperative management of anticoagulation during device
A. Omelchenko et al.
66.
67.
68.
69.
70. 71.
72.
73.
74.
75.
76.
77.
78.
79.
implantation-the UK perspective. Pacing Clin Electrophysiol. 2010;33(4):389–93. Tompkins C, Henrikson CA. Optimal strategies for the management of antiplatelet and anticoagulation medications prior to cardiac device implantation. Cardiol J. 2011;18(1):103–9. Korantzopoulos P, Letsas KP, Liu T, Fragakis N, Efremidis M, Goudevenos JA. Anticoagulation and antiplatelet therapy in implantation of electrophysiological devices. Europace. 2011; 13(12):1669–80. Eriksson BI, Quinlan DJ, Eikelboom JW. Novel oral factor Xa and thrombin inhibitors in the management of thromboembolism. Annu Rev Med. 2011;62:41–57. Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361:2342–52. Hankey GJ, Eikelboom JW. Dabigatran etexilate: a new oral thrombin inhibitor. Circulation. 2011;123:1436–50. Wann LS, Curtis AB, Ellenbogen KA, Estes NA 3rd, Ezekowitz MD, Jackman WM, et al. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (update on dabigatran): a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. J Am Coll Cardiol. 2011;57(11):1330–7. Maegdefessel L, Linde T, Krapiec F, Hamilton K, Steinseifer U, van Ryn J, et al. In vitro comparison of dabigatran, unfractionated heparin, and low-molecular-weight heparin in preventing thrombus formation on mechanical heart valves. Thromb Res. 2010;126: 196–200. van Ryn J, Stangier J, Haertter S, Liesenfeld KH, Wienen W, Feuring M, et al. Dabigatran etexilate: a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost. 2010;103: 1116–27. van Ryn J, Litzenburger T, Waterman A, Canada K, Hauel N, Sarco C, et al. Dabigatran anticoagulant activity is neutralized by an antibody selective to dabigatran in vitro and in vivo models. J Am Coll Cardiol. 2011;57:E1130. Eriksson BI, Quinlan DJ, Weitz JI. Comparative pharmacodynamics and pharmacokinetics of oral direct thrombin and factor Xa inhibitors in development. Clin Pharmacokinet. 2009;48(1):1–22. Mavrakanas T, Bounameaux H. The potential role of new oral anticoagulants in the prevention and treatment of thromboembolism. Pharmacol Ther. 2011;130:46–58. Kaeberich A, Reindl I, Raaz U, Maegdefessel L, Vogt A, Linde T, et al. Comparison of unfractionated heparin, low-molecular-weight heparin, low-dose and high-dose rivaroxaban in preventing thrombus formation on mechanical heart valves: results of an in vitro study. J Thromb Thrombolysis. 2011;32:417–25. Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate. A randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011;124:1573–9. Sié P, Samama CM, Godier A, Rosencher N, Steib A, Llau JV, et al. Surgery and invasive procedures in patients on long-term treatment with direct oral anticoagulants: thrombin or factor-Xa inhibitors. Recommendations of the working group on perioperative haemostasis and the French study group on thrombosis and haemostasis. Arch Cardiovasc Dis. 2011;104:669–76.
Index
A Action potential duration (APD), 46, 49 Activated partial thromboplastin time (aPTT), 231 A disintegrin and metalloproteinases (ADAMs), 406 Advanced catheter location (ACL) technology, 374 AF. See Atrial fibrillation (AF) AFL. See Atrial flutter (AFL) Andersen-Tawil syndrome (ATS), 67, 111 Angiotensin receptor blockers (ARBs), 337–338, 630 ANP. See Atrial natriuretic peptide (ANP) Antiarrhythmic drug assessment. See Cardiac automaticity and conduction system Apixaban, 232–233 ARBs. See Angiotensin receptor blockers (ARBs) Arrhythmia anatomic landmarks cardiac autonomic nervous system, 40 cavotricuspid isthmus, 40 extrinsic-intrinsic cardiac ANS, 61–62 ligament of Marshall and left SVC, 40 lipomatous hypertrophy, interatrial septum, 40 pulmonary veins, 40 septal isthmus, 40 subthebesian pouch, 40 sympathetic-parasympathetic ANS, 61–62 atrial ectopy, 402–403 reentry mechanisms circus movement reentry, 403 leading circle reentry, 403 Moe’s multiple wavelet theory, 403–404 spiral wave reentry, 403 Arrhythmogenic automaticity drug assessment for mechanisms of, 322, 324 multichannel, 325–326 pharmacology of, 322, 323 regionally/origin-selective ion channel, 323–325 Sicilian Gambit classification, 322 upstream modulator-targeting, 326–327 Vaughan-William classification, 322 sick sinus syndrome, 320–321 triggered activity conduction, 322 definition, 320 delayed afterdepolarizations, 321, 322 early afterdepolarizations, 320, 321 AT. See Atrial tachycardia (AT) Atrial arrhythmias ablation, pediatrics atrial flutter, 513 ectopic atrial tachycardia, 512–513
A.S. Kibos et al. (eds.), Cardiac Arrhythmias, DOI 10.1007/978-1-4471-5316-0, © Springer-Verlag London 2014
electrophysiological study, 518 prevention of, 518 surgical correction, 518–519 therapy anticoagulation, 254 atrial flutter, 255 drugs, 255 radiofrequency ablation, 255 rate control, 255 surgical maze procedure, 255 Atrial fibrillation (AF), 199, 376, 377, 597 atrial ectopy, 402–403 atrial tissue remodeling, 406–407 autonomic nervous system, 407 calcium dysregulation, 404 catheter vs. surgery, 443–445 diagnosis of, 222–223 dysrrhythmia, 439 electrophysiology, 402 gain-of-function potassium channel mutations, 67 gap junctions, role of, 406 genetic disorders, 66, 407–408 genome-wide association studies 1q19, 72–73 4q23, 72 16q20, 72 ion channels and atrial electrical remodeling, 406 KCNQ1, 66–67 loss-of-function potassium channel mutations, 68–69 loss-of-function sodium channel mutations, 69 mechanism of, 440 mechanistic subtype AF-1, 67–68 AF-3, 69–70 AF-4, 70–71 AF-5, 71–72 AF-6, 72 molecular mechanisms ADAMs, 406 angiotensin II, 404–405 calcineurin and calpain, 404, 406 CaMKII, 404, 406 matrix metalloproteinases, 404, 406 oxidative stress, 405 PDGF, 404–405 TGF-%, 404–405 reentry mechanisms circus movement reentry, 403 leading circle reentry, 403 Moe’s multiple wavelet theory, 403–404 spiral wave reentry, 403
665
666 single-gene disease, 66 stroke (see Stroke and AF) surgery, 441 surgical ablation bipolar RF ablation, 442 Cox-Maze III lesions, 442 Cox-Maze IV lesion, 442 cut and sew technique, 441 energy source, 441 transmural lesions, 441 tachyarrhythmias, 439 treatment, 440–441 Atrial fibrillation (AF) ablation anti-arrhythmic, 427 catheter ablation adenosine, 424 arrhythmia surgery, 443 clinical results, 427–429 complex fractionated electrograms (CFAEs), 423 discontinuation of anticoagulation, 432 dormant conduction, 426 elderly patients, 431 electroanatomical maps, 421 electrode catheters, 443 far-field electrograms, 424, 425 ganglionated plexi, 421 isoproterenol, 424 lesion sets, 423 line rhythm control therapy, 432 long term outcomes, 428 MAZE procedure, 421 pathophysiology, 420 PV isolation, 426 radiofrequency ablation, 443 risks of, 429–430 structural heart disease, 431–432 technical aspects of, 424 thromboembolism, 427 CFAE, 460 clinical diagnosis anterior and posterior left atrial wall, 453, 455 atrial tachycardia, 453 blanking period, 452 distal coronary sinus, 453 3D mapping system, 455 ECG, 452 evaluate CS activation wave front, 453 flutter waves, 453 observe P wave morphology, 452–453 PVs for potential reconnection, 453 redo study, 452 tachycardia cycle length, 453 ECG recordings, 458 isoproterenol infusion, 458 left atrial structure accessory appendage, 415 anteroseptal ridge, 415 cord-like structure, 415 coronary sinus (CS)/left circumflex coronary (LCx) artery, 415–416 diverticulum, 415 esophagus/atrioesophageal fistula, 416 left atrial appendage (LAA), 415 left lateral ridge, 414–415 pulmonary vein-left atrium junction, 414 SNA, 416 vascular structures, 415–416
Index linear lesions in left and right atrium, 451 MDCT/MR, 416–417 mitral isthmus ablation, 455 pathophysiology, 451–452 patient monitoring, 452 patients follow-up, 458, 460 PMFL, 455 PV antrum isolation, 458 therapy, 455 Atrial flutter (AFL), 199 atrial function after radioablation mitral inflow spectral Doppler, 169 mitral transvalvular flow and diastolic tissue Doppler velocity, 169 pulsed tissue Doppler, lateral mitral annulus, 168 pulsed tissue Doppler, tricuspid annulus, 169 tricuspid inflow spectral Doppler, 169 hemodynamics anterograde and retrograde spectral Doppler flow, 174, 176 M mode, aortic valve, 174, 176 M mode color Doppler, mitral valve, 174, 176 spectral Doppler, aortic flow, 174, 176 tissue Doppler velocity, 174 tricuspid and mitral valve, 174 Atrial flutter catheter ablation echocardiographic characteristics, 467 electrocardiographic characteristics, 467 EnSite noncontact mapping system amplification, 465 bipolar and unipolar electrograms, 465 data acquisition process, 465 electrode catheters, 465 EnSite catheter, 464 filter settings, 465 inverse-solution computations, 465–466 locator system, 464 multielectrode array, 464 single-beat mapping, 465, 466 radiofrequency application, 466 Atrial natriuretic peptide (ANP), 71 Atrial tachycardia (AT) ablation techniques, 519–521 vs. AVRT, AVNRT, and JET (see Supraventricular tachycardias (SVT)) electrocardiographic diagnosis, 519 12-lead resting ECG, 152 prevention of, 518 Atrial tracking preference (ATP) algorithm scheme, 622-623 Atrial tracking recovery (ATR), 622 Atrioventricular (AV) accessory pathways anatomic considerations left free wall, 470–471 myocardial cells, 470 nomenclatures, 470 right free wall, 471–473 septum and paraseptum, 473 electrocardiographic location delta wave analysis, 473–475 retrograde p waves polarity, 475 mapping and ablation ablation principles, 478–479 antegrade conduction mapping, 475–477 catheter ablation, 475, 483–484 electrogram criterion, 475 electrophysiologic study protocol, 475 inferoparaseptal area, 481–482 left free wall, 479–480
Index quadripolar 6F diagnostic catheter, 475 retrograde conduction mapping, 477–478 right free wall, 480 septal and superoparaseptal area, 482–483 steerable decapolar 6F diagnostic catheter, 475 steerable 7F non-irrigated 4 mm tip catheter, 475 Atrioventricular block (AV block) clinical indications, 188 clinical practice, 190 Atrioventricular (AV) nodal dysfunction, 592 Atrioventricular nodal reentry tachycardia (AVNRT), 387 anatomy /normal and abnormal physiology Atypical variants, 393 clinical presentation/variants of AVNRT, 392 dual nodal physiology, 388 echo beat, 390 initiation and termination of AVNRT, 390, 391 QRS, 390, 391 typical AVNRT, 393 vs. AVRT, AT, and JET (see Supraventricular tachycardias (SVT)) clinical presentation, 392 concealed accessory pathway bundle branch block (BBB), 147, 148 localization, 146, 147 negative T wave, 145 orthodromic AVRT, 146–148 ST segment depression, 145 cryoablation, 398–399 diagnosis, 395 fast and slow pathway, 387 induction, 394–395 12-lead resting ECG, 145 pediatrics, 511–512 preexcitation, 149–151 radio frequency ablation AV block, 395 LAO, 395, 396 RAO, 395, 396 three-catheter study, 397 slow pathway (SP), 387 treatment cryoablation, 398–399 diagnosis, 391 EP study in patient, 394induction, 394–395 radio frequency ablation, 395–398 Atrioventricular node (AVN), 36, 544 anatomic and potential approaches, 640 anatomy, 24 atrial systole, 25 Cav1.3, 26 Cx43, 26 dual-pathway physiology atrial tissue posterior and inferior, 13 characteristics, 12 concealed conduction, 12 connexin isoforms, 14 Cx43-positive bundles, 13, 14 functional vertical dissociation, 12 immunohistochemical, 14 jump-up phenomenon, 12 premature stimulation, 13–14 Zipes’s group, 13 electrophysiological characteristics, 640 FP bipolar electrogram, 14 HCN4 channel, 25 Koch’s triangle, 77–8 location of, 77–8
667 microelectrode recordings, 14 morphologic and electrophysiological heterogeneity AN and NH, 10 electrocardiogram recording, 9 molecular basis, 10–12 Tawara’s node, 10 NF160 and Cx43 expression, 15 Nikolski’s group, 14 N myocytesshow, 25 N part, 15 pathophysiology, 26–27 PNE, 16 P wave and QRS complex, 14 structure of, 640–77 ventricular systole, 25 Atrioventricular node (AVN) ablation atrial fibrillation, 597 heart failure patients, 601 non-pharmacological method, 598 pacing AF guidelines, 600 benefit, 598 CRT, 599 DDDR group, 599 ESC guidelines, 600 interventricular and intraventricular dyssynchrony, 599 LV ejection fraction, 598, 599 meta-analysis, 598 trials, 599 patients with CRT indication, 600 sudden death, 599 tachycardiomyopathy, 600–601 Atrioventricular reciprocating tachycardia (AVRT). See Supraventricular tachycardias (SVT) Atrioventricular reentry tachycardia (AVRT) concealed accessory pathway bundle branch block (BBB), 147, 148 localization, 146, 147 negative T wave, 145 orthodromic AVRT, 146–148 ST segment depression, 145 preexcitation, 149–151 ATS. See Andersen-Tawil syndrome (ATS) Autonomic control atrial fibrillation autonomic nervous system, 44, 46 cellular mechanisms, 46–47 cardiac autonomic innervation, 44 VF and autonomic nervous system accentuated antagonism, 55 anti-arrhythmic effect, 54–55 anti-inflammatory action, 55–56 CAO, 53 clinical and preclinical evidence, 47 direct Anti-VF protection, 53 heart failure, 48 heterogeneous electrophysiological control, 50–52 Long QT, 52 muscarinic receptor activation and nitric oxide, 55 PNS and ventricular arrhythmias, 53 SCD, canine model of, 54 sympathetic nervous system and ventricular arrhythmias, 48–50 VNS, non-arrhythmic beneficial effects of, 56 AV block. See Atrioventricular block (AV block) AVNRT. See Atrioventricular nodal reentry tachycardia (AVNRT) AVRT. See Atrioventricular reentry tachycardia (AVRT)
668 B Bachmann’s bundle (BB), 39 Baroreceptor reflex sensitivity (BRS), 47 Biological pacemakers, 115 Biophysical and molecular targets acute and chronic long-term life-threatening effects, 335 cardiac ion channels Brugada syndrome, 336 inherited and acquired cardiac syndrome, 336 Na+ current block, 336 pathophysiological mechanisms, 337 SCN5A mutation, 336 definition, 336 microRNAs biosynthesis, 340 Dicer activity, 340–341 DiGeorge syndrome critical region gene 8, 341 heart development and function, 341 translational repression/cleavage, 339–340 upstream therapy abnormal intracellular Ca2+ signalling, 339 angiotensin-converting enzyme inhibitors, 337–338 angiotensin receptor blockers (ARBs), 337–338 antioxidant vitamins C and E, 338 calcium-/calmodulin-dependent kinase II, 339 calcium channel blocker, 337 cholesterol-lowering statin, 338 n-3 (v-3) polyunsaturated fatty acids, 337 pathological processes, 338 RAAS involvement, 337–338 tissue oxidation and inflammation, 338 Biosense-Webster CARTO system, 212–213 Bradycardias device programming, 594 follow-up, 593–594 home monitoring, 595 leadless pacing, 595 MRI compatibility, 594 pacemaker classification, 591–592 pacemaker implantation, 593 pacing mode selection, 592–593 permanent pacing AV nodal dysfunction, 592 SND, 592 postoperative management, 593, 594 preoperative preparation, 593 Bridging therapy bleeding, 658 cost, 657 disadvantages, 657–659 hemorrhagic complications, 657 LMWH, 656, 657 pericardial perforation/pneumothorax, 658 pocket hematoma, 657–658 thromboembolic risk, 656–657 warfarin, 656 Bundle branches and Purkinje network anatomy, 27–28 Ca2+-handling proteins, 29 Cx43 and Cx40, 27 mRNA level, 23, 28 pathology, 29 stable resting potential, 29 ventricular myocytes, 28
Index C CABANA. See Catheter Ablation versus Antiarrhythmic Drug Therapy (CABANA) Calcium-/calmodulin-dependent kinase II (CaMKII), 339 Calcium-dependent inactivation (CDI), 101 CAO. See Coronary artery occlusion (CAO) Cardiac automaticity and conduction system action potential propagation cardiomyocyte electrotonic coupling, 312 cellular ion channel-mediated excitation, 313, 315 Cx subunits and expression, 312–314 Gap junction channel, 312–315 His-Purkinje myocytes, 308, 314 slow conduction velocity, 313–315 upstrokes, 313 arrhythmogenic (see Arrhythmogenic automaticity) cellular pharmacology of action potentials, 306–308 Ca Sparks and RyR recovery, 307, 311 coupled clock system, 307, 312 definition, 306 depolarization, 307–309 His-Purkinje system, 307 ion channels/exchangers/pumps, 307, 309–311 pharmacological block, 307, 311 repolarization, 307, 309 Strong inward rectification, 308, 312 heartbeat, 305, 306 outcomes, 306 Purkinje fibers, 306, 307 sinoatrial node impulse, 306, 307 upstream modulation arrhythmogenic conduction, 322 autonomic innervation, 315 β1-3-adrenergic receptors, 315 CaMKII signaling, 317, 318 Gαiβγ and Gαqβγ signaling, 317 G-protein-mediated effects, 317, 319 heart rate, 316, 317 ion channel modulation, 316 miRNAs, 317–320 sick sinus syndrome, 320 triggered activity, 320–322 Cardiac conduction system atrioventricular node, 37–38 anatomy, 24 atrial systole, 25 Cav1.3, 26 Cx43, 26 HCN4 channel, 25 N myocytesshow, 25 pathophysiology, 26–27 ventricular systole, 25 bundle branches and Purkinje network anatomy, 27–28 Ca2+-handling proteins, 29 Cx43 and Cx40, 27 mRNA level, 23, 28 pathology, 29 stable resting potential, 29 ventricular myocytes, 28 bundles, 37 crista terminalis, 36 interatrial septum, 37 Koch triangle, 38
Index Purkinje fiber network system, 36 right atrium, 36 SAN, 37 septal components, AV, 37 sinus node anatomy, 20–21 atrial myocardium, 22 K+ currents, 22 mRNA level, 22, 23 pathology, 24 subcellular Ca2+-clock mechanism, 22 voltage-clock mechanism, 22 vascular supply AVN artery, 39 SAN artery, 38 vestibule, 37 Cardiac electrical stability invasive electrophysiological study, 139 noninvasive markers, 139 OAT, 140 prevalence of, 139–140 QRS complex, 139 signal-averaged electrocardiogram, 139–140 spontaneous and induced ventricular arrhythmias, 140–141 thrombolytic therapy, 139 T-wave variability, 140 Cardiac imaging computed tomography imaging data acquisition, reconstruction, and display, 370 fundamentals, 370 3D mapping systems Carto mapping system, 372–373 CFAE, 373 electroanatomical mapping, 374 electromagnetic fields and electrical currents, 369 EnSite mapping system, 373–374 3DRA, 380–381 future applications, 381–383 integration, complex arrhythmia ablation (see Image integration, complex arrhythmia ablation) intracardiac ultrasound, 372 linear imaging techniques, 370 MRI CMR imaging, 371 fundamentals, 370–371 X-ray-based imaging, 371 PET, 371 X-ray fluoroscopy, 369 Cardiac implantable electronic devices (CIED) acute complications air embolism, 641–642 arterial-venous fistula, 642 brachial plexus injury, 642 chylothorax, 641 hemomediastinum, 641 hemopneumothorax, 641 hemothorax, 641 pneumothorax, 641 venous access-related complications, 640–641 common complications, 640 complication rate, 639 definitions, 639 incidence, 639 late complications, 640 device allergy, 648
669 erosion, 647 late pocket infection, 647–648 local pain, 646 migration, 646–647 lead-related complications acute venous thrombosis, 643–644 atrial arrhythmias, 642 chronic venous thrombosis, 644 diaphragmatic stimulation, 644 lead dislodgements, 648 lead displacement, 642 lead infection and lead endocarditis, 648–649 lead injuries, 643, 648 myocardial penetration and perforation, 642–643 tricuspid valve injury, 643 Twiddler’s syndrome, 648 venous thrombosis, 643 ventricular arrhythmias, 642 long-term complications, 649–650 pocket-related complications early pacemaker pocket infection, 644 hematomas, 644 pocket suture dehiscence, 644 specific complications, 640 acute ICD lead-specific complications, 646 acute lead displacement, 645 contrast nephropathy, 646 coronary sinus dissection, 645–646 coronary sinus laceration/perforation, 646 coronary sinus locating and cannulating, 645 diaphragmatic pacing, 645 lead position obtaining, 645 phrenic nerve stimulation, 645 Cardiac magnetic resonance (CMR) imaging, 371 Cardiac mapping activation mapping electroanatomical mapping system, 194, 195 multisite recording technique, 193–194 roving catheter technique, 193 definition, 193 entrainment mapping, 195–196 pace mapping, 195 Cardiac pacing atrioventricular node, 544 atrioventricular optimization, 558–561 device-based algorithms EEHFTM, 558 NICOM, 558 QuickOptTM, 557–558 SMART-AV, 557 SonR, 558 dyssynchrony atrioventricular, 544 CRT, 546 definition, 544 development, 544, 545 electrical, 544 interventricular, 545 intraatrial and interatrial, 544 intraventricular, 545 LVESV, 546 mechanism, 544 optimization method, 546 echocardiographic methods, 548 interventricular optimization, 555, 562–563
670 Cardiac pacing (cont.) intraventricular optimization color TDI, 567 2D-STE, 566 echocardiographic parameters, 568 IV dyssynchrony, 566 role, 565 septal flash, 566 SPWMD, 566 triplane TDI, 567 invasive methods invasive LV dP/dtmax, 556–557 LV pressure and volume loops, 557 left ventricle diastolic function Ishikawa method, 552–553 Ismer’s method, 553 iterative method, 550, 552 Meluzin’s method, 552 mitral inflow VTI, 552 Ritter method, 550–551 left ventricle systolic function CW Aortic VTI, 553 LVOT-VTI, 553–554 TDI, 554 left ventricular function Doppler-derived dP/dTmax, 554–555 MPI/ Tei Index, 555–556 left ventricular lead position classification, 573 CRT, 572 echocardiographic criterion, 573 location, 572 MADIT-CRT trial, 573 myocardial scar tissue, 573–574 RT3DE tissue, 573 segments, 572 TDI optimization method, 573 M-mode echocardiography, 548 optimization method atrioventricular, interventricular and intraventricular, 547 comprehensive assessment, 546 intracardiac electrograms, 548 LV dyssynchron, 547 non-echocardiographic methods, 548 RT3DE, 547–548 pacing site atrioventricular synchrony, 606 DDDR, 607 definitions, 607 heart rate, 606 His-bundle, 609 lead placement, 609–610 left ventricular apex, 609 LV function, 606 physiologic activation and timing patterns, 606–607 RA and RV, 606 rate-response, 606 right ventricular selective, 607–609 RVA, 607 PW TDI and color-coded TDI, 548–549 quadripolar left ventricular lead, 575–578 RT3DE, 550 RVA pacing bifocal RV pacing, 571 CRT, 569, 570
Index detrimental outcomes, 569 Para-Hisian pacing, 570 right ventricular septal location, 570 RV outflow tract, 570–571 side effects, 569 triangle ventricular pacing, 571–572 sequential vs simultaneous BiV pacing, 563–566 sinoatrial node, 544 strain imaging, 549–550 synchrony, 558 TSI, 549 Cardiac resynchronization therapy “ablate and pace” strategy, 631 adjunctive therapy, 631 AV and VV timing optimization, 635–636 AV nodal ablation, 631 benefits, 631 clinical predictor, 635 CONTAK-CD, 631 delayed ventricular depolarization, 630 3D mapping, 633 3D speckle-tracking strain assessment, 634 electrical dyssynchrony, 630 long-term outcomes, 631–632 LV lead position, 635 mechanical dyssynchrony, 630–631 multicenter trials, 631 noncontact mapping system, 633 non-left bundle branch block (LBBB) pattern, 632 nonresponders, 632 radial strain, 634 scar location, 635 speckle tracking, 633, 634 Cardiac resynchronization therapy (CRT), 600, 647 atrial and ventricular activity histogram, 620, 621 atrial oversensing, 622–625 atrial-paced and atrial-sensed events response, 621 atrial undersensing ATP algorithm scheme, 621–622 ATR, 621 functional/pseudo-atrial, 621 iTARP, 621 PVARP, 621, 622 true undersensing, 621 biventricular pacing, 620 CS lead oversensing atrial and ventricular activity histogram, 626, 627 BiV-paced QRS morphology, 625 telemetry strip, 625 triple chamber systems, 626 T-wave oversensing, 626–627 electrical storm, 321–322, 599 LVPP, 620 LVRP, 620 objective, 620 PMT algorithms, 628 rate-smoothing algorithms, 627–628 CartoT system, 490 Catecholaminergic polymorphic ventricular tachycardia, 98 Catheter ablation, 475, 483–484 cryothermal energy cryoablation, 365 lesion formation, 365 limitations, 365 tissue response, 364–365
Index laser energy laser balloon ablation, 365–366 lesion formation, 365–366 limitations of, 366 pediatrics ablation results and complications, 511 accessory pathway ablation, 511 atrial arrhythmias, 512–513 AVNRT ablation, 511–512 practical considerations, 510 substrates, 509 ventricular tachycardia ablation, 513–414 radio frequency energy (see Radio frequency ablation) Catheter Ablation versus Antiarrhythmic Drug Therapy (CABANA), 423 Cavotricuspid isthmus, 84 atrial flutter ablation echocardiographic characteristics, 467 electrocardiographic characteristics, 467 EnSite noncontact mapping system, 464–466 flutter waves, 464 CDI. See Calcium-dependent inactivation (CDI) Cerebral resuscitation techniques (CPR), 280, 281 Channelopathy cardiac Ca2+ channels CACNA1C, 102 CDI, 101 ICaT expression, 103 L-type Ca2+ channels, 101 mineralocorticoid antagonists, 103 Quinidine, 102 α2δ-subunit, 101 Timothy syndrome, 102 T-type channels, 101 voltage-gated calcium channels, 100 cardiac K+ channels acetylcholine-activated inward rectifier K+ current (IK(ACh)), 113 ATP-inhibited inward rectifier K+ current (IK(ATP)), 113 fast and slow transient outward K+ Current (Ito), 108–110 fast delayed rectifier K+ Current (IKr), 106–108 funny (hyperpolarization-activated) channels (If), 114–115 gap junction channels (Ij), 115–116 inward rectifier K+ current (IK1), 110–112 repolarization process, 103 slow delayed rectifier K+ Current (IKs), 103–106 cardiac Na+ channels Brugada syndromes, 98 β-subunit, 96 DMD, 97 FHF1B, 96 genotype/phenotype relationship, 99 1795insD mutation, 100 long QT syndromes, 98 missense mutation, 97 overview of, 97 pharmacological effects, 100 phosphorylation, 100 short QT syndromes, 98 α-subunit, 99 TRP channels and heart disease, 116–117 Chiang’s algorithm, 149 Circus movement reentry, 322, 403 Color-Coded Tissue Doppler Imaging (Color-Coded TDI), 548–549 Complex fractionated atrial electrogram (CFAE), 373 Conduction delay and malignant ventricular tachyarrhythmias (CONTAK-CD), 631
671 Congenital heart disease ablation techniques atrial tachycardia, 519–521 cavotricuspid isthmus, 519–521 electroanatomic mapping, 520 Fontan-Kreutzer technique, 519, 520 VT ablation (see Ventricular tachyarrhythmia (VT) ablation) arrhythmia in mechanisms of, 518 prevention of, 521 risk factors, 517 catheter ablation pediatrics (see Catheter ablation) electrocardiographic diagnosis, 519 pathophysiology, 518–519 Connexin-43 (Cx43) expression cardiac ventricle, 352 conduction velocity, 352–353 connexin and oxidative stress, 358 gap-junctional channels, 352 infarction and ischemia abundance/expression, 354 17β-estradiol, 356 cardioprotective effects, 356 gap junctions, 354 HMG-CoA, 356 nitric oxide, 355 NOS activity, 356 proteasomal and lysosomal inhibitors, 354 ventricular tachycardia, 356 phosphorylation and heart failure, 356–357 predominant function, 351 rotigaptide, 357–358 transmural electrophysiological gradients, 353–355 ventricular remodeling, 353 Continuous Wave Aortic Valve Velocity Time Integral (CW Aortic VTI), 553 Contrast-Enhanced Computed Tomography (CE-CT), 378 Coronary artery occlusion (CAO), 47 Coronary sinus (CS), 640, 41 Cryomapping, 483 Cryothermal energy ablation, 483 cryoablation, 365 cryo-balloon ablation, 460 lesion formation, 365 limitations, 365 tissue response, 364–365
D Dabigatran, 229–230 DADs. See Delayed afterdepolarizations (DADs) Data Sciences International (DSI), 62 Delayed afterdepolarizations (DADs), 29, 51, 241, 245, 320, 403 Diastolic interval (DI), 49 DiGeorge syndrome critical region gene 8 (DGCR8), 341 Digital image fusion (DIF) model, 375 Direct thrombin inhibitors (DTI), 660–661 2D speckle-tracking echocardiography (2D-STE), 550 Dual atrioventricular nodal atrial fibrillation, 2 inferior/posterior extensions, 2myocardial fibers, 2 physiology, 1–2 Dystrophin gene (DMD), 97
672 E Early afterdepolarizations (EAD), 28, 46, 47, 100, 118, 403 Early repolarization syndromes (ERS), 110 Ebstein’s anomaly, 518 Echocardiography atrial fibrillation, 170–173 atrial flutter hemodynamics, 174, 176 tissue Doppler velocity, 174 tricuspid and mitral valve, 174 atrial premature beats, diagnosis, 165 diastolic mitral regurgitation, 184 first-degree atrioventricular block, 177, 180 junctional rhythm, 170–171 left atrial appendage doppler flow, 174 second-degree atrioventricular block, 177, 182 sinus arrest and sinus rhythm recovery mitral inflow spectral Doppler, 177, 179, 180 M mode, mitral valve, 177, 178, 180 M mode, right atrial wall, 177, 178, 181 pulsed tissue Doppler, lateral mitral annulus, 177, 179, 181 sinus tachycardia, 166, 169 supraventricular paroxistic tachycardia disadvantages, 171 mitral inflow spectral Doppler, 166, 168, 181 pulsed tissue Doppler, 166, 168–170 total atrioventricular block, 182–184 ventricular premature beats (see Ventricular premature beats) ventricular tachycardia, 184, 185 ECNA. See Extrinsic cardiac nerve activity (ECNA) Effective refractory period (ERP), 66 Electrical dyssynchrony, 630 Electrical storm (ES) definition, 293 electrocardiographic classification monomorphic VT, 295 polymorphic VT, 295–296 ventricular fibrillation, 296 etiology, 285, 286 ICD patient, 315, 316 incidence, 285–286, 293, 295 non-pharmacologic therapy, 289–290 cardiac resynchronization therapy, 300 catheter ablation therapy, 299–300 implantable cardioverter-defibrillators, 299 intra-aortic balloon pump, 301 invasive adrenergic blockade, 301 pathophysiology beta-adrenergic stimulation, 287 brugada syndrome, 287–288 catecholaminergic polymorphic VT, 287 causes of, 286–287 early afterdepolarization (EAD), 287–288 mechanism, 286 myocardial ischemia, 287 Purkinje fibers, 287 pharmacological management ACLS guidelines, 288 ALIVE trial, 288 amiodarone, 247 anesthetics, 288 antiarrhythmic agents, 289 ARREST trial, 288 %-blockade, 247 brugada syndrome, 289
Index early repolarization syndrome, 289 epinephrine/vasopressin, 288 sodium-channel blocking agents, 247 sympathetic blockade, 288 pharmacologic therapy adrenergic blockade, 296–297 antiarrhythmic agents, 297 pharmacology prognosis, 293–294 risk factors, 293–294 triggers, 293–294 Electroanatomic mapping (EAM) systems, 194, 195, 417 Biosense-Webster CARTO system, 212–213 Ensite NavX system, 213, 214 MediGuide system, 213, 214 St Jude Medical Ensite array system clinical tachycardia, 215 LAO view, 216 MEA, 213 pace-map, 215, 216 PA view, 216 posterior fascicular VT, 217, 218 virtual electrograms, 213 Electrocardiographic (ECG) gating, 370 Electrophysiologic testing (EP test) AV block clinical indications, 188 clinical practice, 190 electrode catheter placement, 189 intracardiac electrograms and cardiac pacing, 187 narrow QRS complex tachycardia clinical indications, 188 clinical practice, 190–192 patient preparation, 189 programmed cardiac stimulation, 189 radiofrequency catheter ablation (RFCA), 187 requirement, 188 risk evaluation, 188 sick sinus syndrome (SSS) clinical indications, 187 clinical practice, 189–190 unexplained syncope clinical indications, 188 clinical practice, 192 wide QRS complex tachycardia clinical indications, 188 clinical practice, 192, 193 WPW syndrome, 188 Ensite NavX system, 213, 214 EnSite noncontact mapping system amplification, 465 bipolar and unipolar electrograms, 465 cardiac imaging, 373–374 data acquisition process, 465 electrode catheters, 465 EnSite catheter, 464 filter settings, 465 inverse-solution computations, 465–466 locator system, 464 multielectrode array, 464 single-beat mapping, 465, 466 Entrainment cardiac mapping, 195–196 Epicardial mapping and ablation substrate, 494, 495 supraventricular arrhythmia, 527–528 ventricular arrhythmia, 528
Index complications, 529 endocardial and epicardial activation, 526–527 energy sources, 529 pericardial space, 525–526 post-procedure management, 529 EP test. See Electrophysiologic testing (EP test) ERS. See Early repolarization syndromes (ERS) Expert Ease for Heart FailureTM (EEHFTM) algorithm, 558 Extrinsic cardiac nerve activity (ECNA), 63
F Familial atrial fibrillation, 98 Fascicular ventricular tachycardia, 153 Fast anatomical mapping (FAM), 374 Fibroblast growth factor homologous factor 1B, 96 Fiducial registration error (FRE), 375 Field scaling algorithm, 375 Fitzpatrick’s algorithm, 149 Framingham Heart Study, 66
G Ganglionic plexi, 40 Ganglionic plexuses (GPs), 44, 45 Gap junction (GJ) channel, 12, 115–116, 312–315 Geometry-based registration, 375 Global utilization of streptokinase and tissue plasminogen activator for occluded coronary arteries (GUSTO), 133–134, 136
H Hansen sensei robotic system (HSRS) efficacy, 540 fluoroscopy, 540 mobile workstation, 538, 539 rationale of, 539–540 safety, 540 Hazard ratio (HR), 498 HCM. See Hypertrophic cardiomyopathy (HCM) Head-up tilt test (HUTT) with pharmacological provocation, 161, 162 protocols, 161 risk of, 162 vasovagal syncope pathophysiology, 160, 161 without pharmacologic provocation, 161 Heart failure treatment. See Cardiac resynchronization therapy Heart rate variability (HRV), 47 High frequency ultrasound (HIFU), 441 His-Purkinje myocytes, 308, 314 Hodgkin-Huxley model, 95 Hounsfield units (HU), 370 HSRS. See Hansen sensei robotic system (HSRS) HUTT. See Head-up tilt test (HUTT) Hybrid cardiac PET/CT imaging, 371 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA), 356 Hypertrophic cardiomyopathy (HCM), 614 after ASA and surgical myectomy bradyarrhythmias, 258 conduction abnormalities, 258 tachyarrhythmias, 259 atrial arrhythmias anticoagulation, 254 atrial flutter, 255 drugs, 255
673 radiofrequency ablation, 255 rate control, 255 surgical maze procedure, 255 clinical benefit long-term follow-up, 260 observational study, 259 randomized controlled trial, 259 DDD pacing, 259 dual-chamber pacing, 259 electrocardiogram (ECG), 253, 255 NSVT, duration of, 255–257 complications, 256–257 LGE, 257 results, 257 sudden cardiac death, 256, 257 ventricular arrhythmias circadian variability, 256 myocardial disarray, 255 small vessel disease, 255 substrate, 255 triggers and mechanism, 255–256
I Idiopathic sick sinus syndrome, 98 Image fusion. See Image integration, complex arrhythmia ablation Image integration, complex arrhythmia ablation image fusion technology atrial fibrillation, 376, 377 atrial tachycardias, 379 corrective and palliative congenital heart surgery, 379–380 ventricular outflow tract and idiopathic tachycardias, 380 ventricular tachycardia (see Ventricular tachycardia (VT)) image registration, 375 image segmentation, 375 pre-procedural image acquisition, 375 registration errors, 375–376 software packages, 374 Implantable cardioverter defibrillators (ICD) implantation vs. antiarrhythmic therapy, 613 complications, 617 historical perspective, 613–614 indications, 614–615, 617 single-center retrospective analysis, 616 surgical outcomes, 616–617 transvenous pacemaker lead implantation, 615–616 Implied total atrial refractory period (iTARP), 621 Intra-aortic balloon pump (IABP), 288, 298, 300 Intracardiac electrograms (IEGMs), 557 Intracardiac tracings, 199, 200 Intracardiac ultrasound (ICE) imaging, 372 Intraventricular mechanical delay (IVMD), 548 Intrinsic cardiac nerve activity (ICNA), 63 Inversion recovery (IR), 371 Ischemic cardiomyopathy (ICMP), 536 Ismer’s method, 553 Isovolumetric contraction velocity, 166–167 Isthmus structures, right atrium anatomical variations, 82, 84 conduction gap, 87 inferior isthmus, 80–81 inferolateral isthmus, 81–82 paraseptal isthmus, 79–80 spontaneous scars, 87 surgical scars, 86–87
674 J Jervell and Lange-Nielsen syndrome (JLNS), 105 Junctional ectopic tachycardia (JET) AHA response, 205, 208 atrial activation, 200 AV block, 203 infants/young children, 199 RP tachycardia, 200 spontaneous oscillations, tachycardia CL, 202 J wave syndromes, 110
K Kernel reconstruction, 370 Kugel anastomotic artery, 40
L Laser energy ablation laser-balloon, 460 lesion formation, 365–366 limitations of, 366 Late gadolinium enhancement (LGE), 257, 378 Late open artery hypothesis acute/chronic myocardial infarction, 133 cellular necrosis, 132–133 clinical trials EMERAS, 138 GUSTO-I, 136 ISIS-2, 138 LATE, 138 TAMI, 136–138 TAMI-6 trial, 138–139 early reperfusion/reductions, 134 ejection fraction electroanatomic chronic scar size, 136, 137 end-systolic volume, 135–136 hyperkinesis vs. dilation, 135 imaging techniques, 135 implantable cardioverter-defibrillators, 135 left ventricular volume, 135 post-infarction healing process, 135 late reperfusion, 134 myocardial infarction, 132 non infarcted myocardium/ventricular remodelling, 133 thrombolyic therapy, 133–134 Lateral wall post-systolic displacement (LWPSD), 548 Leading circle reentry, 403 12-Lead resting ECG atrial tachycardia (AT), 152 AVNRT, 145 AVRT (see Atrioventricular reentry tachycardia (AVRT)) ventricular tachycardia (VT) fascicular VT, 153 LBBB morphology, 153 narrow QRS complex and AV dissociation, 153, 154 positive precordial concordance with RBBB morphology, 153, 154 principles, 152 wide QRS tachycardia, 153 Left anterior oblique (LAO), 216 Left atrial appendage (LAA), 415 Left septal ventricular tachycardia. See Fascicular ventricular tachycardia Left ventricular outflow tract velocity time integral (LVOT-VTI), 553–554
Index Left ventricular protection period (LVPP), 647 Left ventricular refractory period (LVRP), 647 LGE. See Late gadolinium enhancement (LGE) Local atrioventricular interval, 476 Local ventriculoatrial interval, 477 Long QT syndrome (LQTS), 52 Long term electrocardiograph monitoring antiarrhythmic therapy, 160 diagnosis, 158, 159 event recorder, 158 external loop recorder, 158 heart rate variability, 160 Holter monitor, 158 implantable loop recorder, 158 mobile cardiac outpatient telemetry, 158 risk assessment hypertrophic cardiomyopathy, 160 myocardial infarction survivors, 158 premature ventricular complex, 159 ventricular ectopy, 159 types, 157–158 Low-amplitude burst discharge activity (LABDA), 49 Low molecular weight heparin (LMWH), 656, 657
M Magnetic resonance imaging (MRI), 594, 635 CMR imaging, 371 fundamentals, 370–371 ventricular tachycardia, 378–379 X-ray-based imaging, 371 Maximum diastolic potential (MDP), 21 McAllister-Noble-Tsien model, 96 Mechanical dyssynchrony, 630–631 MediGuide system, 213, 214 Meluzin’s method, 552 Moe’s multiple wavelet theory, 403–404 Multi-detector computed tomography (MDCT), 414 Multi-electrode array (MEA), 213, 464 Multielectrode diagnostic catheter, 479 Multifocal atrial tachycardia (MAT), 199 Multisite recording technique, 193–194 Myocardial infarction. See Ventricular arrhythmias Myocardial Performance Index (MPI), 555–556 Mysterious sleep death. See Sudden unexplained death syndrome (SUDS)
N Neural mechanisms, autonomic nervous system extrinsic-intrinsic cardiac ANS, 61–62 structural and functional remodeling, 63–64 sympathetic-parasympathetic, 62–63 Neurocardiogenic syncope. See Vasovagal syncope N(G)-nitro-l-arginine methyl ester (L-NAME), 380 Non-echocardiographic methods invasive LV dP/dtmax, 556–557 LV pressure and volume loops, 557 Noninvasive cardiac output measurement (NICOM), 558
O Occluded artery trial (OAT), 139–141 Optimal Pharmacological Therapy in Implantable Cardioverter Defibrillator Patients (OPTIC), 498
Index Oral anticoagulants therapy bridging therapy (see Bridging therapy) Bruise control study, 659–660 guidelines, 658, 659 hemorrhagic risk, 654 high thrombotic risk patients, 656 low thrombotic risk patients, 656 thromboembolic risk, 655–656 VKA (see Vitamin K antagonist) Orthodromic tachycardia, 475
P Pace cardiac mapping, 195 Pacemapping activation mapping approach, 499 bard EP template matching, 499, 500 biosence webster PASO algorithm, 499, 500 bipolar stimulation, 499 ICD, 501 PVC, 499 QRS morphology, 499 sinus rhythm, 499 slow conduction, 499 unipolar stimulation, 499 PACES. See Pediatric and Adult Congenital Electrophysiology Society (PACES) Paroxysmal supraventricular tachycardia (PSVT). See Supraventricular tachycardias (SVT) Patent foramen ovale (PFO), 37 Peak endocardial acceleration (PEA), 558 Pediatric and Adult Congenital Electrophysiology Society (PACES), 511 Pediatric and congenital heart disease prevention. See Implantable cardioverter defibrillators (ICD) implantation Perimitral flutter (PMFL), 455 PFO. See Patent foramen ovale (PFO) Pocket hematoma, 657–658 Point-based registration, 375 Position emission tomography (PET), 371 Posterior nodal extensions (PNEs), 16 Postero-anterior (PA) view, 215, 216 Post-pacing interval minus tachycardia CL (PPI-TCL), 204, 206 Postventricular atrial refractory period (PVARP), 621, 622 Premature ventricular complexes (PVCs), 499 cardiomyopathy/myocardial scarring, 209 electrophysiological study, 211–212 first-line therapy, 209 impair cardiac function, 209 lead electrocardiogram, 210–212 mapping Biosense-Webster CARTO system, 212–213 Ensite NavX system, 213, 214 MediGuide system, 213, 214 St Jude Medical Ensite array system (see St Jude Medical Ensite array system) radiofrequency ablation, 209 symptoms, 209 tachycardia induced cardiomyopathy, 209 Proarrythmia definition, 345 digitalis toxicity, 346 mechanism, 348 sodium channel block altered defibrillation/pacing threshold, 347 atriventricular conduction, 346–347 “incessant” slow VT, 347
675 torsade de pointes (TdP) electrocardiographic features, 347 genetics, 348–349 management of, 349 mechanisms, 348 QT prolongation, 347 risk factors, 348 Prospective Assessment after Pediatric Cardiac Ablation (PAPCA), 511 Prothrombin time (PT), 231 Pulsed tissue Doppler image isovolumetric contraction velocity, 166–167 supraventricular paroxistic tachycardia, 168, 169 Pulsed wave tissue Doppler imaging (PW TDI), 548–549 Purkinje fibers (PF), 27, 244, 306, 307
R RAAS. See Retrograde atrial activation sequence (RAAS) Radio frequency ablation anatomy, 362 atrioventricular nodal reentry tachycardia AV block, 395 LAO, 395, 396 RAO, 395, 396 three-catheter study, 397 hyperthermia, 361 limitations of, 364 radio frequency current, 361–362 tissue heating blood flow, 362 current, 361–362 electrode size, 362–364 irrigation technology, 363, 364 temperature vs. power-control mode, 363 Radiofrequency catheter ablation (RFCA), 149, 187 Real-time 3D echocardiography (RT3DE), 550 Retrograde atrial activation sequence (RAAS), 201–203 Right atrium anatomy of, 77–79 conduction gap-related isthmus structure, 87 isthmus structures anatomical variations, 82, 84 inferior isthmus, 80–81 inferolateral isthmus, 81–82 paraseptal isthmus, 79–80 scar-related isthmus structures spontaneous scars, 87 surgical approach, 86–87 triangle of Koch, 84, 86 Right ventricular apex pacing (RVA), 569, 570 Right ventricular apical (RVA), 607 Right ventricular outflow tract tachycardia (RVOT) ablation, pediatrics, 513 clinical tachycardia, 215 LAO view, 216 pace-map, 215, 216 PA view, 216 Ritter method, 550–551 Rivaroxaban contact activation pathway, 231 CYP3A4, 231 pharmacokinetic profile, 231 prothrombinase/Stuart-Power factor, 231 PT/aPTT, 231 Rocket AF study, 231–232
676 Rivaroxaban (cont.) stroke and systemic embolism, 232 thrombin pathway, 231 tissue factor pathway, 231 Robotic ablation arrhythmias, 534 catheter ablation, 534 HSRS efficacy, 540 fluoroscopy, 540 mobile workstation, 538, 539 rationale of, 539–540 safety, 540 robotic navigation systems, 540 stereotaxis remote magnetic navigation system (see Stereotaxis remote magnetic navigation system) Romano-Ward syndrome (RWS), 104 Rotigaptide, 357–358 Roving catheter technique, 193
S Septal-to-posterior wall motion delay (SPWMD), 548, 566 Sheath system, 538 Sick sinus syndrome (SSS), 187, 320–321 clinical indications, 187 clinical practice, 189–190 SIDS. See Sudden infant death syndrome (SIDS) Sinoatrial node (SAN), 38, 544 Sinus nodal artery (SNA), 416 Sinus node anatomy, 20–21 atrial myocardium, 22 K+ currents, 22 mRNA level, 22, 23 pathology, 24 subcellular Ca2+-clock mechanism, 22 voltage-clock mechanism, 22 Sinus node dysfunction (SND), 592 Spin-echo, 371 Spiral wave reentry, 403 SSS. See Sick sinus syndrome (SSS) Steerable guide catheter (SGC), 538 Stereotaxis remote magnetic navigation system AF ablation, 536 anatomical structures, 535 catheter ablation, 534 circular mapping, 537 computer-controlled workstation, 535 congenital heart disease, 537 fluoroscopy time, 535 lesion formation, 536 manual catheters, 535 rationale of, 535–536 remote RMN procedures, 537–538 safety, 536 Vdrive controller, 538 VT ablation, 536 St Jude Medical Ensite array system MEA, 213 posterior fascicular VT, 217–218 RVOT clinical tachycardia, 215 LAO view, 216 pace-map, 215, 216 PA view, 216 virtual electrograms, 213
Index Stroke and AF acute cardioembolic stroke, 225 antithrombotic therapy, 226 apixaban, 232–233 bleeding risk, 226–227 CHEST recommendations, 222 dabigatran and RE-LY trial acute ischaemic stroke, 230 creatinine clearance, 230 dose selection/monitoring effect, 230 outcome, 229–230 stroke and systemic embolism, 229 transient ischaemic attack, 230–231 diagnosis Holter monitor, 223 12-lead electrocardiogram (ECG), 222–223 oral anticoagulation, 223–225 transesophageal echocardiography, 223 oral anticoagulation, 222 prevalence of, 222 rivaroxaban contact activation pathway, 231 CYP3A4, 231 pharmacokinetic profile, 231 prothrombinase/Stuart-Power factor, 231 PT/aPTT, 231 Rocket AF study, 231–232 stroke and systemic embolism, 232 thrombin pathway, 231 tissue factor pathway, 231 secondary stroke prevention, 226 Substrate mapping, VT ablation, 490 epicardial ablation, 494, 495 indications, 493 late potentials, 492–493 linear lesions, scar borders, 490–491 Sudden infant death syndrome (SIDS), 108 Sudden unexplained death syndrome (SUDS), 266, 272 causes, 266–268 diagnosis arrhythmogenic marker, 268–269 Brugada ECG pattern, 269–270 clinical profiles and epidemiology, 268 genetic study, 271–272 pharmacological test and high ICS position, 270–271 phallic symbol, 266 treatment of asymptomatic Brugada cases, 272–273 symptomatic, 272 VF substrate and radiofrequency ablation, 273–275 SUDS. See Sudden unexplained death syndrome (SUDS) Supraventricular arrhythmias ablation epicardial mapping, 527–528 Supraventricular paroxistic tachycardia disadvantages, 174 mitral inflow spectral Doppler, 170–173 pulsed tissue Doppler, 171 Supraventricular tachycardias (SVT) aberration, 202–203 atrial-based SVTs, 199 AV block, 203 AV node-dependent tachycardias, 199 baseline observations dual AV node physiology, 201 para-Hisian pacing, 201 ventricular preexcitation, 200–201 ventriculoatrial conduction, 201
Index diagnosis elements, 199–200 diagnostic pacing maneuvers atrial overdrive pacing, 204–205, 208 His refractory ventricular extrastimulus testing, 204, 207 ventricular overdrive pacing (see Ventricular overdrive pacing) electrocardiographic (ECG) features atrial activation, 200 P wave morphology and RP interval, 200 initiation, 202 retrograde atrial activation sequence, 201–202 spontaneous termination, 203, 204 tachycardia CL oscillations, 202 and septal VA time, 201 Surface-based registration, 375 SVT. See Supraventricular tachycardias (SVT)
T Tachycardia cycle length (TCL), 374 Tachycardiomyopathy, 600–601 Three dimensional rotational angiography (3DRA), 380–381 Thrombolysis and angioplasty in myocardial infarction (TAMI), 136–138 Timothy syndrome, 102 Tissue Doppler imaging (TDI), 554 Tissue Doppler velocity atrial flutter, 174, 175 first-degree atrioventricular block, 177, 180 total atrioventricular block, 182, 183 Tissue synchronization imaging (TSI), 549 12-Lead resting ECG atrial tachycardia (AT), 152 AVNRT, 145 AVRT (see Atrioventricular reentry tachycardia (AVRT)) ventricular tachycardia (VT) fascicular VT, 153 LBBB morphology, 153 narrow QRS complex and AV dissociation, 153, 154 positive precordial concordance with RBBB morphology, 153, 154 principles, 152 wide QRS tachycardia, 153 Torsade de pointes (TdP) drug-induced QT prolongation, 347 electrocardiographic features, 347 genetics and LQTS, 348–349 management of, 349 mechanisms, 348 risk factors, 348 Transient ischaemic attack (TIA), 222 Transient receptor potential (TRP) channels, 116–117 Transvalvular Doppler flow sinus tachycardia, 166, 169 supraventricular paroxistic tachycardia, 166, 169 total atrioventricular block, 182, 184 Tricuspid valve (TV), 640 Twiddler’s syndrome, 648
U Unipolar electrogram morphology pattern, 476
V Vagus nerve stimulation (VNS), 53 Vasovagal syncope, 160, 161
677 Vaughan-William classification, 322 VDI. See Voltage-dependent inactivation (VDI) Velocity-time integral method, 552 Ventricular arrhythmias ablation, epicardial mapping, 528 myocardial infarction/ischemia accelerated idioventricular rhythm, 246 action potential changes, 239–240 arrhythmia mechanisms, 239 arrhythmogenic phases, 240 autonomic nervous system, 242 biochemical mechanism, 240–241 electrophysiological mechanism, 240–241 endothelin, 242–243 epidemiology, 238 extrasystoles and couplets, 245–246 free fatty acids, 241 gap junctions, 241–242 genetic factors, 243 historical aspects, 237–238 long-term prognosis, 248 mechanisms of, 243–244 morphology, 239 pre-hospital vf, 247–248 reperfusion arrhythmias, 244–245 risk factors, 238 sustained ventricular arrhythmias, 246 thrombin, 242 treatments, 248 Ventricular overdrive pacing atrial-atrial-ventricular (A-A-V) response, 203, 205 atrial-ventricular (A-V) response, 203, 205 electrogram sequence, 203 entrainment, 203 PPI-TCL, 204, 206 SA-VA time, 204, 206 tachycardia termination without preexcitation, 204, 207 Ventricular premature beats diagnosis, 166 origin identification electromechanical interval, 165–166 intraventricular asynchronism, 165 pulsed tissue Doppler image, 166–169 Ventricular tachyarrhythmia (VT) ablation electrical stimulation activation mapping, 499 amiodarone, 498 catheter ablation therapy, 498 collateral injury, 505 entrainment mapping, 502–503 ICD, 497–498 identification, 498–499 local fractionation and delayed conduction, 503 mortality rate, 497 myocardial conduction, 503 OPTIC, 498 pacemapping, 499–501 SHIELD, 498 substrate mapping, 501–502 transvascular shocks, 498 treatment verification, 503, 505 Ventricular tachycardia (VT), 51 CE-CT, 378 3D activation map, 378, 379 3D anatomical models, 377 echocardiography, 201, 203 fascicular VT, 153
678 Ventricular tachycardia (VT) (cont.) LBBB morphology, 153 MRI, 378–379 narrow QRS complex and AV dissociation, 153, 154 PET/CT three-dimensional reconstruction, 377, 378 positive precordial concordance with RBBB morphology, 153, 154 pre-procedural planning, 377 principles, 152 treatment Cx43 expression (see Connexin-43 (Cx43) expression) wide QRS tachycardia, 153 Ventricular tachycardia (VT) ablation congenital heart disease chronic exposure, 521 congenital malformations, 521 electroanatomic mapping, 521–522 electrocardiographic diagnosis, 521 lesions, 521 myocardial scarring, 521 tetralogy of Fallot, 521 electroanatomical mapping, 490 local bipolar electrograms, 490 low-amplitude and wide-duration electrograms, 490 mapping techniques, 489 multicentric VT ablation study, 489 pediatrics
Index idiopathic left ventricular tachycardia, 513–414 right ventricular outflow tract tachycardia, 513 tetralogy of fallot, 514 substrate mapping, 490 epicardial ablation, 494, 495 indications, 493 late potentials, 492–493 linear lesions, scar borders, 490–491 Verapamil-sensitive ventricular tachycardia. See Fascicular ventricular tachycardia Vitamin K antagonist CRT, 658 new oral anticoagulants DTI, 660–661 factor Xa inhibitors, 661–662 IV UFH, 660 Voltage-dependent inactivation (VDI), 101 VT. See Ventricular tachycardia (VT)
W Warfarin, stroke/systemic embolism, 227 Wolff-Parkinson-White (WPW) syndrome, 149, 188
X Xie’s algorithm, 149
