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Arrhythmia & Electrophysiology Review Volume 8 • Issue 2 • Spring 2019

Volume 8 • Issue 2 • Spring 2019

www.AERjournal.com

High-resolution Mapping in Patients with Persistent AF Marius Andronache, Nikola Drca and Graziana Viola

Atrial Tachycardias and Atypical Atrial Flutters: Mechanisms and Approaches to Ablation Steven M Markowitz, George Thomas, Christopher F Liu, Jim W Cheung, James E Ip and Bruce B Lerman

A Review of Driving Restrictions in Patients at Risk of Syncope and Cardiac Arrhythmias Associated with Sudden Incapacity: Differing Global Approaches to Regulation and Risk Andrei D Margulescu and Mark H Anderson

Implantable Cardiac Electronic Devices in the Elderly Population Wei-Yao Lim, Sandeep Prabhu and Richard J Schilling

2: 1: 3: Lateral Superior Superior 4: MA Lateral MA MA AMC

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B I

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aVF

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III RA 19–20

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Bipolar Voltage Map in AF Showing Low Voltage Areas: Anterior view

CS dist

Basal Left Ventricular Outflow Tract

Electroanatomical Map with the Rhythmia ® System

ISSN – 2050-3369

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Lifelong Learning for Cardiovascular Professionals

AER 8.2 FC + Spine.indd All Pages

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Pulmonary vein potentials seen with Advisor™ HD Grid Mapping Catheter, Sensor Enabled™, not captured on standard mapping catheter

ADVISOR™ HD GRID MAPPING CATHETER, SE

CIRCULAR MAPPING CATHETER

Capture more data for insight into activity that may not be visible with standard configuration catheters

SEE THINGS DIFFERENTLY WITH THE ADVISOR™ HD GRID MAPPING CATHETER, SENSOR ENABLED™ LEARN MORE AT CARDIOVASCULAR.ABBOTT/CLOSETHEGAP

CAUTION: This product is intended for use by or under the direction of a physician. Prior to use, reference the Instructions for Use, inside the product carton (when available) or at manuals.sjm.com or eifu.abbottvascular.com for more detailed information on Indications, Contraindications, Warnings, Precautions and Adverse Events. United States — Required Safety Information Indications: The Advisor™ HD Grid Mapping Catheter, Sensor Enabled™, is indicated for multiple electrode electrophysiological mapping of cardiac structures in the heart, i.e., recording or stimulation only. This catheter is intended to obtain electrograms in the atrial and ventricular regions of the heart. Contraindications: The catheter is contraindicated for patients with prosthetic valves and patients with left atrial thrombus or myxoma, or interatrial baffle or patch via transseptal approach. This device should not be used with patients with active systemic infections. The catheter is contraindicated in patients who cannot be anticoagulated or infused with heparinized saline. Warnings: Cardiac

Untitled-5 1

catheterization procedures present the potential for significant x-ray exposure, which can result in acute radiation injury as well as increased risk for somatic and genetic effects, to both patients and laboratory staff due to the x-ray beam intensity and duration of the fluoroscopic imaging. Careful consideration must therefore be given for the use of this catheter in pregnant women. Catheter entrapment within the heart or blood vessels is a possible complication of electrophysiology procedures. Vascular perforation or dissection is an inherent risk of any electrode placement. Careful catheter manipulation must be performed in order to avoid device component damage, thromboembolism, cerebrovascular accident, cardiac damage, perforation, pericardial effusion, or tamponade. Risks associated with electrical stimulation may include, but are not limited to, the induction of arrhythmias, such as atrial fibrillation (AF), ventricular tachycardia (VT) requiring cardioversion, and ventricular fibrillation (VF). Catheter materials are not compatible with magnetic resonance imaging (MRI). Precautions: Maintain an activated clotting time (ACT) of greater than 300 seconds at all times during use of the catheter. This includes when the catheter is used in the right side of

the heart. To prevent entanglement with concomitantly used catheters, use care when using the catheter in the proximity of the other catheters. Maintain constant irrigation to prevent coagulation on the distal paddle. Inspect irrigation tubing for obstructions, such as kinks and air bubbles. If irrigation is interrupted, remove the catheter from the patient and inspect the catheter. Ensure that the irrigation ports are patent and flush the catheter prior to re-insertion. Always straighten the catheter before insertion or withdrawal. Do not use if the catheter appears damaged, kinked, or if there is difficulty in deflecting the distal section to achieve the desired curve. Do not use if the catheter does not hold its curve and/or if any of the irrigation ports are blocked. Catheter advancement must be performed under fluoroscopic guidance to minimize the risk of cardiac damage, perforation, or tamponade. ™ Indicates a trademark of the Abbott group of companies. © 2019 Abbott. All Rights Reserved. 31672-SJM-ADV-0319-0072

Item approved for global use.

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Volume 8 • Issue 2 • Spring 2019

www.AERjournal.com Official journal of

Editor-in-Chief Demosthenes G Katritsis Hygeia Hospital, Athens

Section Editor – Arrhythmia Mechanisms / Basic Science

Section Editor – Clinical Electrophysiology and Ablation

Section Editor – Implantable Devices

Andrew Grace

Hugh Calkins

Angelo Auricchio

Charles Antzelevitch

Warren Jackman

Douglas Packer

Lankenau Institute for Medical Research, Pennsylvania

Heart Rhythm Institute, University of Oklahoma Health Sciences Center, Oklahoma City

Mayo Clinic, St. Mary’s Campus, Rochester, Minnesota

Uppsala University, Uppsala

Pierre Jaïs University of Bordeaux, CHU Bordeaux

IRCCS Policlinico San Donato, Milan

Johannes Brachmann

University of Cambridge, Cambridge

Johns Hopkins Medicine, Baltimore

Fondazione Cardiocentro Ticino, Lugano

Editorial Board Carina Blomström-Lundqvist

Sunny Po

Klinikum Coburg, II Med Klinik, Coburg

Roy John

Josep Brugada

Vanderilt University Medical Center, Nashville, Tennessee

Heart Rhythm Institute, University of Oklahoma Health Sciences Center, Oklahoma City

Prapa Kanagaratnam

Antonio Raviele

Cardiovascular Institute, Hospital Clínic and Pediatric Arrhythmia Unit, Hospital Sant Joan de Déu, University of Barcelona, Barcelona

Pedro Brugada University of Brussels, UZ-Brussel-VUB

Alfred Buxton

Imperial College Healthcare NHS Trust, London

Josef Kautzner Institute for Clinical and Experimental Medicine, Prague

Karl-Heinz Kuck Asklepios Klinik St Georg, Hamburg

ALFA – Alliance to Fight Atrial Fibrillation, Venice-Mestre

Edward Rowland Barts Heart Centre, St Bartholomew’s Hospital, London

Frédéric Sacher

Pier Lambiase

Bordeaux University Hospital, Electrophysiology and Heart Modelling Institute, Bordeaux

University of Pennsylvania, Philadelphia

Institute of Cardiovascular Science, University College London, and Barts Heart Centre, London

Richard Schilling

A John Camm

Samuel Lévy

Beth Israel Deaconess Medical Center, Boston

David J Callans

St George’s University of London, London

Riccardo Cappato IRCCS Humanitas Research Hospital, Rozzano, Milan

Shih-Ann Chen National Yang Ming University School of Medicine and Taipei Veterans General Hospital, Taipei, Taiwan

Harry Crijns Maastricht University Medical Center, Maastricht

Ken Ellenbogen Virginia Commonwealth University, Richmond

Sabine Ernst Royal Brompton & Harefield NHS Foundation Trust, London

Hein Heidbuchel Antwerp University and University Hospital, Antwerp

Gerhard Hindricks

Cover image © AdobeStock

Carlo Pappone

Aix-Marseille University, Marseille

Cecilia Linde

Barts Health NHS Trust, London

Afzal Sohaib Imperial College London, London

William Stevenson

Karolinska University, Stockholm

Vanderbilt School of Medicine, Nashville

Gregory YH Lip University of Liverpool, Liverpool

Richard Sutton

Francis Marchlinski

National Heart and Lung Institute, Imperial College London, London

University of Pennsylvania Health System, Philadelphia

John Miller Indiana University School of Medicine, Indiana

Panos Vardas Heraklion University Hospital, Heraklion

Marc A Vos

Fred Morady Cardiovascular Center, University of Michigan

University Medical Center Utrecht, Utrecht

Sanjiv M Narayan

Hein Wellens

Stanford University Medical Center

University of Maastricht, Maastricht

Andrea Natale

Katja Zeppenfeld Leiden University Medical Center, Leiden

University of Leipzig. Frankfurt

Texas Cardiac Arrhythmia Institute, St David’s Medical Center, Austin, Texas

Carsten W Israel

Mark O’Neill

JW Goethe University, Frankfurt

St Thomas’ Hospital and King’s College London, London

Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis

Douglas P Zipes

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Published by Radcliffe Cardiology. All information obtained by Radcliffe Cardiology and each of the contributors from various sources is as current and accurate as possible. However, due to human or mechanical errors, Radcliffe Cardiology and the contributors cannot guarantee the accuracy, adequacy or completeness of any information, and cannot be held responsible for any errors or omissions, or for the results obtained from the use thereof. Published content is for information purposes only and is not a substitute for professional medical advice. Where views and opinions are expressed, they are those of the author(s) and do not necessarily reflect or represent the views and opinions of Radcliffe Cardiology. Radcliffe Cardiology, Unit F, First Floor, Bourne End Business Park, Cores End Road, Bourne End, Buckinghamshire SL8 5AS, UK © 2019 All rights reserved ISSN: 2050-3369 • eISSN: 2050–3377

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Established: October 2012 | Frequency: Quarterly | Current issue: Spring 2019

Aims and Scope

Submissions and Instructions to Authors

•  Arrhythmia & Electrophysiology Review aims to assist time-pressured physicians to stay abreast of key advances and opinion in heart failure. • Arrhythmia & Electrophysiology Review comprises balanced and comprehensive articles written by leading authorities, addressing the most pertinent developments in the field. • Arrhythmia & Electrophysiology Review provides comprehensive updates on a range of salient issues to support physicians in continuously developing their knowledge and effectiveness in day-to-day clinical practice.

• Contributors are identified by the Editor-in-Chief with the support of the Editorial Board and Managing Editor. •  Following acceptance of an invitation, the author(s) and Managing Editor, in conjunction with the Editor-in-Chief, formalise the working title and scope of the article. • The ‘Instructions to Authors’ document and additional submission details are available at www.AERjournal.com •  Leading authorities wishing to discuss potential submissions should contact the Managing Editor, Ashlynne Merrifield ashlynne.merrifield@radcliffe-group.com.

Structure and Format • Arrhythmia & Electrophysiology Review is a quarterly journal comprising review articles, expert opinion articles and guest editorials. • The structure and degree of coverage assigned to each category of the journal is the decision of the Editor-in-Chief, with the support of the Editorial Board. • Articles are fully referenced, providing a comprehensive review of existing knowledge and opinion. • Each edition of Arrhythmia & Electrophysiology Review is available in full online at www.AERjournal.com

Reprints

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Abstracting and Indexing

Arrhythmia & Electrophysiology Review is supported by various levels of expertise: • Overall direction from an Editor-in-Chief, supported by the Editorial Board comprising leading authorities from a variety of related disciplines. • Invited contributors who are recognised authorities in their respective fields. • Peer review – conducted by experts appointed for their experience and knowledge of a specific topic. • An experienced team of Editors and Technical Editors.

Arrhythmia & Electrophysiology Review is abstracted, indexed and listed in PubMed, the Emerging Sources Citation Index (ESCI), Scopus and Crossref. All articles are published in full on PubMed Central one month after publication.

Peer Review • On submission, all articles are assessed by the Editor-in-Chief to determine their suitability for inclusion. • The Managing Editor, following consultation with the Editor-in-Chief sends the manuscript to reviewers who are selected on the basis of their specialist knowledge in the relevant area. All peer review is conducted double-blind. • Following review, manuscripts are accepted without modification, accepted pending modification (in which case the manuscripts are returned to the author(s) to incorporate required changes), or rejected outright. The Editor-in-Chief reserves the right to accept or reject any proposed amendments. • Once the authors have amended a manuscript in accordance with the reviewers’ comments, the manuscript is assessed to ensure the revised version meets quality expectations. The manuscript is sent to the Editor-in-Chief for final approval prior to publication.

All articles included in Arrhythmia & Electrophysiology Review are available as reprints. Please contact the Sales Director, Rob Barclay rob.barclay@radcliffe-group.com

Distribution and Readership Arrhythmia & Electrophysiology Review is distributed quarterly through controlled circulation to senior healthcare professionals in the field in Europe.

Open Access, Copyright and Permissions Articles published within this journal are open access, which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly. The author retains all non-commercial rights for articles published herein under the CC-BY-NC 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/ legalcode). Radcliffe Cardiology retain all commercial rights for articles published herein unless otherwise stated. Permission to reproduce an article for commercial purposes, either in full or in part, should be sought from the publication’s Managing Editor. To support open access publication costs, Radcliffe Cardiology charge an Article Publication Charge (APC) to authors upon acceptance of an unsolicited paper as follows: £1,050 UK | €1,200 Eurozone | $1,369 all other countries.

Online All manuscripts published in Arrhythmia & Electrophysiology Review are available free-to-view at www.AERjournal.com. Also available at www.radcliffecardiology.com are articles from other journals within Radcliffe Cardiology’s cardiovascular portfolio – including, Interventional Cardiology Review, Cardiac Failure Review, European Cardiology Review and US Cardiology Review.

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Contents

Foreword What Cannot be Missed: Must-read Papers, 2018

81

Demosthenes G Katritsis DOI: https://doi.org/10.15420/aer.2019.8.2.FO1

Clinical Arrhythmias Monomorphic Ventricular Arrhythmias in Athletes

83

Jeffrey J Hsu, Ali Nsair, Jamil A Aboulhosn, Tamara B Horwich, Ravi H Dave, Kevin M Shannon, Noel G Boyle, Kalyanam Shivkumar and Jason S Bradfield DOI: https://doi.org/10.15420/aer.2019.19.3

A Review of Driving Restrictions in Patients at Risk of Syncope and Cardiac Arrhythmias Associated with Sudden Incapacity: Differing Global Approaches to Regulation and Risk

90

Andrei D Margulescu and Mark H Anderson DOI: hhttps://doi.org/10.15420/aer.2019.13.2

Strategies to Reduce Recurrent Shocks Due to Ventricular Arrhythmias in Patients with an Implanted Cardioverter-Defibrillator

99

Steven H Back and Peter R Kowey DOI: https://doi.org/10.15420/aer.2018.55.5

Long QT Syndrome Modelling with Cardiomyocytes Derived from Human-induced Pluripotent Stem Cells

105

Luca Sala, Massimiliano Gnecchi and Peter J Schwartz DOI: https://doi.org/10.15420/aer.2019.1.1

Electrophysiology and Ablation High-resolution Mapping in Patients with Persistent AF

111

Marius Andronache, Nikola Drca and Graziana Viola DOI: https://doi.org/10.15420/aer.2018.57.1

Idiopathic Outflow Tract Ventricular Arrhythmia Ablation: Pearls and Pitfalls

116

Jackson J Liang, Yasuhiro Shirai, Aung Lin and Sanjay Dixit DOI: https://doi.org/10.15420/aer.2019.6.2

Acquired Long QT Syndrome and Electrophysiology of Torsade de Pointes

122

Nabil El-Sherif, Gioia Turitto and Mohamed Boutjdir DOI: https://doi.org/10.15420.2019.8.3

Atrial Tachycardias and Atypical Atrial Flutters: Mechanisms and Approaches to Ablation

131

Steven M Markowitz, George Thomas, Christopher F Liu, Jim W Cheung, James E Ip and Bruce B Lerman DOI: https://doi.org/10.15420/aer.2019.17.2

Drugs and Devices Pacemaker and Defibrillator Implantation and Programming in Patients with Deep Brain Stimulation

138

Mark Elliott, Sheikh Momin, Barnaby Fiddes, Fahad Farooqi and SM Afzal Sohaib DOI: https://doi.org/10.15420/aer.2018.63.2

Implantable Cardiac Electronic Devices in the Elderly Population

143

Wei-Yao Lim, Sandeep Prabhu and Richard J Schilling DOI: https://doi.org/10.15420/aer.2019.3.4

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Sheraton Hotel & Convention Center

Atrial fibrillation Ventricular Arrhythmias His Pacing Sudden death Syncope Heart failure Anticoagulation update

www.arrhythmias2019.com Secretary General: Oscar Oseroff, M.D.

Organising Committee Presidents: Prof. Shu Zhang; Rodolfo Sansalone, M.D. Scientific Committee Presidents: Claudio de Zuloaga, M.D.; Luis Aguinaga, M.D. Untitled-5 1

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Foreword

What Cannot be Missed: Must-read Papers, 2018

T

he most important papers on arrhythmias and electrophysiology published in 2018, selected by the editors of Arrhythmia and Electrophysiology Review (AER).

Clinical Practice 1. Marrouche NF, Brachmann J, Andresen D, et al. Catheter ablation for atrial fibrillation with heart failure. N Engl J Med 2018;1;378:417–27. https://doi.org/10.1056/NEJMoa1707855; PMID:29385358. 2. Packer DL, Mark DB, Robb RA, et al. Effect of catheter ablation vs antiarrhythmic drug therapy on mortality, stroke, bleeding, and cardiac arrest among patients with atrial fibrillation: the CABANA randomized clinical trial. JAMA 2019. https://doi.org/10.1001/ jama.2019.0693; PMID: 30874766; epub ahead of press. 3. Vaseghi M, Hu TY, Tung R, et al. Outcomes of catheter ablation of ventricular tachycardia based on etiology in nonischemic heart disease: an international ventricular tachycardia ablation center collaborative study. JACC Clin Electrophysiol 2018;4:1141–50. https://doi.org/10.1016/j.jacep.2018.05.007 4. Etheridge SP, Escudero CA, Blaufox AD, et al. Life-threatening event risk in children with Wolff-Parkinson-White syndrome: a multicenter international study. JACC Clin Electrophysiol. 2018;4:433–44. https://doi.org/10.1016/j.jacep.2017.10.009; PMID:30067481. 5. Parkash R, Nault I, Rivard L, et al. Effect of baseline antiarrhythmic drug on outcomes with ablation in ischemic ventricular tachycardia: a VANISH substudy (Ventricular Tachycardia Ablation versus Escalated Antiarrhythmic Drug Therapy in Ischemic Heart Disease). Circ Arrhythm Electrophysiol 2018;11:e005663. https://doi.org/10.1161/CIRCEP.117.005663; PMID: 29305400. 6. Abdelrahman M, Subzposh FA, Beer D, et al. Clinical outcomes of His bundle pacing compared to right ventricular pacing. J Am Coll Cardiol 2018;71(20):2319–30. https://doi.org/10.1016/j.jacc.2018.02.048; PMID: 29535066. 7. Sharma PS, Naperkowski A, Bauch TD, et al. Permanent His bundle pacing for cardiac resynchronization therapy in patients with heart failure and right bundle branch block. Circ Arrhythm Electrophysiol 2018;11:e006613. https://doi.org/10.1161/ CIRCEP.118.006613; PMID: 30354292. 8. Shah AD, Morris MA, Hirsh DS, et al. Magnetic resonance imaging safety in nonconditional pacemaker and defibrillator recipients: a meta-analysis and systematic review. Heart Rhythm 2018;15(7):1001–8. https://doi.org/10.1016/j.hrthm.2018.02.019; PMID:29458192. 9. 9. Dickstein K, Normand C, Auricchio A, et al. CRT Survey II: a European Society of Cardiology survey of cardiac resynchronisation therapy in 11 088 patients – who is doing what to whom and how? Eur J Heart Fail 2018;20(6):1039–51. https://doi.org/10.1002/ ejhf.1142; PMID:29457358. 10. Konig S, Ueberham L, Schuler E, et al. In-hospital mortality of patients with atrial arrhythmias: insights from the German-wide Helios hospital network of 161 502 patients and 34 025 arrhythmia-related procedures. Eur Heart J 2018;39:3947–57. https://doi. org/10.1093/eurheartj/ehy528; PMID:30165430. 11. Holmqvist F, Kesek M, Englund A, et al. A decade of catheter ablation of cardiac arrhythmias in Sweden: ablation practices and outcomes. Eur Heart J. 2019;40(10):820–30. https://doi.org/10.1093/eurheartj/ehy709; PMID: 30452631. 12. Katritsis DG, John RM, Latchamsetty R, et al. Left septal slow pathway ablation for atrioventricular nodal reentrant tachycardia. Circ Arrhythm Electrophysiol 2018;11:e005907. https://doi.org/10.1161/CIRCEP.117.005907; PMID:29540373. 13. Lin YS, Chen YL, Chen TH, et al. Comparison of clinical outcomes among patients with atrial fibrillation or atrial flutter stratified by CHA2DS2-VASc score. JAMA Netw Open 2018;1:e180941. https://doi.org/10.1001/jamanetworkopen.2018.0941; PMID:30646091. DOI: https://doi.org/10.15420/aer.2019.8.2.FO1

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Foreword 14. Hosseini SM, Kim R, Udupa S, et al. Reappraisal of reported genes for sudden arrhythmic death. Circulation 2018;138:1195–205. https:// doi.org/10.1161/CIRCULATIONAHA.118.035070; PMID:29959160. 15. Nordenswan HK, Lehtonen J, Ekström K, et al. Outcome of cardiac sarcoidosis presenting with high-grade atrioventricular block. Circ Arrhythm Electrophysiol 2018;11:e006145. https://doi.org/10.1161/CIRCEP.117.006145. 16. Olgin JE, Pletcher MJ, Vittinghoff E, et al. Wearable cardioverter-defibrillator after myocardial infarction. N Engl J Med 2018;379:1205–15. https://doi.org/10.1056/NEJMoa1800781; PMID:30280654. 17. Sood N, Martin DT, Lampert R, et al. Incidence and predictors of perioperative complications with transvenous lead extractions: realworld experience with National Cardiovascular Data Registry. Circ Arrhythm Electrophysiol 2018;11:e004768. https://doi.org/10.1161/ CIRCEP.116.004768; PMID: 29453324. 18. Dukkipati SR, Kar S, Holmes DR, et al. Device-related thrombus after left atrial appendage closure. Circulation 2018;138:874–85. https://doi.org/10.1161/CIRCULATIONAHA.118.035090; PMID:29752398. 19. Jayaraman R, Reinier K, Nair S, et al. Risk factors of sudden cardiac death in the young: multiple-year community-wide assessment. Circulation 2018;137:1561–70. https://doi.org/10.1161/CIRCULATIONAHA.117.031262; PMID:29269388. 20. Vink AS, Neumann B, Lieve KVV, et al. Determination and interpretation of the QT interval. Circulation 2018;138:2345–58. https://doi.org/10.1161/CIRCULATIONAHA.118.033943; PMID:30571576.

The Future 1. Chatterjee D, Fatah M, Akdis D, et al. An autoantibody identifies arrhythmogenic right ventricular cardiomyopathy and participates in its pathogenesis. Eur Heart J 2018;39:3932–44. https://doi.org/10.1093/eurheartj/ehy567; PMID:30239670. 2. Robinson CG, Samson PP, Moore KM, et al. Phase I/II trial of electrophysiology-guided noninvasive cardiac radioablation for ventricular tachycardia. Circulation 2019;139:313–21. https://doi.org/10.1161/CIRCULATIONAHA.118.038261; PMID:30586734. 3. Witt CM, Dalton S, O’Neil S, et al. Termination of atrial fibrillation with epicardial cooling in the oblique sinus. JACC Clin Electrophysiol 2018;4:1362–8. https://doi.org/10.1016/j.jacep.2018.06.016; PMID: 30336883. 4. Prakosa A, Arevalo HJ, Deng D et al. Personalized virtual-heart technology for guiding the ablation of infarct-related ventricular tachycardia. Nat Biomed Eng 2018;2:732–40. https://doi.org/10.1038/s41551-018-0282-2; PMID:30847259. 5. Walsh KA, Galvin J, Keaney J, Keelan E and Szeplaki G. First experience with zero-fluoroscopic ablation for supraventricular tachycardias using a novel impedance and magnetic-field-based mapping system. Clin Res Cardiol 2018;107:578–85. https://doi.org/10.1007/s00392018-1220-8; PMID:29476203. 6. Katritsis G, Luther V, Kanagaratnam P, Linton NW. Arrhythmia mechanisms revealed by ripple mapping. Arrhythm Electrophysiol Rev 2018;7:261–4. https://doi.org/10.15420/aer.2018.44.3; PMID:30588314. 7. Martin R, Maury P, Bisceglia C, et al. Characteristics of scar-related ventricular tachycardia circuits using ultra-high-density mapping: a multi-center study. Circ Arrhythm Electrophysiol 2018;11:e006569. https://doi.org/10.1161/CIRCEP.118.006569; PMID: 30354406. 8. Livia C, Sugrue A, Witt T, et al. Elimination of Purkinje fibers by electroporation reduces ventricular fibrillation vulnerability. J Am Heart Assoc 2018;7:e009070. https://doi.org/10.1161/JAHA.118.009070; PMID: 30371233. 9. Sramko M, Hoogendoorn JC, Glashan CA, Zeppenfeld K. Advancement in cardiac imaging for treatment of ventricular arrhythmias in structural heart disease. Europace 2019;21:383–403. https://doi.org/10.1093/europace/euy150; PMID:30101352. 10. Hegyi B, Bossuyt J, Griffiths LG, et al. Complex electrophysiological remodeling in postinfarction ischemic heart failure. Proc Natl Acad Sci USA 2018;115:E3036–44. https://doi.org/10.1073/pnas.1718211115; PMID: 29531045.

Demosthenes G Katritsis Editor-in-Chief, Arrhythmia and Electrophysiology Review Hygeia Hospital, Athens, Greece

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Clinical Arrhythmias

Monomorphic Ventricular Arrhythmias in Athletes Jeffrey J Hsu, 1,2 Ali Nsair, 1,2 Jamil A Aboulhosn, 1,2 Tamara B Horwich, 1,2 Ravi H Dave, 1 Kevin M Shannon, 1,2,4 Noel G Boyle, 3 Kalyanam Shivkumar 3 and Jason S Bradfield 1,3 1. UCLA Sports Cardiology Center, Los Angeles, CA, US; 2. Ahmanson-UCLA Cardiomyopathy Center, Los Angeles, CA, US; 3. UCLA Cardiac Arrhythmia Center, Los Angeles, CA, US; 4. UCLA Department of Pediatrics David Geffen School of Medicine at UCLA, Los Angeles, CA, US

Abstract Ventricular arrhythmias are challenging to manage in athletes with concern for an elevated risk of sudden cardiac death (SCD) during sports competition. Monomorphic ventricular arrhythmias (MMVA), while often benign in athletes with a structurally normal heart, are also associated with a unique subset of idiopathic and malignant substrates that must be clearly defined. A comprehensive evaluation for structural and/ or electrical heart disease is required in order to exclude cardiac conditions that increase risk of SCD with exercise, such as hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy. Unique issues for physicians who manage this population include navigating athletes through the decision of whether they can safely continue their chosen sport. In the absence of structural heart disease, therapies such as radiofrequency catheter ablation are very effective for certain arrhythmias and may allow for return to competitive sports participation. In this comprehensive review, we summarise the recommendations for evaluating and managing athletes with MMVA.

Keywords Ablation, arrhythmogenic right ventricular cardiomyopathy, athlete, hypertrophic cardiomyopathy, premature ventricular contraction, sports cardiology, sudden cardiac death, ventricular tachycardia Disclosure: JB has previously received honoraria from Abbott Medical and Biosense Webster. The other authors have no conflicts of interest to declare related to the topics discussed in this manuscript. Received: 24 January 2019 Accepted: 3 April 2019 Citation: Arrhythmia & Electrophysiology Review 2019;8(2):83–9. DOI: https://doi.org/10.15420/aer.2019.19.3 Correspondence: Jason S Bradfield, UCLA Cardiac Arrhythmia Center, 100 Medical Plaza, Suite 660, Los Angeles, CA 90024, US. E: JBradfield@mednet.ucla.edu Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Monomorphic ventricular arrhythmias (MMVA) are not uncommon in athletes,1,2 yet their presence appropriately raises concern among practitioners for possible increased risk of sudden cardiac death (SCD) during sports activity and competition. While all MMVA detected in athletes warrant further evaluation,1 a majority of MMVA in this population are likely to be benign. In some instances of so called ‘idiopathic’ premature ventricular contractions (PVCs)/ventricular tachycardia (VT), the arrhythmia may be unrelated to athletic status or may be a benign manifestation of the physiological changes that may occur in the ‘athlete’s heart’.2 However, this is a matter of debate,3 and the presence of MMVA may also be a manifestation of structural pathology, such as hypertrophic cardiomyopathy (HCM), myocarditis, and arrhythmogenic right ventricular cardiomyopathy (ARVC), or electrical abnormalities such as long QT syndrome or Brugada syndrome, which are associated with increased risks of SCD with exercise. The focus of this review is to discuss the management of athletes found to have MMVA, including diagnostic workup, advanced treatment options and guidance recommendations for this unique population.

Epidemiology MMVA can range from PVCs to non-sustained VT (NSVT) and sustained VT. MMVA can be seen in trained athletes on 12-lead ECG or ambulatory ECG monitoring and in most cases there are no cardiovascular abnormalities detected on further workup.4 The overall prevalence of MMVA does not appear to be higher in the athlete

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population. A recent study found that the prevalence of MMVA in a group of young athletes (16–35 years) in Italy (10%) was similar to that of sedentary controls (11%).5 Similar findings were observed in an older population of athletes (>30 years), although the overall prevalence of MMVA was higher in the older population overall (26% in athletes and 23% in sedentary controls).3 Interestingly, in both studies, the prevalence of MMVA was not associated with the amount and duration of exercise. While there are some data suggesting that MMVA are often either abolished or substantially reduced in frequency with detraining,6 the similar prevalence between athletes and non-athletes suggests that in most patients there is no causeeffect relationship between athlete status and arrhythmia in persons without known structural heart disease. PVCs are not uncommon in athletes, yet whether there is a higher prevalence of PVCs specifically in athletes compared with the general population is unclear. One of the early studies comparing PVC frequency between endurance athletes and healthy sedentary people found a higher prevalence of ventricular ectopy in the athlete group, which included both any ectopy (70% versus 55%) and complex ectopy (25% versus 5%).7 However, subsequent studies have not seen a significant difference in athletes.3,5,8 Younger athletes (mean age 21 years) were found to be more likely to have isolated, rare ectopy (<10 PVCs/24 hours) compared with their sedentary counterparts (49% versus 28%),5 but this difference was not seen in a study of middleaged athletes and sedentary controls (53% versus 50%).3

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Clinical Arrhythmias Figure 1: Flow Diagram of Proposed Evaluation for Athletes with Monomorphic Ventricular Arrhythmias MMVA (PVCs, non-sustained VT, sustained VT)

History and physical • Symptoms, family history

No concerning symptoms ectopy with exercise

Lab testing • Chemistry panel, thyroid Normal

12-lead ECG

Restrict from competition until further workup completed

Exercise stress testing

Ambulatory ECG monitoring • Frequency/burden, symptoms Transthoracic echocardiogram • Structural heart disease

No further workup indicated

Concerning symptoms PVC frequency and/or VT with exercise

Trial of detraining and/or medical therapy and reassessment Advanced studies

Abnormal

• Cardiac MRI • Coronary CTA

Workup for detected/suspected abnormality • Cardiac MRI

• +/– EP study

• Coronary CTA • +/– EP study General recommendations for initial evaluation of an athlete who presents with MMVA, with further management depending on the results of exercise stress testing. CTA = computed tomographic angiography; EP = electrophysiology; MMVA = monomorphic ventricular arrhythmias; PVC = premature ventricular contractions; VT = ventricular tachycardia.

Interestingly, while idiopathic PVCs are often thought to be sympathetically mediated, there appears to be variability in the circadian distribution of PVC occurrence among patients. In a recent study of 101 consecutive unselected patients with frequent monomorphic PVCs referred for radiofrequency catheter ablation (RFA), 50.5% were found to have fast heart rate-dependent PVCs (more PVCs occurred at higher heart rates), whereas 9.9% had slow heart rate-dependent PVCs (more PVCs at lower heart rates).9 No correlation between heart rate and PVC frequency was seen in the rest of the patients (39.6%). However, the circadian variability of PVCs in athletes has not been specifically studied and further data is needed to determine how different subtypes of PVCs/VT should be managed in athletes.

Evaluation The initial diagnosis of MMVA in athletes may present in a variety of ways, including incidental detection on screening ECGs or after workup performed for symptoms such as palpitations. While most of these arrhythmias are likely to be benign, it is crucial to identify features that may be suggestive of underlying structural heart disease, warranting not only further workup but also potentially restriction from sports activity or competition. Beyond the routine history and physical examination that should be performed in all patients presenting with MMVA, important features to assess in athletes include arrhythmia frequency, response of the arrhythmia to exercise and electrocardiographic patterns (Figure 1).

of proportion to the degree of exercise, sudden fatigue, nausea, abdominal pain, or decreased exercise performance. Furthermore, family history should be queried for sudden death, syncope, or known cardiac disease, and basic laboratory tests – including a chemistry panel and thyroid function tests – should be performed to assess for possible contributions from electrolyte or endocrine abnormalities. In addition to the physical exam, non-invasive studies that should be performed in athletes with MMVA are a 12-lead ECG, ambulatory ECG monitor (i.e. 24-hour Holter or 2–4 week event monitor), exercise stress testing and a transthoracic echocardiogram.10 On the 12-lead ECG, the most recent version of the international recommendations on ECG interpretation in athletes should be used to identify abnormal findings,11 which may be suggestive of pathologies (e.g. HCM and ARVC) that can predispose an athlete to MMVA.12 Prior ECGs should be reviewed when available, and it may also be useful to obtain serial ECGs. It is also important to differentiate normal variants associated with different racial groups, such as early repolarisation seen in athletes of Afro-Caribbean descent where the ECG commonly shows elevated ST segments with upward concavity followed by negative T wave in V2-V4.13 The exercise stress testing protocol should be based on maximal effort, not a target heart rate, and attempts should be made to replicate the level and form of exercise achieved in the athlete’s sport.1 The findings on these initial studies may prompt further evaluation, which may include but are not limited to coronary computed tomographic angiography and cardiac MRI.

Clinical Assessment While some athletes who are referred for evaluation of MMVA may be asymptomatic with an incidental finding of irregular heartbeat,3,4,8 it is imperative to perform a detailed history to identify any concerning symptoms that the athlete may not otherwise mention unprompted. Specific symptoms to inquire about include palpitations, light-headedness, dizziness/presyncope, syncopal episodes, typical and atypical chest pain, dyspnoea that is sudden in onset or out

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Arrhythmia Frequency/Burden The frequency/burden of PVCs/VT can be quantified by ambulatory ECG monitoring including 24–48 hour Holter monitoring or 14–30-day event recorders. The type of monitor chosen should be determined by the frequency with which the athlete experiences symptoms; if asymptomatic, a 24–48-hour Holter monitor is a reasonable first option. In a study of 355 athletes with ventricular arrhythmias detected

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Monomorphic Ventricular Arrhythmias in Athletes on a 24-hour Holter monitor obtained because of palpitations and/ or ≥3 PVCs on a resting ECG, 30% of athletes who had ≥2000 PVCs in the 24-hour period were found to have cardiac abnormalities on further workup; of those athletes with abnormalities, ARVC (10%) and mitral valve prolapse (9%) were most common. Conversely, cardiac abnormalities were seen in only 3% and 0% of athletes with ≥100–2000 PVCs or <100 PVCs, respectively.4 Thus, a higher frequency of PVCs (>2000 in a 24-hour period) should raise suspicion for structural heart disease and warrants further evaluation. Furthermore, the presence of multiple (≥2) PVCs on a resting 12-lead ECG should prompt further evaluation, with at least an echocardiogram, an ambulatory ECG monitor and exercise stress testing.11

Response of Arrhythmia to Exercise The response of PVCs to exercise can offer insight into the likelihood of underlying cardiac disease.14 Monomorphic PVCs that decrease or disappear with exercise are generally considered to be benign.1 Conversely, a recent study found that athletes who had increased ventricular arrhythmia (VA) with exercise were more likely to have pathological myocardial substrate on cardiac MRI than those who had decreased VA with exercise.15 In older athletes, the primary concern of increasing ectopy with exercise is an ischaemic aetiology. In a recent meta-analysis of ten studies evaluating exercise-related PVCs during clinical stress testing, exercise-related PVCs correlated with an increased risk of adverse cardiac events, even in asymptomatic patients without overt cardiovascular disease.16 Interestingly, the sensitivity analyses found that only PVCs seen during the recovery phase of stress testing were associated with adverse outcomes. Notably, these studies did not focus on athletes.

Figure 2: Idiopathic (Outflow) Ventricular Tachycardia

A: RAO fluoroscopic view of outflow tracts after simultaneous pulmonary artery and aortic root angiography; B: A similar anatomic view with the RV free wall removed; C: A similar view after completion of a 3D electro-anatomic map (Biosense Webster) prior to RFA; D: 12-lead ECG of a PVC with a left bundle, inferior axis morphology, with precordial transition at lead V3, consistent with outflow origin. AIV = anterior interventricular vein; AO = aorta; CC = coronary cusp; CS = coronary sinus; HIS, = bundle of HIS; LAD = left anterior descending artery; PA = pulmonary artery; RAO = right anterior oblique; RV = right ventricle; RVOT = right ventricular outflow tract; TV = tricuspid valve. Image B is reproduced with permission from the UCLA Cardiac Arrhythmia Center, Wallace MacAlpine Collection.

Figure 3: Monomorphic Ventricular Arrhythmias in the Setting of Arrhythmogenic Right Ventricular Cardiomyopathy Epsilon waves

A

C

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Angio cath

RV

Electrocardiographic Patterns in Risk Stratification Attempts to localise the origin of the PVC/VT may be helpful for risk stratification. PVCs originating from the right ventricular outflow tract (RVOT), suggested by a left bundle branch block (LBBB) pattern, inferior axis and precordial transition at or after V3 are likely to be benign (although this pattern can sometimes be seen in ARVC). The precordial transition is the V-lead in which the QRS changes from a predominantly negative S wave deflection to a positive R wave pattern. PVCs of left ventricular outflow tract (LVOT) origin (i.e. LBBB pattern and inferior axis with early precordial transition) and fascicular origin (i.e. RBBB pattern and superior axis for posterior fascicular sites) are less common, but also generally considered to be benign.17 On the other hand, morphological features that raise concern for pathology include any pattern not typical of a classic idiopathic site of origin, markedly widened QRS intervals (>140 ms) and/or a pleomorphic pattern of PVCs, as these suggest an atypical site of origin or multiple sites of origin. Additionally, the PVC coupling interval can be assessed, and a short coupling interval may raise concern for an increased risk of an R-on-T phenomenon and polymorphic ventricular arrhythmias. When assessing exercise-induced ventricular arrhythmias, Cipriani and colleagues demonstrated that repolarisation abnormalities at baseline, complex VA (couplets, triplets, NSVT) on 24-hour ambulatory ECG monitoring, and repetitive exercise-induced VA with RBBB or polymorphic morphology have been associated with higher risk of structural heart disease on cardiac MRI.15 Slower (<150 BPM), monomorphic patterns are more likely to be benign compared with faster and polymorphic patterns,1 but there are exceptions. For instance, benign idiopathic outflow tract VT can often be very fast (Figure 2), while pathological scar-mediated VT in ARVC may have a slower rate (Figure 3).

RA lead

RV leads

Atypical LBBB VT (non outflow)

D

Basket cath

RA lead

B RV

ABL

RV leads EPI sheath A: Electrocardiographic findings of epsilon waves visualised in lead V1 when the athlete is in normal sinus rhythm; B: Atypical LBBB VT originating from the apical aspect of the right ventricular free wall; C: RAO angiographic view at the time of EP study/RFA demonstrating markedly enlarged RV on angiography (yellow outline); D: Catheter positions during mapping and RFA of VT shown in panel B. RFA was undertaken using a combined endocardial and epicardial approach. ABL = ablation catheter; ANGIO = angiographic; ARVC = arrhythmogenic right ventricular cardiomyopathy; cath = catheter; EPI = epicardial; LBBB = left bundle branch block; MMVA = monomorphic ventricular arrhythmias; RA = right atrium; RV = right ventricle; VT = ventricular tachycardia.

Differential Diagnosis Age has a strong influence on the differential diagnosis: older athletes (>35 years) are more likely to have atherosclerotic coronary artery disease (CAD) and ischaemic heart disease as an aetiology, whereas younger athletes (<35 years) are more likely to have congenital abnormalities, such as anomalous origin of a coronary artery, familial cardiomyopathy or a genetic predisposition to arrhythmia.14

Structural Heart Disease Familial cardiomyopathies include HCM, ARVC, and left ventricular noncompaction cardiomyopathy. These conditions need to be considered in all athletes with VA, but particularly in younger athletes given that HCM and ARVC may manifest as VA at an early age. In a seminal study from 1996 by Maron et al. on SCD in young athletes, HCM

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II. Moderate (10–20%) I. Low (<10%)

Increasing static component

III. High (>30%)

Figure 4: Classification of Sports by Static and Dynamic Components Bobsledding/luge Field events (throwing) Gymnastics*† Martial arts Rock climbing Sailing Waterskiing*† Weight lifting*† Windsurfing*†

Body building*† Downhill skiing Skateboarding*† Snowboarding*† Wrestling*

Boxing Canoeing Kayaking Cycling*† Decathlon Rowing Speed skating Triathlon*†

Archery Auto racing*† Diving*† Equestrian*† Motorcycling*†

American football* Field events (jumping) Figure skating Rodeoing*† Rugby Running (sprint) Surfing Synchronised swimming† 'Ultra' racing

Basketball* Ice hockey* Cross-country skiing (skating technique) Lacrosse* Running (middle distance) Swimming Team handball Tennis

Bowling Cricket Curling Golf Riflery Yoga

Baseball/softball Fencing Table tennis Volleyball

Badminton Cross-country skiing (classic technique) Field hockey* Orienteering Race walking Racquetball/squash Running (long distance) Soccer*

A. Low (<50%)

B. Moderate (50–75%)

C. High (>75%)

Increasing dynamic component

General guidelines classifying sports based on the peak static and dynamic components typically reached during competition (although higher values can be achieved). *Sport presents danger of bodily collision. †Sport carries increased risk if syncope occurs. Source: Levine et al., 2015.59 Reproduced with permission of Levine et al. and the Journal of the American College of Cardiology.

was found to be the most common structural cardiovascular cause of death, followed by anomalous origin of the coronary arteries.18 A more recent 10-year study from Australia similarly found that a familial cardiomyopathy (HCM or ARVC) contributed to approximately 33% of sport-related SCD in children,19 and an analysis of a UK registry found that myocardial disease (including left ventricular hypertrophy and fibrosis, HCM and ARVC) accounted for 40% of SCD in athletes.20 Interestingly, HCM was found to be a more common cause of SCD in male athletes, while anomalous origin of the coronary arteries was the more common cause in female athletes.21 However, the SCD reported in studies of patients with HCM is often related to polymorphic VT/VF, although they can also present with MMVA. In older athletes with MMVA, atherosclerotic CAD should be considered, as it is the most common aetiology of sport-related SCD in this group, presumably due to ischaemic scar-related VA.19 Other structural pathologies that can lead to MMVA in athletes of any age include arrhythmogenic inflammatory cardiomyopathy (including sarcoidosis and myocarditis)22,23 and valvular abnormalities (e.g. mitral valve prolapse).24,25

Electrical Heart Disease While structural heart disease needs to be evaluated in athletes with MMVA, the most common finding in athletes who experienced SCD is a structurally normal heart,26 and the most common cause of SCD in children and adolescent athletes is sudden arrhythmic death syndrome (SADS).20 Presumably, SADS is because of undiagnosed inherited arrhythmia disorders, such as ion channelopathies.27 These channelopathies include long QT syndrome, Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia, but more commonly manifest as polymorphic VA and are thus outside of the scope of this review on MMVA.

Management The management of any athlete with known or possible cardiovascular disease, especially MMVA, can be particularly challenging because of the large role that physical activity and competitive sports plays in the athlete’s personal and/or professional life. Management decisions

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therefore require a shared-decision making approach that emphasises the need to prioritise the athlete’s safety, including providing a temporary or indefinite recommendation to refrain from strenuous exercise or competition. However, it should be noted that certain sporting organisations may require medical ‘clearance’ for competitive participation and the athlete may have less autonomy in these situations.

Restriction from Competitive Sports Before an athlete with known or suspected MMVA can be cleared to return to competitive sport participation, a cardiac evaluation – comprising at least of an exercise stress test targeting maximal performance, echocardiogram and ambulatory ECG monitoring – is recommended.1,10 Based on the American Heart Association (AHA) and American College of Cardiology (ACC) recommendations, absent of any structural or electrical heart disease or high-risk ECG features, athletes who demonstrate no greater than PVC couplets during maximal exercise testing, ideally recapitulating their sport of choice, can participate in all competitive sports.1 The European Society of Cardiology (ESC) recommendations also include stipulations that there be no family history of SCD, no increased PVC frequency during exercise, and overall PVC burden <2000 per 24 hour for clearance to participate in all sports.28 If exercise testing results in increased VA frequency, repetitive forms of PVCs, NSVT or sustained VT, then the athlete should be given the recommendation to refrain from participation in competitive sports until further evaluation and/or treatment are performed.1,28 Athletes found to have structural heart disease or evidence of myocarditis should be advised to restrict themselves to playing low intensity (Class IA) sports, such as bowling and golf (Figure 4). In particular, while expert opinion suggests that those with myocarditis may potentially be able to return to higher-intensity sports after evaluation for complete resolution of their condition,1,28 athletes with a diagnosis of ARVC should be counselled extensively on the importance of refraining from strenuous exercise indefinitely, as exercise in these patients is associated with a high risk of a lethal VT.29–31 High-intensity exercise, independent of exercise duration, increases risk in patients with ARVC,32 and exercise restriction has indeed been found to reduce VT frequency.33 Athletes without overt ARVC, but who have a desmosomal mutation associated with ARVC, are at increased risk of developing ARVC, heart failure, and/or lethal VT with endurance and/ or frequent exercise.34 These athletes should also be counselled to refrain from endurance exercise and high-intensity sports (above Class IA), but can likely still safely adhere to the AHA’s minimal exercise recommendations (450 to 750 metabolic equivalent-minutes weekly).35 Interestingly, it has been reported that high-intensity endurance exercise itself may result in ARVC-like pathology, including an increased risk of VT, without any detected genetic mutation (‘gene-elusive’).36–38 In addition, a recent study found a distinct pattern of isolated subepicardial RVOT scar associated with MMVA in high-level endurance athletes that is amenable to RFA.39 However, little is known about the potential need for post-ablation exercise limitations in this patient population. Further, a small study of seven asymptomatic athletes with extensive subepicardial late gadolinium enhancement on cardiac MRI found that six of the seven developed symptomatic VT or progressive LV dysfunction.40 The aetiology of the subepicardial scar was unknown in these athletes, and this study supports comprehensive evaluation and close follow-up in those athletes found to have myocardial fibrosis on cardiac MRI.

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Monomorphic Ventricular Arrhythmias in Athletes Prescribed Deconditioning In athletes without structural or electrical heart disease, prescribed periods of deconditioning (ranging from 12–24 weeks) have been shown to reduce the frequency of MMVA.6 The beneficial effects of periods of deconditioning on frequency reduction appear to persist after a resumption of intensive training, when compared with the MMVA frequency prior to deconditioning.41 However, in practice, athletes are often reluctant to participate in deconditioning periods. Reassuringly, one study assessed 120 athletes with no obvious structural heart disease found to have a modest burden of PVCs (>100/24 hours) on routine pre-participation screening.42 Continued sports activity in these athletes did not result in any deaths or development of overt heart disease, and overall modest PVC burden actually decreased over the median follow-up period of 84 months. Thus, as long as there is no evidence of overt structural or electrical heart disease, deconditioning is an optional recommendation for many athletes with MMVA.

Medical Management In symptomatic athletes, medical therapy can be considered to reduce symptoms and MMVA frequency. For athletes with symptomatic PVCs or a high PVC burden, beta-blocker therapy can be effective at reducing PVC frequency, and the ESC recommends beta-blockers as first-line medical therapy for the treatment of MMVA.43 Additionally, beta-blockers can be considered for athletes with NSVT induced by exercise, and documentation of resolution of NSVT with exercise on beta-blocker therapy is required before an athlete can be cleared to return to competitive sport participation.1 However, it should be noted that beta-blockers may have limited utility/tolerance in athletes given the high baseline parasympathetic tone (and associated resting bradycardia) seen in elite athletes, as well as the possible adverse effects these medications may have on athletic performance. Further, some sporting organisations actually prohibit the use of beta-blockers in athletes during competition, and physicians should review and remind their athlete patients to review the list of prohibited classes of medications prior to prescribing any new medication. Of note, there is no evidence at this time to support the use of antiarrhythmic medications to suppress benign PVCs in athletes.14 For patients with PVC-induced cardiomyopathy, however, there are recent data to suggest the safety and efficacy of class IC antiarrhythmic medications, such as flecainide in an unselected patient population.44 For athletes with idiopathic MMVT, medical therapy can be considered if RFA is not possible or not desired,45,46 and the location of VT origin can be influential in guiding therapy. For instance, fascicular VT has been found to be responsive to the non-dihidropyridine calcium channel blocker verapamil, as well as beta-blockers. For outflow tract VT, class IC and class III antiarrhythmic medications are more effective than beta-blockers or calcium channel blockers, and can be considered as long as there is no evidence of structural heart disease.46 However, the side effect profiles of antiarrhythmic medications need to be strongly considered prior to initiation in any athlete and beta-blockers are usually the first choice given the safety profile.

Radiofrequency Catheter Ablation Many athletes, particularly younger ones, are reluctant to take medications because of concerns about their side effects and their possible impact on athletic performance. Fortunately, RFA of MMVT – previously limited to experienced academic centres – is

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now being increasingly performed internationally as more cardiac electrophysiologists gain advanced training in the procedure.47 For athletes with symptomatic PVCs, RF ablation of PVCs may be considered if the PVCs are refractory to medications or if the athlete is unable or unwilling to take medications.1 In contrast to medications, RFA can be curative of MMVAs. In fact, for PVCs with an RVOT origin, RFA was found to be more effective than antiarrhythmic drug therapy in preventing recurrence,48 and a multi-centre study found RFA to have an 84% acute success rate with a low complication rate (2.4% major complications and 2.8% minor complications).49 Complications were most commonly related to vascular access, but rare complications including cardiac tamponade and atrioventricular block can occur. Notably no procedure-related stroke or deaths were seen in the 1,185 patients included in the study.49 Furthermore, given the association of PVC frequency with an increased risk of heart failure (PVC-induced cardiomyopathy),50 it is reasonable to consider RFA in athletes with a high PVC burden and/or a reduction in systolic function due to PVCs.43 RFA of PVCs originating from the LVOT, aortic cusp, or epicardial origin should only be undertaken at experienced centres. For athletes with idiopathic, monomorphic sustained VT, RFA is also a reasonable therapeutic option.1 In patients with MMVT associated with structural heart disease, such as ARVC and HCM, RFA can be considered, particularly if they are highly symptomatic or are experiencing frequent ICD therapies. A recent retrospective study of VT ablation in patients with non-ischaemic cardiomyopathy found that the outcomes of VT ablation differed based on the underlying etiology.51 Patients with ARVC had the highest VT-free survival 1 year after RFA (82%), while patients with HCM had a relatively higher rate of VT recurrence after ablation. In another recent study focused on patients with ARVC VT, RF ablation was associated with similar outcomes compared to drug therapy, although combined epicardial-endocardial RF ablation resulted in lower VT recurrence compared with an endocardial alone approach.52 Similarly, in a small, highly selected group of patients with MMVT associated with HCM, combined epicardial-endocardial RFA was effective at preventing recurrence of ICD shocks in 78% of patients at a median follow-up of 37 months.53 Thus, RFA can be an effective option for select patients with ARVC and HCM. However, given the presence of structural heart disease, RFA therapy does not allow for return to athletic competition, even if successful, as the procedure may eliminate the clinical arrhythmia but does not resolve the underlying pathology and future development of new VT circuits is possible.

Device Implantation The decision to implant an ICD in athletes is a particularly challenging one, as it may impact their ability to continue competition in their chosen sports.54 Additionally, potential complications of ICDs include inappropriate shocks, device-related infections and lead failure. In particular, with transvenous ICD systems, repetitive arm motion during athletic activity may result in lead dislodgement with resulting sensing failure or in lead fracture and inappropriate shocks.55 The recently available subcutaneous ICD may have a lower risk of lead malfunction.56 The recommendations for ICD implantation in athletes follow the same guideline recommendations for primary and secondary prevention in the general population. The AHA/ACC guidelines state that athletes who have survived a cardiac arrest due to MMVA should have an ICD placed.1 Additionally, athletes who have had documented symptomatic rapid monomorphic VT from a

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non-reversible cause should also have an ICD placed if not idiopathic in origin.1 In a multinational registry of 440 athletes with implanted transvenous ICDs and median follow-up of 44 months, the proportion receiving appropriate shocks during competition/practice was 11%; ARVC was the only clinical factor associated with receiving a shock. The estimated lead survival free of malfunction was 95% at 5 years and 85% at 10 years; there were no generator malfunctions.57 Notably, the AHA/ACC guidelines reiterate that the desire of an athlete to continue participation in athletic competition does not qualify as an indication for ICD implantation, and it is inappropriate to implant an ICD solely to allow for return to athletic competition.1

Return to Competitive Sports and Physical Activity After comprehensive evaluation of an athlete with MMVA, the recommendations on continued participation in competitive sports hinges on the presence of structural and/or electrical heart disease as well as response to therapy. In athletes without structural heart disease who have single PVCs and no greater than ventricular couplets during maximal exercise testing, participation can be allowed in all competitive sports without further evaluation.1 If PVCs either increase in frequency or cause symptoms during exercise (such as light-headedness, excessive fatigue, or excessive dyspnoea), the athlete should be restricted to sports below the exertional level at which these occurred until further evaluation (e.g. echocardiography, cardiac MRI, electrophysiological testing) has been performed and structural heart disease ruled out and treatment initiated. If the athlete has been started on drug therapy such as beta-blockers, return to participation should only occur if there is documentation on either exercise or electrophysiological testing that the MMVA no longer occurs under the physiological conditions in which it previously occurred prior to medical therapy. In athletes who have had successful RFA of their MMVA, return to full competitive activities can be allowed if there is no evidence of spontaneous or induced VA at least 3 months after the date of their procedure in the setting of a structurally normal heart.1 Athletes with structural heart disease with documented NSVT should be restricted to low-intensity class IA sports (Figure 4), even if they have undergone successful RFA of the MMVA.1 Notably, the data supporting this recommendation are limited (Class IC recommendation from the AHA/ACC). As mentioned above, continued high-intensity physical activity can promote progression of conditions such as ARVC, and athletes with these diagnoses should be counselled extensively on these risks. However, in athletes whose MMVA are a result of a transient inflammatory process such as myocarditis, re-evaluation for return to competition is recommended after there is clinical and laboratory evidence of resolution of the inflammation; if there is reasonable evidence to suggest that the pathology has fully resolved, the athlete may return to competition a minimum of 3 months after clinical resolution.1 However, in inflammatory conditions such as cardiac sarcoidosis, there can be recurrence of the inflammatory process after dormant periods and complete resolution may not occur.

1.

Z ipes DP, Link MS, Ackerman MJ, et al. Eligibility and disqualification recommendations for competitive athletes with cardiovascular abnormalities: Task Force 9: Arrhythmias and conduction defects: A scientific statement from the American Heart Association and American College of Cardiology. J Am Coll Cardiol 2015;66:2412–23. https://doi. org/10.1016/j.jacc.2015.09.041; PMID: 26542670.

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2.

3.

For athletes who have had an ICD, participation in class IA sports is permitted if there is no evidence of MMVA requiring device therapy for at least 3 months. Participation in higher-intensity sports may be considered after extensive discussion with the athlete on the risks involved, including ICD pocket-site injury in impact sports.1 These decisions will be diagnosis-dependent, as athletes with diagnoses that are known to be negatively impacted by exercise, such as ARVC, should be advised against participation in higher-intensity sports. The ICD Sports Safety Registry of athletes with ICDs implanted who continue to participate in competitive sports, including high-risk sports, has helped to inform sports cardiologists and patients on the outcomes of these athletes.57,58 In longer-term follow-up of the 440 participants in the registry, while there were appropriate and inappropriate ICD shocks in some of the athletes, there were no failures to terminate arrhythmias and no physical injuries due to the ICD. Freedom from lead malfunction (definite or possible) was 85% at 10 years.57

Conclusion Athletes with MMVA warrant comprehensive evaluation by a sports cardiology program, with experience and expertise as needed in paediatric cardiology, adult congenital cardiology, advanced cardiac imaging, interventional cardiology, electrophysiology and advanced exercise testing. While most of these MMVA will be of a benign nature, it is crucial to evaluate for the presence of structural and/or electrical heart disease, as continued competitive sport participation may expose the athlete to an increased risk of SCD in conditions such as ARVC and HCM. In the absence of structural heart disease, the improved outcomes of therapeutic procedures such as RFA and improved understanding of the management of MMVA in athletes have allowed many athletes to be guided safely back towards competition with the guidance of a sports cardiologist. In all cases, shared decision making should be central to formulating the treatment plan for each athlete.

Clinical Perspective • MMVA, including premature ventricular complexes as well as non-sustained and sustained VT, are not uncommon in athletes and always raise concern about whether an athlete can continue to participate in competitive sports. • Initial assessment includes a comprehensive history and physical examination and review of all available ECGs. • Identifying high-risk features, particularly response to maximal exercise testing and presence of structural heart disease, is critical to determine safety of continued competitive sport participation. • Echocardiography and frequently cardiac MRI are required to evaluate for structural heart disease, as certain conditions (i.e. ARVC, HCM) pose an elevated risk of sudden cardiac death during competition. • Treatment options include observation and monitoring, exercise restriction, medical therapy, and interventions such as RFA and ICD implantation.

 aron BJ, Pelliccia A. The heart of trained athletes: cardiac M remodeling and the risks of sports, including sudden death. Circulation 2006;114:1633–44. https://doi.org/10.1161/ CIRCULATIONAHA.106.613562; PMID: 17030703. Zorzi A, Mastella G, Cipriani A, et al. Burden of ventricular arrhythmias at 12-lead 24-hour ambulatory ECG monitoring in middle-aged endurance athletes versus sedentary

4.

controls. Eur J Prev Cardiol 2018;25:2003–11. https://doi. org/10.1177/2047487318797396; PMID: 30160531. Biffi A, Pelliccia A, Verdile L, et al. Long-term clinical significance of frequent and complex ventricular tachyarrhythmias in trained athletes. J Am Coll Cardiol 2002;40:446–52. https://doi.org/10.1016/S07351097(02)01977-0; PMID: 12142109.

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prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC). Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). Eur Heart J 2015;36:2793–867. https://doi.org/10.1093/eurheartj/ehv316; PMID: 26320108. Hyman MC, Mustin D, Supple G, et al. Class IC antiarrhythmic drugs for suspected premature ventricular contractioninduced cardiomyopathy. Heart Rhythm 2018;15:159–63. https:// doi.org/10.1016/j.hrthm.2017.12.018; PMID: 29405947. Lai E, Chung EH. Management of arrhythmias in athletes: Atrial fibrillation, premature ventricular contractions, and ventricular tachycardia. Curr Treat Options Cardiovasc Med 2017;19:86. https://doi.org/10.1007/s11936-017-0583-x; PMID: 28990149. Saeid AK, Klein GJ, Leong-Sit P. Sustained ventricular tachycardia in apparently normal hearts: Medical therapy should be the first step in management. Card Electrophysiol Clin 2016;8:631–9. https://doi.org/10.1016/j.ccep.2016.04.012; PMID: 27521096. Bradfield JS, Shivkumar K. Anatomy for ventricular tachycardia ablation in structural heart disease. Card Electrophysiol Clin 2017;9:11–24. https://doi.org/10.1016/j.ccep.2016.10.002; PMID: 28167079. Ling Z, Liu Z, Su L, et al. Radiofrequency ablation versus antiarrhythmic medication for treatment of ventricular premature beats from the right ventricular outflow tract: prospective randomized study. Circ Arrhythm Electrophysiol 2014;7:237–43. https://doi.org/10.1161/CIRCEP.113.000805; PMID: 24523413. Latchamsetty R, Yokokawa M, Morady F, et al. Multicenter Outcomes for Catheter Ablation of Idiopathic Premature Ventricular Complexes. JACC Clin Electrophysiol 2015;1:116–23. https://doi.org/10.1016/j.jacep.2015.04.005; PMID: 29759353. Dukes JW, Dewland TA, Vittinghoff E, et al. Ventricular ectopy as a predictor of heart failure and death. J Am Coll Cardiol 2015;66:101–9. https://doi.org/10.1016/j.jacc.2015.04.062; PMID: 26160626. Vaseghi M, Hu TY, Tung R, Vet al. Outcomes of catheter ablation of ventricular tachycardia based on etiology in nonischemic heart disease: An international ventricular tachycardia ablation center collaborative study. JACC Clin Electrophysiol 2018;4:1141–50. https://doi.org/10.1016/j. jacep.2018.05.007; PMID: 30236386. Mahida S, Venlet J, Saguner AM, et al. Ablation compared with drug therapy for recurrent ventricular tachycardia in arrhythmogenic right ventricular cardiomyopathy: Results from a multicenter study. Heart Rhythm 2019;16:536–43. https:// doi.org/10.1016/j.hrthm.2018.10.016; PMID: 30366162. Dukkipati SR, d’Avila A, Soejima K, et al. Long-term outcomes of combined epicardial and endocardial ablation of monomorphic ventricular tachycardia related to hypertrophic cardiomyopathy. Circ Arrhythm Electrophysiol 2011;4:185–94. https://doi.org/10.1161/CIRCEP.110.957290; PMID: 21270104. Heidbuchel H, Carré F. Exercise and competitive sports in patients with an implantable cardioverter-defibrillator. Eur Heart J 2014;35:3097–102. https://doi.org/10.1093/eurheartj/ehu130; PMID: 24713647. Lampert R, Cannom D, Olshansky B. Safety of sports participation in patients with implantable cardioverter defibrillators: a survey of heart rhythm society members. J Cardiovasc Electrophysiol 2006;17:11–15. https://doi.org/10.1111/ j.1540-8167.2005.00331.x; PMID: 16426392. Bardy GH, Smith WM, Hood MA, et al. An entirely subcutaneous implantable cardioverter-defibrillator. N Engl J Med 2010;363:36–44. https://doi.org/10.1056/NEJMoa0909545; PMID: 20463331. Lampert R, Olshansky B, Heidbuchel H, et al. Safety of Sports for Athletes With Implantable Cardioverter-Defibrillators: Long-term results of a prospective multinational registry. Circulation 2017;135:2310–2. https://doi.org/10.1161/ CIRCULATIONAHA.117.027828; PMID: 28584032. Lampert R, Olshansky B, Heidbuchel H, et al. Safety of sports for athletes with implantable cardioverterdefibrillators: results of a prospective, multinational registry. Circulation 2013;127:2021–30. https://doi.org/10.1161/ CIRCULATIONAHA.112.000447; PMID: 23690453. Levine BD, Baggish AL, Kovacs RJ, et al, American Heart Association Electrocardiography and Arrhythmias Committee of Council on Clinical Cardiology, Council on Cardiovascular Disease in Young, Council on Cardiovascular and Stroke Nursing, Council on Functional Genomics and Translational Biology, and American College of Cardiology. Eligibility and disqualification recommendations for competitive athletes with cardiovascular abnormalities: Task Force 1: Classification of Sports: Dynamic, static, and impact: A scientific statement from the American Heart Association and American College of Cardiology. Circulation 2015;132:e262–6. https://doi. org/10.1161/CIR.0000000000000237; PMID: 26621643.

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Clinical Arrhythmias

A Review of Driving Restrictions in Patients at Risk of Syncope and Cardiac Arrhythmias Associated with Sudden Incapacity: Differing Global Approaches to Regulation and Risk Andrei D Margulescu and Mark H Anderson Morriston Cardiac Centre, Department of Cardiology, Morriston Hospital NHS Trust, Swansea, UK

Abstract The ability to drive is a highly valued freedom in the developed world. Sudden incapacitation while driving can result in injury or death for the driver and passengers or bystanders. Cardiovascular conditions are a primary cause for sudden incapacitation and regulations have long existed to restrict driving for patients with cardiac conditions at high risk of sudden incapacitation. Significant variation occurs between these rules in different countries and legislatures. Quantification of the potential risk of harm associated with various categories of drivers has attempted to make these regulations more objective. The assumptions on which these calculations are based are now old and less likely to reflect the reality of modern driving. Ultimately, a more individual assessment of risk with a combined assessment of the medical condition and the patient’s driving behaviour may be appropriate. The development of driverless technologies may also have an impact on decision making in this field.

Keywords Driving, incapacitation, sudden death, medical regulation, ethics, ICD, road accidents, driving restrictions, arrhythmia, risk of harm Disclosure: The authors have no conflicts of interest to declare. Received: 9 January 2019 Accepted: 9 April 2019 Citation: Arrhythmia & Electrophysiology Review 2019;8(2):90–8. DOI: https://doi.org/10.15420/aer.2019.13.2 Correspondence: Mark H Anderson, Morriston Cardiac Centre, Department of Cardiology, Morriston Hospital NHS Trust, Swansea, SA6 6NL, UK. E: andersoncardiology@gmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Motor vehicle travel and driving has become a major component of daily living in the developed world. Sudden incapacity occurring while driving can result in accidents that may be fatal both for the driver and for bystanders. The regulatory approach aims to balance the risk to bystanders against the highly valued individual freedom of motorised mobility. In this article we review some of the concepts that are pivotal to this balancing act, compare variations in national approaches to regulation and ask whether it is time for some of the accepted tenets to be revised.

Syncope and Incapacitation as a Result of Arrhythmia Sudden incapacity can result from a syncopal event, a sudden cardiac death (SCD), or a neurological event such as seizure or stroke. Syncope is defined as a transient loss of consciousness event that results from general brain hypoperfusion.1 Syncope can be neurally mediated, caused by orthostatic hypotension or by cardiac conditions – mostly arrhythmic events (either brady- or tachyarrhythmias). SCD is an unexpected death from a cardiac cause, which occurs within one hour from the start of any cardiac-related symptoms. It is irreversible if prompt resuscitation is not applied. SCD is mostly arrhythmic in nature, with ventricular tachycardia (VT) and VF responsible for >75% of cases.2 Cardiac pacemakers are used to treat patients with – or those at risk of developing – significant bradyarrhythmias, while ICDs are

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used to treat patients who are at high risk of SCD as a result of VT/ VF. While pacemakers can effectively prevent the occurrence of bradyarrhythmias, ICDs do not prevent VT/VF but treat those rhythms once they happen by either overdrive antitachycardia pacing (ATP) or internal cardioversion. Syncope may still occur in patients who develop VT/VF despite having an ICD because of the time delay between arrhythmia occurrence, effective treatment and restoration of normal brain perfusion. The following discussion will focus on the driving restrictions in patients at risk of syncope and cardiac arrhythmias associated with sudden incapacity.

Risk Estimate of Motor Vehicle Accident Fatalities in Patients at Risk of Syncope and Cardiac Arrhythmias Driving Licence Categories Driving licences are generally divided into private (group 1), and commercial (group 2). The definition of private and commercial drivers varies somewhat between countries (Table 1) but, in general, a private driver is a licensed driver who does not earn a living from driving and a commercial driver is a driver who earns a living from driving and/ or is licensed to drive large passenger or goods-carrying vehicles. Categories for taxi drivers vary between group 1 and group 2 standards and may be locally determined.

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Syncope and Cardiac Arrhythmias Table 1: Definition of Driving Licence Groups EU

UK

US

Canada

Australia

Japan

Group 1

Ordinary motorcycles, cars, small vehicles with or without a trailer (categories A, B)

Similar to EU. Maximal vehicle weight <3,500 kg

Any not fulfilling commercial driver criteria

- Driver who drives <36,000 km/year, OR spends <720h/year behind the wheel AND - Drives a vehicle weighing <11 tonnes AND - Does not earn a living from driving

Drivers of cars and light rigid vehicles. Cars are defined as vehicles of <4.5 tonnes, and seating up to 12 adults (including the driver). Light rigid vehicles are defined as vehicles of between 4.5 and 8 tonnes (or 9 tonnes if having a trailer)

- Driver of motorcycles, automobiles, other vehicles with or without a trailer, AND - Does not earn a living from driving

Group 2

Drivers of vehicles weighing >3.5 tonnes. Drivers of passengercarrying vehicles with more than 8 seats including the driver (categories C, D and E [vehicles with a trailer])

Similar to EU.

Any driver of: vehicles Any not fulfilling private Any two-axle or Driver who earns a living weighing >26,001 driver criteria three-axle rigid from driving, including pounds; truck with vehicle of >8 tonnes taxi, bus, ambulance double/triple trailers; (or 9 tonnes with a truck carrying trailer) hazardous materials; passenger vehicles designed to carry >16 passengers including the driver

Source: Watanabe E et al.10; DVLA 201833; EUR-Lex Directive 2006/126/EC39; The Expert Group on Driving and Cardiovascular Disease40; Lococo et al.2; Canadian Council of Motor Transport Administration43; Austroads.44

General Statistics on Road Traffic Accidents

Acceptable Risk of Road Traffic Accidents

Driving a car is a central part of life in developed societies. For example, more than 85% of Americans own a car and almost 270 million vehicles are registered in the US alone (of which more than 190 million are “light duty, short wheel base” vehicles).3 However, motor vehicle accidents are a leading cause of death worldwide. Road injuries – including accidents involving all forms of road transportation systems, and pedestrians – killed more than 1.4 million people in 2016.4 In UK, 1,793 people were killed in road accidents in 2017, 44% of which were drivers.5

Driving carries risk but is a major part of life in many societies, so it follows that these societies accept an intrinsic risk of harm (RH) to self and others because of driving. Nationally defined regulations have implicitly balanced risk and benefit for decades. An attempt to formalise this balancing act emerged from a Canadian Cardiovascular Society conference in 1992 (updated in 2003).11 In this document, the annual RH as a result of driving was defined as:

The risk of death related to driving is highly variable between countries. Road traffic death rates in low- and middle-income countries are more than double those in high-income countries.6 However, wide disparities exist even among developed countries. For example, per capita road fatalities in the US are almost double those in Denmark, and in 2016 there was almost a fourfold difference in road accident fatalities between the ‘safest’ and the ‘least safe’ European countries: Norway (26 fatalities per million population) and Romania (97 fatalities per million population).7,8 While some of the difference may relate to mileage driven, cultural approaches to risk are also an important factor.

where: • TD is the time spent driving; • V is the type of vehicle; • SCI is the risk of sudden incapacitation; and • Ac is the probability that an episode of sudden incapacitation will result in a fatal or injury-producing accident. - TD is 0.25 (25%) for professional drivers because the average time spent driving is 6 hours per day; and 0.04 (4%) for social drivers because they spend, on average, 1 hour driving per day. - V is 1 for trucks and 0.28 for family cars because, on average, accidents involving trucks cause 7.2% of fatalities, despite causing only 2.0% of road accidents (2.0 ÷ 7.2% = 0.28). - SCI is 0.01 (1%), which was the estimated annual risk of SCD of a truck driver who had not had an acute MI within the previous 3 months, is in functional class I (asymptomatic), has a negative exercise tolerance test, is able to perform at least seven metabolic equivalents of task during the treadmill test, and has no documented ventricular arrhythmias. This driver was historically allowed to drive by Canadian laws, so this was set as the acceptable risk threshold in the RH formula. The 1% mortality per year also holds true for men in the Western population aged >65 years and this limit has been used for maximal annual risk allowance for commercial pilots in aviation risk assessment (the 1% rule).12

Accident and fatality rates also vary according to age. The rate of death in car accidents is highest in individuals aged 20–29 years and those older than 80 years – 16.0 per million population in the UK – and lowest in the middle-aged population – 6.8 per million population in the UK – in those aged 40–49 years.9 In young adults aged 20–29, road traffic accidents are the leading cause of death worldwide.6 Elderly people are at risk of road traffic accidents for a variety of reasons, such as a slower reaction time, depth perception change, vision and hearing problems, decreased ability to focus and medical problems. Compared with younger individuals – for who speed is a major cause of road accidents while driving – physiological and perceptual decline is the major cause of road accidents while driving in older individuals.10

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RH = TD × V × SCI × Ac

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Clinical Arrhythmias - Ac is 0.02 (2%) because only 2% of accidents caused by drivers suffering SCD or sudden incapacity while driving has resulted in harm or death of other road traffic users or bystanders. Using these assumptions, the annual risk of death or injury to others from allowing a truck driver to drive is approximately 1 in 20,000 (0.005%). It can be estimated that a private driver has a 22-times lower RH compared with a professional driver (TDprofessional ÷ TDsocial × Vtruck ÷ Vcar= 0.25 ÷ 0.04 × 1.00 ÷ 0.28). In other words, a private driver with a SCI of 22% has the same RH as a professional driver with a SCI of 1%.11 There are some important caveats associated with the RH formula. Importantly, TD and V were calculated based on the Ontario Road Safety Annual Report from 1987. The Ac was estimated from reports published between 1974 and 1990. However, road traffic accident rates have declined over the years in high-income countries, but increased in low-income countries.6 In addition, the safety (for drivers, passengers and pedestrians) of new cars sold by respected manufacturers has dramatically increased in the last 20 years. For example, in 1997, all but one of the 20 cars tested by the European New Car Assessment Programme received less than 3/5 stars at crash-tests and the one exception received 4/5 stars, while in 2017 – under far more stringent crash-test safety assessment criteria – 44 of 70 (63%) of the tested cars received the maximum 5/5 stars.13 The actual RH may now be less than the 0.005% calculated in 1992. An assumption in the Canadian model is that all groups of drivers share the same maximum RH threshold, but this ignores the possibility that society would place a different value on different types of driving, for example delivering food or medical supplies versus private driving for pleasure or leisure. Ideally, societally acceptable RH should be calculated at least nationally, based on specific country road accident profiles, type of roads, types of vehicles, age and gender, individual times spent driving, and so on. In future, it is conceivable that individual medical risk and driving behaviour could be tested against a societal RH threshold using knowledge of an individual patient’s medical condition and a black box device to monitor distance travelled and driving behaviour.

Overall, patients with a history of syncope have a higher risk of motor vehicle accidents compared with asymptomatic subjects. A Danish nationwide survey identified more than 41,000 patients with syncope and compared their motor vehicle accident rate to the general Danish population.18 During an average 2-year follow up, 4.4% of patients had a vehicle accident, 23.7% of which led to major injury and 0.3% to death. When an accident occurred there was no difference in the risk of serious injury between the syncope and general populations. The crude incidence rate of motor vehicle accident was 1.83-times higher in patients with syncope compared with the general population (20.6 per 1,000 person-years versus 12.1 per 1,000 person-years). The 5-year accident risk in patients aged 18 to 69 years with syncope was 8.2%, compared with 5.1% in the general population. The risk of syncope recurrences is highest in the first year after the initial event, then it gradually tapers off and reaches a plateau after 5 years. About one-quarter of syncopal episodes while driving remain undiagnosed. The annual recurrence rate of undiagnosed syncope (15–21%) lies in between the recurrence rate of neurally mediated syncope and syncope of other aetiologies, but the actual risk of recurrence of syncope while driving is low at <1.1% per year, which is similar to the risk of SCI in the RH formula.15 It follows that the highest risk of recurrence while driving actually resides with neurally-mediated syncope, but the actual RH of this type of syncope rarely reaches the threshold of unacceptable societal risk (0.005% per year). Bradyarrhythmic syncope recurrences are usually mitigated by implantation of a permanent pacemaker. AVNRT and AVRT are effectively treated and even cured with radiofrequency ablation. The case of VT/VF will be discussed below, under the headings for ICDs. See Table 2 for full details of syncope guidance depending on country or guideline document. We endorse the recommendations valid in the UK on driving restrictions for patients with syncope, supraventricular tachycardia, following ablation procedures and with pacemaker devices. Our personal opinion regarding private drivers with ICDs will be discussed briefly below.

ICDs

Risk Assessment for Patients at Risk of Syncope and Cardiac Arrhythmias Associated with Sudden Incapacity Syncope Data from the Framingham Heart Study suggest that the incidence of syncope in the general population is between 3% and 6% at 10 years.14 Among patients with syncope, 3–10% of syncopal events appear while driving; 85% of these patients have recurrent syncope but in a few the first syncope occurs while driving.15 The causes of syncope while driving are the same as for the general population; 35–38% are neurally mediated, 5–7% are caused equally by orthostatic hypotension, bradyarrhythmias and VTs, and 2–4% are caused by supraventricular tachycardias (almost all of them either atrioventricular nodal re-entrant tachycardia [AVNRT] or atrioventricular re-entrant tachycardia [AVRT]).16 During long-term follow up (8 years), the recurrence rate of syncope was similar in patients who had experienced the first syncopal event while driving and those who had not; 34–39% for neurallymediated syncope, 7–13% for bradyarrhythmias, and 3–4% for VT and supraventricular tachycardias. Malignant arrhythmias causing SCD (fast VT/VF) are rare. A retrospective study performed in Germany estimated that 0.4% of all road traffic accidents are caused by the driver having a SCD event while driving.17

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In 2011, around 400,000 ICDs were implanted each year worldwide, two-thirds of which were new implants.19 ICDs are implanted for primary or secondary prevention of SCD. Primary prevention refers to patients who have never had but are at risk of having a VT/VF event. Secondary prevention refers to patients who have had a VT/VF event. There are a variety of conditions that may predispose a patient to SCD and each carries a particular risk. In the adult population, the majority of SCD events – approximately 80% – appear in patients with coronary artery disease.20,21 ICDs are effective in treating sudden ventricular tachyarrhythmic events that can cause SCD. However, ICDs do not prevent such events. With VF, loss of consciousness is usual as the ICD typically takes 10–15 seconds to deliver therapy (longer for subcutaneous ICDs). As such, establishing the risk of syncopal events caused by VT/VF in patients with ICDs is important to assess the RH. The average annual risk of shock while driving in patients with ICDs is approximately 1.5%.22 Studies have documented that the risk of syncope associated with appropriate ICD shocks in patients who have had an ICD implanted for secondary prevention ranges from 2.0% to 16.0% (average 11.2%).10 For primary prevention, the risk of syncope

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Australia

Japan

Germany

Canada

UK

US

EHRA (professional guideline) Legal document

Legal document

Legal document

Guideline

EC recommendations 2013 (proposal to update Directive 2006/126/EC)

Legal document

Proposal to update legal document

Guideline

Guideline

1. Isolated – no restrictions.

2. Recurrent / severe – no driving until symptom control.

1. Isolated – no restriction unless driving with a high-risk activity.

3. Unexplained – no restrictions, unless severe structural heart disease, no prodrome, or occurring while driving (no driving until treatment established).

1. Typical vasovagal with cause unlikely to occur while driving – no restrictions.

2. Recurrent / severe / unexplained – no driving until effective treatment.

4. Recurrent unexplained blackouts – no driving for 10 years, then to annual review.

3. Isolated unexplained blackout – no driving for 5 years, then to annual review.

2. Cardiovascular syncope – no driving for 6 months.

4. Recurrent unexplained blackouts – no driving for 12 months, then to annual review.

3. Isolated unexplained blackout – no driving for 6 months, then to annual review.

-

2. All other cases of recurrent syncopal episodes – no driving for 6 months.

2. Recurrent 2.1. typical vasovagal, with prodrome a) while standing – no restrictions b) while sitting: may drive if risk of recurrence is <20%/year.

2.2. vasovagal without prodrome / unexplained: no driving for 12 months.

2. Unexplained 2.1. isolated – no driving for 1 year 2.2. recurrent within 12 months – no driving for 1 year.

1. Typical vasovagal 1.1. isolated – no restrictions 1.2. recurrent within 12 months – no driving for 1 year.

1. Single syncope or recurrent syncopal episodes occurring in known low-risk circumstances – no restrictions.

-

1. Isolated 1.1. typical vasovagal: a) if standing – no driving b) if sitting – no driving for >3 months, requires investigations 1.2. unexplained: no driving for 12 months if no cause identified.

1. Isolated - no 1. Mild – no driving for restrictions, in the 1 month. absence of any indication of 2. Severe, treated – no a high risk of driving for 6 months. recurrence. 3. Severe, untreated – 2. Recurrent – no no driving until effective driving until effective treatment established. treatment established.

1. Isolated 1. Isolated – no 1. Mild – no restrictions. 1. Typical vasovagal 1. Typical vasovagal 1.1. typical vasovagal: restrictions. - isolated – no restrictions with cause unlikely to a) if standing – no restriction 2. Severe, treated – no - recurrent within occur while driving – b) if sitting – may drive only if risk 2. Recurrent – no driving for 3 months. 12 months – no driving no restrictions. of recurrence is <20%/year driving for >6 months, for 1 week. pending additional 3. Severe, untreated – 2. Cardiovascular 1.2. unexplained: investigations. no driving until effective 2. Unexplained syncope – no driving no driving for 6 months if no treatment established. - isolated – no driving for for 4 weeks. cause identified. 1 week - recurrent within 12 months – no driving for 3 months.

Europe

Table 2: Recommendations of Driving Restrictions

Group 1

Cardiovascular Driving condition licence group

Syncope

Group 2

1.Single syncope or recurrent syncopal episodes occurring in known low-risk circumstances – no restrictions. 2. All other cases of recurrent syncopal episodes – permanent ban.

2. Recurrent 2.1. typical vasovagal, with prodrome a) while standing – no driving b) while sitting: no driving, can resume driving only if risk of recurrence is <2%/year 2.2. vasovagal without prodrome / unexplained: no driving for 10 years.

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Pacemaker

Ablation

-

-

Group 2

-

Group 2

Group 1

-

Group 1

-

Group 2

Legal document

UK

2. With syncope – no driving for 1 month, need cardiology follow-up

Resume driving only if: underlying cause has been identified; arrhythmia has been controlled for at least 3 months; LV ejection fraction is at least 40%.

No driving for 1 week.

2. arrhythmia causing incapacity: no driving for 6 weeks. Can drive anytime (but no driving for 1 week if pacemaker dependant).

After recovery from the procedure.

After recovery from the procedure.

2. Symptoms – no driving until symptoms controlled

1. No / minimal symptoms – no restrictions

Guideline

Australia

Legal document

Japan

No driving for 1 week, and correct pacemaker function.

No driving for 1 week after discharge.

No driving for 2 days after discharge.

As per Group 1

No driving for 4 weeks.

No driving for 2 weeks.

No driving for 4 weeks.

No driving for 2 days.

No driving until pacemaker integrity confirmed.

No driving for 1 week.

-

-

Recurrent arrhythmias causing syncope / presyncope – no driving until definite treatment or according to pacemaker / ICD guidelines

Recurrent arrhythmias causing syncope / presyncope – no driving until definite treatment or 2. Impaired consciousness according to pacemaker – no driving until / ICD guidelines. symptoms controlled, as follows: a) medical therapy – no driving for 3 months b) successful ablation – no restrictions.

1. No impaired consciousness – no restrictions.

Legal document

Canada

No driving for 1 week Can drive anytime (but No driving for 1 month, (4 weeks if dependant no driving for 4 weeks if and correct pacemaker or history of syncope). pacemaker dependant). function.

Can drive anytime.

1. arrhythmia not causing incapacity: no driving for 2 weeks.

-

1. No syncope – no restrictions

Resume driving after 2 days.

1. No / minimal symptoms – no restrictions.

Guideline

US

2. Syncope – no driving until effective 2. Symptoms – no treatment established. driving until symptoms controlled.

1. No syncope – no restrictions.

Legal document

Germany

No driving if arrhythmia caused / is likely to cause incapacity

Driving allowed after No driving for 6 weeks. adequate function and wound healing (at least 2 weeks).

Driving allowed after adequate function and wound healing (no time limit).

-

-

If history of syncope: no driving until the condition has been satisfactorily controlled /treated and risk of recurrence is low. In case of pre-excitation, driving may only be allowed after specialist assessment.

If history of syncope: no No driving if arrhythmia caused / driving until the condition is likely to cause incapacity. has been satisfactorily controlled /treated. Resume driving only if cause identified and arrhythmia controlled for at least 4 weeks.

Proposal to update legal document

Guideline

-

EC recommendations 2013 (proposal to update Directive 2006/126/EC)

Europe

EHRA (professional guideline)

Supraventricular Group 1 arrhythmias

Cardiovascular Driving condition licence group

Table 2: Continued

Clinical Arrhythmias

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Syncope and Cardiac Arrhythmias Table 2: Continued Cardiovascular Driving condition licence group

Canada

Australia

Japan

Germany

US UK

Europe EHRA (professional guideline)

Legal document

Legal document

Guideline

Legal document

Legal document

EC recommendations 2013 (proposal to update Directive 2006/126/EC) Guideline

Proposal to update legal document

2. Post-therapies associated with impaired consciousness or disabling symptoms – 6 months.

Permanent ban.

3. Generator change – 2 weeks.

Permanent ban.

2. Generator change – 1 week.

2. Post-therapies: 2.1. appropriate, no driving for 3 months 2.2. inappropriate: a) no symptoms – no restrictions b) syncope – 3 months.

No driving for: 1. Post-implant – 1 week.

Permanent ban.

3. Generator change – 1 week.

2. Post-therapies: 2.1. appropriate, no driving for 3 months 2.2. inappropriate: a) no symptoms – no restrictions b) syncope – 3 months.

No driving for: 1. After implant: 6 months.

No driving for: 1. After implant – 3 months. 2. Lead revision – 1–2 weeks. 3. Box change – 1 week.

Permanent ban.

2. Post-therapies associated with symptoms of haemodynamic compromise – 4 weeks.

No driving for: 1. After implant – 6 months after cardiac arrest (or 2 weeks after implant, whichever the longest).

No driving for 6 months. No driving for: 1. After implant – 1 week, plus post-VT/VF banning period: a) 3 months after last sustained VT episode without impaired consciousness b) 6 months after syncopal VT/VF.

Guideline

2. Lead revision – 1 month. 2. ICD therapies: 2.1. appropriate: no driving 3. Box change – 1 week. for 3 months;

4. Appropriate ATP or shock, associated with symptoms, but NO incapacity – 6 months.

1. Post-implant: No driving No driving for: Post-implant: 1. After implant – 6 months. No driving for 3 for 3 months. months. ICD therapies: 2.2. inappropriate: no driving until measures are taken to prevent inappropriate therapies.

4. ICD therapies: 4.1. appropriate ATP/ shock – 3 months 4.2. inappropriate shock – can drive once cause removed.

Permanent ban.

Permanent ban.

Permanent ban.

Permanent ban. Permanent ban.

5. ANY therapy with incapacity (ATP/shock; appropriate/ inappropriate) – 2 years, except: a) inappropriate shocks because of AF / programing issues – 1 month b) appropriate ATP/shocks for VT/ VF but steps to control arrhythmia were taken (antiarrhythmics, ablation) and no recurrence – 6 months.

Group 2

2. All others as per secondary prevention.

Permanent ban.

3. Generator change – 2 weeks

Group 1

2. ICD therapies: 2.1. appropriate – no driving for 3 months

Permanent ban.

Permanent ban.

No driving for: No driving for 4 No driving for: 1. Post-implant – 2 weeks. 1. Post-implant – 1 month. weeks.

ICD – secondary Group 1 prevention

ICD – primary prevention ICD therapies: -

2.2. inappropriate – no driving until measures are taken to prevent inappropriate therapies.

Permanent ban. Permanent ban.

Permanent ban.

No driving for: Post-implant: No Post-implant: No driving No driving for: driving for 1–2 weeks. for 1 week 1. After implant – 4 weeks. 1. After implant – 2 weeks. 2. Post-therapies associated with impaired 2. Post-therapies associated with consciousness or symptoms of disabling symptoms – haemodynamic 6 months. compromise – 4 weeks.

Group 2

Permanent ban but may drive if risk of events is <1%/year.

Recommendations of driving restrictions in patients at risk of syncope and cardiac arrhythmias associated with sudden incapacity, in different countries. The type of document (legal or guidelines only) is also displayed. Adapted from: Watanabe E et al.10; DVLA 201833; Task Force members 200934; Epstein et al. 199635; Epstein et al. 200736; Klein et al.37; EUR-Lex Directive 2006/126/EC39; The Expert Group on Driving and Cardiovascular Disease40; Lococo et al.42; Canadian Council of Motor Transport Administration43; Austroads44; Oginosawa et al.45; Sumiyoshi.46 AF = atrial fibrillation; ATP = antitachycardia pacing; EC = European Commission; EHRA = European Heart Rhythm Association; VT = ventricular tachycardia

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Clinical Arrhythmias associated with appropriate ICD shocks ranges from 0.6% to 4.3% (average 1.6%).10 The Triggers of Ventricular Arrhythmias (TOVA) study suggested that the absolute risk of ICD shock for VT/VF within 1 hour of driving is approximately one episode per 25,116 person-hours spent driving. Interestingly, the increased risk of shock was observed primarily in the 30-minute period after driving (RR 4.46; 95% CI [2.92–6.82]) rather than during the driving episode itself (RR 1.05; 95% CI [0.48–2.30]).23 Fewer data are available regarding the risk of sudden incapacitation associated with inappropriate ICD shocks. Data from a study performed in Japan suggest that only 0.7% of patients who experience inappropriate ICD therapies also have syncope, e.g. because of fast AF resulting in syncope but terminated by ICD shock, or VF induced by inappropriate ICD shock-on-T-wave as a result of T-wave oversensing.24 The calculated RH for inappropriate ICD therapies associated with syncope was <0.0008% for both primary and secondary prevention ICD indications, leading the authors to conclude that inappropriate ICD shocks should not result in a driving ban.24 Current data suggest that there is an increased risk of ICD shocks early after ICD implantation – for both primary and secondary prevention – and following appropriate or inappropriate ICD shocks, but the risk rapidly diminishes over the next 6 months. Thijssen et al. analysed data from 2,786 patients with primary and secondary prevention ICDs. Using the societal threshold for the RH of 0.005%, the 95% CI of the annual RH following ICD implantation was always below the threshold for both primary and secondary prevention, suggesting that no specific period of restriction after implantation is appropriate for private drivers. Following appropriate ICD shocks – and using a historical estimated risk of syncope associated with appropriate ICD shocks of 31% – the 95% CI of the annual RH fell below the threshold at 6 months for primary prevention ICDs, and at 3 months for secondary prevention ICDs. For commercial drivers, the RH was always above the threshold, supporting a permanent driving ban.25 However, newer data on contemporary ICD patient populations with modern ICD programing – and a more contemporary estimated risk of syncope associated with ICD shocks of 14% – suggest that the RH falls below 0.005% only 1 month after appropriate shocks.26 Thijssen et al. also estimated the RH after inappropriate shocks, but they assumed that the risk of syncope associated with ICD shocks is identical (31%) regardless of whether the shock was appropriate or not, which likely resulted in significantly overestimated RH (the 95% CI of the annual RH fell below 0.005% at 1 month and 3 months for appropriate and inappropriate shocks, respectively).25 As mentioned, newer data suggest that driving restrictions may not be necessary after inappropriate shock therapy.24 It is important to realise though that there are several important limitations regarding the RH assessment in patients with ICDs. First, as discussed, the RH threshold of 0.005% has been historically accepted for Canadian populations based on Canadian road traffic accident data from more than 30 years ago. Second, the risk of SCD and ICD shocks has been largely based on populations from the 1990s and early 2000s but there has been an almost 70% reduction of mortality in patients with coronary artery disease and heart failure in the last 20 years and a 44% reduction in SCD rates between 1995 and 2014 in patients with heart failure and reduced ejection fraction.27,28 These dramatic changes were a result of more effective drug treatment, e.g. angiotensin converting enzyme inhibitors, early revascularisation in patients with acute coronary syndromes, implementation of cardiac

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resynchronisation therapy, and so on. Indeed, in non-ischaemic dilated cardiomyopathy, the Danish Study to Assess the Efficacy of ICDs in Patients with Non-ischemic Systolic Heart Failure on Mortality (DANISH) failed to show a benefit of ICDs in reducing mortality, compared with the 11-year older Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT). However, the overall absolute 5-year mortality rate in the DANISH was approximately 10% lower than in the SCD-HeFT.29,30 As such, the risk of sudden incapacity while driving in contemporary patients with ICD may well be lower than the historical data upon which the current recommendations and legislations are based would suggest. Based on the summary above, we think that the current driving restrictions for patients with ICDs holding a group 1 driving licence are, in some cases, too restrictive. We propose that the following driving restrictions should suffice for these patients, if they drive in countries where the road safety statistics are similar to the countries mentioned in Table 2: - after ICD implantation or box-change (both primary and secondary prevention) = 1 week; - following appropriate ICD shock whether or not associated with incapacity = 1 month; and - following inappropriate ICD shock whether or not associated with incapacity = no restriction if cause corrected.

Legislation and Disclosure of Patient Information Driving Regulations and Expert Consensus Documents In many countries driving regulations have evolved over time as new data on clinical outcomes have become available. For example, in the UK, driving with an ICD was initially completely prohibited. By 1994 driving was allowed 2 years after ICD implant and by 2000 the regulations evolved to allow driving 1 month after a primary prevention ICD and 6 months after a secondary prevention ICD.31–33 Regulations are made to provide a balance between the privilege of driving and the potential to harm others from driving. It can be argued that, based on cultural and social mentality, national legislation will find different levels of equilibrium between these two opposing forces. In addition to national regulations, professional bodies have published guidance relating to particular areas of interest, such as licensing in ICD patients.34–36 The different national regulations and physician recommendations are summarised in Table 2. In some areas there is general consensus on no professional driving for patients with ICDs, in other areas there is more variation. In the UK, driving regulations are governed by the Driver and Vehicle Licensing Agency for England, Wales and Scotland, and Driver and Vehicle Agency for Northern Ireland.33 In Germany, assessment of fitness to drive is governed by the German Federal Highway Research Institute.37 In Europe in 1991, recognising substantial variation in the detail and implementation of driving regulation among EU Member States, the European Council established a Directive regarding the minimal physical and mental fitness standards for driving a vehicle, but the recommendations of this document for cardiovascular disease were vague. The Directive explicitly stated that driving is incompatible with the presence of “any disease capable of exposing [the driver] to a sudden failure of the cardiovascular system such that there is a sudden impairment of the cerebral functions”, and with the

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Syncope and Cardiac Arrhythmias presence of “serious arrhythmias” (a condition left undefined), while patients with cardiac pacemakers may drive if adequate follow up and checks are established.38 The presence of ICDs or ablation of cardiac arrhythmias is not found anywhere in the Directive, which was issued before these interventions were widely implemented in clinical practice. The latest amendment of this Directive (Directive 2006/126/EC, Annex III), which is still in force, made no changes to these definitions.39 This Directive has been widely incorporated into several legal frameworks and was legally binding in some European countries. Fortunately, the European Council has undertaken efforts to update the Directive 2006/126/EC Annex III with more extensive, up-to-date and specific recommendations for driving in patients with cardiovascular diseases.40 These changes have already been implemented in those EU member countries where the prior legislation was in effect until very recently, e.g. Romania.41 The legal framework of driving restrictions in the US is highly variable between states as there is no over-ruling federal law governing licensing decisions on medically at-risk drivers. For example, some states have a Medical Advisory Board (MAB) to guide decisions, while others do not. In addition, in some states medical professionals review cases, while in others administrative staff perform reviews. In some states, MABs employ medical professionals (e.g. Maine, North Carolina), while in others it is administrative staff who employ medical professionals (e.g. Texas, Wisconsin). Other states have no MAB, but again it is either medical professionals who perform reviews (e.g. Oregon), or administrative staff (e.g. Ohio, Washington).42 In Canada, the individual provinces and territories can legally develop their own policies but for consistency a central body – The Canadian Council of Motor Transport Administrators – has established a Driver Fitness Overview Group to advise on uniform medical standards. These standards are highly detailed and, unusually, allow for the possibility of commercial driving in recipients of a primary prevention ICD, in subgroups where the annual risk of incapacitation is below 1%.43 In Australia, Austroads and the National Transport Commission have issued guidelines on driving in patients with cardiovascular diseases.44 In Japan, regulations for drivers with cardiovascular diseases are governed by a Road Traffic Act issued by the Japanese National Police Agency.10,45,46

In a situation where a physician becomes aware that a patient is not adhering to the local driving code, an ethical issue arises about what to do. In the US, the recommended ethical action for doctors who are involved in the care of patients with conditions that constitute a ban from driving is to disclose that information to the police, after informing the patient, even if the patient refuses to obey.36 The reasoning is that ethical responsibilities of beneficence (do good and avoid evil) and non-maleficence (do no harm) take precedence over the principle of confidentiality in this setting. In Canada, disclosure of patients’ information by physicians is mandatory in most states, but not in all (for example, reporting is discretionary in Alberta, Nova Scotia and Quebec).11 In the UK, doctors should inform patients about conditions and treatments that might affect their ability to drive and remind them of their duty to tell the appropriate agency.33 If a patient refuses or is found not to have told the appropriate agency, doctors should ask for a patient’s consent to disclose information to the authorities, unless the information “is required by law or if it is not safe, appropriate or practicable to do so”.48 In Germany, because of confidentiality law, the doctor should only inform the patient regarding the loss of fitness to drive; informing the authorities is not permitted.37 In Japan, the doctor should advise patients not to drive if they have had syncope or are at risk of syncope. Also, the doctor is recommended to advise about conditions or treatments that might affect the patient’s ability to drive to the National Public Safety Commission (Watanabe E, personal communication).

Conclusion Driving regulations for patients at risk of syncope and cardiac arrhythmias associated with sudden incapacity attempt to balance the perceived RH against protection of individual freedom and the right to drive. There is significant national variation in regulation and the approach to its implementation. Much of the scientific data that back up current recommendations are historical and may not accurately reflect changes in vehicles and the driving environment, along with possible changes in societal acceptance of risk. In future, for private drivers, a method to estimate the individual RH while driving – based on individual assessment of the time spent behind the wheel, age, driving profile, car safety, and so on – may prove useful. The development of new technologies such as driverless vehicles may have an impact on society’s willingness to accept excess risk as a result of medical conditions.

Patient Confidentiality and Duty to Report Nonadherence In general, it is a physician’s responsibility to be familiar with the regulatory framework in the country where they practise. They are responsible for informing the patient what regulations apply and whether the patient should be notifying the driving authorities of their condition. Adherence with physician recommendations regarding driving is low in patients with ICD, with approximately one-third of patients not adhering to these recommendations.22 Patients frequently perceive the driving restrictions as a loss of independence and change in self-image. Often patients resume driving because of a misunderstanding about their condition and the risks involved, or because they think it is their decision not others to make.47 Education about the rationale for driving restrictions is important for ICD patients.

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Clinical Perspective • There is significant national variation in regulation of fitness to drive in patients at risk of sudden incapacitation, and the approach to its implementation. • Much of the scientific data that back up current recommendations are historical and may not accurately reflect changes in vehicles and the driving environment, along with possible changes in societal acceptance of risk. • In future, methods to estimate the individual risk of harm while driving may prove useful. • The development of new technologies such as driverless vehicles may have an impact on society’s willingness to accept excess risk as a result of medical conditions.

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2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13. 14.

15.

16.

17.

18.

19.

 rignole M, Moya A, de Lange FJ, et al. 2018 ESC Guidelines B for the diagnosis and management of syncope. Eur Heart J 2018;39:1883–948. https://doi.org/10.1093/eurheartj/ehy037; PMID: 29562304. Bayés de Luna A, Coumel P, Leclercq JF. Ambulatory sudden cardiac death: mechanisms of production of fatal arrhythmia on the basis of data from 157 cases. Am Heart J 1989;117: 151–9. https://doi.org/10.1016/0002-8703(89)90670-4; PMID: 2911968. Bureau of Transportation Statistics. Number of U.S. Aircraft, Vehicles, Vessels, and Other Conveyances. Available at: www. bts.gov/content/number-us-aircraft-vehicles-vessels-andother-conveyances (accessed 12 April 2019). World Health Organization. The Top 10 Causes of Death. May 2018. Available at: www.who.int/en/news-room/factsheets/detail/the-top-10-causes-of-death (accessed 12 April 2019). Department for Transport. Reported road casualties Great Britain 2017. 2017. Available at: https://assets.publishing. service.gov.uk/government/uploads/system/uploads/ attachment_data/file/744078/infographic-2017-annual-report. pdf (accessed 12 April 2019). World Health Organization. Global status report on road safety 2015. WHO, 2015. Available at: www.who.int/violence_injury_ prevention/road_safety_status/2015/en (accessed 29 November 2018). Redelmeier DA, Raza S. Syncope and the Risk of a Subsequent Motor Vehicle Crash. JAMA Intern Med 2016;176:510–1. https:// doi.org/10.1001/jamainternmed.2015.8617; PMID: 26926948. GOV.UK. International comparisons of road accidents (RAS52). 2018. Available at: www.gov.uk/government/statisticaldata-sets/ras52-international-comparisons#internationalcomparisons-of-road-accidents-excel-data-tables (accessed 12 April 2019). Casualties involved in reported road accidents (RAS30). 2018. Available at: www.gov.uk/government/statistical-data-sets/ ras30-reported-casualties-in-road-accidents#table-ras30013 (accessed 12 April 2019). Watanabe E, Haruhiko A, Watanabe S. Driving restrictions in patients with implantable cardioverter defibrillators and pacemakers. J Arrhythm 2017;33:594–601. https://doi. org/10.1016/j.joa.2017.02.003; PMID: 29255507. Simpson C, Dorian P, Gupta A, et al. Assessment of the cardiac patient for fitness to drive: drive subgroup executive summary. Can J Cardiol 2004;20:1314–20. PMID: 15565193. Katritsis DG, Anderson M, Webb-Peploe MM. Regulations concerning individual risk and public safety. In: A John Camm, Thomas F Lüscher, Gerald Maurer and Patrick W Serruys (eds). European Society of Cardiology Textbook of Cardiovascular Medicine (ESC CardioMed), 3rd ed. Oxford: Oxford University Press; 2018; Euro NCAP. Ratings and Rewards. 2019. Available at: www. euroncap.com/en/ratings-rewards (accessed 12 April 2019). Soteriades ES, Evans JC, Larson MG, et al. Incidence and prognosis of syncope. N Engl J Med 2002;347:878–85. https:// doi.org/10.1056/NEJMoa012407; PMID: 12239256. Sorajja D, Nesbitt GC, Hodge DO, et al. Syncope while driving: clinical characteristics, causes, and prognosis. Circulation 2009;120:928–34. https://doi.org/10.1161/ CIRCULATIONAHA.108.827626; PMID: 19720940. Dhala A, Bremner S, Blanck Z, et al. Impairment of driving abilities in patients with supraventricular tachycardias. Am J Cardiol 1995,75:516–8. PMID: 7864002. Büttner A, Heimpel M, Eisenmenger W. Sudden natural death at the wheel: a retrospective study over a 15-year time period (1982–1996). Forensic Sc Int 1999;103: 101–12. PMID: 10481263. Numé AK, Gislason G, Christiansen CB, et al. Syncope and Motor Vehicle Crash Risk: A Danish Nationwide Study. JAMA Intern Med 2016;176:503–10. https://doi.org/10.1001/ jamainternmed.2015.8606; PMID: 26927689. 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. https://doi.org/10.1111/j.15408159.2011.03150.x; PMID: 21707667.

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20. P  riori SG, Blomström-Lundqvist C, Mazzanti A, et al. 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC). Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). Eur Heart J 2015;36:2793–867. https://doi. org/10.1093/eurheartj/ehv316; PMID: 26320108. 21. Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS Guideline 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 on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2018;72:e91–220. https://doi.org/10.1016/​ j.jacc.2017.10.054; PMID: 29097296. 22. Mylotte D, Sheahan RG, Nolan PG, et al. The implantable defibrillator and return to operation of vehicles study. Europace 2013;15:212–8. https://doi.org/10.1093/europace/ eus254. 23. Albert CM, Rosenthal L, Calkins H, et al. Driving and implantable cardioverter-defibrillator shocks for ventricular arrhythmias: results from the TOVA study. J Am Coll Cardiol 2007;50:2233–40. https://doi.org/10.1016/j.jacc.2007.06.059; PMID: 18061071. 24. Watanabe E, Okajima K, Shimane A, et al. Inappropriate implantable cardioverter defibrillator shocks-incidence, effect, and implications for driver licensing. J Interv Card Electrophysiol 2017;49:271–80. https://doi.org/10.1007/s10840-017-0272-4; PMID: 28730420. 25. Thijssen J, Borleffs CJ, van Rees JB, et al. Driving restrictions after implantable cardioverter defibrillator implantation: an evidence-based approach. Eur Heart J 2011;32:2678–87. https:// doi.org/10.1093/eurheartj/ehr161; PMID: 21646229. 26. Merchant FM, Hoskins MH, Benser ME, et al. Time Course of Subsequent Shocks After Initial Implantable Cardioverter-Defibrillator Discharge and Implications for Driving Restrictions. JAMA Cardiol 2016;1:181–8. https://doi. org/10.1001/jamacardio.2015.0386; PMID: 27437889. 27. Bryg RJ, Bryg DJ, Akhondi AB, et al. Change in Mortality in the Past 20 Years in Heart Failure Trials. J Card Fail 2010;16(8S): S91–S92. https://doi.org/10.1016/j.cardfail.2010.06.322. 28. Shen L, Jhund PS, Petrie MC, et al. Declining Risk of Sudden Death in Heart Failure. N Engl J Med 2017;377:41–51. https://doi. org/10.1056/NEJMoa1609758; PMID: 28679089. 29. Køber L, Thune JJ, Nielsen JC, et al. Defibrillator Implantation in Patients with Nonischemic Systolic Heart Failure. N Engl J Med 2016;375:1221–30. https://doi.org/10.1056/NEJMoa1608029; PMID: 27571011. 30. Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 2005;352:225–37. https://doi.org/10.1056/ NEJMoa043399; PMID:15659722. 31. The Driver and Vehicle Licensing Agency – Medical Advisory Branch. At a glance guide to the current medical standards of fitness to drive. Swansea: DVLA, September 1993 32. The Driver and Vehicle Licensing Agency – Drivers Medical Unit. At a glance guide to the current medical standards of fitness to drive. Swansea: DVLA, March 2001 33. The Driver and Vehicle Licensing Agency. Assessing fitness to drive – a guide for medical professionals. Swansea: DVLA, August 2018. Available at: www.gov.uk/guidance/assessing-fitnessto-drive-a-guide-for-medical-professionals (accessed 12 April 2019). 34. Task force members, Vijgen J, Botto G, et al. Consensus statement of the European Heart Rhythm Association: updated recommendations for driving by patients with implantable cardioverter defibrillators. Europace 2009;11: 1097–107. https://doi.org/10.1093/europace/eup112; PMID: 19525498. 35. Epstein AE, Miles WM, Benditt DG, et al. Personal and public safety issues related to arrhythmias that may affect consciousness: implications for regulation and physician recommendations. A medical/scientific statement from the

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American heart association and the North American Society for Pacing and Electrophysiology. Circulation 1996;94:1147–66. PMID: 8790068. Epstein AE, Baessler CA, Curtis AB, et al. Addendum to ‘Personal and public safety issues related to arrhythmias that may affect consciousness: implications for regulation and physician recommendations. A medical/scientific statement from the American heart association and the North American Society for Pacing and Electrophysiology’. Public safety issues in patients with implantable defibrillators. A Scientific statement from the American Heart Association and the Heart Rhythm Society. Circulation 2007;115:1170–6. https://doi. org/10.1161/CIRCULATIONAHA.106.180203; PMID: 17287391. Klein HH, Sechtem U, Trappe HJ. Fitness to drive in cardiovascular disease. Dtsch Arztebl Int 2017;114:692–702. https://doi.org/10.3238/arztebl.2017.0692; PMID: 29082864. EUR-Lex. Council Directive of 29 July 1991 on Driving Licenses (91/439/EEC); Annex 3, Section 9. 1991. Available at: https://eur-lex.europa.eu/legal-content/EN/ TXT/?uri=celex:31991L0439 (accessed 12 April 2019). EUR-Lex. Directive 2006/126/EC of the European Parliament and of the Council of 20 December 2006 on driving licences. Available at: https://eur-lex.europa.eu/legal-content/EN/ TXT/?uri=celex:32006L0126 (accessed 12 April 2019). The Expert Group on Driving and Cardiovascular Disease. New Standards for Driving and Cardiovascular Diseases. Brussels: The Expert Group on Driving and Cardiovascular Disease, October 2013. Available at: https://ec.europa.eu/transport/ road_safety/sites/roadsafety/files/pdf/behavior/driving_and_ cardiovascular_disease_final.pdf (accessed 12 April 2019). Order 1530/2017 of the Ministry of Health for approval of norms regarding the minimal physical and mental aptitudes required for driving a vehicle; to modify Order no. 1162/2010 of the Ministry of Health. Published in the Official Monitor of Romania, no. 1041; Publication date: 29/12/2017; Page number: 00004-00005. https://eur-lex.europa.eu/legalcontent/EN/TXT/?uri=NIM%3A254110 (accessed 20 April 2019). Lococo KH, Stutts J and Staplin L. Medical review practices for driver licensing Volume 1: A case study of guidelines and processes in seven U.S. States (Report No. DOT HS 812 331). Washington, DC: National Highway Traffic Safety Administration, October 2016. Available at: www. nhtsa.gov/sites/nhtsa.dot.gov/files/documents/812331medreviewforlicensing.pdf (accessed 12 April 2019). Canadian Council of Motor Transport Administration. Determining Driver Fitness in Canada. Part 1: A Model for the Administration of Driver Fitness Programs Part 2: CCMTA Medical Standards for Drivers. Ontario: CCMTA, March 2017. Available at: www.ccmta.ca/images/pdf-documents-english/CCMTAMedical-Standards-2017-English.pdf (accessed 12 April 2019). Austroads. Assessing Fitness to Drive for commercial and private vehicle drivers. Sydney: Austroads, August 2017. Available at: https://austroads.com.au/__data/assets/ pdf_file/0022/104197/AP-G56-17_Assessing_fitness_to_ drive_2016_amended_Aug2017.pdf (accessed 12 April 2019). Oginosawa Y, Abe H, Kohno R, et al. Resume driving after a refuelling pit stop. Circ J 2010;74:2283–4. PMID: 20962424. Sumiyoshi M. Driving restrictions for patients with reflex syncope. J Arrhythm 2017;33:590–3. https://doi.org/10.1016/j. joa.2017.03.009; PMID: 29255506. Johansson I, Strömberg A. Experiences of driving and driving restrictions in recipients with an implantable cardioverter defibrillator--the patient perspective. J Cardiovasc Nurs 2010;25:E1–E10. https://doi.org/10.1097/ JCN.0b013e3181e0f881; PMID: 20938245. General Medical Council. Patients’ fitness to drive and reporting concerns to the DVLA or DVA. GMC, 2019. Available at: www. gmc-uk.org/ethical-guidance/ethical-guidance-for-doctors/ confidentiality---patients-fitness-to-drive-and-reportingconcerns-to-the-dvla-or-dva/patients-fitness-to-drive-andreporting-concerns-to-the-dvla-or-dva (accessed 12 April 2019).

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Clinical Arrhythmias

Strategies to Reduce Recurrent Shocks Due to Ventricular Arrhythmias in Patients with an Implanted Cardioverter-Defibrillator Steven H Back 1 and Peter R Kowey 1,2 1. Lankenau Medical Center, Lankenau Institute for Medical Research, Wynnewood, PA, US; 2. Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA, US

Abstract Ventricular arrhythmias are a therapeutic challenge, owing to their relatively unpredictable and deadly nature. Many patients are treated with an implantable cardioverter-defibrillator for either primary or secondary prevention of ventricular arrhythmias, meaning those who are at high risk of versus those who have experienced ventricular arrhythmias or sudden cardiac arrest, respectively. Despite the lifesaving benefit, ICD comes with the risk of recurrent shocks for both appropriate and inappropriate rhythms. Patients with recurrent shocks have a poor quality of life and increased mortality rates. In this article, we review data for optimal device settings, medical management and radiofrequency ablation strategies to minimise the frequency of ICD shock, with a focus on treatment of ventricular arrhythmias, to reduce patient morbidity and mortality, and to maximise wellbeing and quality of life.

Keywords Ventricular arrhythmia, implanted cardioverter-defibrillator, antiarrhythmic, ablation, amiodarone, sotalol Disclosure: SHB has no conflicts of interest to declare. PRK has provided ad hoc consultation to Sanofi, Allergan and Gilead. Received: 4 October 2018 Accepted: 2 April 2019 Citation: Arrhythmia & Electrophysiology Review 2019;8(2):99–104. DOI: https://doi.org/10.15420/aer.2018.55.5 Correspondence: Steven H Back, Lankenau Medical Center, 100 E. Lancaster Avenue, 356 Medical Office Building East Wynnewood, PA 19096, US. E: backs@mlhs.org Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Ventricular arrhythmias are a therapeutic challenge. They occur frequently in clinical practice, are found in patients with and without structural heart disease, and most importantly, are unpredictable and potentially deadly. Patients with a history of sustained ventricular tachycardia (VT) and VF or those at high risk for such arrhythmias, may require an ICD to prevent sudden cardiac arrest. However, despite life-saving benefit, recurrent device therapy, both appropriate and inappropriate, can have a profound psychological impact, reduce quality of life and is associated with an increase in mortality.1 About one-third of patients receive a shock from their defibrillator within 4–5 years of implantation, and 16–18% of these are inappropriate.2–4 Shock prevention includes a combination of optimised device settings as well as treatment with antiarrhythmic medication and ablation. The purpose of this paper is to review clinical trial data and propose a strategy to reduce the number of shocks in patients who require ICD implantation to prevent sudden cardiac death, with a focus on the treatment of ventricular arrhythmias. The specific treatment of narrow complex tachycardias such as AF and atrial flutter is beyond the scope of this review.

Optimal Device Programming Optimal device programming minimises the occurrence of device therapy, improves quality of life and, in many cases, improves mortality rates. As seen below, many device parameters have been evaluated to achieve these goals. An additional perspective on optimal device settings is provided in an excellent review by Spragg and Berger.5

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Device therapy with antitachycardia pacing (ATP) improves the efficiency of ICD function by decreasing the incidence of ICD delivered shocks. The Pacing Fast Ventricular Tachycardia Reduces Shock Therapies (PainFREE Rx 2) trial randomised patients to receive either ATP or defibrillation for fast ventricular tachycardia (FVT) (188–250 bpm). Patients included in the study were diagnosed with both ischaemic and non-ischaemic cardiomyopathy and had ICDs implanted for either primary or secondary prevention. Primary prevention criteria included ICD implantation in patients without a prior diagnosis of VF, sustained VT or a combination of unexplained syncope with inducible VT. The trial data found that 72% of FVT could be terminated with the first attempted ATP. Patients treated with ATP compared to shock had an improvement in both mental and physical quality of life scores.6 The Primary Prevention Parameters Evaluation (PREPARE) trial authors studied the strategy of ATP to terminate FVT in patients requiring an ICD for primary prevention. The investigators of this study performed a prospective cohort-controlled trial of 700 patients, using patients from the Comparison of Empiric to Physician-Tailored Programming of Implantable Cardioverter Defibrillators Trial (EMPIRIC) and Multicenter InSync Implantable Cardioversion Defibrillation Randomized Clinical Evaluation (MIRACLE ICD) trials as controls. They found that treating patients with one sequence of ATP before defibrillation in an FVT zone between 182–250 bpm reduced the number of patients receiving a first all-cause shock within the first 12 months from 17% in the control group to 9% in the study population and decreased mortality in the study group.7

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Clinical Arrhythmias Antitachycardia pacing delivery method was analysed in the Randomized Study to Compare Ramp Versus Burst Antitachycardia Pacing Therapies to Treat Fast Ventricular Tachyarrhythmias in Patients With Implantable Cardioverter Defibrillators (PITAGORA ICD) trial. In this study, the investigators randomised 206 patients with both ischaemic and nonischaemic cardiomyopathy as well as those with ICD for both primary and secondary prevention to either ramp or burst ATP as an initial therapy for FVT. The investigators found that 54% of FVT episodes were successfully treated in the ramp arm versus 75% of FVT episodes in the burst arm, providing evidence that burst-style ATP is more effect than ramp-style.8 The investigators in the Multicenter Automatic Defibrillator Implantation Trial: Reduce Inappropriate Therapy (MADIT-RIT) trial studied the effects of limiting device therapy to a high rate cutoff or delaying therapy at slower rates. The trial randomised 1500 patients to three arms that compared standard device programming to programming a high-rate VT detection zone greater than 200 bpm before delivery of device therapy, programming with a 60-second delay for VT greater than 170 bpm or a 12-second delay at 200 bpm before delivery of device therapy. The primary endpoint was first occurrence of inappropriate device therapy. Secondary endpoints included death from any cause or first episode of syncope. Patients with programming that included a high rate cutoff or a delay to therapy had a lower cumulative probability of first inappropriate therapy as well as a decrease in all-cause mortality. The hazard ratio of first occurrence of inappropriate therapy and death in the high-rate versus conventional therapy was 0.21 and 0.45, respectively. The hazard ratio for the same parameters in the delayed versus conventional therapy was 0.24 and 0.56, respectively.9 While the MADIT trial did not directly evaluate the effects of dualzone detection and therapy settings, the results of the study implied that dual-zone therapy settings reduced inappropriate shocks. This observation was previously studied in the ALTITUDE Real World Evaluation of Dual-zone ICD and CRT-D Programming Compared to Single-zone Programming (REDUCES) study. In this retrospective study, the authors reviewed device data in patients who received single-chamber, dual-chamber and dual-chamber, biventricular ICDs who enrolled in the Boston Scientific LATITUDE remote monitoring program. Patients were grouped based on the parameters of single or dual-zone detection and therapy at detection rates of ≤170 bpm, 170–200 bpm, or ≥200 bpm. The primary endpoint in this analysis was time from ICD implantation until the first occurrence of ICD therapy or death. Patients programmed with dual-zone detection and therapy parameters had a significant decrease in both all-cause and inappropriate shocks in the detection rate groups of ≤170 bpm and 170–200 bpm. There was a trend towards decreased all-cause and inappropriate shocks in the ≥200 bpm rate detection group. They also noted that atrial rhythms were the cause of the majority of shocks occurring at rates below 180 bpm.10 Given the ability of dual chamber devices to monitor rhythms in both the atria and ventricles, studies were designed to test the hypothesis that dual-chamber devices could prevent inappropriate therapy via rhythm discrimination. The Dual Chamber and Atrial Tachyarrhythmias Adverse Events Study (DATAS) trial randomised 334 patients with an ACC/AHA Class I indication for a single chamber (SC)-ICD to one of three arms: SC-ICD, DC-ICD or a dual chamber (DC)-ICD programmed as SC-ICD, termed a simulated SC-ICD. The primary endpoint was a composite of five predetermined clinically significant adverse events:

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all-cause mortality, invasive intervention due to cardiovascular cause, hospitalisation greater than 24 hours or prolongation of hospitalisation due to cardiovascular cause, inappropriate shocks and sustained symptomatic atrial tachycardia that required urgent termination or lasted more than 48 hours leading to therapeutic intervention. The authors developed a scoring system based upon the number of clinically significant events the patient experienced during the study period. They concluded that patients with a DC-ICD had a lower rate of clinically significant events compared to patients randomised to receive a SC-ICD. However, the study was not powered to make statistical comparisons for any single component of the primary endpoint and could not make conclusions on how implantation of a DC-ICD directly affected rates of inappropriate therapy or mortality.11 The Reduction And Prevention of Tachyarrhythmias and Shocks Using Reduced Ventricular Pacing with Atrial Algorithms Study (RAPTURE) trial compared the rate of inappropriate therapy in patients with a dual-chamber ICD to those with a single-chamber ICD. The authors randomised 100 patients who met indications for primary prevention to either a dual or single chamber ICD. The primary endpoint was the proportion of patients receiving an inappropriate shock within the first 12 months after ICD implantation. During an average follow-up of 12.0 ± 2.6 months, there was no statistical difference in the proportion of patients receiving inappropriate therapy between groups.12 While there has been no consistent data to suggest that upgrading to a DC-ICD from a single chamber device for the purpose of rhythm discrimination is beneficial to patients, there is data to suggest that rhythm discrimination algorithms programmed into dual-chamber devices in patients who require pacing for diagnoses, such as sinus node dysfunction or conduction disease has improved shock prevention. In a study by Dorian et al., 149 patients with a DC-ICD and a history of sustained VT or VF were randomised to either an enhanced therapy group or rate-only control group. The patients followed-up at regular intervals of 3, 6 and 12 months, if the patient was symptomatic or received device therapy. The primary endpoint was the time to first inappropriate therapy. The primary endpoint occurred less frequently in the enhanced therapy group resulting in a hazard ratio of 0.468 (95% CI [0.266–0.822]), reflecting a 53.2% reduction in the risk of inappropriate therapy (p = 0.011).13 Table 1 summarises the device programming trials.

Medical Therapy Medical prevention of ICD shock begins with optimal treatment of the underlying medical condition. Heart failure should be corrected using guideline-directed medical therapy being careful to monitor volume and electrolyte concentrations. Patients with chronic systolic heart failure should be continuously evaluated for cardiac resynchronisation therapy. Patients with coronary artery disease should be evaluated for active ischaemia. Treatment of hypertension and other important medical conditions such as diabetes must be optimised. While no pharmacological agent is currently labelled to prevent recurrent ICD therapy, several antiarrhythmics have been studied to determine their value in reducing ICD shocks and pace termination. Below is a summary of studies examining potential medications to reduce shocks due to ventricular arrhythmias. Another perspective on this topic is provided in an excellent review by Abboud and Ehrlich.14

Sotalol Sotalol, a beta-blocker with class III antiarrhythmic properties, was studied in patients who received an ICD for secondary prevention for

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Strategies to Reduce Recurrent Shocks Table 1: Summary of Device Programming Studies Study 6

Design

Comparison

Outcome

Randomised, single-blinded

ATP vs defibrillation in terminating FVT

72% of FVT terminated with first round of ATP

PREPARE7

Cohort-controlled

ATP for FVT in primary prevention of SCD

Reduction in first all-cause shocks during 12-month follow-up

PITAGORA ICD8

Randomised

Burst vs ramp ATP

Ramp ATP more effective at terminating FVT

Randomised

Standard programming vs high-rate cutoff or delayed therapy

Reduction in probability of first inappropriate therapy; decrease in all-cause mortality

ALITUDE REDUCES10 Retrospective

Single vs dual-zone detection and therapy in patients with an ICD

Dual-zone detection and therapy settings reduces appropriate and inappropriate shocks

DATAS11

Randomised

Single vs dual-chamber ICD to prevent inappropriate shocks

Dual-chamber ICD decreases composite score of clinically significant events

RAPTURE12

Randomised

Single vs dual-chamber ICD to prevent inappropriate shocks

No difference in the rate of inappropriate therapy between groups

Dorian et al.13

Randomised

Rhythm discrimination algorithms to prevent inappropriate shocks in patients with DC-ICD

Rhythm discrimination algorithm reduced inappropriate therapy

PainFree Rx 2

MADIT-RIT

9

ATP = anti-tachycardia pacing; DC-ICD = dual chamber ICD; FVT = fast ventricular tachycardia; SCD = sudden cardiac death.

its efficacy in preventing shocks and death. Patients were randomly assigned to placebo or sotalol treatment and were followed for 12 months. Patients who were randomised to sotalol were initiated on 120 mg twice daily; however, this dose could be adjusted to a minimum of 80 mg or a maximum of 160 mg twice daily depending on efficacy and side-effects of the drug. The primary endpoints of the study were death from any cause or shock for any reason. Significantly fewer patients treated with sotalol reached the primary endpoint compared with the placebo.15 Despite this benefit, sotalol can induce bradycardia in patients on concomitant beta-blocker therapy, limiting its use and creating the need for alternative medical options.

sustained VT or patients who experienced cardiac arrest and had an EF of ≤40% and randomised them to placebo, 75 mg or 125 mg of azimilide. The two primary endpoints in the study were (1) the combined incidence of all-cause shocks plus symptomatic tachyarrhythmias terminated by ATP and (2) all-cause shocks. Patients receiving azimilide had a dose-dependent relative risk reduction of the first primary endpoint of 57% and 47%, respectively, as well as a dose-dependent relative risk reduction of the second primary endpoint of 28% and 17%, respectively; however, none of these values reached statistical significance.17

Celivarone Amiodarone Investigators in the Optimal Pharmacological Therapy in Cardioverter Defibrillator Patients (OPTIC) trial compared treatment with sotalol to combination therapy with amiodarone and beta-blocker. They randomised 412 patients with a history of sustained VT, VF or cardiac arrest as well as an ejection fraction (EF) of less than 40% to receive sotalol, beta-blocker or amiodarone plus beta-blocker. Patients receiving sotalol received 240 mg per day in divided doses if their creatinine clearance was above 60 ml/min. If their creatinine clearance was between 30–60 ml/min, this dose was reduced to 160 mg per day. Patients receiving amiodarone were loaded with 400 mg twice per day for two weeks, followed by 400 mg per day for four weeks and then treated with 200 mg per day until the end of the study. Patients randomised to the beta-blocker arm or amiodarone arm were treated with either metoprolol 100 mg per day, carvedilol 50 mg per day or bisoprolol 10 mg per day. Patients were followed for 12 months with the primary outcome being first occurrence of any shock. Patients treated with the combination therapy of amiodarone and beta-blocker had a reduced risk of shock compared to betablocker use alone or sotalol use alone. The hazard ratio comparing the combination treatment to beta-blocker alone or sotalol alone was 0.27 and 0.43, respectively. When sotalol was compared to betablocker, there was a trend towards reduced risk of shock; however, this result was not significant.16

Azimilide Azimilide, a class-III agent, has also been studied to reduce recurrent ICD therapy. Authors of the Shock Inhibition Evaluation with Azimilide (SHIELD) trial recruited patients with an ICD who had spontaneous,

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Celivarone, an antiarrhythmic with class I, II, III and IV properties was also studied to reduce the recurrence of ventricular tachycardia. The authors of the Dose Ranging Study of Celivarone with Amiodarone as Calibrator for the Prevention of Implantable Cardioverter Defibrillator Interventions or Death [ALPHEE] study designed a multiple dose, randomised, double blind, placebo-controlled trial with amiodarone as a calibrator. Patients with a left ventricular EF of ≤40% as well as an ICD for primary prevention with at least one ICD intervention for VT/VF in the previous month, as well as patients with an ICD for secondary prevention with ICD implantation in the previous month or at least one ICD intervention for VT/VF were randomised. They received once-daily therapy for 6 months with placebo or celivarone 50, 100 or 300 mg, or amiodarone 600 mg for 10 days followed by 200 mg daily thereafter. The primary efficacy endpoint was the occurrence of VT/VF- triggered ICD interventions (shocks or antitachycardia pacing) or sudden death, analysed with a time to first event approach. The hazard ratio for the primary endpoint comparing the study drug to placebo ranged from 0.86 for the celivarone 300-mg group to 1.199 for the celivarone 50-mg group; however, none were statistically significant.18

Ranolazine Ranolazine is an antianginal and anti-ischaemic drug with possible antiarrhythmic properties via late sodium channel blockade. Ranolazine reduced episodes of VT lasting at least eight beats in the first week of rhythm monitoring after admission for an acute coronary syndrome.19,20 These data sparked interest in the drug’s ability to reduce appropriate ICD therapy. The Ranolazine in High-Risk Patients with Implanted Cardioverter-Defibrillators (RAID) trial was a double blind, placebocontrolled trial evaluating the efficacy of ranolazine in treating

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Clinical Arrhythmias Table 2: Summary of Medical Therapy Studies Study

Design

Comparison

Outcome

Randomised, double-blind, placebo-controlled

Sotalol vs placebo in preventing ICD therapy or death

Reduction in both all-cause shock and all-cause death in the sotalol group

OPTIC16

Randomised, blinded adjudication

Amiodarone + beta blocker vs sotalol vs beta blocker in reducing first all-cause shock

Amiodarone + beta blocker reduced risk of shock compared to sotalol or beta blocker alone

SHIELD17

Randomised, double-blind, placebo-controlled

Azimilide vs placebo in reducing all-cause shocks and ATP

Non-significant trend towards relative risk reduction in all-cause shocks and ATP

ALPHEE18

Randomised, double-blind, placebo-controlled

Celivarone vs placebo reducing appropriate ICD therapy or sudden death

No significant difference compared with placebo

RAID21

Randomised, double-blind, placebo-controlled

Ranolazine vs placebo in preventing time to appropriate ICD therapy or death

Non-significant trend towards relative risk reduction of appropriate ICD therapy or death

Pacifico et al.

15

ATP = antitachycardia pacing.

Table 3: Summary of Ablation Studies Study Segal et al.

22

SMASH-VT23 VTACH24 Frankel et al.

25

Design

Comparison

Outcome

Prospective cohort

Mean shock frequency for VT pre/post ablation

Reduction in mean shock frequency post ablation

Randomised

VT ablation vs no ablation in primary and secondary prevention patients

Reduction in ICD therapy in ablation group

Randomised

Prophylactic VT ablation + ICD implantation vs ICD alone post MI

Reduction in recurrent VT in ablation group

Prospective cohort

Ablation after first VT episode vs ablation after subsequent episodes

Reduction in additional VT during follow-up in early ablation group

MI = myocardial infarction; VT = ventricular tachycardia.

recurrent VT/VF or death in patients with ischaemic and non-ischaemic cardiomyopathy. The patient population consisted of high-risk patients with an ICD or cardiac resynchronisation therapy with defibrillator (CRT-D) for secondary prevention with documented VT, VF or cardiac arrest, or primary prevention patients regardless of date of device implantation with an ejection fraction of ≤35%. Patients had at least one of the following high-risk criteria: blood urea nitrogen of ≥26 mg/dl, QRS duration of ≥120 milliseconds, documented paroxysmal or permanent atrial fibrillation, non-sustained VT or >500 premature ventricular contractions on Holter monitoring. Patients were randomly assigned ranolazine or placebo in a 1:1 fashion. Patients were started on 500 mg twice daily for one week with an increase in dosage to 1,000 mg twice daily if the drug was tolerated. The primary endpoint of the study was a composite consisting of the time to VT or VF (requiring ATP therapy or ICD shock), or death, whichever occurred first. In the pre-specified intention-to-treat analysis, the primary endpoint of VT or VF requiring ICD therapy (ATP or shock), or death, occurred in 174 patients (34.1%) in the ranolazine arm and in 198 (39.4%) in the placebo arm (HR: 0.84; 95% CI [0.67–1.05]; p=0.117). While the results did not reach statistical significance, the study was underpowered based on pre-specified statistical criteria. In a pre-specified secondary analysis, patients randomised to ranolazine had a marginally significant lower risk of ICD therapies for recurrent VT or VF (hazard ratio: 0.70; 95% confidence interval: 0.51–0.96; p=0.028).21 See Table 2 for a summary of medical therapy studies.

frequency post ablation reduced from 6.8 ± 7.3 per month in the year prior to ablation to 0.05 ± 0.12 per month after ablation, with over 24.7 ± 18.9 months of follow-up (p<0.0001).22 The authors of Substrate Mapping and Ablation in Sinus Rhythm to Halt Ventricular Tachycardia (SMASH-VT) studied the ability of ablation therapy to reduce VT in patients with an ICD for secondary prevention as well patients with an ICD for primary prevention who subsequently received an appropriate shock. They randomised 128 patients to receive targeted ablation versus no additional therapy. The patients were then followed for up to 24 months post ablation. Results of the study showed that 12% of the ablation group received ICD therapy (shock or ATP) versus 31% of the control group.23 Despite the improved rates of ICD therapy, the results of the SMASH-VT trial reinforce the fact that patients with structural heart disease should still receive an ICD given the limited efficacy of ablation.

Ablation Therapy

The Ventricular Tachycardia Ablation in Coronary Heart Disease (VTACH) study investigators evaluated prophylactic VT ablation in patients with a history of myocardial infarction, stable clinical VT (defined as a VT not leading to cardiac arrest or syncope and during which the systolic blood pressure was higher than 90 mmHg) and an ejection fraction under 50%. Patients were randomised to ablation plus ICD implantation or ICD implantation alone and were followed for approximately 2 years (22.5 months). At follow-up, fewer patients in the ablation group experienced recurrent VT/VF; 47% of patient in the ablation group did not experience recurrent VT/VF versus only 29% for the ICD only group. However, this benefit was only manifest in patients with an ejection fraction above 30%.24

Multiple studies have provided evidence for the effectiveness of ablation to reduce the recurrence of ventricular tachycardia in patients with structural heart disease. A study published by Segal et al. in 2005 reported the results of catheter ablation for myocardial infarction-related VT in a group of 40 patients who were followed for 24 ± 18 months. These patients underwent targeted VT ablation with the mean shock

Frankel et al. completed a prospective cohort study to evaluate the timing of VT ablation. Their data suggested that if ablation for VT is considered, the procedure should be completed earlier in the course of disease. They followed 98 consecutive patients with structural heart disease referred to their centre for VT ablation. Patients were stratified

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Strategies to Reduce Recurrent Shocks into early and late referral, meaning those patients referred after a first episode of VT versus experiencing two or more episodes. The results of their study showed that 75% of patients referred early for VT ablation remained free of additional episodes in the following year, versus 50% of patients referred late.25 See Table 3 for summary of ablation studies.

Hybrid Therapy While the goal of ablation for some patients may be to discontinue use of antiarrhythmic therapy, medical management and catheter ablation may be pursued as a dual strategy. In studies of patients with cardiomyopathy who underwent VT ablation for VT/VF, the number of patients with recurrence of VT during follow-up was related to withdrawal of antiarrhythmics; 68% of patients who had medication changes had recurrent VT compared to 41% of patients who did not have medications changes following ablation in the follow-up period.26 A meta-analysis of randomised controlled trials confirmed that both catheter ablation and antiarrhythmic drugs reduce the number of appropriate shocks, while antiarrhythmic drugs decreased the number of inappropriate shocks. However, a comparison between catheter ablation and use of antiarrhythmic drugs did not show a reduction of recurrent VT relative to the other.27 The 2016, the Ventricular Tachycardia Ablation versus Escalated Antiarrhythmic Drug Therapy in Ischemic Heart Disease (VANISH) trial compared escalating the dose of antiarrhythmic therapy versus catheter ablation using the primary endpoints of composite death, VT storm or appropriate ICD shock. Patients with ischaemic cardiomyopathy and an ICD who experienced ventricular tachycardia despite antiarrhythmic therapy were randomised to increasing doses of antiarrhythmic therapy or catheter ablation. The dose of amiodarone administered to patients assigned to the escalation arm was based on baseline medical therapy. If the patient was on antiarrhythmic therapy other than amiodarone, the patient was initiated on 400 mg twice-daily amiodarone for two weeks, followed by 400 mg daily for four weeks, then 200 mg daily thereafter. If the patient was currently on a dose of amiodarone less than 300 mg daily, the patient was treated with a loading dose of 400 mg twice daily of amiodarone for two weeks followed by 400 mg daily for one week, then 300 mg daily thereafter. If the patient was currently taking at least 300 mg daily of amiodarone, their current dose was continued and mexiletine was added at a dose of 200 mg, three times daily. The patients assigned to ablation therapy underwent a procedure that followed a standardised approach that specifically targeted all inducible ventricular tachycardias. Patients who received ablation had a lower rate of the primary outcome of death, VT storm or appropriate ICD shock. The primary outcome occurred in 59.1% of patients in the ablation group and 68.5% of those in the escalated-therapy group (hazard ratio in the ablation group, 0.72; 95% CI [0.53â&#x20AC;&#x201C;0.98]; p=0.04). In a subgroup analysis, patients treated with a baseline regimen of amiodarone had a lower incidence of the primary outcome (hazard ratio 0.55; 95% CI [0.38â&#x20AC;&#x201C;0.80]; p=0.001). Patients who were not on amiodarone at baseline but were initiated on the drug as a part of the trial showed no difference in the primary outcome of the composite of death, VT storm or appropriate ICD shock as compared to patients treated with VT ablation.28

Conclusion Minimizing recurrent ICD shocks will be dependent on optimal ICD programming, medical therapy and strategic ablation. Figure 1 suggests an algorithm to guide management. If a patient experiences a defibrillation, the underlying rhythm should be analysed to determine if the device therapy was appropriate or inappropriate. Narrowcomplex tachycardias such as atrial fibrillation or flutter should be

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Figure 1: Suggested Algorithm to Treat Patients with ICD Therapy

ICD therapy

Yes

Secondary causes

Yes

Appropriate

No

GDT for narrow complex tachycardia Review device settings

No Electrolyte repletion Heart failure treatment ACS treatment Review medications

Review device settings

On medical therapy for VT/VF? No

Add beta-blocker/ amiodarone or sotalol

Yes Evaluate for VT ablation

ACS = acute coronary syndrome; GDT = guideline-directed therapy; VT = ventricular tachycardia.

Table 4: List of Rhythms that Can Cause Inappropriate Shocks Causes of Inappropriate Shocks Sinus tachycardia Supraventricular tachycardia AF/flutter Non-sustained ventricular tachycardia

managed according to current guidelines. Inappropriate shocks caused by narrow complex tachycardias can be reduced with higher rate thresholds. Specific rate cut-off settings should be adjusted to the clinical context; however, the data suggests that the majority of atrial tachycardias occur at rates below 180 bpm. Appropriate shocks can be minimised by including dual-zone therapy programming, burstATP before attempted defibrillation of FVT and time-delay before device therapy, as many episodes of VT will spontaneously terminate. Patients with dual-chamber devices would benefit from programming rhythm discrimination algorithms to reduce frequency of inappropriate shocks; however, there is not enough evidence to support upgrading from a single chamber ICD to a dual chamber ICD for the sole purpose of rhythm discrimination. A discussion of rhythm discrimination algorithms is provided in a review by Spragg and Berger.5 A list of rhythms causing inappropriate shocks is provided in Table 4. Evaluate the patient for secondary causes of VT/VF including, but not limited to, medication effect, electrolyte depletion, acute heart failure or active ischemia. Chronic systolic heart failure patients should be evaluated for cardiac resynchronisation therapy. If there are no underlying aetiologies, or the patient continues to experience recurrent VT/VF despite correction of underlying aetiologies, VT/VF can be minimised by treatment with the combination therapy of amiodarone and a beta-blocker. Amiodarone dosing includes an initial loading period followed by a maintenance period. Patients in the trials noted above, who were not previously taking amiodarone received 400 mg twice per day for 2 weeks, followed by 400 mg once per day for 4 weeks, followed by 200 mg per day for the remainder of the trial period as maintenance dosing. If the patient is intolerant of amiodarone, sotalol can be used as a

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Clinical Arrhythmias second-line therapy. Patients treated with sotalol can receive a maximal dose of 160 mg twice per day; however, sotalol dosing may need to be decreased based on tolerance of side-effects, QT interval prolongation or renal function. Additionally, potential candidates for sotalol may be limited given the high prevalence of beta-blocker use for comorbid conditions. If VT/VF persists, or the patient is intolerant of medical therapy, the patient should be evaluated for targeted radiofrequency ablation of the focus of VT/VF. Given current data, proceeding with VT ablation earlier in the course of disease may be beneficial as opposed to intensifying medical therapy. Patients on medical therapy who undergo ablation for VT/VF would likely benefit from remaining on medical therapy post-ablation if tolerated. Ultimately, the decision to treat a patient with ablation versus medical therapy will depend upon

1.

 owell BD, et al. Survival after shock therapy in implantable P cardioverter-defibrillator and cardiac resynchronization therapy-defibrillator recipients according to rhythm shocked. The ALTITUDE Survival by Rhythm study. J Am Coll Cardiol 2013;62:1674–9. https://doi.org/10.1016/j.jacc.2013.04.083; PMID: 23810882. 2. Bardy GH, et al. Amiodarone or an implantable cardioverterdefibrillator for congestive heart failure. N Engl J Med 2005;352:225–37. http://dx.doi.org/10.15420/AER.2016.10.2; PMID: 27617090. 3. Saxon LA, et al. Predictors of sudden cardiac death and appropriate shock in the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) Trial. Circulation 2006;114:2766–72. https://doi.org/10.1161/ CIRCULATIONAHA.106.642892; PMID: 17159063. 4. Saxon LA, et al. Long-term outcome after ICD and CRT implantation and influence of remote device follow-up: the ALTITUDE survival study. Circulation 2010;122:2359–67. https://doi.org/10.1161/CIRCULATIONAHA.110.960633; PMID: 21098452. 5. Spragg DD, Berger RD. How to avoid inappropriate shocks. Heart Rhythm 2008;5:762–5. https://doi.org/10.1016/j. hrthm.2008.01.015; PMID: 21098452. 6. Wathen MS, et al. Prospective randomized multicenter trial of empirical antitachycardia pacing versus shocks for spontaneous rapid ventricular tachycardia in patients with implantable cardioverter-defibrillators: Pacing Fast Ventricular Tachycardia Reduces Shock Therapies (PainFREE Rx II) trial results. Circulation 2004;110:2591–6. https://doi.org/10.1161/01. CIR.0000145610.64014.E4; PMID: 15492306. 7. Wilkoff BL, et al. Strategic programming of detection and therapy parameters in implantable cardioverter-defibrillators reduces shocks in primary prevention patients: results from the PREPARE (Primary Prevention Parameters Evaluation) study. J Am Coll Cardiol 2008;52:541–50. https://doi. org/10.1016/j.jacc.2008.05.011; PMID: 18687248. 8. Gulizia MM, et al. A randomized study to compare ramp versus burst antitachycardia pacing therapies to treat fast ventricular tachyarrhythmias in patients with implantable cardioverter defibrillators: the PITAGORA ICD trial. Circ Arrhythm Electrophysiol 2009;2:146–53. https://doi.org/10.1161/ CIRCEP.108.804211; PMID: 19808459. 9. Moss AJ, et al. Reduction in inappropriate therapy and mortality through ICD programming. N Engl J Med 2012;367:2275–83. DOI: 10.1056/NEJMoa1211107. 10. Gilliam FR, et al. Real world evaluation of dual-zone ICD and CRT-D programming compared to single-zone

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11.

12.

13.

14.

15.

16.

17.

18.

19.

the patient’s comorbidities as well as their preference and tolerance of procedural risk versus medication side-effects.

Clinical Perspective This review will provide insight and advice for physicians caring for patients with recurrent ICD therapy due to ventricular arrhythmias in the following areas: • Adjustment of ICD setting • Adjustment or addition of specific medications • Timing of VT ablation

programming: the ALTITUDE REDUCES study. J Cardiovasc Electrophysiol 2011;22:1023–9. https://doi.org/10.1111/j.15408167.2011.02086.x; PMID: 21627705. Almendral J, et al. Dual-chamber defibrillators reduce clinically significant adverse events compared with singlechamber devices: results from the DATAS (Dual chamber and Atrial Tachyarrhythmias Adverse events Study) trial. Europace 2008;10:528–35. https://doi.org/10.1093/europace/eun072; PMID: 18390985. Friedman PA, et al. A prospective randomized trial of single- or dual-chamber implantable cardioverterdefibrillators to minimize inappropriate shock risk in primary sudden cardiac death prevention. Europace 2014;16:1460–8. https://doi.org/10.1093/europace/euu022; PMID: 24928948. Dorian P, et al. Randomized controlled study of detection enhancements versus rate-only detection to prevent inappropriate therapy in a dual-chamber implantable cardioverter-defibrillator. Heart Rhythm 2004;1:540–7. https:// doi.org/10.1016/j.hrthm.2004.07.017; PMID: 15851216. Abboud J, Ehrlich J. Antiarrhythmic drug therapy to avoid implantable cardioverter defibrillator shocks. Arrhythm Electrophysiol Rev 2016;5:117–21. http://dx.doi.org/10.15420/ AER.2016.10.2; PMID: 27617090. Pacifico A, et al. Prevention of implantable-defibrillator shocks by treatment with sotalol. d,l-Sotalol Implantable Cardioverter-Defibrillator Study Group. N Engl J Med 1999; 340:1855–62. https://doi.org/10.1056/NEJM199906173402402; PMID: 10369848. Connolly SJ, et al. 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;295:165–71. https://doi. org/10.1056/NEJM199906173402402; PMID: 10369848. Dorian P, et al. Placebo-controlled, randomized clinical trial of azimilide for prevention of ventricular tachyarrhythmias in patients with an implantable cardioverter defibrillator. Circulation 2004;110:3646–54. https://doi.org/10.1161/01. CIR.0000149240.98971.A8; PMID: 15533855. Kowey PR, et al. Efficacy and safety of celivarone, with amiodarone as calibrator, in patients with an implantable cardioverter-defibrillator for prevention of implantable cardioverter-defibrillator interventions or death: the ALPHEE study. Circulation 2011;124:2649–60. https://doi.org/10.1161/ CIRCULATIONAHA.111.072561; PMID: 22082672. Morrow DA, et al. Effects of ranolazine on recurrent cardiovascular events in patients with non-ST-elevation

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27.

28.

acute coronary syndromes: the MERLIN-TIMI 36 randomized trial. JAMA 2007;297:1775–83. https://doi.org/10.1001/ jama.297.16.1775; PMID: 17456819. Scirica BM, et al. Effect of ranolazine, an antianginal agent with novel electrophysiological properties, on the incidence of arrhythmias in patients with non ST-segment elevation acute coronary syndrome: results from the Metabolic Efficiency With Ranolazine for Less Ischemia in Non ST-Elevation Acute Coronary Syndrome Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36) randomized controlled trial. Circulation 2007;116:1647–52. https://doi. org/10.1161/CIRCULATIONAHA.107.724880; PMID: 17804441. Zareba W, et al. Ranolazine in high-risk patients with implanted cardioverter-defibrillators: the RAID trial. J Am Coll Cardiol 2018;72:636–45. https://doi.org/10.1016/j. jacc.2018.04.086; PMID: 30071993. Segal OR, et al. Long-term results after ablation of infarct-related ventricular tachycardia. Heart Rhythm 2005;2:474–82. https://doi.org/10.1016/j.hrthm.2005.01.017; PMID: 15840470. Reddy VY, et al. Prophylactic catheter ablation for the prevention of defibrillator therapy. N Engl J Med 2007;357:2657– 65. DOI: 10.1056/NEJMoa065457. Kuck KH, et al. Catheter ablation of stable ventricular tachycardia before defibrillator implantation in patients with coronary heart disease (VTACH): a multicentre randomised controlled trial. Lancet 2010. 375:31–40. https://doi. org/10.1016/S0140-6736(09)61755-4; PMID: 20109864. Frankel DS, et al. Ventricular tachycardia ablation remains treatment of last resort in structural heart disease: argument for earlier intervention. J Cardiovasc Electrophysiol 2011;22:1123– 8. https://doi.org/10.1111/j.1540-8167.2011.02081.x; PMID: 21539642. Marchlinski FE, et al. Hybrid therapy for ventricular arrhythmia management. Cardiol Clin 2000;18:391–406. https://doi.org/10.1016/S0733-8651(05)70148-X. Santangeli P, et al. Comparative effectiveness of antiarrhythmic drugs and catheter ablation for the prevention of recurrent ventricular tachycardia in patients with implantable cardioverter-defibrillators: A systematic review and meta-analysis of randomized controlled trials. Heart Rhythm 2016;13:1552–9. https://doi.org/10.1016/j.hrthm.2016.03.004; PMID: 26961297. Sapp JL, et al. Ventricular tachycardia ablation versus escalation of antiarrhythmic drugs. N Engl J Med 2016;375:111–21. https://doi.org/10.1056/NEJMoa1513614; PMID: 27149033.

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Clinical Arrhythmias

Long QT Syndrome Modelling with Cardiomyocytes Derived from Human-induced Pluripotent Stem Cells Luca Sala, 1 Massimiliano Gnecchi 2–4 and Peter J Schwartz 1,5,6 1. Istituto Auxologico Italiano, IRCCS, Laboratory of Cardiovascular Genetics, Milan, Italy; 2. Coronary Care Unit and Laboratory of Experimental Cardiology for Cell and Molecular Therapy, IRCCS Policlinico San Matteo Foundation, Pavia, Italy; 3. Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Pavia, Italy; 4. Department of Medicine, University of Cape Town, Cape Town, South Africa; 5. Istituto Auxologico Italiano, IRCCS, Center for Cardiac Arrhythmias of Genetic Origin, Milan, Italy; 6. Cardiovascular Genetics Laboratory, Hatter Institute for Cardiovascular Research in Africa, Department of Medicine, University of Cape Town, Cape Town, South Africa

Abstract Long QT syndrome (LQTS) is a potentially severe arrhythmogenic disorder, associated with a prolonged QT interval and sudden death, caused by mutations in key genes regulating cardiac electrophysiology. Current strategies to study LQTS in vitro include heterologous systems or animal models. Despite their value, the overwhelming power of genetic tools has exposed the many limitations of these technologies. In 2010, human-induced pluripotent stem cells (hiPSCs) revolutionised the field and allowed scientists to study in vitro some of the disease traits of LQTS on hiPSC-derived cardiomyocytes (hiPSC-CMs) from LQTS patients. In this concise review we present how the hiPSC technology has been used to model three main forms of LQTS and the severe form of LQTS associated with mutations in calmodulin. We also introduce some of the most recent challenges that must be tackled in the upcoming years to successfully shift hiPSC-CMs from powerful in vitro disease modelling tools into assets to improve risk stratification and clinical decision-making.

Keywords Long QT syndrome, cardiac arrhythmias, stem cells, human-induced pluripotent stem cells, cardiomyocytes, precision medicine, life-threatening arrhythmias, sudden cardiac death Disclosure: The authors have no conflicts of interest to declare. Acknowledgement(s): Maria-Christina Kotta for discussion and suggestions on the genetic aspects of LQTS. This work was supported by a Marie Skłodowska-Curie Individual Fellowship (H2020-MSCA-IF-2017 No. 795209) to Luca Sala, and by the Leducq Foundation for Cardiovascular Research grant 18CVD05 “Towards Precision Medicine with Human iPSCs for Cardiac Channelopathies”. Pinuccia De Tomasi for expert editorial support. Received: 17 December 2018 Accepted: 18 February 2019 Citation: Arrhythmia & Electrophysiology Review 2019;8(2):105–10. DOI: https://doi.org/10.15420/aer.2019.1.1 Correspondence: Peter J Schwartz, Istituto Auxologico Italiano IRCCS, Via Pier Lombardo, 22, 20135 Milano, MI, Italy. E: peter.schwartz@unipv.it or p.schwartz@auxologico.it Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Long QT Syndrome Long QT syndrome (LQTS) is a potentially severe arrhythmogenic disorder, affecting more than one in 2,000 people worldwide.1 It is characterised by a marked prolongation of the QT interval on the electrocardiogram and major cardiac events, such as syncope, cardiac arrest or sudden death, especially under conditions of physical or emotional stress.2,3 The current diagnostic criteria and options for effective management have been recently reviewed.4 As the first manifestation of the disease is frequently a lethal arrhythmic event, early diagnosis and therapy are extremely important and recent advances in genetics offer new opportunities.3 Besides its central role for the discovery of the molecular basis of LQTS and for the identification of the first gene-specific therapy, genetics became pivotal for the identification of the disease-causing genes and mutations in routine diagnostic practice and for gene-specific management.3–5 However, the low and variable penetrance exhibited by LQTS and the many confounding factors represent challenges to diagnosis and obstacles for the implementation of successful proactive treatments.6 In this context, multiple groups including

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ours have started to investigate and identify factors – either genetic, pharmacological or environmental – able to modify the clinical course of the disease by acting as modifiers of gene/protein function, expression or regulation.7 People with identical pathogenic mutations, even members of the same family, may display different degrees of clinical severity, symptoms or even be silent carriers of the mutation, which complicates the possibility of having unambiguous predictions of disease phenotypes simply based on the presence of disease-causing mutations in LQTS genes or when someone has a family history of the disease.7–12 Diagnosis of LQTS may also be hindered by the presence of uncharacterised rare variants; given that the pace by which modern genetic tools can extract huge amounts of information is  unprecedented, the field is progressively accumulating a growing number of  rare genetic variants associated with LQTS  subpopulations; these, initially defined variants of unknown/uncertain significance (VUS), are variants short-listed in the genetic analysis but for which evidence of being benign or pathogenic does not allow to draw univocal conclusions.13,14

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Clinical Arrhythmias The complexity behind some of the puzzling LQTS clinical manifestations has still to be fully unveiled and this leaves many patients, who might need clinical attention during the course of their lives, undiagnosed and unprotected. Therapies should be personalised for these subjects, but current tools and knowledge do not allow sufficient predictivity or mutation-specific remedies. To study such a high complexity, the need for valid and reliable experimental models intensifies; traditional models as heterologous systems are incapable of completely recapitulating genetic and phenotypic features, while animal models, particularly in rodents, do have electrophysiological characteristics that are often species-specific and very different from humans.15 This hampers the possibility of promptly translating results obtained in vitro directly to the clinics, with significant delays occurring between the discovery of promising treatments and their clinical application. For all these reasons, new experimental models, more predictive of human physiology and less limited by costs and ethics, are required and cardiomyocytes (CMs) derived from induced pluripotent stem cells (iPSC-CMs) have emerged in the past few years as a leading platform for these studies. Almost 10 years after the first LQTS model with human iPSC-CMs (hiPSC-CMs) was published, we will briefly discuss the state of the art, some of the obstacles that need to be solved and the fascinating transition of hiPSC-CMs as precision medicine tools that are used to preliminarily investigate experimental therapies and guide pharmacological treatments.16 We will focus on the main forms of LQTS.

Human-induced Pluripotent Stem Cells In 2006, Shinya Yamanaka and Kazutoshi Takahashi discovered that somatic cells could be reprogrammed to a pluripotent state by transfecting four factors – OCT4, SOX2, KLF4, cMYC – subsequently called Yamanaka factors.17,18 These reprogrammed cells, called iPSCs, can be derived from virtually anyone and represent an unprecedented source of human-based material that can be differentiated into multiple cell types through tailored differentiation protocols, including cardiomyogenic differentiation.19 Originally, iPSCs were derived from skin fibroblasts, which requires a biopsy, often difficult to propose for young children or to vulnerable subjects often already daunted by life-threatening diseases. Thus, new methods have been developed to obtain somatic cells from more accessible and less invasive tissues samples such as blood or urine.20,21 In addition to the obvious electrophysiological and molecular advantages of being of human origin, these cells share genotypes with their donors; this feature makes iPSCs candidate experimental models to study diseases of genetic origin, with LQTS and cardiac channelopathies being among the first to be reproduced with this technology. In 2010, the pioneering work of Alessandra Moretti et al., demonstrated that hiPSC-CMs could become powerful tools to study the functional effects of ion channel mutations identified in LQTS patients.16 However, as the molecular and functional characteristics of hiPSC-CMs are still far from those of adult CMs, multiple protocols were invented to promote their maturation. 22 These strategies include the use of prolonged cultures, chemically-defined media, the generation of tridimensional structures tailored for electrical stimulation protocols or co-cultures of CMs with other relevant cell types.23–31 Overall, these experimental models are progressively improving and the techniques to study the phenotype of hiPSC-CMs have advanced in parallel.

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Methods for the study of Long QT Syndrome with Human-induced Pluripotent Stem Cells The in vitro investigation of LQTS has the primary endpoint to ascertain whether and how the CMs’ electrophysiology has been modified as a consequence of LQTS-causing gene mutations. The patch clamp technique is the reference platform of choice to precisely quantify the phenotype of hiPSC-CMs. Although limited by its low throughput and disruptiveness, patch clamp allows quantitative recordings of action potentials (AP) and ion currents; furthermore, the combination of real-time computational ion current simulations with in vitro experiments has merged in the dynamic clamp technique.32 Although not particularly new at the time hiPSC-CMs were first derived, it was embraced to compensate the intrinsically reduced inward rectifier potassium current (IK1) magnitude, typical of isolated hiPSC-CMs,33–35 with an artificial IK1 injected in real-time. This technique transforms the action potential (AP) of hiPSC-CMs into one with more mature features as greater upstroke velocity and the presence of the AP notch, allowing voltage-gated ion channels to properly work as they were in more physiological conditions; this proved particularly relevant to capture the electrophysiological alterations caused by LQTS pathogenic mutations.33,34 However, since the heart is a functional syncytium, measurements of the downstream effects of LQTS mutations have greater translational power when performed on multicellular networks. At sufficient density, hiPSC-CMs do form functional beating mono- or multilayered sheets, which can be scrutinised with the multielectrode array (MEA) technology. Originally developed to study neuronal circuits, MEAs have gained interest in recent years with the development of stem cell-based cardiac disease models.36 Furthermore, the MEA technology has also been defined as one of the platforms of choice in the context of the US Food and Drug Administration’s Comprehensive in vitro Proarrhythmia Assay (CiPA), a task group which aims to identify the most suitable platform and protocols for drug screening and safety pharmacology.37 Other technologies with low invasiveness have been implemented as chemical or genetically-encoded voltage or calcium indicators, optogenetic actuators or imaging algorithms to investigate specific parameters of the diseased phenotype as a contraction and they all became widely used to obtain functional information with mediumhigh throughput.38–44

Long QT Syndrome Subtypes Studied with Human-induced Pluripotent Stem Cell Cardiomyocytes As expected by the high prevalence in patients, the first three forms of LQTS are also those primarily modelled in vitro.1 However, other LQTS types have been identified and successfully reproduced with hiPSC-CMs (Figure 1); we will focus on these three main types and on the extremely severe forms related to mutations on the genes encoding for calmodulin (CaM). Common in vitro phenotypes across all LQTS subtypes include prolonged AP durations (APDs), measured with patch clamp or voltage-sensitive indicators, prolonged field potential (FP) durations (FPD) measured with MEAs or prolonged Ca2+ and contraction transients (Figure 2). Some of the cell lines also experienced arrhythmogenic events as delayed after depolarizations (DADs) and early after depolarizations (EADs) in baseline conditions or after a pharmacological challenge.36

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Long QT Syndrome Modelling

LQTS type 1 (LQT1) is the most prevalent form of congenital LQTS, accounting for approximately 40–55% of all cases and its heterozygous form, called Romano-Ward syndrome, was the first LQTS type to be recapitulated with hiPSC-CMs.45–48 The severe homozygous form, when associated with deafness, is defined as Jervell and Lange-Nielsen syndrome (JLNS).49,50 People with LQT1 and JLNS are affected by mutations in KCNQ1 that induce loss of functions in Kv7.1, an important potassium channel responsible for the slow delayed rectifier potassium current (IKs). Although IKs is not straightforward to record in hiPSC-CMs due to their limited cell capacitance, which reduces the total current density, and to a late IKs onset during CM development,51 partially mitigated by certain maturation strategies,25 in vitro models of LQT1/ JLNS were able to recapitulate the pathological phenotype and exhibited marked reductions in IKs magnitude when compared to hiPSC-CMs from healthy donors or to isogenic controls52–54; detailed investigation of IKs with patch clamp also revealed the possibility for hiPSC-CMs to perfectly discriminate between homozygosity and heterozygosity.51–55 The similarities between hiPSC-CMs and clinical disease features extend also to triggers of arrhythmias; as previously described in humans, an increased activation of the sympathetic cascade is a clear arrhythmogenic trigger for LQT1/JLNS.56 When this is reproduced in vitro by stimulating hiPSC-CMs with beta-adrenergic agonists, their effect on L-type Ca2+ current outweighs the repolarisation capacity of the limited IKs magnitude available in LQT1/JLNS cells, leading to APD prolongation, abnormal Ca2+ transients and arrhythmogenic events (Figure 3).

Long QT Syndrome Type 2

Q4

LQTS type 2 (LQT2) is the second most common form of LQTS, accounting for 30–45% of cases.45 It is characterised by mutations in the KCNH2 gene, which encodes for the human ether a-go-gorelated gene (hERG, Kv11.1), a potassium channel responsible for the rapid delayed rectifier potassium current (IKr), pivotal for the cardiac repolarisation phase.46 LQT2 mutations may induce loss of function in IKr through four main mechanisms.57 The in vitro phenotype in hiPSC-CMs is generally clear, with marked reductions in IKr coupled to consistent APD prolongation.58–68 Clinical LQT2 triggers of arrhythmias include sudden auditory stimuli or loud noises and while these cannot be properly mimicked in vitro, alternatives as a stimulation with positive inotropes, alone or in combination with IKs blockers, are a widely used strategy to exacerbate arrhythmias in these cells.56,69 Since the majority of LQT2 mutations affect IKr through defective protein trafficking with hERG channels incapable of maturing and reaching the CMs’ membrane, researchers have adopted several strategies to restore proper hERG expression or function.70 Some rescued the LQT2 phenotype with compounds able to increase the conductance of wild type hERGs, other with proteasome inhibitors59,61,67 or, more recently, through a drug repurposing strategy which promoted the maturation of mutant hERGs in vitro.58,62 This drug repurposing strategy was very rapidly translated to the two LQT2 patients whose iPSC-CMs were previously tested in vitro and proved that, besides the expected discrepancies between the clinical and in vitro conditions, the data obtained in patient-specific iPSC-CMs do offer a certain degree of predictivity in the clinical situation.71

Long QT Syndrome Type 3 LQTS type 3 (LQT3) is the third most common form of LQTS, accounting for 5–13% of all congenital LQTS cases.45,46 It is the

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Figure 1: Number of Human-induced Pluripotent Stem Cell Lines with Long QT Syndrome Mutations Published So Far in the Literature Number of published hiPSC lines with LQTS mutations 15 Number of hiPSC lines

Long QT Syndrome Type 1 and Jervell and Lange-Nielsen Syndrome

LQTS type JLNS LQT1 LQT2

10

LQT3 LQT7

5

LQT8 LQT9 LQT14

0 LQT1 LQT2 LQT3 LQT7 LQT8 LQT9 LQT14 LQT15 Mixed LQTS type Mixed refers to hiPSC lines generated from patients with a mixed clinical phenotype that includes LQTS. hiPSC = Human-induced Pluripotent Stem Cell; LQTS = Long QT syndrome.

LQT15 Mixed

Figure 2: Long QT Syndrome Generates Prolongation of QT Interval at the ECG, Action Potential Duration Measured with Patch Clamp and Field Potential Duration Recorded with Multielectrode Array ECG

Action potential

Field potential

Calcium transient

Contraction

Healthy LQTS LQTS = Long QT syndrome.

Figure 3: Effect of Beta-adrenergic Stimulation on Cardiomyocytes From Long QT Syndrome Type 1/Jervell and Lange-Nielsen Syndrome Patients WT

LQT1/JLNS

ICaL

Control + beta-adrenergic agonist IKs

AP

Beta-adrenergic stimulation increases both the L-type Ca2+ current (ICaL) and the slow delayed rectifier potassium current (IKs ). In cardiomyocytes from healthy people, the increase in IKs is sufficient to counterbalance that of ICaL, leading to APD shortening in humans. In the presence of loss-of-function mutations in KCNQ1, as in LQT1/JLNS patients, the IKs is not sufficient to counterbalance the ICaL enhancement, leading to APD prolongation and arrhythmias. AP = action potential; LQT1 = Long QT syndrome type 1; JLNS = Jervell and Lange-Nielsen Syndrome Patients; WT = wild-type (healthy control).

consequence of gain-of-function mutations in the SCN5A gene, leading to an increase in the cardiac sodium current (INa); different biophysical changes induced by LQT3 mutations may increase either

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Clinical Arrhythmias the peak INa or also affect its late component (INa,L), the latter involved in electrophysiological abnormalities in multiple tissues, such as pancreatic beta-cells, cardiomyocytes or neurons.72,73 Despite INa overall current magnitude is lower in hiPSC-CMs compared with adult CMs and published hiPSC-CM models of LQT3 did correctly recapitulate increases in INa and other features of LQTS as EADs or prolonged calcium transients; APD was prolonged in the majority of models even though some authors described larger than ideal inter-line and inter-cell phenotypic variability.66,74–77 Furthermore, hiPSC-CMs with LQT3 mutations reproduced the expected effect of pharmacological therapies based on sodium channel blockers, which were able to rescue the prolonged APD and FPD and to suppress arrhythmogenic events in a dose-dependent way.74,76,78 Of note, some authors were also able to model through hiPSC-CMs some cardiac disorders with overlapping phenotypes of LQT3 and Brugada syndrome.75

Long QT Syndrome Type 14 and 15 LQTS types 14 (LQT14), 15 (LQT15), and the upcoming LQTS type 16 (LQT16), which is not yet officially approved, are characterised by mutations in one of the three genes (CALM1–3) encoding for CaM.79 Discovered by our group as associated with severe forms of LQTS and later investigated with hiPSC-CMs, these mutations impair the activity of CaM by either reducing its Ca2+-binding affinity or by altering its capacity to interact with downstream targets.33,80–82 Since CaM is a ubiquitous protein, present in CMs in limited pools, the consequences are dramatic, with very young people experiencing severe arrhythmias since birth and for whom current therapies are insufficient or inappropriate.83–85 These severe phenotypic characteristics have been perfectly captured by the hiPSC technology, with hiPSC-CMs from patients with CALM mutations exhibiting pathologically slowed ICaL Ca2+-dependent inactivation and massively prolonged APDs. A phenotypic rescue has been attempted in hiPSC-CMs through novel pharmacological or biotechnological strategies, with promising results that have already obtained preliminary translation to patients.33,81,82,86

Latest Challenges The aforementioned disease models represent a good approximation of the clinical condition and have pushed scientists to explore potential applications for hiPSC-CMs. A few of the most recent challenges of the cardiac hiPSC field will be discussed below.

Data Variability and Gene Editing The correlation between in vitro and in vivo data is still either uncharted territory or has resulted in contradictory findings in the literature. Although evidence has demonstrated that a fair correlation between clinical and in vitro recordings exists (i.e. LQTS cell lines generally do have prolonged APD/FPD in vitro), we still do not know precisely its extent and whether and how different reprogramming or maturation strategies could modify the magnitude and the time course of the in vitro equivalents of clinically relevant parameters as the QT interval or the RR interval. In the years since the application of hiPSC technology to disease modelling, it has become clear that cell lines from different donors have innate characteristics that are independent of the specific pathogenic mutation, thus they are likely to be associated with donor-specific characteristics.87,88 Electrophysiological properties as APD, which length should directly correlate with the presence of LQTS mutations, seem cell-line specific or differentiation-method specific rather than disease-specific and the same applies to FPD-RR relationships measured with MEAs; this can be attributed to potential confounding factors as manual pipetting,

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cell passage number and donor’s gender or ethnicity, suggesting the need of great care when data have to be interpreted on a translational perspective.62,88,89 In this vein, one of the most important additions in the LQTS field has been the concept of isogenic lines61; gene editing techniques, either based on zinc finger nucleases (ZFN), transcription activator-like effector nuclease (TALEN) or clustered regularly Interspaced short palindromic repeats (CRISPR)/Cas9. 90­–93 This technology can introduce pathogenic mutations, homozygous or heterozygous, into hiPSC lines from healthy donors, or correct them without altering the cell’s genetic background. This has proved to be important for introducing more robust standards to evaluate the functional consequences of point mutations and for precision medicine approaches.12,55,61,62,82,94,95

Precision Medicine Genetics, hiPSCs and cellular electrophysiology are progressively providing better chances of tailoring therapies to the specific mutation of the patient, and it is clear that the partnership between clinical cardiologists and basic scientists can be very fruitful96. One of the biggest advantages of hiPSC-CMs is that they share their genetic background with patients. This link can be harnessed to correlate clinically relevant information as genetic data to in vitro physiological and pharmacological responses. Patients with similar characteristics can be clustered according to their phenotype or genetic data to obtain homogenous cohorts of people who share similar characteristics. HiPSC-CMs are generated from these subjects and subsequently screened with molecular and functional assays that are able to generate data of translational relevance. Gene editing tools are used here to validate the results in the presence of identical genetic backgrounds.95 This strategy may have important consequences for risk stratification and therapeutic responses, as patients with certain VUSs would ideally be given different drug dosages based on the preliminary results of the in vitro screenings in hiPSC-CMs. In the context of precision medicine, the identification of novel clinical applications of drugs that have already received approval from regulatory agencies (drug repurposing) has increased. When combined with hiPSCs, it allows marketed drugs that are used to treat other disorders to be tested in vitro with a remarkable throughput on differentiated cells of human origin. In this view, our group has identified that lumacaftor (LUM), a compound currently prescribed for the treatment of specific mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, associated with defects trafficking in CFTR channels, could also rescue the disease phenotype in hiPSC-CMs derived from a specific class of people with LQT2 affected by hERG trafficking problems.58 Since LUM is already marketed for the treatment of cystic fibrosis in combination with ivacaftor and its safety profile is known, we were sufficiently confident to start a clinical trial.71 The mechanisms by which LUM may rescue hERG trafficking defects are still unknown and these results will require extensive confirmation from clinical data and from other hiPSC lines from more LQT2 donors to verify whether these effects could be cell-line- or mutation-specific or whether their mechanism could be exploited for broader applications.

Conclusion hiPSC technology has brought significant contributions to the way LQTS and cardiac arrhythmias are modelled at preclinical level97; however, more efforts are required to offer an exhaustive comprehension of the translational relevance of hiPSC findings. In our view, shared and

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Long QT Syndrome Modelling open protocols, tighter standards from researchers, journals, funding agencies as well as the implementation of large publicly available informatic tools and datasets are the sole way to revolutionise how the iPSC technology interacts with the clinics and shift hiPSC-CMs from useful in vitro preclinical tools to something able to produce

relevant information for prompt clinical decision-making. It is also clear that genetics, combined with the most recent advances in hiPSCCMs technology, bioinformatics and artificial intelligence, will unveil future possibilities and targets for the diagnosis, risk stratification and treatment of LQTS.

Clinical Perspective • LQTS is a potentially lethal arrhythmogenic disorder that affects more than 1 in every 2,000 children. Our knowledge of genetics in LQTS has progressively increased over the years, and we reached a mismatch between the amount of genetic information available and the functional data that allow us to interpret this genetic information. • The emerging role of variants of unknown/uncertain significance (VUS) require in vitro experimental models capable of effectively integrating the genetic component and to extract predictive information relevant for clinical use. • Human induced pluripotent stem cell-derived cardiomyocytes from LQTS patients, as they share the patients’ genotype, have proven to be a useful platform for in vitro investigation of the effect of pathogenic mutations of LQTS and VUS on the cardiac phenotype, and may represent the optimal tool, in combination with gene editing strategies, for large-scale investigation of the functional consequences of genetic variants. • Large precision medicine approaches could combine the benefits of large-scale genetic studies with reliable functional readouts operating at medium to high throughput. • Some of the current limitations of the hiPSC technology can be addressed only with combined and bidirectional efforts between clinicians and scientists.

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60. M  atsa E, Dixon JE, Medway C, et al. Allele-specific RNA interference rescues the long-QT syndrome phenotype in human-induced pluripotency stem cell cardiomyocytes. Eur Heart J 2014;35:1078–87. https://doi:10.1093/eurheartj/eht067; PMID: 23470493. 61. Bellin M, Casini S, Davis RP, et al. Isogenic human pluripotent stem cell pairs reveal the role of a KCNH2 mutation in longQT syndrome. EMBO J 2013;32:3161–75. https://doi:10.1038/ emboj.2013.240; PMID: 24213244. 62. Sala L, Yu Z, Ward-van Oostwaard D, et al. A new hERG allosteric modulator rescues genetic and drug-induced longQT syndrome phenotypes in cardiomyocytes from isogenic pairs of patient induced pluripotent stem cells. EMBO Mol Med 2016;8:1065–81. https://doi:10.15252/emmm.201606260; PMID: 27470144. 63. Terrenoire C, Wang K, Tung KWC, et al. Induced pluripotent stem cells used to reveal drug actions in a long QT syndrome family with complex genetics. J Gen Physiol 2013;141:61–72. https://doi:10.1085/jgp.201210899; PMID: 23277474. 64. Lahti AL, Kujala VJ, Chapman H, et al. Model for long QT syndrome type 2 using human iPS cells demonstrates arrhythmogenic characteristics in cell culture. Dis Model Mech 2012;5:220–30. https://doi:10.1242/dmm.008409; PMID: 22052944. 65. Itzhaki I, Maizels L, Huber I, et al. Modelling the long QT syndrome with induced pluripotent stem cells. Nature 2011;471:225–9. https://doi:10.1038/nature09747; PMID: 21240260. 66. Spencer CI, Baba S, Nakamura K, et al. Calcium transients closely reflect prolonged action potentials in iPSC models of inherited cardiac arrhythmia. Stem Cell Reports 2014;3:269–81. https://doi:10.1016/j.stemcr.2014.06.003; PMID: 25254341. 67. Mura M, Mehta A, Ramachandra CJ, et al. The KCNH2 -IVS928A/G mutation causes aberrant isoform expression and hERG trafficking defect in cardiomyocytes derived from patients affected by Long QT Syndrome type 2. Int J Cardiol 2017;240:367–71. https://doi:10.1016/j.ijcard.2017.04.038; PMID: 28433559. 68. Fatima A, Ivanyuk D, Herms S, et al. Generation of human induced pluripotent stem cell line from a patient with a long QT syndrome type 2. Stem Cell Res 2016;16:304–7. https:// doi:10.1016/j.scr.2015.12.039; PMID: 27345990. 69. Matsa E, Rajamohan D, Dick E, et al. Drug evaluation in cardiomyocytes derived from human induced pluripotent stem cells carrying a long QT syndrome type 2 mutation. Eur Heart J 2011;32:952–62. https://doi:10.1093/eurheartj/ehr073; PMID: 21367833. 70. Anderson CL, Delisle BP, Anson BD, et al. Most LQT2 Mutations reduce Kv11.1 (hERG) current by a class 2 (trafficking-deficient) mechanism. Circulation 2006;113:365–73. https://doi:10.1161/CIRCULATIONAHA.105.570200; PMID: 16432067. 71. Schwartz PJ, Gnecchi M, Dagradi F, et al. From patient-specific induced pluripotent stem cells to clinical translation in Long QT Syndrome type 2. Eur Heart J 2019. https://doi:10.1093/ eurheartj/ehz023; PMID: 30753398. 72. Zaza A, Belardinelli L, Shryock JC. Pathophysiology and pharmacology of the cardiac ‘late sodium current’. Pharmacol Ther 2008;119:326–39. https://doi:10.1016/j. pharmthera.2008.06.001; PMID: 18662720. 73. Rizzetto R, Rocchetti M, Sala L, et al. Late sodium current (INaL) in pancreatic β-cells. Pflügers Arch – Eur J Physiol 2015;467:1757–68. https://doi:10.1007/s00424-014-1613-0; PMID: 25236919. 74. Ma D, Wei H, Zhao Y, et al. Modeling type 3 long QT syndrome with cardiomyocytes derived from patient-specific induced pluripotent stem cells. Int J Cardiol 2013;168:5277–86. https:// doi:10.1016/j.ijcard.2013.08.015; PMID: 23998552. 75. Okata S, Yuasa S, Suzuki T, et al. Embryonic type Na+ channel β-subunit, SCN3B masks the disease phenotype of Brugada syndrome. Sci Rep 2016;6:34198. https://doi:10.1038/ srep34198; PMID: 27677334. 76. Malan D, Zhang M, Stallmeyer B, et al. Human iPS cell model of type 3 long QT syndrome recapitulates drugbased phenotype correction. Basic Res Cardiol 2016;111:11–4. https://doi:10.1007/s00395-016-0530-0; PMID: 26803770. 77. Fatima A, Kaifeng S, Dittmann S, et al. The disease-specific phenotype in cardiomyocytes derived from induced pluripotent stem cells of two long QT syndrome type 3 patients. PLoS One 2013;8:e83005. https://doi:10.1371/journal. pone.0083005; PMID: 24349418.

78. P  ortero V, Casini S, Hoekstra M, et al. Anti-arrhythmic potential of the late sodium current inhibitor GS-458967 in murine Scn5a-1798insD+/− and human SCN5A-1795insD+/− iPSC-derived cardiomyocytes. Cardiovasc Res 2017;113:829–38. https://doi:10.1093/cvr/cvx077; PMID: 28430892. 79. Badone B, Ronchi C, Kotta M-C, et al. Calmodulinopathy: functional effects of CALM mutations and their relationship with clinical phenotypes. Front Cardiovasc Med 2018;5:176. https://doi:10.3389/fcvm.2018.00176; PMID: 30619883. 80. Crotti L, Johnson CN, Graf E, et al. Calmodulin mutations associated with recurrent cardiac arrest in infants. Circulation 2013;127:1009–17. https://doi:10.1161/ CIRCULATIONAHA.112.001216; PMID: 23388215. 81. Yamamoto Y, Makiyama T, Harita T, et al. Allele-specific ablation rescues electrophysiological abnormalities in a human iPS cell model of long-QT syndrome with a CALM2 mutation. Hum Mol Genet 2017;26:1670–7. https://doi:10.1093/ hmg/ddx073; PMID: 28335032. 82. Limpitikul WB, Dick IE, Tester DJ, et al. A precision medicine approach to the rescue of function on malignant calmodulinopathic Long-QT Syndrome. Circ Res 2017;120:39– 48. https://doi:10.1161/CIRCRESAHA.116.309283; PMID: 27765793. 83. Wu X, Bers DM. Free and bound intracellular calmodulin measurements in cardiac myocytes. Cell Calcium 2007;41:353– 64. doi:10.1016/j.ceca.2006.07.011; PMID: 16999996. 84. Maier LS, Ziolo MT, Bossuyt J, et al. Dynamic changes in free Ca-calmodulin levels in adult cardiac myocytes. J Mol Cell Cardiol 2006;41:451–8. https://doi:10.1016/j.yjmcc.2006.04.020; PMID: 16765983. 85. Crotti L, Spazzolini C, Tester DJ, et al. Calmodulin mutations and life-threatening cardiac arrhythmias: Insights from the International Calmodulinopathy Registry. Eur Heart J (In press). 86. Webster G, Schoppen ZJ, George AL. Treatment of calmodulinopathy with verapamil. BMJ Case Rep 2017;2017: pii: bcr-2017-220568. https://doi:10.1136/bcr-2017-220568; PMID: 28784889. 87. Liang P, Sallam K, Wu H, et al. Patient-specific and genomeedited induced pluripotent stem cell-derived cardiomyocytes elucidate single-cell phenotype of Brugada syndrome. J Am Coll Cardiol 2016;68:2086–96. https://doi: 10.1016/j. jacc.2016.07.779. PMID: 27810048. 88. Kilpinen H, Goncalves A, Leha A, et al. Common genetic variation drives molecular heterogeneity in human iPSCs. Nature 2017;546:370–5. https://doi:10.1038/nature22403; PMID: 28489815. 89. Sala L, Bellin M, Mummery CL. Integrating cardiomyocytes from human pluripotent stem cells in safety pharmacology: Has the time come? Br J Pharmacol 2017;174:3749–65. https:// doi:10.1111/bph.13577; PMID: 27641943. 90. Urnov FD, Rebar EJ, Holmes MC, et al. Genome editing with engineered zinc finger nucleases. Nat Rev Genet 2010;11:636– 46. https://doi:10.1038/nrg2842; PMID: 20717154. 91. Mussolino C, Morbitzer R, Lütge F, et al. A novel TALE nuclease scaffold enables high genome editing activity in combination with low toxicity. Nucleic Acids Res 2011;39:9283–93. https://doi:10.1093/nar/gkr597; PMID: 21813459. 92. Hsu PD, Lander ES, Zhang F. Development and applications of CRISPR-Cas9 for genome engineering. Cell 2014;157:1262–78. https://doi:10.1016/j.cell.2014.05.010; PMID: 24906146. 93. Freedman LP, Gibson MC, Ethier SP, et al. Reproducibility: changing the policies and culture of cell line authentication. Nat Methods 2015;12:493–7. https://doi:10.1038/nmeth.3403; PMID: 26020501. 94. Wang Y, Liang P, Lan F, et al. Genome editing of isogenic human induced pluripotent stem cells recapitulates long QT phenotype for drug testing. J Am Coll Cardiol 2014;64:451–9. https://doi:10.1016/j.jacc.2014.04.057; PMID: 25082577. 95. Ma N, Zhang JZ, Itzhaki I, et al. Determining the pathogenicity of a genomic variant of uncertain significance using CRISPR/Cas9 and human-induced pluripotent stem cells. Circulation 2018;138:2666–81. https://doi:10.1161/ CIRCULATIONAHA.117.032273; PMID: 29914921. 96. Schwartz PJ, Sala L. Precision vs traditional medicine. Clinical questions trigger progress in basic science: a favor not always returned. Circ Res 2019;124:459–61. https:// doi:10.1161/CIRCRESAHA.119.314629; PMID: 30763224. 97. Gnecchi M, Stefanello M, Mura M. Induced pluripotent stem cell technology: Toward the future of cardiac arrhythmias. Int J Cardiol 2017;237:49–52. https://doi: 10.1016/j. ijcard.2017.03.085. PMID: 28408106.

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Electrophysiology and Ablation

High-resolution Mapping in Patients with Persistent AF Marius Andronache, 1 Nikola Drca 2 and Graziana Viola 3 1. Clermont Ferrand Centre, France; 2. Karolinska Institute, Stockholm, Sweden; 3. Ospedale San Francesco, Nuoro, Italy

Abstract Ablation of AF through electrical isolation of the pulmonary veins is a well-established technique and a cornerstone in the ablation of AF, although there are a variety of techniques and ablation strategies now available. However, high numbers of patients are returning to hospital after ablation procedures such as pulmonary vein isolation (PVI). Scar tissue (as identified by contact voltage mapping) is found to be present in many of these patients, especially those with persistent AF and even those with paroxysmal AF. This scarring is associated with poor outcomes after PVI. Cardiac mapping is necessary to locate triggers and substrate so that an ablation strategy can be optimised. Multipolar mapping catheters offer more information regarding the status of the tissue than standard ablation catheters. A patient-tailored catheter ablation approach, targeting the patient-specific low voltage/fibrotic substrate can lead to improved outcomes.

Keywords Atrial fibrosis, AF, catheter ablation, multipolar catheters, pulmonary vein isolation Disclosure: Nikola Drca has received consultancy fees from Biosense Webster. Marius Andronache and Graziana Viola have no conflicts of interest to declare. Acknowledgement: Katrina Mountfort and Bettina Vine of Medical Media Communications (Scientific) Ltd provided medical writing and editing support to the authors, funded by Biosense Webster. Received: 25 January 2019 Accepted: 22 March 2019 Citation: Arrhythmia & Electrophysiology Review 2019;8(2):111–5. DOI: https://doi.org/10.15420/aer.2018.57.1 Correspondence: Nikola Drca, Department of Cardiology, Karolinska Institute, Karolinska University Hospital, Stockholm SE-141 86, Sweden. E: nikola.drca@sll.se Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

AF is the most common sustained cardiac arrhythmia in clinical practice. It is associated with increased risk of stroke and heart failure (HF), and is a significant global health challenge.1 Catheter ablation procedures, which isolate the pulmonary veins (PV) from the left atrium and prevent AF initiation, are effective and safe treatment options, and have emerged as the preferred rhythm control strategy for symptomatic paroxysmal AF refractory or intolerant to at least one antiarrhythmic medication.2,3 This procedure is associated with a high success rate (>70%) in paroxysmal AF, but with persistent AF, the success rate after a stand-alone pulmonary vein isolation (PVI) approach remains lower (about 50–60%).1 Due to worse long-term outcomes in patients with persistent AF, additional substrate ablation is frequently performed.4 Scar tissue is present in many of these patients, especially those with persistent AF, but is also seen in those with paroxysmal AF. This scarring is associated with poor outcomes after PVI.5–7 This has led to the development of ablation strategies to eliminate low voltage regions caused by scarring in the left atrium. This article aims to discuss the challenges of atrial scarring in patients with persistent AF and substrate mapping strategies, which allow improved arrhythmia freedom rates after catheter ablation therapy targeting arrhythmogenic atrial substrate.

The challenges of atrial scarring Understanding the AF substrate is essential to improving outcomes in catheter ablation of patients with persistent AF, and it can enable individualised treatment approaches.8–10 A growing body of evidence indicates that pre-existing or iatrogenic atrial fibrosis, or scarring, plays

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a role in the maintenance of AF.10,11 Animal studies have shown that propagation of fibrillation waves is promoted by endocardial bundles in acute AF and by epicardial bundles in persistent AF.12 Atrial fibre bundle rearrangement results in more perpendicular orientation of epicardial to endocardial bundles, causing endo-to-epicardial dissociation of electrical activity and the formation of a 3D AF substrate.12 However, while the definition of ventricular scar is well established, this approach has been more challenging in the atrium, due to the structure of the atrial wall and the difficulty of detecting atrial fibrosis with existing imaging techniques.13 Atrial fibrosis can separate cardiomyocyte bundles, which can hinder electrical coupling and slow electrical conduction.14 The presence of left atrial (LA) scarring in AF patients has therefore been associated with an abnormal electroanatomic substrate causing lower regional voltage, increased proportion of low voltage, slowed conduction and increased proportion of complex signals compared with controls.7 In a study of 700 consecutive patients undergoing PVI for the first time, pre-existing LA scarring was a strong independent predictor of procedural failure and was associated with a lower ejection fraction (EF), larger LA size, and increased inflammatory markers, with patients experiencing left atrial scarring having a significantly higher AF recurrence (57%) compared with patients without scarring (19%, p=0.003).5 In a multicentre, prospective, observational cohort study of patients diagnosed with paroxysmal and persistent AF undergoing their first catheter ablation with PVI, atrial tissue fibrosis estimated by delayed enhancement MRI (n=272) was independently associated with the risk of recurrent arrhythmia.6

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Electrophysiology and Ablation Table 1: Currently Available Multipolar Catheters for Mapping Atrial Scar

persistent AF. Ablation of non-PV triggers, if found, was given a class IIa recommendation.24

Name

Details

PentaRay (Biosense Webster)

20 electrodes arranged in 5 soft radiating splines (1 mm electrodes separated by 2 mm interelectrode spacing if 2–6–2 mm used)

The most commonly used cardiac mapping approach is isochronal or activation mapping, which is based on non-fluoroscopic visualisation of mapping catheters and a partial model of the wavefront excitation sequence created by the manipulation of a mapping catheter. Mapping systems create a 3D reconstruction of the area of interest and enable the location of catheters, maps of the atria, colour-coded activation and voltage maps and the tagging of regions of interest.25

AFocus II Duo-decapolar 20 electrodes with 4-4-4 mm spacing (Abbott) LASSO (Biosense Webster)

Circular mapping catheter, 20-polar catheter, 1 mm electrodes, 2–6–2 mm spacing

INTELLAMAP ORION (Boston Scientific)

64 electrodes: 8 splines with 8 electrodes per spline, 0.4 mm2 electrode size, 2.5 mm spacing

EnSite (Abbott)

Grid catheter, 16 electrodes (1 mm electrodes with 4 mm electrode spacing)

Advisor HD (Abbott)

Circular mapping catheter, 10 electrodes. 2 sizes: 15 mm diameter (3–3–3 mm spacing) and 20 mm (5–5–5 spacing)

Achieve (Medtronic)

Circular mapping catheter, 8 electrodes. 2 sizes: 15 mm diameter (4 mm spacing) and 20 mm diameter (6 mm spacing)

A promising new strategy for ablation of AF is atrial scar-based catheter ablation to modify low voltage regions that may indicate scar and/or zones of non-uniform anisotropic conduction in the left atrium and convert them into electrically silent regions.9,15,16 In a study that compared the two-year outcomes in patients with paroxysmal AF and severe LA scarring identified by 3D mapping, undergoing PVI-only or PVI plus scar homogenisation, the latter group had significantly better long-term outcomes than those who had PVI alone. While single procedures had a low success rate, ablation of non-PV triggers during repeat procedures resulted in significantly better outcomes.17

Methods of Analysing the Extent and Severity of Scarring Pre-procedure A number of studies have concluded that substrate mapping is a useful tool to guide personalised AF substrate modification in patients undergoing AF ablation (Table 1).9,10,18–20 In a study that compared electrophysiologic abnormalities in 80 patients with AF (30 paroxysmal AF, 22 persistent AF and 28 long-standing AF), with 20 matched controls, high-density 3D electroanatomic mapping showed that the low voltage index increased gradually from control to paroxysmal AF, persistent AF and long-standing AF.21 In a singlecentre randomised study, individually tailored substrate modification guided by voltage mapping was associated with a significantly higher arrhythmia-free survival rate compared with a conventional approach applying linear ablation according to AF type.22 A recent meta-analysis concluded that voltage-guided substrate modification by targeting low-voltage areas in addition to PVI is more effective and safer than conventional ablation approaches, though cautioned that more randomised studies are needed.23 The 2017 Heart Rhythm Society expert consensus document assigned a class IIb recommendation to mapping and ablation of areas of abnormal myocardial tissue identified with voltage mapping as an initial or repeat ablation strategy for persistent AF. A class IIb recommendation was also given to creation of linear ablation lines (in the absence of documented macro-reentrant flutter), ablation of complex fractionated atrial electrograms, rotor ablation, extensive posterior wall ablation or targeting of autonomic ganglionic plexi in

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The most widely available electroanatomical-mapping systems are the CARTO® (Biosense Webster), the EnSite NavX and the EnSitePrecision® system (Abbott).26–28 The CARTO system comprises three active weak magnetic fields (5×10−6 to 5×10−5 Tesla), produced by a three-coil location pad placed underneath the patient’s thorax. Its catheter tips contain a magnetic mini-sensor that continually measures the strength of the magnetic field and calculates the catheter’s exact position.29 The CARTO-3 system features the HD colouring/confidence algorithm, which allows for automated map acquisition. The EnSite Precision system has new features including the EnSite AutoMap Module, which allows the physician to map arrhythmias faster than current systems.28 These systems have been shown to reduce radiation and the duration of procedures.27,30 More recently, the Rhythmia HDx (Boston Scientific) mapping system has been introduced. This uses a combination of magnetic-based tracking for a sensor at the catheter tip and impedance-based tracking for all electrodes, enabling the rapid and automatic acquisition of maps with high resolution and without the need for extensive manual annotation.31–33 Mapping approaches may be challenging. Cardiac mapping can be difficult if scarring is present because of lack of capture in these areas of low voltage.34 The difficulties arise from a poor understanding of events such as collision waves and anisotropy in the low voltage and fragmented areas and how to modify these abnormal electrical areas to eliminate or homogenise them. It can also be difficult to define what is healthy and what is diseased myocardium. The optimal voltage threshold that defines scar areas has yet to be defined for voltage maps created with conventional ablation catheters and for multipolar catheters. The conventional voltage cut-off is set at <0.5 mV for defining scar areas that have been targeted during ablation. Recent studies suggest that other cut-off values could be used in detecting deceased atrial myocardium.35,36 Scar maps obtained by electroanatomic mapping have emerged as a useful tool to guide personalised AF substrate modification in patients undergoing AF ablation, and is supported by a growing body of evidence.16,36 There are currently no data on ablation of atrial fibrosis guided by delayed-enhancement MRI. The ongoing Efficacy of Delayed Enhancement MRI-Guided Ablation versus Conventional Catheter Ablation of Atrial Fibrillation (DECAAFII) (NCT02529319) randomised study aims to recruit 888 participants. Before the availability of the multipolar mapping catheters, it was much more challenging to map arrythmias in scarred atria. The large tip catheter made it difficult to see any signals in scarred tissue. Large parts of the atria appeared to be completely silent and it was challenging to map the arrhythmia. Localised reentries in scarred tissue were sometimes impossible to see. The use of a multipolar mapping catheter offers an important addition to the voltage map, helping clinicians better understand the arrhythmias (Figures 1 and 2).

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High-resolution Mapping in Patients with Persistent AF The Multipolar Mapping Catheter as a Tool for Substrate Mapping in Clinical Practice

Figure 1: Bipolar Voltage Map in Sinus Rhythm

The standard catheter for mapping the left atrium is a linear catheter with a 3.5 mm distal electrode separated by 2 mm from a proximal 2 mm electrode, resulting in a centre-to-centre interelectrode spacing of 4.75 mm.34 In recent years, a number of multi-electrode contactbased catheters have been introduced into clinical practice. Used in conjunction with a 3D mapping system they allow the sampling of multiple points of cardiac mapping data. The devices usually contain more than 20 electrodes. The catheters’ contact with the endocardium surface is atraumatic and provides a high-density map with an interelectrode spacing down to 1 mm.20 Multielectrode catheters were introduced in the 1990s for the diagnosis of supraventricular tachycardia; however, their use for scar mapping did not begin until the 2000s with the introduction of electro-anatomical mapping systems.37 Compared with pointby-point voltage maps, multipolar maps have been shown to have significant advantages, such as higher mapping resolution that can identify heterogeneity in the area of low voltage, localising channels of surviving bundles; the ability to record higher bipolar voltage amplitude with shorter electrogram duration; and pacing with capture at lower output because of increased electrical density.34,38 Electrogram voltages are dependent on the electrode size and spacing, and the angle of the incoming wavefronts to the catheter. Several multipolar electrode systems are available (Table 1). Circular mapping catheters are the most established. The LASSO circular catheter (Biosense Webster) has 10–20 electrodes and its utility has been demonstrated in a number of studies. A study of 40 maps from 20 patients showed a shorter LA mapping time with greater high definition LA mapping compared with an ablation catheter (13.3 versus 34.4 minutes to reconstruct LA voltage map with 923 versus 228 points).39 More recent systems include the PentaRay® (Biosense Webster) and the AFocus II® Duo-decapolar® (Abbott) catheters. The AFocus II Duodecapolar catheter has 20 electrodes with 4-4-4 mm spacing and has been used in VT and AF mapping.40,41 The PentaRay catheter has 20 electrodes arranged in five soft radiating splines (1 mm electrodes separated by 2 mm interelectrode spacing) laid out flat to cover an area with a 3.5 cm diameter. It can only be used with the CARTO mapping sytems.26 The multi-branch configuration provides broader access to information with high resolution. The use of the PentaRay catheter has been demonstrated in a number of case reports and studies of patients with AF.19,20,34,42,43 In a recent prospective study – Substrate Ablation Guided by High Density Mapping in Atrial Fibrillation (SUBSTRATE HD) (NCT02093949), AF was sequentially mapped in both atria of 105 patients admitted for AF ablation, using the PentaRay catheter. Radiofrequency times and procedure times were shorter with the PentaRay catheter compared with a validation set in which a conventional ablation approach was used.19

Figure 2: Bipolar Voltage Map in Sinus Rhythm

with the Precision platform. The four-spline design reduces variability of maps associated with differences in orientation of the catheter relative to the propagating wavefront. Early clinical data suggests that this system enables the rapid collection of a high density of voltage points.48 Other catheters include the Advisor HD™ (Abbott), which is a 20-pole circular mapping catheter, and the Achieve™ advanced mapping catheter (Medtronic).49 These catheters have a low bipolar electrical resolution because of long interelectrode distances.50 Each of these catheters have their own unique characteristics and it is important to individualise scar thresholds.

Conclusion

The IntellaMap Orion™ (Boston Scientific) multipolar catheter has 64 electrodes. This system comprises eight splines with eight electrodes per spline, 0.4 mm2 electrode size and 2.5 mm interelectrode spacing and is used in combination with the Rhythmia mapping system.44–47

Catheter ablation for the treatment of persistent AF is associated with suboptimal outcomes, largely due to the presence of scar tissue. AF recurrence is frequently reported, and patients often undergo repeat ablations after conventional PVI procedures. Substrate-based modification via targeting areas of scar in the left atrium has therefore emerged as a promising therapeutic strategy. Multipolar catheters with smaller electrodes and shorter interelectrode distances are more effective tools for high-density mapping than conventional catheters. Their use has facilitated the visualisation of areas of low-voltage or scar and has allowed the operator to effectively modulate or eliminate arrhythmogenic substrate and improve the prognosis of patients with highly symptomatic AF.

The EnSite high density grid catheter has 16 electrodes (1 mm electrodes with 4 mm electrode spacings), and is designed for use

In order to optimise accuracy and reproducibility of scar maps, there is a need for standardised protocols and uniform cut-offs for scar

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Electrophysiology and Ablation detection. While large randomised controlled trials are needed to confirm the benefits, clinical evidence to date suggests that the use of

the multipolar mapping catheters may facilitate successful ablation of scar-related AF.

Clinical Perspective • Pulmonary vein isolation is the cornerstone of catheter ablation of atrial AF. • Atrial fibrosis has been demonstrated to predict likelihood of success after AF ablation. A new strategy for ablation of AF is substratebased ablation of fibrotic areas visualised as low-voltage areas on electroanatomical maps. The PentaRay® catheter (Biosense Webster) allows for fast mapping with high density and high resolution facilitating the creation of voltage maps. • The use of large-tip catheters caused difficulties and occasionally the inability to detect signals in scarred tissue. Localised reentries in scarred tissue were sometimes impossible to see. • Multipolar catheters with closer spacing and smaller electrodes have higher resolution which allows the detection of signals in previously ‘silent’ areas.

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Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur J Cardiothorac Surg 2016;50:e1–88. https://doi.org/10.1093/ejcts/ezw313; PMID: 27663299. Nyong J, Amit G, Adler AJ, et al. Efficacy and safety of ablation for people with non-paroxysmal atrial fibrillation. Cochrane Database Syst Rev 2016;11:CD012088. https://doi. org/10.1002/14651858.CD012088.pub2; PMID: 27871122. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/ HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014;130:2071–104. https://doi.org/10.1161/ CIR.0000000000000040; PMID: 24682348. Darby AE. Recurrent atrial fibrillation after catheter ablation: considerations for repeat ablation and strategies to optimize success. J Atr Fibrillation 2016;9:1427. https://doi.org/ 10.4022/ jafib.1427; PMID: 27909521. Verma A, Wazni OM, Marrouche NF, et al. Pre-existent left atrial scarring in patients undergoing pulmonary vein antrum isolation: an independent predictor of procedural failure. J Am Coll Cardiol 2005;45:285–92. https://doi.org/10.1016/j. jacc.2004.10.035; PMID: 15653029. Marrouche NF, Wilber D, Hindricks G, et al. Association of atrial tissue fibrosis identified by delayed enhancement MRI and atrial fibrillation catheter ablation: the DECAAF study. JAMA 2014;311:498–506. https://doi.org/10.1001/jama.2014.3; PMID: 24496537. Teh AW, Kistler PM, Lee G, et al. Electroanatomic remodeling of the left atrium in paroxysmal and persistent atrial fibrillation patients without structural heart disease. J Cardiovasc Electrophysiol 2012;23:232–8. https://doi. org/10.1111/j.1540-8167.2011.02178.x; PMID: 21955090. Kottkamp H, Berg J, Bender R, et al. Box Isolation of Fibrotic Areas (BIFA): a patient-tailored substrate modification approach for ablation of atrial fibrillation. J Cardiovasc Electrophysiol 2016;27:22–30. https://doi.org/10.1111/jce.12870; PMID: 26511713. Rolf S, Kircher S, Arya A, et al. Tailored atrial substrate modification based on low-voltage areas in catheter ablation of atrial fibrillation. Circ Arrhythm Electrophysiol 2014;7:825–33. https://doi.org/10.1161/CIRCEP.113.001251; PMID: 25151631. Jadidi AS, Lehrmann H, Keyl C, et al. Ablation of persistent atrial fibrillation targeting low-voltage areas with selective activation characteristics. Circ Arrhythm Electrophysiol 2016;9: e002962. https://doi.org/10.1161/CIRCEP.115.002962; PMID: 26966286. Heijman J, Algalarrondo V, Voigt N, et al. The value of basic research insights into atrial fibrillation mechanisms as a guide to therapeutic innovation: a critical analysis. Cardiovasc Res 2016;109:467–79. https://doi.org/10.1093/cvr/cvv275; PMID: 26705366. Maesen B, Zeemering S, Afonso C, et al. Rearrangement of atrial bundle architecture and consequent changes in anisotropy of conduction constitute the 3-dimensional substrate for atrial fibrillation. Circ Arrhythm Electrophysiol 2013;6:967–75. https://doi.org/10.1161/CIRCEP.113.000050; PMID: 23969531. Kapa S, Desjardins B, Callans DJ, et al. Contact electroanatomic mapping derived voltage criteria for characterizing left atrial scar in patients undergoing ablation for atrial fibrillation. J Cardiovasc Electrophysiol 2014;25:1044–52. https://doi.org/10.1111/jce.12452; PMID: 24832482. 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. https://doi.org/10.1161/ hc5001.100833; PMID: 11748102. Nery PB, Thornhill R, Nair GM, et al. Scar-based catheter ablation for persistent atrial fibrillation. Curr Opin Cardiol 2017;32:1–9. https://doi.org/10.1097/HCO.0000000000000349; PMID: 27875475.

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16. Saini A, Huizar JF, Tan A, et al. Scar homogenization in atrial fibrillation ablation: evolution and practice. J Atr Fibrillation 2017;10:1645. https://doi.org/10.4022/jafib.1645; PMID: 29250241. 17. Mohanty S, Mohanty P, Di Biase L, et al. Long-term followup of patients with paroxysmal atrial fibrillation and severe left atrial scarring: comparison between pulmonary vein antrum isolation only or pulmonary vein isolation combined with either scar homogenization or trigger ablation. Europace 2017;19:1790–7. https://doi.org/10.1093/europace/euw338; PMID: 28039211. 18. Santangeli P, Marchlinski FE, Techniques for the provocation, localization, and ablation of non-pulmonary vein triggers for atrial fibrillation. Heart Rhythm 2017;14:1087–96. https://doi. org/10.1016/j.hrthm.2017.02.030; PMID: 28259694. 19. Seitz J, Bars C, Theodore G, et al. AF ablation guided by spatiotemporal electrogram dispersion without pulmonary vein isolation: a wholly patient-tailored approach. J Am Coll Cardiol 2017;69:303–21. https://doi.org/10.1016/j. jacc.2016.10.065; PMID: 28104073. 20. Mastrine L, Greenberg YJ, Uang F, et al. Utilization of the PentaRay NAV catheter during atrial fibrillation ablations. EP Lab Digest 2014;14. Available at: https://www.eplabdigest. com/articles/Utilization-PentaRay-NAV-Catheter-During-AtrialFibrillation-Ablations (accessed 14 February 2019). 21. Lin Y, Yang B, Garcia FC, et al. Comparison of left atrial electrophysiologic abnormalities during sinus rhythm in patients with different type of atrial fibrillation. J Interv Card Electrophysiol 2014;39:57–67. https://doi.org/10.1007/s10840013-9838-y; PMID: 24113851. 22. Kircher S, Arya A, Altmann D, et al. Individually tailored vs. standardized substrate modification during radiofrequency catheter ablation for atrial fibrillation: a randomized study. Europace 2018;20:1766–75. https://doi.org/10.1093/europace/ eux310; PMID: 29177475. 23. Blandino A, Bianchi F, Grossi S, et al. Left atrial substrate modification targeting low-voltage areas for catheter ablation of atrial fibrillation: a systematic review and metaanalysis. Pacing Clin Electrophysiol 2017;40:199–212. https://doi. org/10.1111/pace.13015; PMID: 28054377. 24. Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation: executive summary. J Arrhythm 2017;33:369–409. https://doi. org/10.1016/j.joa.2017.08.001; PMID: 29021841. 25. Barbhayia CR, Kumar S, Michaud GF. Mapping atrial fibrillation: 2015 update. J Atr Fibrillation 2015;8:1227. https://doi. org/10.4022/jafib.1227; PMID: 27957220. 26. Nedios S, Sommer P, Bollmann A, et al. Advanced mapping systems to guide atrial fibrillation ablation: electrical information that matters. J Atr Fibrillation 2016;8:1337. https:// doi.org/ 10.4022/jafib.1337; PMID: 27909489. 27. Khaykin Y, Oosthuizen R, Zarnett L, et al. CARTO-guided vs. NavX-guided pulmonary vein antrum isolation and pulmonary vein antrum isolation performed without 3-D mapping: effect of the 3-D mapping system on procedure duration and fluoroscopy time. J Interv Card Electrophysiol 2011;30:233–40. https://doi.org/10.1007/s10840-010-9538-9; PMID: 21253840. 28. Ptaszek LM, Moon B, Rozen G, et al. Novel automated point collection software facilitates rapid, high-density electroanatomical mapping with multiple catheter types. J Cardiovasc Electrophysiol 2018;29:186–95. https://doi. org/10.1111/jce.13368; PMID: 29024200. 29. 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. https://doi.org/10.1161/01.CIR.95.6.1611; PMID: 9118532. 30. Estner HL, Deisenhofer I, Luik A, et al. Electrical isolation of pulmonary veins in patients with atrial fibrillation: reduction of fluoroscopy exposure and procedure duration by the use of a non-fluoroscopic navigation system (NavX). Europace

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High-resolution Mapping in Patients with Persistent AF using continuous sampling from a high-density basket (Orion™) catheter. J Cardiovasc Electrophysiol 2015;26:1153–4. https://doi.org/10.1111/jce.12685; PMID: 25867547. 46. Bollmann A, Hilbert S, John S, et al. Insights from preclinical ultra high-density electroanatomical sinus node mapping. Europace 2015;17:489–94. https://doi.org/10.1093/europace/ euu276; PMID: 25349222. 47. Hilbert S, Kosiuk J, John S, et al. A guide to the porcine

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anatomy for the interventional electrophysiologist. Fluoroscopy and high density electroanatomical mapping. J Cardiovasc Transl Res 2015;8:67–75. https://doi.org/10.1007/ s12265-015-9610-z; PMID: 25630688. 48. Karim N, Srinivasan N, Garcia J, et al. Early experience using the Advisor HD grid to map atrial fibrillation. EP Europace 2018;20(Suppl 4):iv33–4. https://doi.org/10.1093/europace/ euy205.015.

49. Otsubo T, Tsuchiya T, Yamaguchi T, et al. Left atrial low-voltage zone ablation of persistent atrial fibrillation in a patient with myotonic dystrophy: a case report. J Arrhythm 2018;34:302–4. https://doi.org/10.1002/joa3.12059; PMID: 29951149. 50. Berte B, Relan J, Sacher F, et al. Impact of electrode type on mapping of scar-related VT. J Cardiovasc Electrophysiol 2015;26:1213–23. https://doi.org/10.1111/jce.12761; PMID: 26198475.

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Electrophysiology and Ablation

Idiopathic Outflow Tract Ventricular Arrhythmia Ablation: Pearls and Pitfalls Jackson J Liang, Yasuhiro Shirai, Aung Lin and Sanjay Dixit Electrophysiology Section, Division of Cardiology, Hospital of the University of Pennsylvania, Philadelphia, PA, US

Abstract Idiopathic outflow tract ventricular arrhythmias (VAs) occur typically in patients without structural heart disease. They are often symptomatic and can sometimes lead to left ventricular systolic dysfunction. Both activation and pace mapping are utilised for successful ablation of these arrhythmias. Pace mapping is particularly helpful when the VA is infrequent and/or cannot be elucidated during the ablation procedure. VAs originating from different sites in the outflow tract region have distinct QRS patterns on the 12-lead ECG and careful analysis of the latter can help predict the site of origin of these arrhythmias. Successful ablation of these VAs requires understanding of the detailed anatomy of the OT region, which can be accomplished through electroanatomic mapping tools and intracardiac echocardiography.

Keywords Catheter ablation, idiopathic, ventricular premature depolarisation, premature ventricular contraction, outflow tract Disclosure: The authors have no conflicts of interest to declare. Received: 7 January 2019 Accepted: 20 March 2019 Citation: Arrhythmia & Electrophysiology Review 2019;8(2):116–21. DOI: https://doi.org/10.15420/aer.2019.6.2 Correspondence: Sanjay Dixit, Electrophysiology Section, Division of Cardiology, Hospital of the University of Pennsylvania, 9 Founders Pavilion, 3400 Spruce Street, Philadelphia, PA 19104, US. E: sanjay.dixit@uphs.upenn.edu Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Idiopathic ventricular arrhythmias (VAs) are comprised of ventricular premature depolarisations, non-sustained ventricular tachycardia (VT) and rarely sustained VT, and these typically occur in the absence of structural heart disease. In general, idiopathic VAs tend to have a benign prognosis, although a high burden of VAs can result in left ventricular (LV) systolic dysfunction and cardiomyopathy and, rarely, outflow tract (OT) VAs can serve as a trigger for idiopathic VF. The mechanism of these arrhythmias tends to be triggered activity or abnormal automaticity and this usually manifests as a focal source. The 12-lead ECG morphology of the VA is helpful in predicting the site of origin (SOO). Both activation and pace mapping are utilised in localising the SOO and successfully targeting it during catheter ablation. Idiopathic VAs tend to originate most commonly from the ventricular outflow tract (OT) region, but they can also arise from the His-Purkinje system, the papillary muscles, and other perivalvular locations. OT VAs can originate from the right and left ventricular outflow tracts (RVOT or LVOT), either above or below the pulmonic and aortic valves. They can also originate in the vicinity of the great cardiac vein and/or the anterior inter-ventricular vein, and the LV summit region. This review summarises electrocardiographic localisation of different OT VAs, our general approach to mapping and ablation of these VAs, and strategies for managing some challenging scenarios.

ECG Localisation of Outflow Tract Ventricular Arrhythmias Differentiating Site of Origin Analysing the 12-lead electrocardiogram morphology of the VA is the most important aspect of pre-procedural planning.1 Table 1 summarises characteristic patterns of VAs originating from different

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sites in the OT region. While all OT VAs will exhibit an inferior axis in the limb leads, the precordial leads are especially helpful in localising the precise SOO. Generally, OT VAs with right bundle branch block (RBBB) morphology (predominantly positive forces in lead V1) originate from the LVOT. Meanwhile, those with left bundle branch block (LBBB) morphology (predominantly negative forces in lead V1) can originate from either the RVOT or septal aspect of the LVOT. The precordial QRS transition can be helpful in differentiating between the two. OT VAs with LBBB and late precordial transition (V4 or later) are more likely to be successfully ablated from the RVOT, while those with early transition (V1 or V2) usually originate from the LVOT (above or below the aortic valve), or the LV summit. Frequently, OT VAs will exhibit a V3 precordial transition, and these VAs can originate from either the RVOT or LVOT. Calculating the V2 precordial transition ratio can help predict RVOT versus LVOT SOO for patients with OT VAs exhibiting V3 precordial transition. The V2 transition ratio is defined as [R/(R+S) during VA]/[R/(R+S) in sinus rhythm].2 A V2 transition ratio ≥0.6 predicts LVOT origin with >90% accuracy. While this methodology can accurately localise the SOO in the majority of cases, calculating the ratio can be tedious. A simpler and more practical approach is to compare the precordial transition of the VA versus the QRS transition during sinus rhythm. When the precordial QRS transition of the VA occurs later than QRS transition observed during sinus rhythm, the VA SOO is most likely to be from the RVOT and vice versa.2 Of note, the V2 transition ratio and/or the more simpler approach described above may not accurately predict VA SOO in patients with baseline conduction system disease such as underlying RBBB, LBBB, or left

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Idiopathic Outflow Tract Ventricular Arrhythmia Ablation Table 1: Electrocardiographic Morphology of Outflow Tract Ventricular Tachycardias Site of Origin

Lead V1

Precordial Transition

Lead I

Additional

≥V4

Site 1 + Site 2 +/− Site 3 −

Notching in inferior leads

V3 or V4

Site 1 + Site 2 +/− Site 3 −

Right coronary cusp

V2 or V3

+

Notching in downstroke of V1 suggests junction of RCC and LCC

Left ventricular summit

V2 or V3

− or +/−

Pattern break in V2 with more net negativity than V1 or V3

Left coronary cusp

+/−

+ throughout or V2

M or W configuration common in V1

Aortomitral continuity

qR

+ throughout

+/−

+

+ throughout

Septum + lateral −

RVOT free wall

Septal RVOT

Superior mitral annulus

All outflow tract ventricular tachycardias are positive in the inferior leads (II, III and aVF). + = positive. +/−; isoelectric or biphasic; − = negative; RVOT = right ventricular outflow tract. Adapted from: Liang et al. 2015.1 Used with permission from Springer Nature.

anterior fascicular block, as these patients were excluded or not well represented in the original study cohort.2 Another relatively simpler method to differentiate RVOT from LVOT SOO of VAs manifesting LBBB morphology and inferior axis is to calculate the V2S/V3R ratio during OT VA. Yoshida et al. showed that a V2S/V3R cutoff value of ≤1.5 predicted LVOT origin with 89% sensitivity and 94% specificity.3 Furthermore, for PVCs with LBBB and rightward inferior

Figure 1: Representation of the Right Ventricular Outflow Tract Free Wall and Septal Right Ventricular Outflow Tract RVOT free wall (RAO view) Site 3

Site 2 Site 1

I II III aVR aVL

axis (with R<S in leads I and V1), measuring the R wave amplitude in lead I can differentiate RVOT from LVOT SOO. For these patients, Xie et al. showed that the presence of R wave amplitude ≥0.1 mV in lead I predicted site of successful ablation from the aortic sinuses of Valsalva or LV endocardium with 75% sensitivity and 98.2% specificity.4

aVF V1

Right Ventricular Outflow Tract

V2

OT VAs can originate from the septal or free wall aspect of the RVOT beneath the pulmonic valve, or from above the pulmonic valve. Our group has previously reported typical ECG findings of OT VAs from different locations within the RVOT based on pace mapping in structurally normal hearts.5–7 Septal versus free wall RVOT site of origin can be distinguished based on QRS morphology. Leads II, III and aVF tend to be taller and narrower for septal compared versus free wall sites within the RVOT. Meanwhile, VAs originating from the free wall of the RVOT tend to manifest later precordial transition (≥V4) and more frequently exhibit notching of the QRS in the inferior leads.5

V3 V4 V5 V6

Septal RVOT (PA view) Site 3 Site 2 Site 1 I II III

The septal and free wall aspects of the subpulmonic RVOT can be further segmented into nine different anatomic sites (Figure 1).7 Sites 1–3 represent the most superior sites just beneath the pulmonic valve, with site 1 being most posterior and site 3 being most anterior. Sites 4–6 are just inferior to sites 1–3, while sites 7–9 are the most inferior sites and within close proximity to the bundle of His region (RV inflow tract). Lead I can be helpful in differentiating between the posterior (more rightward, positive QRS morphology in lead I) and anterior (more leftward, negative QRS morphology in lead I) sites in the superior RVOT (sites 1,2 and 3 in Figure 1). RVOT VAs are increasingly being recognised to originate from supravalvular myocardial extensions above the pulmonic valve.8–12 These VAs manifest similar ECG features as those arising from the

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aVR aVL aVF V1 V2 V3 V4 V5 V6 The right ventricular outflow tract (RVOT) is divided into nine sites. Sites 1, 4, and 7 are the posterior sites and 3, 6, and 9 are the anterior sites. The right side shows 12-lead electrocardiogram pace maps from sites 1–3 along the RVOT free wall (top, right) and septal RVOT (bottom, right). PA = posterior-anterior; PV = pulmonic valve; RAO = right anterior oblique; RVOT = right ventricular outflow tract; TV = tricuspid valve.

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Electrophysiology and Ablation Figure 2: 12-lead ECG Pace Maps from the Basal Left Ventricular Outflow Tract 2: 1: 3: Lateral Superior Superior 4: MA Lateral MA MA AMC I II III aVR aVL aVF V1 V2 V3 V4 V5 V6 12-lead ECG pace maps from the following sites in the basal left ventricular outflow tract. 1: Lateral mitral annulus (MA). 2: Superior lateral MA. 3: Superior MA. 4: Aortomitral continuity. AMC = aortomitral continuity; AV = aortic valve; MA = mitral annulus; MV = mitral valve.

Figure 3: 12-lead ECG Pace Maps from the Sinuses of Valsalva and Junction

RSV

R/L junction

LSV

I II III aVR aVL aVF V1 V2 V3 V4 V5 V6 12-lead ECG pace maps from the right and left sinuses of Valsalva and the junction between them. LSV = left sinus of Valsalva; NSV = noncoronary sinus of Valsalva; R/L = right/left; RSV = right sinus of Valsalva.

superior RVOT (beneath the pulmonic valve), although they tend to be more likely to have earlier QRS transition (V2 or V3), aVL/aVR Q wave ratio >1, Qs or rS pattern in lead I, and larger V2 R/S amplitude.12

Basal Left Ventricle, Left Ventricular Outflow Tract and Aortic Sinuses of Valsalva Our more contemporary experience shows that OT VAs are increasingly targeted from the basal LV, and the LVOT both above and below the aortic valve. The superior interventricular septum is comprised of the anterior aspect of the LVOT and the posterior aspect of the RVOT. The aortic valve sits slightly inferior to the pulmonic valve and is tilted rightward such that the anterior-most sinus of Valsalva (the right sinus of Valsalva; RSV) sits adjacent to the posterior septal aspect of the superior RVOT, while the commissure between the RSV and left sinus of Valsalva (LSV) are closer to the anterior septal aspect of the superior RVOT and the pulmonic valve. Supravalvular muscle sleeves extending above the LSV and RSV are common sites of OT VA origin.13 Furthermore, due to the anatomic proximity of the RSV and LSV to the LV summit region, these locations can be used as a vantage point for targeting OT VAs originating from the LV summit.

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VAs from the basal LV endocardium manifest a RBBB morphology with inferior axis, except for VAs from the high left interventricular septum which may manifest LBBB morphology with early precordial transition (≤V2). We have previously demonstrated distinct ECG features with pace mapping from the different sites such as aortomitral continuity (AMC), and superior, lateral, and superolateral mitral annular regions within the basal LV endocardium in patients with structurally normal hearts (Figure 2).14 Pace maps from the AMC region typically manifest a unique qR pattern in V1 with a predominantly positive QRS complex in lead I, while mitral annular sites typically will have monophasic R waves in V1 with either positive precordial concordance or very late S wave (≥V5).14 Pace mapping studies have clarified the typical QRS pattern of OT VAs originating from the aortic sinuses of Valsalva (Figure 3).15 OT VAs from the LSV manifest early precordial transition (V1 or V2) with multiphasic QRS complex with M or W patterns in V1. Meanwhile, those from the RSV tend to have LBBB with slightly later transition (V2 or V3). OT VAs from the RSV/LSV junction frequently exhibit a unique ECG pattern with a QS morphology in lead V1 with prominent notching of the downward deflection.16 Importantly, as patients age, the orientation between the LV and aortic root can alter and this can influence the QRS morphologies of OT VAs originating from the aortic sinuses of Valsalva. Specifically, older patients tend to manifest less positive forces in the inferior leads for VAs originating in the RSV because this region tends to shift more inferiorly with age.17

Left Ventricular Summit The LV summit refers to the triangular region of myocardium located at the most superior, septal and epicardial aspect of the LV (Figure 4). Idiopathic VAs are increasingly being recognised to originate from this location and this site is typically in close anatomic proximity to the epicardial coronary arteries which can be a challenge for ablating these arrhythmias. VAs originating from the LV summit typically manifest either RBBB pattern or LBBB pattern with early (V2 or V3) transition and inferior axis. LV summit VAs usually have Q wave in lead I, with lead III to lead II ratio >1.25 and QS amplitude ratio in leads aVL and aVR >1.75.18 LV summit arrhythmias can be targeted from a number of vantage points: • • • •

LV endocardium beneath the aortic valve; aortic sinus of Valsalva; septal RVOT; coronary venous system (great cardiac vein and/or anterior interventricular vein); and • direct epicardial approach. The latter can be performed in the EP laboratory (using the Sosa technique for epicardial access) or surgically. In rare instances, ablation of LV summit VAs has also been accomplished from the left atrial appendage.19 ECG characteristics can be helpful to predict the success of an epicardial ablation approach for LV summit VAs. VAs with larger maximal deflection index (≥0.55) and longer intrinsicoid deflect time (interval to peak R in V2) (>85 ms) are likely to have epicardial origin. Hayashi et al. described that the presence of a V2 pattern break (defined as abrupt loss of R wave amplitude in V2 versus V1 and V3) suggests SOO adjacent to the anterior interventricular groove, likely

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Idiopathic Outflow Tract Ventricular Arrhythmia Ablation within close proximity to the left anterior descending coronary artery.20 Lin et al. proposed using the aVL/aVR Q wave ratio for predicting the successful ablation site for LV summit VAs.21 In their study, an aVL/aVR ratio ≤1.415 was associated with successful ablation from the aortic sinuses of Valsalva, a ratio of 1.416–1.535 for successful ablation from the subvalvular LV, a ratio of 1.536–1.740 for successful ablation from the great cardiac vein/anterior inter-ventricular vein, while a ratio of >1.74 required direct epicardial ablation approach. In our experience, ECG predictors of successful ablation of LV summit VAs via a direct epicardial approach include aVL/aVR Q wave ratio >1.85, a V1 R/S ratio >2, and absence of Q waves in V1.22

Pearls and Pitfalls for Mapping and Ablation Since the underlying mechanism of idiopathic OT VAs is most frequently triggered activity and the source is focal, activation mapping is the most effective method of identifying the SOO. Typically, with good catheter–tissue contact, the local bipolar electrogram at the SOO should have a sharp component which precedes the QRS onset by ≥20 ms and the unipolar electrogram at this location should manifest a QS morphology with a sharp downward slope. The ideal approach is to perform dense sampling (5–10 locations) at and around the site manifesting early activation to localise the precise ablation target which should manifest on the electroanatomic map as a small (1–2 mm) focal red area. Importantly, when such mapping results in a diffuse area (≥3 mm) of early activity, the true SOO is likely to be from another location (adjacent chamber), and further detailed mapping should be performed at other locations prior to ablation. To accomplish successful ablation, multiple locations in more than one chamber may need to be mapped to determine the ideal target. The presence of frequent VAs at the time of the ablation procedure is an important predictor of success, as it allows for detailed activation mapping. Unfortunately, some patients, despite having high-burden VAs clinically, may have infrequent or no ventricular premature depolarisations at the time of the ablation procedure. To prevent this scenario, all beta-blockers, calcium channel blockers, and antiarrhythmic medications should be withdrawn, ideally for at least five half-lives prior to the procedure date. If amiodarone is being used to achieve arrhythmia control, then our practice is to hold this drug for at least 2 weeks in advance. Ablation should be performed with minimal anaesthesia if possible, as sedation frequently can suppress these VAs. We usually avoid using propofol and benzodiazepines for sedation during these procedure and instead use remifentanyl due to its ultra-short half-life.23 Frequently, with administration of even minimal sedation at the beginning of the case (i.e. for urinary catheter insertion or venous/arterial access), VAs may disappear completely. It is therefore vital that at least some examples of the clinical VA are captured on the recording system at the beginning of the case. Having this allows for pace mapping, which can be helpful to identify the SOO. We have found that automatic pace mapping algorithms, such as PASO (CARTO, Biosense Webster) and AutoMap Score Threshold (EnSite Precision™) can be helpful to facilitate pace mapping. However, in our experience, the pace mapping algorithms utilised by different electroanatomic mapping platforms are not completely reliable because they can show a high level of similarity (>90%) between the pace maps and the VA over a large area (5–10 mm). Stimulation protocols are often required for patients with rare or absent clinical VA on the day of the procedure. The choice of the stimulation protocol may be determined according to the patient’s

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Figure 4: CT Image Demonstrating the Anatomy of the Left Ventricular Summit I II III aVR aVL aVF V1 V2 V3 V4 V5 V6 The left ventricular summit (LVS) is a triangular region of the epicardial left ventricle. The apex of the triangle is formed by the bifurcation of the left anterior descending and left circumflex (LCx) arteries, while the base is formed by an arc connecting the first septal perforator branch with the LCx (white dotted line). The great cardiac vein bisects the LVS, separating it into two regions (blue and yellow dotted lines). The proximal portion (blue dotted lines) is less accessible for ablation due to the proximity of the coronary arteries as well as the presence of a thicker layer of epicardial fat. The right side depicts 12-lead ECG of typical morphology of ventricular ectopic beat originating from the LVS. Adapted from: Santangeli et al. 2015.22 Used with permission from Wolters Kluwer Health.

medical history, which may provide insights on the VA triggers. The most common triggers for these VAs are anxiety, exercise and caffeine, which imply catecholaminergic mediation and this is mimicked during the procedure by decrements in overdrive pacing (from the atria or ventricles) and/or by infusing isoproterenol, epinephrine, aminophylline, etc. Less commonly phenylephrine and calcium chloride can be effective in inducing VAs in the laboratory. Recognising diurnal variations in the occurrence of VAs can help guide the timing of the procedure. In addition, awareness of the strong influence that hormonal changes can have on OT VAs in women can be helpful in procedure planning.24 In rare cases, unusual stressors may need to be explored. For example, we have encountered occasional patients whose OT VAs would only manifest when they were asked to think about stressors (spouse, recent motor vehicle accident, etc). In some patients, sleep deprivation was a trigger and we asked them to stay up the night before the procedure and avoided any sedation during the ablation procedure. One patient who underwent ablation at our centre had a clinical history of VAs triggered with red wine and required consumption of red wine in the EP laboratory to bring out the clinical arrhythmia, which was then successfully targeted. For patients with rare or absent VAs despite the above interventions, pace mapping can be a helpful approach in identifying the ablation target. Pace mapping should be performed at or slightly above threshold output with cycle length which mimics the rate or coupling interval of the clinical VA. Ideally the pace map should be a perfect match (in all 12 ECG leads) of the VA. It is important to recognise that overall, pace mapping is inferior to activation mapping in identifying the ablation target for OT VAs.25 It is important that ablation guided by a pace mapping approach should be delivered to the site(s) that are perfect matches.26 Recent advances in electroanatomic mapping systems, including the PASO and Score

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Electrophysiology and Ablation Map modules, which automatically compare the morphology of the paced versus the clinical QRS morphology and calculate percentage match, can provide a quantitative assessment of pace map match. However, these algorithms are prone to overlooking subtle variations, such as the presence or absence of notches in different ECG leads between the VA and the pace map. Thus ideal pace mapping requires simultaneous comparison of the paced QRS complexes with clinical VA on the electroanatomic mapping system as well as the EP recording system. In our opinion, the latter is a better platform for a qualitative comparison, but it requires a trained electrophysiologist to perform the analysis. It is also important to recognise that the accuracy of pace mapping for accurately predicting the SOO of the clinical VA may be chamber dependent. For example, while pace mapping in the RVOT can accurately replicate the clinical VA, the same is not true when pace mapping from the aortic sinuses of Valsalva. In the latter case pacing at high outputs may be necessary to capture ventricular tissue and those pace maps may not correlate perfectly with the clinical VA originating from this region. Also, clinical VAs originating in the cusp region may manifest multiple exits or ‘preferential conduction’ and the pace maps are not always able to mimic this. Yamada et al. have reported that in 25% of patients with ASV VAs, pace maps from the RVOT were actually a closer match than from the ASV region.25

General Approach to Mapping and Ablation Intracardiac echocardiography is being increasingly used to guide ablation of OT VAs. In our experience the CARTOSOUNDTM module (CARTO, Biosense Webster) can be especially helpful since it allows for rapid creation of the anatomic shell of the LVOT, RVOT, aortic sinuses of Valsalva and coronary arteries. Once the anatomy of the entire region is created, the detailed electroanatomic mapping information acquired by catheter manipulation can be superimposed. For OT VAs with LBBB morphology and late precordial transition (≥ V4), catheter mapping in the RVOT region is typically performed first. A steerable sheath (i.e. Agilis sheath [Abbott]) can be helpful for mapping in the RVOT region. However, for OT VA manifesting LBBB morphology but with an early transition (≤V3), we will usually map the LVOT first or when an early site is not identified in the RVOT region. Our preferred approach for mapping LVOT VAs is the retrograde aortic approach (via femoral arterial access). Sheaths can be helpful to maintain catheter stability when accessing the LV via retrograde aortic approach. While we usually use a 23 cm or 45 cm sheath advanced to the descending aorta, in cases with aortic dilatation, aortic calcification or calcification of the aortic valve in patients in whom we wish to avoid repeated crossing of the aortic valve, a long sheath such as an 81 cm SL-1 (Abbott) or a 102 cm (82 cm usable length) Agilis sheath, advanced over an ablation catheter across the aortic valve, can be helpful. In cases where we suspect the focus to be deep intramural or at an inaccessible epicardial location (LV summit region), alternative strategies can be attempted, including using half normal saline as the catheter irrigant, simultaneous unipolar or bipolar ablation, coronary venous ethanol ablation, or ablation with an irrigated needle tip catheter.27–31

Challenging Situations QRS Morphology Shift During Ablation The myocardial network in the OT region is extremely complex, and the wavefront from the VA origin site can spread based on myofibre orientation, resulting in variable exit sites.26 As such, on some occasions, ablation at the site of earliest activation may result in

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change in QRS morphology and intracardiac activation pattern (often with initial transient suppression but late recurrence with different QRS morphology during the waiting period). In our experience, this phenomenon occurs in 4% of cases.32 In the majority (65%) of these cases, repeat mapping identified a new earliest site in the adjacent chamber within close proximity to the initial ablation site, while 35% of patients had the altered recurrent VA originating from the same chamber where the original VA was targeted. Regardless of the origin of the altered VA, repeat ablation of the new site was highly effective in achieving durable VA elimination.32

Ablation of Outflow Tract Ventricular Arrhythmias with Earliest Activation from the Coronary Venous System When the earliest activation site of OT VA is recorded within the coronary venous system, ablation can be challenging and different ablation strategies should be considered. We have previously reported outcomes of ablation of VAs from the coronary venous system demonstrating that ablation delivery at the earliest activation site, although effective, is precluded in the majority (62%) of cases due to anatomic constraints (inability to advance ablation catheter and proximity to coronary arteries).33 In these scenarios we have successfully utilised the strategy of getting as close as possible to the SOO from adjacent locations such as the basal LV endocardium, cusp region and/or the septal RVOT. We recently reported the outcome of this strategy in 53 consecutive patients where the earliest activation site was localised to the coronary venous system.34 We were able to successfully target the clinical VA from adjacent locations in nearly half of these cases. We found that the anatomical distance between the coronary venous system site and the adjacent ablation site to be the only factor in predicting success. A cut-off distance >12.8 mm between the SOO and the ablation site strongly predicted failure. In those cases alternative ablation strategy such as simultaneous unipolar or bipolar ablation from two anatomically adjacent sites, half-normal saline use or retrograde coronary venous ethanol infusion may be considered.

Conclusion Catheter ablation is a safe and effective treatment option for patients with OT VAs. The 12-lead ECG of the clinical VA is the most important piece of information for procedural preparation. Ablation success rates are highest when VA is spontaneous or inducible at the time of procedure, which allows for detailed activation mapping. While OT VAs with SOO that are intramural or adjacent to coronary arteries can be challenging to treat, different strategies can be attempted to overcome these difficulties. Use of intracardiac echocardiography has enhanced our ability to map and successfully target the vast majority of OT VAs.

Clinical Perspective • Catheter ablation is a safe and effective treatment option for outflow tract (OT) ventricular arrhythmias (VAs). • The 12-lead ECG is critical in accurately predicting the site of origin of OT VAs. • Ablation success rates are highest when VA is spontaneously seen or reproducibly induced at the time of procedure, which allows for both activation and pace mapping. • Ablation of OT VAs can be sometimes challenging due to anatomic constraints. Different strategies can be utilised to overcome these difficulties.

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Idiopathic Outflow Tract Ventricular Arrhythmia Ablation 1.

L iang JJ, Han Y, Frankel DS. Ablation of outflow tract ventricular tachycardia. Curr Treat Options Cardio Med 2015;17:363. https://doi.org/10.1007/s11936-014-0363-9; PMID: 25665821. 2. Betensky BP, Park RE, Marchlinski FE, et al. The V(2) transition ratio: a new electrocardiographic criterion for distinguishing left from right ventricular outflow tract tachycardia origin. J Am Coll Cardiol 2011;57:2255–62. https://doi.org/10.1016/ j.jacc.2011.01.035; PMID: 21616286. 3. Yoshida N, Yamada T, McElderry HT, et al. A novel electrocardiographic criterion for differentiating a left from right ventricular outflow tract tachycardia origin: the V2S/ V3R Index. J Cardiovasc Electrophysiol 2014;25:747–53. https://doi. org/10.1111/jce.12392; PMID: 24612087. 4. Xie S, Kubala M, Liang JJ, et al. Lead I R-wave amplitude to differentiate idiopathic ventricular arrhythmias with left bundle branch block right inferior axis originating from the left versus right ventricular outflow tract. J Cardiovasc Electrophysiol 2018;29:1515–22. https://doi.org/10.1111/ jce.13747; PMID: 30230106. 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;14:1–7. https://doi. org/10.1046/j.1540-8167.2003.02404.x; PMID: 12625602. 6. Movsowitz C, Schwartzman D, Callans DJ, et al. Idiopathic right ventricular outflow tract tachycardia: narrowing the anatomic location for successful ablation. Am Heart J 1996;131:930–6. PMID: 8615312. 7. Jadonath RL, Schwartzman DS, Preminger MW, et al. Utility of the 12-lead electrocardiogram in localizing the origin of right ventricular outflow tract tachycardia. Am Heart J 1995;130:1107–13. PMID: 7484743. 8. Liao Z, Zhan X, Wu S, et al. Idiopathic ventricular arrhythmias originating from the pulmonary sinus cusp: Prevalence, electrocardiographic/electrophysiological characteristics, and catheter ablation. J Am Coll Cardiol 2015;66:2633–44. https://doi. org/10.1016/j.jacc.2015.09.094; PMID: 26670064. 9. Hasdemir CAN, Aktas S, Govsa F, et al. Demonstration of ventricular myocardial extensions into the pulmonary artery and aorta beyond the ventriculo-arterial junction. Pacing Clin Electrophysiol 2007;30:534–9. https://doi.org/10.1111/j.15408159.2007.00704.x; PMID: 17437578. 10. Liu CF, Cheung JW, Thomas G, et al. Ubiquitous myocardial extensions into the pulmonary artery demonstrated by integrated intracardiac echocardiography and electroanatomic mapping: Changing the paradigm of idiopathic right ventricular outflow tract arrhythmias. Circ Arrhythm Electrophysiol 2014;7:691–700. https://doi.org/10.1161/ CIRCEP.113.001347; PMID: 24917663. 11. Tada H, Tadokoro K, Miyaji K, et al. Idiopathic ventricular arrhythmias arising from the pulmonary artery: prevalence, characteristics, and topography of the arrhythmia origin. Heart Rhythm 2008;5:419–26. https://doi.org/10.1016/ j.hrthm.2007.12.021; PMID: 18313601. 12. Sekiguchi Y, Aonuma K, Takahashi A, et al. Electrocardiographic and electrophysiologic characteristics

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Electrophysiology & Ablation

Acquired Long QT Syndrome and Electrophysiology of Torsade de Pointes Nabil El-Sherif, 1,2 Gioia Turitto 4 and Mohamed Boutjdir 1,2,3 1. SUNY Downstate Medical Center, NY, US; 2. VA NY Harbor Healthcare System, NY, US; 3. NYU School of Medicine, New York, NY, US; 4. Weill Cornell Medical College, NewYork-Presbyterian Brooklyn Methodist Hospital, NY, US

Abstract Congenital long QT syndrome (LQTS) has been the most investigated cardiac ion channelopathy. Although congenital LQTS remains the domain of cardiologists, cardiac electrophysiologists and specialised centres, the much more frequently acquired LQTS is the domain of physicians and other members of healthcare teams required to make therapeutic decisions. This paper reviews the electrophysiological mechanisms of acquired LQTS, its ECG characteristics, clinical presentation, and management. The paper concludes with a comprehensive review of the electrophysiological mechanisms of torsade de pointes.

Keywords Long QT syndrome, torsade de pointes, electrophysiology Disclosure: The authors have no conflicts of interest to declare. Acknowledgement(s): Supported in part by Cardiovascular Research Program, the Narrows Institute for Biomedical Research and Education, and a MERIT Award Number I01 BX002137 from the Biomedical Laboratory Research & Development Service of the Veterans Affairs Office of Research and Development. Received: 28 November 2018 Accepted: 4 April 2019 Citation: Arrhythmia & Electrophysiology Review 2019;8(2):122–30. DOI: https://doi.org/10.15420.2019.8.3 Correspondence: Nabil El-Sherif, VA NY Harbor Healthcare System, 800 Poly Place, 10th Floor, Brooklyn, NY 11209, US. E: nelsherif@aol.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Since its initial description by Jervell and Lange-Nielsen in 1957,1 congenital long QT syndrome (LQTS) has been the most investigated cardiac ion channelopathy. A prolonged QT interval on the surface ECG is a surrogate measure of prolonged ventricular action potential duration (APD). Congenital as well as acquired alterations in certain cardiac ion channels can affect their currents in such a way as to increase the APD and hence the QT interval. The inhomogeneous lengthening of the APD across the ventricular wall results in dispersion of APD, i.e. dispersion of repolarisation (DR). This, together with the tendency of prolonged APD to be associated with oscillations at the plateau level, termed early afterdepolarisations (EADs), provides the substrate of ventricular tachyarrhythmia (VT) associated with LQTS, usually referred to as torsade de pointes (TdP) VT.2

3 beats (the definition of non-sustained VT) up to 117 beats (Figure 1A), with an average length of 16 ± 8 beats.2 The cycle length (CL) of these episodes ranged from 193 to 364 ms, with an average of 279 ± 47 ms. The VT was frequently preceded by a variable period of bigeminal rhythm due to one or two premature ventricular beats coupled to the prolonged QT segment of the preceding basic beat (Figure 1A and C). This ‘short-long cardiac sequence’ is seen in both acquired and congenital LQTS, and the arrhythmogenic mechanism may be related to increased dispersion of repolarisation (DR).6

Acquired LQTS is by far, more prevalent than congenital LQTS. The vast majority of acquired LQTS is the result of the adverse effect of drugs3 and/or electrolyte abnormalities,4 which, in the majority of cases, interact with the human ether-à-go-go-related gene (hERG) encoding the pore-forming subunits (Kv11.1) of the rapidly activating delayed rectifier current, IKr. However, recent reports suggest that some drugs can also increase the late sodium current, which may contribute to their proarrhythmic effect.5

Following termination of an episode of fast VT, it is not uncommon to see one or more ectopic beats of variable configuration occurring at much longer CL compared to that of the VT (see beats marked by arrowheads in Figure 2). The change in QRS configuration during VT can take several forms. During a very fast VT, periodic decrease in the amplitude of the entire QRS-T complex is seen with less distinct shifts in QRS axis (Figure 1A). In VTs with slower rates, the classic twisting of the QRS axis from a predominantly positive to a predominantly negative configuration with a variable number of transitional complexes and vice versa is commonly seen as originally described by Dessertenne (Figure 1B).7 Sometimes, a polymorphic QRS configuration is seen without any of the two previously characteristic patterns (as verified in multiple simultaneous leads, Figure 2C, middle recording). Different patterns can be seen in different VT episodes from the same patient (Figure 1C).

Acquired Long QT Syndrome

QT/T Wave Alternans and Torsade de Pointes

ECG Characteristics of Torsade de Pointes

It has long been known that tachycardia-dependent T wave alternans (TWA) occurs in patients with the congenital or acquired form of LQTS and may presage the onset of TdP (Figure 2).2,8

In an analysis of 150 different episodes of sustained VT obtained from 62 patients with acquired LQTS, the arrhythmia ranged in length from

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Acquired Long QT Syndrome In an analysis of 1,103 LQTS patients with QTc interval >0.44 seconds from the International LQTS Registry, TWA was recorded in 30 patients.8 The frequency of occurrence of TWA was directly proportional to the length of the QTc interval on the enrolment ECG. TWA occurred in one or more occasions during an average 4-year follow­up in 21% of patients with QTc >0.60 seconds, but in <0.2% of patients with QTc <0.50 seconds. Patients with advanced forms of TWA (those with bidirectional beat-to­beat changes in T wave polarity; n=21) were younger, had longer QTc values, had a higher incidence of complex VT, and were more likely to experience a cardiac event (syncope or cardiac arrest) than those with less advanced forms of TWA (those without bidirectional beat-to-beat changes in T wave polarity; n=9). In contrast to TWA in congenital LQTS, the incidence of TWA in acquired LQTS is unknown. It has been reported in acquired LQTS due to hypokalaemia and hypomagnesemia (Figure 3)4 as well as in association with medications that prolong the QT interval (Figure 3).9 Patients with acquired LQTS and TWA are likely to develop TdP (Figures 2 and 3). Although overt TWA in the ECG is not common, in recent years, digital signal processing techniques have made it possible to detect subtle degrees of TWA.10 This suggests that the phenomenon may be more prevalent than previously recognised and may represent an important marker of vulnerability to VT. A recent report confirms this view, showing that microvolt TWA is far more prevalent in LQTS patients than previously reported and is strongly associated with TdP history.11 Interest in TWA is attributed to the hypothesis that it reflects a greater degree of underlying DR.12

Aetiology of Acquired Long QT Syndrome The vast majority of acquired LQTS is the result of adverse effects of drugs that interact with the hERG gene, and the IKr. However, although most drugs that cause TdP do so via hERG channel blockade, TdP is not necessarily a potential consequence of all drugs blocking the hERG pathway. Milberg et al.13 compared the TdP induction ability of two hERGblocking drugs, DL-sotalol and amiodarone. While both drugs can increase the QT interval, the former causes transmural DR and triangulation of the action potential by prolonging phase 3, and triggers both EADs and TdP. However, amiodarone does not usually cause DR, EADs, or TdP, and prolonging phase 2 results in a squared-shaped action potential. While squared-shaped action potentials are considered antiarrhythmic, triangulated action potentials are considered proarrhythmic.14 Several authors have suggested that DR, attributed to preferential prolongation of the APD of M cells, is a preclinical marker of drug-induced proarrhythmia.15 However, the existence, location, and clinical contribution of M cells has been a matter of debate.16 Recent studies have shown that some drugs designated as arrhythmogenic IKr blocker can generate arrhythmias by augmenting INa-L through the PI3K pathway.5 For example, while acute exposure of flecainide to adult mouse cardiomyocyte that lack IKr produced no change in ion currents and action potential duration, extended exposure up to 48 hours of the drug generated up to a 15-fold increase in INa-L and resulted in arrythmogenic EADs. However, not all IKr blockers modulate INa-L, and this diversity of effects, in return, may contribute to the apparent difference in TdP frequency across culprit drugs.5 A major implication of this data has to be that relying on an assay to assesses acute block of IKr may not provide a comprehensive assessment of a candidate drug arrhythmogenic potential.

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Figure 1: Electrocardiographic Examples of Acquired Long QT Syndrome (LQTS) and Torsade de Pointes (TdP) A II 1 sec

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A: 23-year-old woman, human immunodeficiency virus (HIV)-positive, receiving pentamidine. The patient was admitted with severe diarrhoea and hypokalaemia. B: 62-year-old man with hypertension and chronic atrial fibrillation, receiving digoxin and hydrochlorothiazide, with a potassium level of 3.2 mEq/L. TdP tachycardia developed 12 hours after the patient received a total of four tablets of quinidine gluconate in an attempt to restore normal sinus rhythm. C: 64-year-old man receiving procainamide for suppression of very frequent ventricular premature complexes. NB: Pentamidine, quinidine and procainamide are considered drugs with high risk of drug-induced acquired QT syndrome. Their use is currently curtailed. Source: El-Sherif N, et al. 1999.2 Reproduced with permission from © Wiley Periodicals, Inc.

Antidepressant and antipsychotic drugs modulate the cardiac APD by blocking a variety of cardiac ion channels. 17 Some antidepressant and antipsychotic drugs increase the risk of VT and SCD by prolonging the QT interval and inducing TdP arrhythmia. Other antidepressant and antipsychotic drugs increase arrhythmic risk by inducing a Brugada syndrome phenotype. Antipsychotic drugs generally have a higher torsadogenic potential than antidepressants. Based on recent literature, the risk of QT/QTc prolongation with newer nonSSRI antidepressants at therapeutic doses is low. 18 Other causes of acquired LQTS include electrolyte abnormalities (hypokalaemia, hypomagnesaemia, and hypocalcaemia [Figure 3]), hypothyroidism, hypothermia, and marked bradycardia, (sinus bradycardia as in Figure 4, or atrioventricular block).19 Any of these factors can cause acquired LQTS or contribute to the risk of drug-induced LQTS. In addition, there is recent evidence of the high prevalence of QTc interval prolongation in patients with anti-SSA/Ro antibodies, as well as autoimmune and inflammatory diseases. 20–22 Several recent reports from this laboratory have provided strong evidence for a pathogenic role of autoimmune and inflammatory conditions in the development of QTc prolongation. Anti-Ro antibodies from patients with autoimmune disease were shown to inhibit IKr by directly cross-reacting with the hERG channel, likely at the pore region where homology between 52Ro antigen and hERG channel was demonstrated.23 In addition, an animal model of autoimmuneassociated QTc prolongation was established, for the first time,

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Electrophysiology & Ablation Figure 2: Twelve-lead ECG from a Patient with Hypokalaemia and Hypomagnesaemia

(IKr, Ito, or the slow activating components of the delayed K+ current [IKs]) and/or an increase of ICaL.24,25

A

In another report,26 we tested the hypothesis that IL-6 may cause QT prolongation by suppressing IKr. Electrophysiological and biochemical assays were used to assess the impact of IL-6 on the functional expression of IKr in HEK293 cells and adult guinea-pig ventricular myocytes. In HEK293 cells, IL-6 alone or in combination with the soluble IL-6 receptor (IL-6R), produced a significant depression of IKr peak and tail current densities. Block of IL-6R or Janus kinase (JAK) reversed the inhibitory effects of IL-6 on IKr. In adult guineapig ventricular myocytes, IL-6 prolonged APD, which was further prolonged in the presence of IL-6R. Similar to heterologous cells, IL-6 reduced endogenous guinea-pig ERG channel mRNA and protein expression. The data are first to demonstrate that IL-6 inhibition of IKr and the resulting prolongation of APD is mediated via IL-6R and JAK pathway activation and forms the basis for the observed clinical QT interval prolongation. In summary, cardiac or systemic inflammation promotes QTc-interval prolongation via cytokine-mediated effects and this may increase SCD risk.

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A: Marked QTU prolongation and QTU alternans (arrowheads). B–D: Representative rhythm strips from the same patient showing tachycardia-dependent QTU alternans and torsade de pointes. Source: El-Sherif N, et al. 2011.4 Reproduced with permission from © Via Medica.

Figure 3: Efavirenz-associated QT Prolongation and Torsade de Pointes Arrhythmia A

B

C Representative ECG recordings from a 63-year old woman with HIV who developed efavirenz-related QT prolongation and torsade de pointes arrhythmia. A: Sinus rhythm at 95 bpm and QT alternans. B: Sinus bradycardia, marked QT interval prolongation and onset of a TdP arrhythmia that required cardioversion for termination. C: The arrhythmia could be suppressed by overdrive ventricular pacing at a rate of 100 bpm. QT prolongation and non-sustained TdP episodes developed when the pacing rate was lowered to <100 bpm. QT returned to normal several days after discontinuation of the long-acting efavirenz. Source: Castillo R, et al. 2002.9 Reproduced with permission from © SAGE Publications.

whereby induction of anti-SSA/Ro antibodies by immunisation resulted in QTc prolongation on the surface ECG.23 Conversely, inflammatory channelopathies are related to systemically or locally released inflammatory cytokines (mainly TNF-a, interleukin-1, and interleukin-6) able to directly affect the expression and/or function of several cardiac ion channels, resulting in a decrease of K+ currents

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A single channelopathy per se is not able in most cases to induce symptoms, and rarely even the related clinical phenotype.25 This is well demonstrated for inherited forms, including LQTS, Brugada syndrome, and catecholamine polymorphic VT, where provocative tests can unmask latent genetic defects. Consistent data are also available for drug-induced, autoimmune and inflammatory/feverinduced channelopathies. Indeed, only a small proportion of the large number of exposed subjects develops drug-induced LQTS-related arrhythmias, despite the resulting channel dysfunction. Similarly, cytokines, and anti-ion channel autoimmune antibodies induce cardiac channelopathy and QTc prolongation. However, inflammatory, and autoimmune-induced phenotypes and arrhythmias occur only in a fraction of the subjects at risk. Such evidence strongly suggests that multiple, often-redundant ion channel mechanisms are implicated in preserving normal AP genesis, thus rendering the clinical phenotype unapparent, despite subtle channel dysfunction. Therefore, more than one single component needs to be impaired for ECG/clinical symptoms to emerge, and the number of required hits will depend on the functional impact of each single offending factor. In a single patient, multiple QT-prolonging factors are concomitantly required to significantly disrupt repolarisation. Accordingly, patients developing marked QTc prolongation and TdP concomitantly present multiple risk factors. In a recent analysis, 18 of 40 consecutive unselected patients with TdP, an average of more than four factors per subject were detectable (electrolyte imbalances, cardiac and extracardiac diseases, drugs, anti-Ro/SSA antibodies, and inflammation), with a high prevalence of acquired channelopathies.24,25

Pharmacogenetics of Acquired Long QT Sydrome The susceptibility to acquired QT interval prolongation can be influenced by genetic variations.27 This is supported by the fact that the heritability of QT interval duration in the general population (excluding congenital LQTS patients) is estimated to be around 35%.28,29 Further, first-degree relatives of patients with congenital LQTS have a higher risk of drug-induced QT prolongation than nonrelated individuals.30 In genome-wide association studies (GWAS), a large number of genes associated with QT interval duration has been identified.31 The gene with the strongest signal related to QT

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Acquired Long QT Syndrome interval duration is the nitric oxide synthase 1 adaptor protein gene (NOS1AP), located on chromosome 1 (1q23.3),31,32 which inhibits L-type calcium channel and influences impulse propagation.33 Other findings from GWAS included polymorphisms within genes known to be mutated in congenital LQTS, genes associated with intracellular calcium handling, as well as genes previously not known to influence cardiac repolarisation.34 A recent study that compared 188 patients with drug-induced LQTS and more than 1000 patients with congenital LQTS found disease-causing mutations in 28% of patients with druginduced LQTS.35 Of interest, under basal conditions, the QTc of druginduced LQTS patients (453 ± 39 ms) was significantly longer than that of control subjects (406 ± 26 ms).35

Figure 4: Correlation Between Specific Molecular Changes of Na Channel in Canine Surrogate Model of Long QT Syndrome Type 3, Electrophysiological Consequence, and Final Phenotype Presentation of Long QT Syndrome and Torsade de Pointes A

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It is important to consider pharmacogenetics of drug-induced LQTS as related to both pharmacokinetic and pharmacodynamic properties.27,34 Pharmacokinetics constitute the effect of the body on the drug, which is usually categorised into effect on absorption, distribution, metabolism, and elimination of the drug. Pharmacokinetic genetic susceptibility is mainly characterised by variation in genes encoding drug-metabolising cytochrome P450 or drug transporter like the P-glycoprotein. However, the pharmacodynamics component of genetic susceptibility is mainly characterised by genes known to be associated with QT prolongation in the general population and genes in which the causal mutations of congenital LQTS are located.35

Incidence of Drug-induced Long QT Syndrome The overall incidence of drug-induced LQTS in a given population is difficult to estimate. One study estimated that between 5% and 7% of reports of VT, VF, or SCD were in fact drug-induced LQTS and TdP.36 European pharmacovigilance centres in Sweden, Germany and Italy have found an annual reporting rate of drug-induced LQTS or TdP of approximately 0.8 to 1.2 per million person-years36 An epidemiological study of drug-induced LQTS in Germany found the reporting rate for symptomatic acquired LQTS to be 2.5% per million person-years for men and 4.0% per million person-years for women, with 60% attributed to drugs.37 QT prolongation is one of the most common reasons for drug withdrawal from the market, despite the fact that these drugs may be beneficial for certain patients and not harmful in every patient.34 Since 1989, 14 clinically important drugs have been removed from the market due to TdP,38 and development of an unknown number has been stopped, due to concerns that these might pose a risk of causing QT prolongation and TdP.38 In the 1990s, the US Food and Drug Administration (FDA) and the European Medicine Agency (EMA) began requiring routine preclinical and clinical testing to determine whether drugs have the potential to cause QT prolongation.39 Today, according to the CredibleMeds website, which has become the standard reference for drug-induced TdP, 38 marketed drugs are recognised for their potential to cause TdP and another 72 to cause QT prolongation.40 In the past decade, hERG channel-mediated cardiac toxicity, manifested as QT interval prolongation, has become a major safety issue in drug development, superseding liver injury as the main cause of drug withdrawals. In vitro electrophysiological testing of the drug’s effects on the function of the hERG channel may be cheaper, faster, and potentially more sensitive than other current surrogates for TdP risk, such as in vivo QT prolongation and action potential prolongation in cardiomyocytes.41

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M END 500 ms A: Cell-attached patch clamp recordings of the Na channel during control and following superfusion with sea anemone toxin ATXII. This neurotoxin faithfully reproduces the molecular changes associated with the clinical mutations of the Na channel in patients with LQT3. Sequential recordings of single Na channel current responses during depolarising steps from -120 to -20 mV from rabbit cardiomyocytes. Left panel shows control recordings and right panel shows recordings from a patch exposed to 100 nM of ATXII that resulted in long-lasting bursts consisting of repetitive long opening interrupted by brief closures. Ensemble current from this patch shows markedly slowed relaxation. B: Action potential recordings from a Purkinje fibre (PF) and a mid-myocardial (M) cell, both isolated from a 10-week-old puppy and placed in the same chamber perfused with 50 mg/l anthopleurin-A (AP-A) and stimulated at 3000 ms. The PF shows a series of early afterdepolarisations (EADs) that increased gradually in amplitude before final repolarisation. C: Simultaneous recordings from a subepicardial cell (EPI), M cell and a subendocardial cell (END) from a transmural strip isolated from the left ventricle of a 12-week-old puppy and transfused with 50 mg/l AP-A and stimulated at 4000 ms. Because of the different ionic characteristics of different myocardial fibres, AP-A resulted in marked differential prolongation of the action potential of the M cell resulting in asynchronous activation in the preparation, which is a substrate of reentrant excitation. D: Tridimensional activation maps of a 12-beat run of TdP from the in vivo canine surrogate AP-A model of LQT3 helps summarise the final electrophysiological mechanism of TdP in the LQTS. The first beat of a TdP is due to an EAD-triggered beat from the subendocardial Purkinje network that acts on the transmural dispersion of myocardial repolarisation to induce reentrant excitation in the form of circulating tridimensional wave fronts (the thick continuous line that traces the activation wave front from one beat to the next).14 The twisting QRS pattern of the classic TdP is attributed in this example to transient bifurcation of a predominantly single rotating wavefront into two separate simultaneous wave fronts rotating around the left and right ventricular cavities.15 Source: Sherif N, et al., 2015.67 Reproduced with permission from © 2015 Published by Elsevier Inc.

Ethnicity and Gender Differences in Drug-induced Long QT Syndrome As ethnic differences ultimately reflect genetic variation, it is useful to study ethnicity with regard to susceptibility to drug-induced QT interval prolongation and TdP. However, the role of ethnic differences has not been well established in published studies on drug-induced QT interval prolongation. In 20 QT/QTc studies, only 10% of the total study population was African-American and only 7% was Asian.42 Nevertheless, the frequency of polymorphisms in genes known from congenital LQTS showed varying distribution among ethnic groups.43 African-Americans had the highest risk of prolonged QT interval after acute overdose of QT-prolonging drugs, while Hispanics had the lowest risk compared to all other ethnic groups.44 Females with inherited LQTS demonstrate pronounced gender difference in cardiac repolarisation and arrhythmic risk. Adult women with LQT1 and LQT2 have longer QT intervals, a more pronounced transmural QT dispersion, and a higher risk of TdP and SCD than men.45,46 Interestingly, in female patients with LQT2, the arrhythmogenic risk remains elevated after menopause, suggesting that other genderrelated factors besides sex hormones may contribute to gender difference in arrhythmogenesis.47

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Electrophysiology & Ablation Gender is a risk factor for adverse drug reactions.48,49 The concept of reduced repolarisation reserve in females compared to males has been used to explain sex differences in arrhythmia risk in acquired LQTS.50 The reduced repolarisation reserve of the female heart is attributed to lower repolarising K+ currents. This difference was thought to be primarily due to testosterone-mediated increase in IKr and IK1 resulting in shorter APD and QTc interval in male hearts. However, in a recent review, the effects of sex hormones go well beyond their modulation of K+ currents.51 The underlying mechanisms can be summarised as follows:52 an estradiol-induced decrease in Ikr as well as increase of ICaL, NCX expression and activity, RyR2 leakiness, Ca2+ transient amplitude, and a1- and b2-adrenoreceptor responsiveness; a testosterone-induced increase in Ikr, Iks, and Ik1, increased SERCA activity, and shortened Ca2+ transient; and a progesterone-induced increase in Iks, increased CERCA expression and activity, and increased ICA-L current sensitivities with reduced Ca2+ oscillations upon sympathetic stimulation. In a recent study, we have shown that modulation of voltage-Ca2+ uncoupling53 may provide one more attractive electrophysiological mechanism for the increased vulnerability of female to drug-induced LQTS.

Acute and Long-term Management of Acquired Long QT Syndrome The American College of Cardiology (ACC), American Heart Association (AHA), and European Society of Cardiology (ESC) published guidelines for management of ventricular arrhythmias, including drug-induced TdP,54 in 2006 and the key recommendations have been endorsed in a more recent ACC/AHA statement.55 When monitoring for drug-induced prolonged QT interval, a baseline QTc should be obtained. If any one of the following conditions are observed during QT interval monitoring the patient should be admitted to the hospital for telemetry: QTc >500 ms; QTc increase >60 ms above baseline; QT prolongation accompanied by syncope; any evidence of ECG instability, specially TWA, AV block, QRS widening, or ventricular ectopy. The offending drug should be discontinued, electrolyte abnormalities corrected, and a defibrillator placed at bedside.55 Non self-terminating TdP with hemodynamic collapse should obviously be cardioverted with adequate post-cardioversion management. More typical TdP occurs as recurrent self-terminating episodes. In these cases, the first line of management is intravenous administration of magnesium sulphate as a single 2 g (8 mmol) dose over 1â&#x20AC;&#x201C;2 minutes followed by a second dose if necessary. Magnesium sulphate is effective in suppressing TdP without reducing the QT interval.56 The mechanism of action may be related to suppression of late calcium influx via L-type calcium current and reduction in the amplitude of EADs.57 If magnesium sulphate fails to suppress TdP, the next step is to increase the heart rate, typically by transvenous pacing. In the interim if necessary, isoproterenol administration could promptly increase the heart rate while waiting for insertion of pacing electrode. Increasing the heart rate is associated with shortening of the QT interval and suppression of TdP. At the same time, the culprit drug should be discontinued and acid-base and electrolytes should be corrected as necessary. There are novel experimental drugs that can enhance the delayed rectifier conductance 52 or activate the cardiac ATP-sensitive potassium channel,58 which may have future value for the treatment of acquired LQTS.

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Long-term management of acquired LQTS is important. All patients with previous drug-induced prolongation of the QT interval should be instructed about the importance of subsequent avoidance of QT-prolonging drugs and should have a list of QT-prolonging medications provided by their physicians. In patients with acquired LQTS, the risk of further episodes of TdP is reduced once the culprit drug is removed and other aggravating situations as electrolyte abnormalities or marked bradycardia are corrected. This should result in normalisation of the QTc interval. If it does not, the patient and symptomatic first-degree family members should be considered for genetic testing for the presence of LQTS-associated mutations.55,59 This is especially important for relatives of patients with drug-induced case fatality.

Comprehensive Electrophysiological Mechanisms of Torsade de Pointes Experimental Models of Long QT Syndrome Both drug-induced and genetically modified animal models of various species have been generated and utilised to investigate the electrophysiological mechanisms of arrhythmogenesis in LQTS and potential pro- and antiarrhythmic agents. However, due to species differences in features of cardiac electrical function, particularly in repolarisation currents, these models do not completely recapitulate all aspects of the electrophysiology of the human disease. Genetically modified animal models, such as mice and rabbit are commonly used to investigate the arrhythmogenicity of LQTS. Current transgenic LQTS rabbit models have already been instrumental to increasing our understanding of the role of spatial and temporal dispersion of repolarisation to provide an arrhythmogenic substrate, genotype differences in the mechanisms for EAD formation and arrhythmia maintenance, and mechanisms of hormonal modification of arrhythmogenesis.60 In contrast, two dog model of LQTS and TdP have been extensively investigated. One model is the dog with induced complete atrioventricular conduction block (AVB). Complete AVB results within few weeks in hypertrophy and remodelling of the left ventricle associated with prolongation of the QT interval, APD, as well as spatial DR.61 When the animal is challenged with a drug that blocks the IKr, like dofetilide, it results in further prolongation of the QT interval and creation of a drug-induced model of acquired LQTS and TdP.62 The other dog model of LQTS and TdP is the Anthopleurin-A (AP-A) canine surrogate model of LQT3 that was developed in this laboratory.63 The model is created by the neurotoxin anthopleurin-A or ATX2.64 that faithfully reproduces the molecular changes associated with clinical mutations of the Na channel in patients with LQT3.65 Of interest, the experimental surrogate model of LQT3 anticipated the first description of the clinical LQT37 by 7 years.66 Figure 4 is a representative composite of the salient experimental techniques that were utilised to investigate the model and illustrate the correlation between the modulation of a cardiac ion current, its electrophysiological consequence and the final phenotype presentation as LQTS and TdP.

Electrophysiological Mechanisms of the Trigger of Torsade de Pointes in the Long QT Syndrome There is an almost complete agreement that the initiating one or two beats of TdP are due to EAD-triggered focal activity from the subendocardial Purkinje network.60,66â&#x20AC;&#x201C;70 A study by Caref et al. has confirmed beyond reasonable doubt the subendocardial origin of the trigger of TdP.7171 In this study the canine surrogate model of

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Acquired Long QT Syndrome LQT3 was placed on cardiopulmonary bypass and chemical ablation of the endocardial Purkinje network was obtained using Lugol’s iodine following which spontaneous TdP were no longer observed. However, a properly timed premature stimulus-induced reentrant Veterans Administration (VA) based on the underlying marked DR. However, the perpetuation of TdP remains controversial and could be attributed to focal activity, reentrant excitation, or a combination of both mechanisms. The ionic mechanism(s) that underlie the generation of EADs have been widely investigated. The central hypothesis on the generation of EADs suggests that a spontaneous release of calcium from the sarcoplasmic reticulum would temporarily increase cytosolic calcium concentration with a subsequent sudden activation of the sodium-calcium exchanger inward current. This inward current could ‘re-depolarise’ the sarcolemmal membrane to a potential from which sodium or calcium currents become reactivated, triggering an afterdepolarisation.72 Although this model has been primarily discussed to explain delayed afterdepolarisations, there is also evidence that this mechanism may be the trigger for EADs.73 This hypothesis is also supported by studies that showed that inhibition of the sodium-calcium exchanger suppresses TdP in the intact heart model of LQTS2 and LQTS3.74

Electrophysiological Mechanisms of Perpetuation of Torsade de Pointes Contrary to the established mechanism of the trigger of TdP, the perpetuation of TdP remains controversial and could be attributed to focal activity, reentrant excitation, or a combination of both mechanisms.75,76 Both reentrant and focal activity are assumed to be non-stationary. For reentrant excitation this could be due to a heterogeneity-induced drift of a reentrant circuit,77 or a meandering reentrant spiral wave78 (Figure 1D). Alternatively, ectopic beats originating from different locations may explain the perpetuation of TdP. The original description of TdP by Dessertenne attributed the pattern to two variable opposing foci (deux foyers)7. In computational modelling as well as experimental observation of the canine chronic AVB model, both multiple competing foci and reentrant excitation could develop depending on heterogeneity of repolarisation in comparison to the surrounding tissue.75 Large heterogeneities can produce ectopic TdP, while smaller heterogeneities will produce reentrant type TdP. The authors of an experimental study in the same model reported that short-lasting episode of TdP had a focal mechanism while long-lasting episodes were maintained by reentrant excitation.76 However, the results were criticised because of the controversial definition of focal versus reentrant excitation.79

Figure 5: Early and delayed afterdepolarizations in Long QT Syndrome A EAD

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A: Transmembrane action potential recording from a Purkinje fiber-superfused with 20 mM caesium chloride showing both early and delayed afterdepolarisations. B: ECG recording from an in vivo canine anthopleurin-A surrogate model of LQT3. F = focal discharge; R = reentrant excitation. Source: El-Sherif, 2001.84 Reproduced with permission from © Futura Publishing Company, Inc. 2001.

Figure 6: ECG Recordings from an In Vivo Canine Anthopleurin-A Surrogate Model of Long QT Syndrome Type 3

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It remains an open question as to why and how ectopic beats emerge and compete, and what their relationship is to observe EAD activity. EADs arising from subendocardial Purkinje network conducted to overlying myocardium through Purkinje-muscle junctions (PMJ). Electrotonic interactions across PMJs can modulate APD locally. A recent study has proposed that, dependent on resistive properties across PMJs, large spatial gradient of APD can develop at the endocardium and the transmural plane.80 This may provide a better explanation compared to the concept of mid-myocardial (M) cells with different ionic characteristics.81

The recordings are arranged chronologically, a few minutes apart. A: Stable bigeminal and trigeminal rhythm due to subendocardial discharge attributed to EAD-triggered activity from the same focus. This was followed several minutes later by runs of four- or five-beat polymorphic VT with remarkable repetition of the same QRS morphology (panels B and C). The first beat of each run arose from the same site of the bigeminal/ trigeminal beats in panel A. The second and third beats of each run arose from two different subendocardial focal sites; the fourth beat was reentrant in origin. The fifth beat in a five-beat run again was focal in origin and arose well after the end of the reentrant excitation and could be attributed to DAD-triggered activity. After approximately 10 minutes of repetitive non-sustained VT, the same three initial focal beats were followed by reentrant excitation that degenerated into ventricular fibrillation (VF) (panel D). F = focal discharge; R = reentrant excitation. Source: El-Sherif, 2001.84 Reproduced with permission from © Futura Publishing Company, Inc. 2001.

One of the problems of sustained fast EAD-induced focal activity is that the short cycle length will be associated with short APD that would suppress further EADs generation unless there is some form of

protected islands of prolonged APD with EADs capable of conduction across PMJs to activate the ventricular myocardium. A study that combined computational simulation and experimental observations

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Electrophysiology & Ablation Figure 7: Isochronal Maps of Nonsustained and Sustained Ventricular Tachyarrhythmia Shown in Figure 6

observation strongly suggests that some VT and ectopic beats in LQTS could be secondary to DADs.

A

Figure 5B shows a corroboration of this observation from the canine surrogate model of LQT3.84 The top ECG tracing was obtained 10 minutes after infusion of AP-A and shows moderate prolongation of the QT interval and a run of non-sustained monomorphic VT at a rate of 150 bpm. The VT starts with a late coupled beat that is well beyond the end of the QT interval of the preceding sinus beat. Tridimensional mapping of activation showed that the VT arose as a focal discharge (F) from the same subendocardial site. For all practical purposes, the focal discharge could be attributed to DAD-triggered activity.

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(A) Selected electrograms of the five-beat nonsustained ventricular tachyarrhythmia shown in Figure 6C (V1–V5) and the first five beats of the ventricular tachyarrhythmia that degenerated into ventricular fibrillation shown in Figure 6D (V1–V5). A limited activation map of both V3 beats is shown. The electrophysiological mechanism of the different consequences of the same V3 ectopic beat in the two episodes is shown. The inter-ectopic intervals V l–V2 and V2–V3 increased by approximately 30–40 ms in the second episode compared with the first episode (the equivalent of a slight slowing of the discharge of the focal activity). This resulted in lengthening of local repolarisation following the V2 beat by 30–40 ms. However, the degree of lengthening of repolarisation was disparate at contiguous sites, resulting in functional conduction block and the initiation of a more complex reentrant wavefront. One such site where new conduction block developed during the NST TdP is shown in the electrograms between sites D and E, as well as in the isochronal maps on the right side of the figure (lower panel B). The numbers without brackets represent cycle lengths in milliseconds, and the numbers in brackets represent activation-recovery intervals. Source: El-Sherif, 2001.84 Reproduced with permission from © Futura Publishing Company, Inc. 2001.

in isolated myocytes showed that in electrically homogeneous tissue models, chaotic EADs synchronise globally when the tissue is smaller than a critical size. However, when the tissue exceeds the critical size, electronic coupling can no longer globally synchronise EAD, resulting in regions of partial synchronisation that shift in time and space. These regional partially synchronised EADs then form premature ventricular complexes that propagate into recovered tissue without EADs, thus creating ‘shifting’ foci that resemble polymorphic VT.82

The bottom ECG tracing was obtained from the same experiment 10 minutes later and shows further prolongation of the QT interval. The ectopic beats labeled F now seem to be coupled to the end of the prolonged QT interval of the preceding sinus beats. The middle of the tracing illustrates a six-beat run of polymorphic VT. Tridimensional mapping shows that the first beat arose from a subendocardial focal site and could be safely attributed to EAD-triggered activity, whereas subsequent beats were due to reentrant excitation in the form of continuously varying scroll waves.

Electrophysiological Mechanisms of Self-terminating versus Non-self-terminating Torsade de Pointes Ventricular Tachyarrhythmia The majority of TdP episodes terminate spontaneously (self-terminating [ST]), (Figure 1). However, a minority can degenerate in VF (non-selfterminating [NST]). The electrophysiological mechanisms of the NST episodes of TdP have never been elucidated. Obviously this is a more important issue than the ‘twisting and turning’ to see if perpetuation of TdP VT is due to focal or reentrant activation.79 Figures 6 and 7 obtained from the canine surrogate model of LQT3 provides one possible electrophysiological mechanism.84 The lesson gained from this example is that subtle changes in underlying spatial DR and conduction characteristics can result in fractionation of activation wavefronts and VF. It also demonstrates clearly the difficulty in predicting which TdP episodes will be ST of NST.

Delayed After Depolarisation-triggered Activity Contributes to VA in the Long QT Syndrome

Future Directions

The electrophysiological mechanism of VT in LQTS is somewhat more complex than that described earlier. Figure 5A was obtained from one of the classic reviews of cellular mechanisms of cardiac arrhythmias by Hoffman and Rosen.83 It shows transmembrane AP recording from a canine Purkinje-fiber-superfused with 20-mM caesium chloride (a surrogate experimental model for LQT2). The recording illustrates the classic bradycardia-dependent prolongation of AP duration associated with membrane oscillation on late phase 2/early phase 3 of the repolarisation phase characteristic of EADs. But it also shows that complete repolarisation of the AP is followed by a sub­ threshold delayed afterdepolarisation (DAD). The latter is simply explained on the basis of increased intracellular Ca2+ associated with the prolonged AP duration triggering a transient inward current. This, almost forgotten,

Although congenital LQTS remains the domain of cardiologists, cardiac electrophysiologists and specialised centres, the far more frequently acquired drug-induced LQTS is the domain of all physicians and other members of healthcare teams who are required to make therapeutic decisions. To support better prescribing of medicines, clinical decision support systems to date have issued alerts that warn of potential harm from a prescribing decision.85 However, the impact of these systems has been limited. Moving away from the use of alerts to signal prescribing errors, the concept of ‘medical autopilots’ has been suggested as a preferred approach.86 These programs will monitor the electronic medical record and send signals to guide prescribers toward decisions that result in maximum benefit and minimal risk of TdP.

1.

2.

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J ervell A, Lange-Nielsen F. Congenital deaf-mutism, functional heart disease with prolongation of the Q-T interval and sudden death. Am Heart J 1957;54:59–68. DOI: https://doi. org/10.1016/0002-8703(57)90079-0; PMID: 13435203. El-Sherif N, Turitto G. The long QT syndrome and torsade de pointes. PACE 1999;22:91–110. DOI: https://doi. org/10.1111/j.1540-8159.1999.tb00305.x; PMID: 9990606. Kannankeril P, Roden DM, Darbar D. Drug-induced long QT

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Electrophysiology and Ablation

Atrial Tachycardias and Atypical Atrial Flutters: Mechanisms and Approaches to Ablation Steven M Markowitz, George Thomas, Christopher F Liu, Jim W Cheung, James E Ip and Bruce B Lerman Department of Medicine, Division of Cardiology, Weill Cornell Medical Center, New York, US

Abstract Atrial tachycardias (ATs) may be classified into three broad categories: focal ATs, macroreentry and localised reentry – also known as ‘microreentry’. Features that distinguish these AT mechanisms include electrogram characteristics, responses to entrainment and pharmacological sensitivities. Focal ATs may occur in structurally normal hearts but can also occur in patients with structural heart disease. These typically arise from preferential sites such as the valve annuli, crista terminalis and pulmonary veins. Macro-reentrant ATs occur in the setting of atrial fibrosis, often after prior catheter ablation or post atriotomy, but also de novo in patients with atrial myopathy. High-resolution mapping techniques have defined details of macro-reentrant circuits, including zones of conduction block, scar and slow conduction. Localised reentry occurs in the setting of diseased atrial myocardium that supports very slow conduction. A characteristic feature of localised reentry is highly fractionated, low-amplitude electrograms that encompass most of the tachycardia cycle length over a small diameter. Advances in understanding the mechanisms of ATs and their signature electrogram characteristics have improved the efficacy and efficiency of catheter ablation.

Keywords Atrial tachycardia, atrial flutter, macroreentry, micro-reentry, catheter ablation Disclosure: SMM has received consulting fees from Boston Scientific and Preventice. Received: 18 January 2019 Accepted: 6 March 2019 Citation: Arrhythmia & Electrophysiology Review 2019;8(2):131–7. DOI: https://doi.org/10.15420/aer.2019.17.2 Correspondence: Steven M Markowitz, Division of Cardiology, Starr 4, Weill Cornell Medical College, 525 East 68th Street, New York, NY 10065, US. E: smarkow@med.cornell.edu Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Pioneering electrophysiology studies in the 1990s defined the anatomical boundaries of typical atrial flutter, identified regions for effective catheter ablation of this arrhythmia and described procedural endpoints to minimise recurrences after ablation. Activation and entrainment mapping demonstrated that typical flutter arises from reentry around the tricuspid annulus.1 Criteria to confirm bidirectional conduction block in the cavotricuspid isthmus (CTI) became standard procedural endpoints and improved freedom from long-term recurrences. Principles learned from these studies of typical flutter have permitted better understanding of more complex atrial arrhythmias. Through the use of multielectrode catheters and electroanatomical mapping, as well as entrainment, atypical atrial flutters and atrial tachycardias (ATs) of various mechanisms have been defined. The demonstration of bidirectional conduction block across linear lesions has been adopted as an important endpoint in ablating atypical flutters in both atria. The purpose of this review is to summarise current concepts of atypical flutters and ATs which are not dependent on the CTI.

Focal Atrial Tachycardias Focal ATs are defined as arrhythmias that arise from a circumscribed site of early activation and propagate to the atria in a centrifugal pattern. These types of AT can occur in patients with structurally normal atria as well as those with structural heart disease. The mechanisms that give

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rise to focal ATs are triggered activity and automaticity. A consistent feature of focal ATs is sensitivity to adenosine, which terminates tachycardias due to triggered activity and transiently suppresses tachycardias related to enhanced automaticity but does not affect reentrant ATs (Figure 1).2 Focal ATs can arise from anywhere in the atria, but typically cluster in particular anatomical distributions. Common locations in the right atrium (RA) include the tricuspid annulus, the crista terminalis and coronary sinus ostium. Para-Hisian ATs demonstrate properties consistent with tachycardias from other sites around the tricuspid annulus and are thus best considered to be a subset of annular ATs.3,4 In the LA, common sites include the pulmonary veins and the mitral annulus, particularly the left aortomitral continuity. Other locations include the proximal coronary sinus, the atrial appendages and the septum.

Electrocardiographic Features The P-wave morphology of focal ATs depends on the site of origin and conduction characteristics of the atria (Figure 2). In contrast to macro-reentrant ATs, focal ATs are more likely to demonstrate an isoelectric interval on the surface ECG.5 However, the presence of an isoelectric interval is only modestly sensitive and specific for a focal mechanism.6,7 Some focal ATs do not demonstrate isoelectric intervals if the atrial rate is very rapid and conduction times across the atria

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Electrophysiology and Ablation Figure 1: Responses of Atrial Tachycardias to Adenosine A

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A: Focal atrial tachycardia from the lateral tricuspid annulus terminates with adenosine. B: In the same case as A, the electrogram at the successful ablation site shows a QS unipolar configuration with a sharp downstroke (on Lat TA 1 uni), which precedes other right atrial (RA) electrograms. RA electrograms are shown from a multipolar catheter looped around the lateral RA. C: Microreentrant tachycardia in a patient with prior ablation of AF. The tachycardia was localised to the anterior ridge between the left superior pulmonary vein and left atrial appendage. It was insensitive to adenosine. D: In the same case as C, multipolar PentarayŠ catheter shows fragmented long-duration electrograms on two splines that encompass most of the tachycardia cycle length. CS = coronary sinus; dist = distal; lat = lateral; prox = proximal; TA = tricuspid annulus; uni = unipolar.

are slow relative to the tachycardia rate. Conversely, some macroreentrant ATs demonstrate isoelectric intervals when conduction proceeds through a narrow isthmus that does not generate sufficient voltage to produce a deflection on the surface ECG.

It should be noted that P-wave morphologies of focal ATs may be altered in the presence of extensive prior ablation, atrial surgery or significant atrial myopathy.

Mapping and Ablation Focal ATs that originate from the RA often have negative deflections in lead V1, particularly if they arise from more anterior structures such as the tricuspid annulus. Focal ATs from other RA sites, such as the crista terminalis, may generate biphasic positive/negative or even positive P-waves.8 The P-wave axis reflects the tachycardia origin in the inferior or superior part of the RA.9 Thus, ATs that originate from the high crista terminalis, high RA and appendage generate positive P-waves in the inferior leads. Para-Hisian ATs have narrower P-wave durations compared with sinus rhythm because centrifugal activation from a septal focus leads to parallel activation of the RA and LA; the inferior leads may be either negative, positive or biphasic; and lead V1 is often biphasic but sometimes has isoelectric components.3 Focal ATs that originate from the LA usually demonstrate positive deflections in V1 and across the precordial leads because the LA is attitudinally posterior in the chest.9 A negative or isoelectric P-wave in lead I was found to be 100% specific but not sensitive for an LA focus.10 ATs arising from the right pulmonary veins show monophasic P-waves, whereas those from the left pulmonary veins are broader and have notching in V1 and the inferior leads. Tachycardias arising from the mitral annulus have diverse P-wave morphologies depending on their origin in the annulus; they usually show initial small negative components followed by positive deflections.8 ATs that arise from the interatrial septum also characteristically demonstrate narrow P-waves.

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Electroanatomical mapping has proved useful in identifying the origin of focal tachycardias, demonstrating centrifugal activation from a discrete location. The site of earliest activation should precede the P-wave onset by at least 30 msec, and the unipolar electrogram demonstrates a QS configuration with a steep negative deflection preceding the P-wave (Figure 1B). Ablation can be accomplished with radiofrequency (RF) energy using solid 4-mm electrodes, irrigated RF or large tip electrodes. In the LA, ablation with an irrigated catheter is preferred to minimise the likelihood of thrombus formation. Cryoablation is useful in regions near critical structures, such as near the phrenic nerve or atrioventricular (AV) node. Successful ablation of ATs that demonstrate early RA activation near the His bundle require an understanding of the septal anatomy and the relationship among the tricuspid annulus, mitral annulus and aortic root. Para-Hisian ATs are commonly ablated in the non-coronary cusp of the aortic valve. Ablation in this location minimises the risk of AV block and it is often effective even if activation is slightly later than the para-Hisian site in the RA (Figure 3).11â&#x20AC;&#x201C;13 ATs that arise from the septal mitral annulus also demonstrate early RA activation in the His bundle region, but left atrial (LA) mapping identifies even earlier activation and localises the site of effective ablation.11,14 A step-wise approach may be employed to mapping para-Hisian ATs: Careful mapping of the tricuspid annulus and RA septum may identify early activation

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Atrial Tachycardias and Atypical Atrial Flutters at some distance (>1 cm) from the His bundle, where ablation can be successfully and safely performed. When the His bundle region demonstrates earliest RA activation, mapping and ablation of the noncoronary cusp should be attempted. If this is not successful, mapping of the LA septum should be considered. In some patients, mapping of the LA may precede the non-coronary cusp based on suspected site of origin and perceived risk of aortic access. Finally, ablation can also be performed in a true para-Hisian location in the RA, where cryoablation may minimise the chances of irreversible AV block.

Macroreentrant Atrial Tachycardias Macro-reentrant ATs other than typical CTI-dependent atrial flutter often occur in patients with atrial disease, such as those with cardiomyopathies, prior atrial ablation or prior cardiac surgery. In the present era of ablation for AF, macro-reentrant ATs most commonly occur after linear ablation in the LA or RA. The incidence of AT after AF ablation varies, depending on the techniques and lesion sets employed to treat AF. Subsequent ATs are less common after pulmonary vein isolation (approximately 5% incidence) compared with patients treated with linear lesions and ablation of complex electrograms (about 25%).15–18 While macro-reentrant arrhythmias are the most common form of AT following AF ablation, focal arrhythmias also occur in a minority of such patients. A hallmark of macroreentry is the ability to entrain the tachycardia with fusion; this property is inconsistent with a truly focal source. Another feature of macroreentry is identification of activation throughout the tachycardia cycle length with adjacent zones of ‘early’ and ‘late’ activation relative to a fiducial point. Macro-reentrant tachycardias are consistently insensitive to adenosine, which results in AV block but does not interrupt the tachycardia (Figure 1C).2 The locations and dimensions of macro-reentrant circuits in the atria vary considerably, but several common variants are recognised, which are described below.

Figure 2: P-morphologies of Focal Atrial Tachycardias High CT

Principles of Mapping and Ablation of Macroreentrant Tachycardias When a macro-reentrant circuit is suspected, it is important to verify that the entire cycle length is accounted for in the electroanatomical map. Missing segments of the cycle length could be related to areas of slow conduction that were not annotated on the map. Such areas typically exhibit low-amplitude and fractionated electrograms, with amplitudes as low as 0.05 mV or less.19 Alternatively, the inability to annotate all segments of the tachycardia cycle length might indicate the presence of a focal AT. Fractionated and prolonged electrograms pose a challenge to activation mapping, in that it is difficult to assign a single activation time to an electrogram with multiple components.

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PL TA

Para His

LPV

I II III aVR

aVL

aVF V1

V2 V3 V4 V5 V6 CT = crista terminalis; LPV = left pulmonary vein; PL = posterolateral; TA = tricuspid annulus.

Figure 3: Para-Hisian Atrial Tachycardia

Electrocardiographic Features The flutter wave morphologies in macro-reentrant ATs are highly variable and there are few invariable features that identify specific reentrant circuits. Atypical flutters from the RA often demonstrate predominantly negative deflections in V1. However, other RA tachycardias, such as counterclockwise CTI-dependent atrial flutter, have positive deflections in V1, typically preceded by an isoelectric or negative component. Atypical flutters from the LA often show broad positive deflections in V1 but may show initial negative followed by positive deflections. The limb and precordial leads in LA flutters often show very lowamplitude signals, particularly in patients who had prior ablation. These generalisations are often violated, as the extent and distribution of atrial scar influence the resulting flutter wave morphology.

Mid CT

A aVF

100 msec RAO

B

V1 NCC HB His prox His mid

CS

His dist CS 9,10 CS 7,8 CS 5,6 CS 3,4 CS 1,2 NCC dist

LAO

C NCC HB

NCC prox LA sept dist

CS

LA sept prox A: Intracardiac recording shows early activation of the atrial electrogram on the His bundle catheter (vertical line), which precedes the P wave onset. Mapping in the non-coronary cusp (NCC) is slightly later than the right para-Hisian region, and the left atrial septum is even later. The tachycardia was ablated in the NCC despite slightly later activation. B: Right anterior oblique fluorosocopic image. C: Left anterior oblique fluorosocopic image. CS = coronary sinus; dist = distal; HB = bundle of His; LA = left atrium; LAO = left anterior oblique; NCC = non-coronary cusp; prox = proximal; RAO = right anterior oblique; sept = septum.

Newer display and annotation techniques can account for deflections in complex electrograms by visually representing deflections. One such technique, known as ripple mapping, dynamic bars that extend from the surface of the map to

multiple multiple displays indicate

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Electrophysiology and Ablation Figure 4: Incisional Reentry in the Lateral Right Atrium in a Patient with Prior Repair of Atrial Septal Defect A

B

200 ms

I aVF V1 RA 19–20

236

RA 1–2 234

210 CS prox

CS dist A: Electroanatomical map with the Rhythmia® system demonstrates reentry around a line of conduction block (indicated by blue tags) in the lateral right atrium (RA). B: Entrainment from poles 7–8 of a multipolar catheter loop in the lateral RA shows a post-pacing interval nearly identical to the tachycardia cycle length. Note that electrograms on more proximal poles RA 11–12 and 13–14, which are activated earlier, are entrained orthdromically with delay. This is an example of downstream overdrive pacing seen with reentrant arrhythmias. CS = coronary sinus.

changes in the electrogram voltage.20 Another technique uses a window of interest to highlight regions that activate at particular times. These techniques can identify zones of slow conduction that might not be recognised by annotating single activation times.21 Entrainment confirms that a particular site participates in the tachycardia circuit when the post-pacing interval is within 30 msec of the tachycardia cycle length. In the case of macro-reentrant tachycardias, this criterion is fulfilled in two or more different segments of the atrium. For example, if both lateral and septal LA participate in the tachycardia, the tachycardia is likely to be peri-mitral reentry.22 Conversely, if both the posterior and anterior walls of the LA are within the circuit, the mechanism is likely to be ‘roof-dependent’ reentry. Downstream overdrive pacing is identified when pacing from electrodes that are activated ‘late’ results in orthodromic capture of the ‘earlier’ electrograms (Figure 4).23 This property is highly suggestive of a macro-reentrant mechanism. The post-pacing interval can also provide information about the distance of the pacing site from tachycardia location, regardless of the mechanism being focal, microreentrant or macro-reentrant.

barriers including scar and anatomical structures. Ultra-high-density mapping now allows better resolution of scar, conduction block, zones of slow conduction and wave front collisions. As such, it may be possible to identify a ‘practical isthmus’, which is usually the narrowest part of the circuit and may be more effectively ablated than other components which require long linear lesions (Figure 5).25 Regardless of the location of macroreentry or the length of the ablative lesion, bidirectional conduction block is an important endpoint for ablation. Conduction block can be confirmed by the following criteria:26 • During pacing from one side of the line, activation mapping demonstrates a detour of the wave front around an anatomical barrier or scar, resulting in late activation of the opposite side. • Differential pacing reveals that pacing further away from the line results in earlier activation of the opposite side. • Double potentials may be demonstrated along the line, particularly when pacing from one side.

Right Atrial Macroreentry High-density mapping for atypical flutters is valuable because it identifies complex patterns of activation, including dual-loop reentry and protected channels. Information from high-density mapping can be supplemented with judicious use of entrainment pacing, but some limitations of entrainment should be considered. Overdrive pacing can potentially interrupt or transform a tachycardia. Also, entrainment could potentially fail to identify a participating segment if rapid pacing causes further slowing of conduction in diseased myocardium, resulting in a long but misleading post-pacing interval.24 Once the tachycardia mechanism and dimensions have been defined, ablation should target a critical component of the tachycardia. Macroreentrant ATs are ablated with linear lesions between unexcitable

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Other than CTI-dependent atrial flutter, the most common form of macroreentry in the RA is free wall reentry (Figure 4). This circuit arises when scar is present in the RA free wall, usually as a result of right atriotomies but also as a spontaneous phenomenon in myopathic atria.27–30 Reentry in the RA free wall may coexist with another circuit, such as peri-tricuspid reentry or lower loop reentry around the inferior vena cava (IVC), to form a dual-loop tachycardia.31 A second form of macroreentry in the RA is known as upper loop reentry, which involves a circuit around the superior vena cava (SVC), possibly also encompassing patchy scar in the high RA adjacent to the SVC. Ablation of lateral wall reentry in the RA is accomplished with a linear lesion between the preexisting scar and an anatomical boundary,

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Atrial Tachycardias and Atypical Atrial Flutters Figure 5: Left Atrial Roof-Dependent Reentry in a Patient with Prior Mitral Valve Repair and Maze Procedure

Electroanatomical mapping demonstrates reentry around the right pulmonary vein with a gap in a prior ablation line in the inferior posterior wall. Bipolar electrograms in the gap demonstrated an amplitude of <0.05 mV (circled star and electrogram in inset). This zone was considered the ‘practical isthmus’, a more efficient target for ablation than a linear lesion across the left atrial roof. PA = posterior-anterior; RAO = right anterior oblique.

Figure 6: Line of Block after Ablation of the Lateral Right Atrium from Atriotomy Scar to Inferior Vena Cava A

RAO

C

D 200 ms

RA I aVF

V1 CS

RA 19–20

190

B

LAO RA RA 1–2

11-12

195

CS prox CS CS dist 1-2

A and B: Fluoroscopic images of multipolar catheter in the lateral right atrium. C: Line of block (double line) is verified by pacing from either side of the ablation line. The location of the atriotomy is depicted by the white line and ablation lesions in red. Pacing anterior to the line (from RA 1–2) results in late activation of electrograms on the other side of the line with craniocaudal activation. D: Similarly, pacing from posterior to the line (from RA 11–12) results in late activation anterior to the line (RA 1–2). CS = coronary sinus; dist = distal; HB = bundle of His; LA = left atrium; LAO = left anterior oblique; prox = proximal; RAO = right anterior oblique.

such as the IVC, tricuspid annulus or SVC. When ablation is extended along the lateral wall to the IVC, conduction block can be verified with a multipolar catheter looped around the RA while pacing is performed both anterior and posterior to the line (Figure 6).32 Often, this lateral wall lesion is combined with ablation in the CTI. During ablation in the lateral RA, caution is required to avoid injury to the phrenic nerve.

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Left Atrial Macroreentry The vast majority of LA flutters occur in patients with atrial disease, such as those with prior atriotomies, previous catheter ablations or those who have developed LA myopathies. These arrhythmias take the form of single or dual loops, and multiple-loop reentry has also been described.

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Electrophysiology and Ablation Reentry around the mitral annulus, known as peri-mitral reentry, is a common form of LA flutter. Recent studies using ultra-high-density mapping show that some peri-mitral circuits do not necessarily encompass the entire mitral annulus but detour around patches of scar in the LA.25 Peri-mitral reentry is usually interrupted by linear ablation in a ‘mitral isthmus’. The lateral mitral isthmus refers to the corridor between the mitral annulus and the left inferior pulmonary vein. Interruption of tachycardia in this location may require additional ablation in the coronary sinus to target epicardial fibers or connections between the coronary sinus and LA, including the ligament of Marshall.33 An alternative linear lesion may be created between the anterior mitral annulus and the left superior pulmonary vein or LA roof.34 Peri-mitral reentry can also be treated with linear ablation from the septal mitral annulus to the right superior pulmonary vein. It is worth noting that traditional criteria for block, with reversal of activation sequence and prolonged conduction times, might not distinguish slow conduction from complete block after ablation of peri-mitral reentry. In the lateral mitral isthmus, epicardial connections can result in slow conduction and the appearance of ‘pseudo-block’, but yet give rise to complex reentrant rhythms.35 These connections can be interrupted by targeting insertion sites in the proximal to mid coronary, or the ridge between the LA appendage and left pulmonary veins. Another common form of LA flutter is reentry around an ipsilateral pair of pulmonary veins, also referred to as ‘roof-dependent LA flutter’ (Figure 5). Roof-dependent reentry is usually treated with linear ablation between the superior pulmonary veins. It is also possible to ablate between the inferior pulmonary veins across the posterior wall, but caution is required to avoid esophageal injury. Many variants of macroreentry occur in the LA, depending on the particular pattern of native scar and prior ablation lesions. For example, reentrant circuits confined to the LA septum have been described,14 as have arrhythmias involving the coronary sinus or limited to the posterior wall.

Effective ablation of microreentrant ATs usually occurs at sites with highly fractionated, low-amplitude electrograms. These electrogram characteristics are highly sensitive but not specific for microreentrant circuits. In particular, low-amplitude and long-duration electrograms could be present at bystander sites which do not actively participate in the circuit. Also, electroanatomical maps can produce ‘pseudo’ localised reentry, which is actually related to incomplete rotation of an impulse and collision with an invading wave front.38 For this reason, entrainment is a useful manoeuvre to verify an active component of the circuit and appropriate target for ablation.

Outcomes After Catheter Ablation Outcomes after ablation of ATs vary widely depending on the mechanism of arrhythmia, the degree of atrial myopathy and coexisting arrhythmias such as AF. The acute success rate for ablation of focal ATs is approximately 85–90%, and freedom from recurrence without antiarrhythmic drug therapy is 60–90%.39,40 Higher success is achievable in patients with single foci and structurally normal hearts. For patients having ablation of post-incisional right ATs (many of whom also have CTI-dependent flutter), acute success of up to 96% has been reported with freedom from long-term tachyarrhythmia recurrences of 65%.29 Most of the recurrences are AF or ATs arising from different locations. In a series of patients having ablation of scar-related atypical atrial flutters in either atrium, acute success was approximately 90% and long-term success was 77%.41 Higher success was reported in those having prior catheter ablation or atrial surgery compared to those with idiopathic scar.

Conclusion High-resolution mapping, in addition to entrainment responses, define the mechanisms of AT and identify sites of origin and critical isthmuses that are targets for ablation. With the aid of these mapping techniques, more focused lesions can be created to avoid ineffective ablations and proarrhythmia from excessive ablation. Understanding the atrial substrate for tachyarrhythmias may help minimise iatrogenic ATs that occur after catheter ablation of AF or following cardiac surgery.

Microreentrant Atrial Tachycardias An interesting subset of ATs is best described as ‘micro-reentry’ or ‘localised reentry’. This mechanism occurs in patients with prior catheter ablation, prior atrial surgery and sometimes de novo in patients with atrial myopathy. Localised reentry is arbitrarily defined as a circuit with a diameter <2–3 cm. 22 The circuits often occur adjacent to prior ablation lesions or near patchy areas of scar that are identified with electroanatomical mapping. These tachycardias characteristically demonstrate low-amplitude continuous electrograms encompassing >85% of the tachycardia cycle length (Figure 1D). Recent studies with ultra-high-density mapping show that localised atrial reentrant circuits may have multiple sequential zones of very slow conduction and occur in lowvoltage areas of the atria.36 A notable feature of localised reentry is insensitivity to adenosine, a property which is common with macroreentrant tachycardias (Figure 1C). 37

1.

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Clinical Perspective • Atrial tachycardias (ATs) can be classified as focal AT, macroreentry or localised reentry. The mechanisms may be distinguished by high-density mapping and responses to pharmacological agents such as adenosine. • Focal ATs in patients with structurally normal hearts often arise from particular anatomical locations, such as the crista terminalis and valve annuli, including the para-Hisian region. • High-density mapping of reentry may demonstrate an isthmus of slow conduction, which is a suitable target for ablation. • Areas of slow conduction occur in patients with prior catheter ablation, cardiac surgery or atrial myopathy. • These sites are characterised by electrograms of extremely low voltage, fractionation and long duration.

properties of para-Hisian atrial tachycardia. Heart Rhythm 2011;8:1245–53. https://doi.org/10.1016/j.hrthm.2011.03.011; PMID: 21397044. Ip JE, Liu CF, Thomas G, et al. Unifying mechanism of sustained idiopathic atrial and ventricular annular tachycardia. Circ Arrhythm Electrophysiol 2014;7:436–44. https:// doi.org/10.1161/CIRCEP.113.001368; PMID: 24837827. Brown JP, Krummen DE, Feld GK, et al. Using

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tachycardias after mitral valve surgery: mechanisms and outcomes of catheter ablation. Heart Rhythm 2017;14:520–6. https://doi.org/10.1016/j.hrthm.2016.12.002; PMID: 27919764. Yang JD, Sun Q, Guo XG, et al. Right atrial dual-loop reentrant tachycardia after cardiac surgery: prevalence, electrophysiological characteristics, and ablation outcomes. Heart Rhythm 2018;15:1148–57. https://doi.org/10.1016/j. hrthm.2018.03.039; PMID: 29625278. Kanagasundram AN, Baduashvili A, Liu CF, et al. A novel criterion for conduction block after catheter ablation of right atrial tachycardia after mitral valve surgery. Circ Arrhythm Electrophysiol 2013;6:39–47. https://doi.org/10.1161/ CIRCEP.112.976340; PMID: 23243191. Jais P, Hocini M, Hsu LF, et al. Technique and results of linear ablation at the mitral isthmus. Circulation 2004;110:2996–3002; https://doi.org/10.1161/01.CIR.0000146917.75041.58; PMID: 15520313. Tzeis S, Luik A, Jilek C, et al. The modified anterior line: an alternative linear lesion in perimitral flutter. J Cardiovasc Electrophysiol 2010;21:665–70. https://doi.org/10.1111/j.15408167.2009.01681.x; PMID: 20050958. Barkagan M, Shapira-Daniels A, Leshem E, et al. Pseudoblock of the posterior mitral line with epicardial bridging connections is a frequent cause of complex perimitral tachycardias. Circ Arrhythm Electrophysiol 2019;12:e006933. https://doi.org/10.1161/CIRCEP.118.006933; PMID: 30606034. Frontera A, Mahajan R, Dallet C, et al. Characterizing localized reentry with high-resolution mapping: Evidence for multiple slow conducting isthmuses within the circuit. Heart Rhythm 2018. https://doi.org/10.1016/j.hrthm.2018.11.027; PMID: 30500614; epub ahead of press. Markowitz SM, Nemirovksy D, Stein KM, et al. Adenosineinsensitive focal atrial tachycardia: evidence for de novo micro-re-entry in the human atrium. J Am Coll Cardiol 2007;49:1324–33. https://doi.org/10.1016/j.jacc.2006.11.037; PMID: 17394965. Luther V, Sikkel M, Bennett N, et al. Visualizing localized reentry with ultra-high-density mapping in iatrogenic atrial tachycardia: beware pseudo-reentry. Circ Arrhythm Electrophysiol 2017;10. https://doi.org/10.1161/CIRCEP.116.004724; PMID: 28356307. Busch S, Forkmann M, Kuck KH, et al. Acute and long-term outcome of focal atrial tachycardia ablation in the real world: results of the German Ablation Registry. Clin Res Cardiol 2018;107:430–6. https://doi.org/10.1007/s00392-018-1204-8; PMID: 29344680. Manolis AS, Lazaridis K. Focal atrial tachycardia ablation: highly successful with conventional mapping. J Interv Card Electrophysiol 2018. https://doi.org/10.1007/s10840-018-0493-1; PMID: 30506178. Coffey JO, d’Avila A, Dukkipati S, et al. Catheter ablation of scar-related atypical atrial flutter. Europace 2013;15:414–9. https://doi.org/10.1093/europace/eus312; PMID: 23385050.

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Pacemaker and Defibrillator Implantation and Programming in Patients with Deep Brain Stimulation Mark Elliott 1 , Sheikh Momin 1 , Barnaby Fiddes 2 , Fahad Farooqi 1 and SM Afzal Sohaib 1 1. Department of Cardiology, King George Hospital, Ilford, UK; 2. Barking, Havering and Redbridge University Hospitals NHS Trust, Romford, UK

Abstract The need for cardiac device implantation in patients receiving deep brain stimulation (DBS) is increasing. Despite the theoretical risk of the two systems interacting, there are no clear guidelines for cardiologists carrying out cardiac device implantation in this population. We performed a review of the literature and describe 13 case reports in which patients have both DBS and a cardiac pacemaker or ICD implanted. Except for one early study, in which an ICD shock reset the deep brain stimulator, no significant interactions have been reported. We discuss the potential interactions between DBS and cardiac devices, and provide practical advice for implanting cardiologists. We conclude that, provided that specific precautions are taken, cardiac device implantation is likely to be safe in patients with DBS.

Keywords Deep brain stimulation, Parkinson’s disease, device implantation, device programming, pacemaker, ICD Disclosure: The authors have no conflicts of interest to declare. Received: 1 November 2018 Accepted: 21 March 2019 Citation: Arrhythmia & Electrophysiology Review 2019;8(2):138–42. DOI: https://doi.org/10.15420/aer.2018.63.2 Correspondence: SM Afzal Sohaib, Department of Cardiology, King George Hospital, Barley Lane, Goodmayes, Ilford, IG3 8YB, UK. E: afzalsohaib@hotmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Deep brain stimulation (DBS) is an expanding neurosurgical treatment for refractory neurological conditions such as Parkinson’s disease and essential tremor, with over 120,000 devices implanted worldwide.1 The rate of cardiac implantable electronic device (CIED) implantation is rising annually, with 739 pacemaker implants per million and 141 ICD implants per million in western Europe in 2015.2 There are no data in the literature on the incidence of cardiac device implantation in patients with pre-existing DBS or vice versa. However, in an ageing population, the need for cardiac device implantation in patients receiving DBS is likely to become increasingly frequent. There is a theoretical risk of interference between these two systems as well as practical issues that must be taken into consideration during the implantation procedure. In this article, we will discuss the indications and physiology around DBS and review the evidence in the literature for CIED implantation in patients receiving DBS. We will then summarise the potential interactions and practical considerations for patients with both systems, with advice for cardiologists in managing such patients.

Deep Brain Stimulation DBS is an intervention whereby electrodes are implanted through a neurosurgical procedure into stereotactically mapped brain regions, which are selected based on the indication, and connected by wires to an implanted pulse generator (IPG; Figure 1 and Figure 2). The IPG is usually situated in the left subclavicular region. Bilateral brain electrodes can be connected to either separate bilateral IPGs or to a single IPG.

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Before the long-term electrode is implanted, physiological verification is carried out by passing a microelectrode into the anatomical target to record neuronal activity, and short intervals (0.5–1 second) of high-frequency test stimulation (100–300  Hz) are delivered to the awake patient intraoperatively to observe both beneficial and adverse effects. The procedure is therefore initially carried out under general anaesthesia, with sedation interrupted for microelectrode recording. Several weeks following the procedure, the IPG is programmed by a neurologist to determine the optimal settings, with voltage, amplitude and pulse width usually manipulated.3,4 DBS is being used for increasingly wide applications. It is most commonly used for movement disorders such as Parkinson’s disease, essential tremor and dystonia when medical treatment is ineffective or causes intolerable adverse effects. It has also been used experimentally for treating psychiatric disorders (such as refractory depression and obsessive–compulsive disorder), obesity and chronic pain states.5 It is best established for late-stage Parkinson’s disease in patients who are levodopa sensitive, where the subthalamic nucleus or internal segment of the globus pallidus are targeted unilaterally or bilaterally. The goal in these patients is to improve their motor function and reduce their levodopa-effective dose. The precise mechanism of DBS is debated. It is theorised that in Parkinson’s disease, DBS at a high frequency can override the pathological low-frequency, beta-wave, oscillatory activity (11–30  Hz) and start a higher rate of neuronal activity (>60 Hz) in the dopaminergic pathways, which can treat symptoms such as bradykinesia and rigidity.

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Pacemaker and Defibrillator Implantation and Programming Figure 1: Deep Brain Stimulation Device

Figure 2: Deep Brain Stimulation Impulse Generator and Typical Dual Chamber Pacemaker Generator

A

B

Deep brain stimulation impulse generator (51 mm × 47 mm) and typical dual chamber pacemaker generator (51 × 45 mm) for comparison. Reproduced with permission from Medtronic.

Literature Review A systemic review of the literature was performed based on the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines.8 We performed a comprehensive search of major biomedical databases (including PubMed, EMBASE and AMED) using variations of the following terms: ‘deep brain stimulation cardiac pacemaker’; ‘neurostimulator cardiac pacemaker’; ‘deep brain stimulation implantable cardioverter-defibrillator’; ‘neurostimulator implantable cardioverter-defibrillator’; and ‘deep brain stimulation cardiac defibrillator’. The final search was conducted on 10 September 2018. The reference lists from the included articles were also searched. We used a focused search strategy to include all studies that referred to DBS and cardiac pacemakers or ICDs. Prior to the search, inclusion and exclusion criteria were determined. Articles were included if they were primary studies and referred to the use of DBS and pacemakers or ICDs. Articles were excluded if they were individual views, such as commentaries or letters, or if they were secondary research, such as literature reviews. Electronic abstracts were screened using the inclusion and exclusion criteria. After applying the inclusion and exclusion criteria, we included six articles for pacemaker and DBS and eight articles for ICD and DBS. The methodology is summarised in Figure 3. The cases described in these articles are summarised in Table 1.

Current Evidence While device manufactures have provided some guidance, there are no specific guidelines for the implantation of CIEDs in patients with DBS

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Eligibility

Conversely, high-frequency stimulation may hold the low-frequency oscillations underlying tremor in a refractory state, thus helping to relieve this symptom.6 Hence, traditionally, a high frequency (>100 Hz) has been used, although this may be different in select patients.7

Included

Reproduced with permission from Medtronic.

Screening

Identification

Figure 3: PRISMA Flow Diagram

Records identified through database searching (n=76)

Additional records identified through other sources (n=1)

Records screened (n=77)

Records excluded (n=56)

Abstracts assessed for eligibility (n=21)

Studies excluded (n=8)

Studies included in qualitative synthesis (n=13)

devices, and the evidence in the literature is limited to case reports and small cases series (Table 1).9 The first description of a CIED in a patient with DBS was by Tavernier et al. in 1999.10 The patient had bilateral DBS with IPGs in both left and right pectoral regions. An ICD was implanted in the left abdominal position for secondary prevention after a cardiac arrest. While the DBS devices did not have an impact on the ICD function, a 34 J shock from the ICD was found to completely reset both DBS devices, resulting in them reverting to the ‘off’ position. Five further studies reported successful implantation of ICDs in patients with DBS; however, in these cases, there was no reported interaction between the devices, with DBS function continuing as normal after defibrillator threshold testing (DFT) or ICD shocks.11–15 Cases of cardiac pacemaker implantation in patients with DBS have, similarly, found no adverse interactions between the two systems.13,16–18 More recently, novel devices have been employed in patients with bilateral DBS pulse generators who require ICD or pacemaker implantation. Borgioni et al. described the implantation of a leadless

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Drugs and Devices Table 1: Summary of Case Reports Study

No. of patients

Which device first?

PPM/ICD generator location

PPM sensing mode

DBS mode

DBS pulse generator location

Follow-up duration (months)

Interaction

Senatus et al. (2004)23

2

PPM PPM

Left SC Left SC

B B

B U

Bilateral AB Bilateral AB

22

None None

Capelle et al. (2005)16

6

PPM PPM DBS* PPM PPM PPM

Right SC NS NS NS NS NS

B B B B B B

B B B B U B

Left SC Right SC Left SC and AB Left SC Left SC Left SC

4–48 (mean 25.3)

None None None None None None

Ozben et al. (2006)17

1

DBS

Right SC

B

NS

Left SC

6

None

Ashino et al. (2009)

Pacemakers and DBS

1

DBS

Left SC

B

NS

Bilateral SC

36

None

Ooi et al. (2011)13

1

NS

Right SC

B

B

Left SC

14

None

Bongiorni et al. (2016)19

1

DBS

Leadless PPM

B

Both

Bilateral SC

6

None

Tavernier et al. (1999)10

1

DBS

Left AB

B

Both

Bilateral SC

1

ICD shock reset DBS

Obwegeser et al. (2001)11

1

DBS

Right SC

B

Both

Left SC

4

None

Rosenow et al. (2001)

18

ICD and DBS

1

DBS

Left AB

B

Both

Bilateral SC

<1

None

Ooi et al. (2011)13

1

NS

Left SC

B

B

Right SC

34

None

Karimi et al. (2012)14

1

DBS

Left AB

B

Both

Bilateral SC

<1

None

Bader et al. (2015)

1

DBS

Left Lateral (S-ICD)

N/A

Both

Right SC

12

None

1

DBS

Left Lateral (S-ICD)

N/A

U

Bilateral SC

12

None

1

DBS

Left SC

NS

Both

Right SC + Left Lateral

<1

None

12

20

Tejada et al. (2017)21 Tsukuda et al. (2018)

15

AB = abdominal; B = bipolar; DBS = deep brain stimulation; NS = not stated; PPM = permanent pacemaker; S-ICD = subcutaneous ICD ;SC = subclavicular; U = unipolar. *Patient had one DBS system followed by a PPM followed by a further DBS system.

pacemaker in a patient with bilateral BDS without any reported interaction.19 Bader and Weinstock, and Tejada et al. demonstrated the successful implantation of subcutaneous ICD (S-ICD) systems in patients with DBS, again with no interference between the devices.20,21

Potential Interactions Several practical and theoretical interactions should be taken into consideration for patients with both DBS and a cardiac device. The most concerning of these is the potential for one of the devices to impact on the activity of the other. One study reported the complete reset of bilateral DBS devices after a shock from an implanted ICD; however, there have been no other reports of similar interactions.10 While brief interruption of DBS is unlikely to cause significant morbidity or mortality, the inhibition of a cardiac pacemaker or ICD could result in syncope or sudden cardiac death. ECG artefacts have been reported in patients with DBS and detection of such activity by a cardiac device could potentially inhibit pacing or trigger an inappropriate ICD shock.22 There have been no reports of any inappropriate sensing by a CIED in patients with DBS. Nevertheless, several precautions can be taken to minimise the risk of any interference. Medtronic recommends that both the DBS and cardiac device sensing should be programmed to a bipolar configuration.9 Ensuring the CIED is in bipolar mode for sensing significantly reduces the size of the electrical circuit, thus decreasing the potential for it to detect the DBS signal.

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Capelle et al. demonstrated that changing the atrial sensing configuration of a cardiac pacemaker from unipolar to bipolar significantly reduced the intracardiac ECG artefact from a unipolar DBS system, though neither configurations resulted in inappropriate atrial sensing.16 The vast majority of modern CIEDs are programmable to bipolar sensing, but this is an important consideration for patients with older devices. There are no reported cases in the literature where a patient with a DBS device has a cardiac device using unipolar sensing configuration. S-ICDs have much larger bipoles for sensing compared to transvenous systems; however, two cases demonstrated no evidence of inappropriate sensing in patients with DBS.20,21 DBS systems can also be programmed to either unipolar or bipolar mode. When in bipolar mode, the circuit is small and limited to the electrode implanted in the brain. In unipolar mode, the circuit is much larger, running from the brain electrode down to the IPG in the chest. It is generally recommended that both the cardiac device and DBS device are set to bipolar mode, and it has been shown that doing so eliminates any interference on both the surface and intra-cardiac ECG.13,16,23 The setting of the DBS, however, depends on the requirements of the patient, and can change the efficacy of the treatment, with some patients requiring unipolar configuration for optimal symptom control. Unipolar configuration of a DBS system has been reported along with a CIED without any significant interference.10–12,15,16,19–21,23 A further precaution to take is to ensure there is an adequate distance between the generators of DBS and cardiac devices. Medtronic

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Pacemaker and Defibrillator Implantation and Programming recommends that the DBS IPG and CIED generator are implanted on contralateral sides at a distance of at least 20 cm.9 This recommendation is seen elsewhere in the literature.11,13,16,17,24 While there are reports of generators being implanted in close proximity without any interaction, ensuring a maximum distance between the two minimises the potential for interference in electrical circuits.18 One study reported a possible interaction between a DBS IPG and a cardiac pacemaker that were close to each other.24 This patient had a bilateral DBS system with IPGs in both subclavicular regions as well as a left-sided cardiac pacemaker. They presented with neurological symptoms of imbalance, tingling and weakness, which resolved when one IPG was moved from the left subclavicular to an abdominal location. While the authors suggest this had been an interaction between the DBS and cardiac pacemaker, there was no objective evidence of device malfunction.

Table 2: Steps to Minimise Issues During Deep Brain Stimulation and Cardiovascular Implantable Electronic Device Implantation

After implantation of a CIED in a patient with DBS (or vice versa), the programmed parameters of each device should be checked. It is prudent to programme the devices for ‘worse case scenario’ events. This involves trialling both unipolar and bipolar settings for the DBS, and programming the DBS to maximum tolerated settings and the cardiac device to the maximum sensitivity.13,23 Medtronic recommends that the DBS is set to a minimum frequency of 60 Hz.9 For ICD implantation, defibrillator threshold testing can be used to detect any impact of ICD shocks on DBS settings or function.

There has been a case report of severe central nervous system damage secondary to an interaction between diathermy and DBS.27 It is therefore wise to avoid diathermy in patients with DBS systems. If diathermy is absolutely required, options include turning off the DBS device before the procedure or ensuring bipolar diathermy is used.

Practical Considerations During the actual implantation of a cardiac pacemaker or ICD in a patient with DBS, there are several factors to take into consideration. The DBS system incorporates unilateral or bilateral electrodes implanted into the brain with wires running subcutaneously down to an IPG, which is usually located in the subclavicular region. CIEDs should be implanted on the contralateral side to the IPG, not only to avoid potential interaction as discussed, but also because there is unlikely to be sufficient physical space on the ipsilateral side for two generators. Furthermore, this minimises the risk of damaging the DBS system during implantation or future box changes. Ensuring adequate physical separation between the generators also reduces the chance of inadvertent disturbance of the incorrect system when using magnet or electronic programming devices.13 Some patients have bilateral IPGs occupying both subclavicular spaces, which creates an additional challenge for cardiac device implantation. In such cases, options include: relocating one of the IPGs; implanting the CIED generator in an abdominal position; or using novel devices such as leadless pacemakers or S-ICDs.10,12,14,15,19–21 Another issue during cardiac pacemaker or ICD implantation is the use of electrical diathermy. This is a common tool used for both dissection and haemostasis. Diathermy can potentially interfere with the activity of the DBS, though brief interruption of the system is unlikely to have much of a clinical effect. Of more concern is that the energy from diathermy can theoretically be transferred via the DBS system to the brain and cause damage at the site of the implanted electrode.25,26

1.

2.

 amani C, Florence G, Heinsen H, et al. Subthalamic H nucleus deep brain stimulation: basic concepts and novel perspectives. eNeuro 2017;4:pii:ENEURO.0140-17.2017. https:// doi.org/10.1523/ENEURO.0140-17.2017; PMID: 28966978. National Institute of Cardiovascular Outcomes Research. National Audit of Cardiac Rhythm Management Devices: Aprill 2015–March 2016. London: NICOR; 2017. Available at: www.ucl.ac.uk/ nicor/audits/cardiacrhythm/documents/annual-reports/

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3.

4.

• Multidisciplinary team approach with neurology input. • Implant cardiac device on the contralateral side to the implanted pulse generator. • Ensure there is at least 20 cm between the two generators. • Use bipolar sensing configuration for the cardiac device. • Ideally, use bipolar deep brain stimulation settings with a minimum frequency of 60 Hz. • Consider leadless pacemaker in patients with bilateral IPGs. • Avoid diathermy during cardiovascular implantable electronic device implantation. • Programme devices for ‘worst case scenario’ settings during testing.

Conclusion While the reports of cardiac pacemaker or ICD implantation in patients with DBS are limited, the evidence suggests that both systems can be implanted without significant interaction, provided that certain precautions are taken. Patients receiving DBS who require CIED implantation should be managed in a multidisciplinary setting with input from neurologists to optimise DBS settings prior to the procedure. Several practical steps can be taken by the cardiologist to minimise the risk of interference (Table 2). Since the published outcome data in patients with cardiac devices and DBS is limited to case reports, it is possible that significant interactions are under-reported. A large, prospective, observational study is needed in this patient population to more clearly assess safety and accurately determine the risk of complications and interaction between cardiac devices and DBS.

Clinical Perspective • Cardiac devices can be safely implanted in patients receiving deep brain stimulation (DBS) provided that certain precautions are taken • Patients should be managed with a multidisciplinary approach including neurology input • Cardiac device generators and DBS implantable pulse generators should be implanted on contralateral sides with >20 cm distance between them • Both the cardiac and DBS systems should be in bipolar configuration

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20. B  ader Y, Weinstock J. Successful implantation of a subcutaneous cardiac defibrillator in a patient with a preexisting deep brain stimulator. HeartRhythm Case Rep 2015;1:241–4. https://doi.org/10.1016/j.hrcr.2015.03.014; PMID: 28491558. 21. Tejada T, Merchant FM, El-Chami MF. Subcutaneous implantable cardioverter-defibrillator implantation in a patient with bilateral pectoral deep brain stimulators. HeartRhythm Case Rep 2017;4:109–12. https://doi.org/10.1016/ j.hrcr.2017.12.005; PMID: 29707486. 22. Khan I. Differential electrocardiographic artifact from implanted thalamic stimulator. Int J Cardiol 2004;96:285–6. https://doi.org/10.1016/j.ijcard.2003.04.061; PMID: 15262047. 23. Senatus P, McClelland S, Ferris A, et al. Implantation of bilateral deep brain stimulators in patients with Parkinson disease and preexisting cardiac pacemakers. Report of two cases. J Neurosurg 2004;101:1073–7. https://doi.org/10.3171/ jns.2004.101.6.1073; PMID: 15597774. 24. Sharma M, Talbott D, Deogaonkar M. Interaction between cardiac pacemakers and deep brain stimulation pulse generators: technical considerations. Basal Ganglia 2016;6: 19–22. https://doi.org/10.1016/j.baga.2015.11.001. 25. Davies R. Deep brain stimulators and anaesthesia. Br J Anaesth 2005;95:424. https://doi.org/10.1093/bja/aei579; PMID: 16076924. 26. Khetarpal M, Yadav M, Kulkarni D, Gopinath R. Anaesthetic management of a patient with deep brain stimulation implant for radical nephrectomy. Indian J Anaesth 2014;58:461–3. https:// doi.org/10.4103/0019-5049.139009; PMID: 25197118. 27. Nutt J, Anderson V, Peacock J, et al. DBS and diathermy interaction induces severe CNS damage. Neurology 2001;56:1384–6. https://doi.org/10.1212/WNL.56.10.1384; PMID: 11376192.

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Drugs and Devices

Implantable Cardiac Electronic Devices in the Elderly Population Wei-Yao Lim, Sandeep Prabhu and Richard J Schilling 1. Department of Cardiac Electrophysiology, St Bartholomew’s Hospital, London, UK

Abstract The use of cardiac implantable electronic devices in the management of patients with heart rhythm conditions is well established. As the population ages, the use of cardiac implantable electronic devices in the elderly is likely to increase. This review provides a summary of the indications, implantation considerations and pragmatic advice on how to approach the use of these devices in this group of patients.

Keywords Cardiac implantable electronic devices, pacemakers, cardiac resynchronisation therapy, ICDs, elderly Disclosure: The authors have no conflicts of interest to declare. Received: 3 January 2019 Accepted: 9 April 2019 Citation: Arrhythmia & Electrophysiology Review 2019;8(2):143–6. DOI: https://doi.org/10.15420/aer.2019.3.4 Correspondence: Wei-Yao Lim, Department of Cardiac Electrophysiology, St Bartholomew’s Hospital, West Smithfield, London, EC1A 7BE, UK. E: Wei-Yao.Lim@bartshealth.nhs.uk Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

The number of cardiac implantable electronic devices (CIED) has been increasing year-on-year.1 This, coupled with improvements in life expectancy,2 means that more elderly patients will meet the criteria for a CIED. National and international guidelines set out clear criteria and make recommendations for CIED use based on available evidence.3–6 However, the majority of clinical trials include few, if any, elderly patients (>80 years), with supposed benefits in the elderly population extrapolated from data derived from younger patients. The aim of this review is to give an overview of the different types of CIEDs and to discuss our approach on their use in the elderly population (>75 years) going beyond guideline recommendations.

Implantable Loop Recorders Falls are a common presentation among elderly patients admitted to hospitals.7 These include mechanical falls or those resulting from a transient loss of consciousness. In the majority of cases, a detailed history, physical examination (including lying and standing blood pressure) and simple investigations such as an ECG may help determine the cause.8 The challenge lies with patients in whom a cause is not apparent but an arrhythmia is suspected either clinically or epidemiologically. Given the short duration of Holter monitoring, there is often a low yield in correlating arrhythmia with clinical symptoms. In contrast, implantable cardiac monitors can be useful in determining any correlation between symptoms and rhythms, aiding in the diagnosis of a clinically relevant arrhythmia. They are particularly helpful for patients whose initial investigations have been negative with a normal baseline ECG.9,10 The elderly population are much more likely than younger patients to have brady-arrhythmia as a cause of their syncope. Understanding the background to the fall or loss of consciousness is also critical to the decision-making process, and the following characteristics are typical of an event that may be bradycardia related:

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• Sudden loss of consciousness without any preceding symptoms. • The patient is unconscious before they hit the floor (and may have facial injury as they have not put their hands out to save themselves). • The patient feels better almost as soon as they regain consciousness. • The loss of consciousness occurs while sitting or lying (slumping over while have a meal with friends or family is a classic warning that the patient has a cardiac rhythm problem). In patients with some degree of underlying conduction disease on ECG (bifascicular or trifascicular block, marked first-degree atrio-ventricular [AV] block) then this, combined with a compelling clinical history of syncope, may warrant implantation of a pacemaker without evidence of higher-degree block correlating with symptoms.5 However, the obvious disadvantage of the loop recorder is the necessity of another syncopal episode for its diagnostic utility, minimising its suitability for high-risk patients. Although loop recorders are often used to investigate infrequent palpitations, in a patient with preserved ejection fraction (EF) and no evidence of inherited arrhythmogenic tendency, palpitations will usually represent a benign symptomatic problem. In such mildly symptomatic patients, implantation of a loop recorder is unlikely to change the management plan. Alternatives such as the hand-held, smartphone-based ECG recording devices can instead be offered to the patient or they can purchase them themselves. These may yield similar results without the need for invasive monitoring. Loop recorders can be useful to screen for asymptomatic AF, particularly in high CHA2DS2-VASc score patients who have had cryptogenic stroke.11

Pacemakers Over 80% of pacemakers are implanted in the elderly patient (mean age 75±10 years).12 The most common indication is AV block and

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Drugs and Devices Figure 1: Decision Aid for Monitoring and Pacing

Baseline conduction disease with good history Bundle brunch block First-degree AV block Bi/trifascicular block Mobitz type I

Suspected cardiac arrythmia

YES NO

CHB Mobitz type II

Offer pacing up-front

NO Implantable loop recorder

YES Pacemaker

YES

NO

CRT-P (see below)

Normal LV

Covert AF in stroke Palpitations not suitable for holter recording Cardiomyopathy/channelopathy (less relevant in elderly)

Dual-chamber PPM unless Permanent AF Frail and emergency patients (see text)

Avoiding complications Vascular access

ICDs Passive leads

Active fixation leads at septum

Extra-thoracic

Subclavian

AV = atrio-ventricular; CHB = complete heart block; CRT-P = cardiac resynchronisation therapy alone; LV = left ventricle; PPM = pacemaker.

sinus node disease. All patients with complete heart block and type 2 second-degree AV block should be implanted with a pacemaker regardless of symptoms as this has prognostic significance.5 Beyond this, pacing is generally only carried out if bradycardia is accompanied by symptoms. Elderly patients are more prone to complications. A meta-analysis by Armaganijan et al. showed that elderly patients undergoing device implantation are at increased risk of complications, in particular pneumothorax and lead dislodgements. 13 Pneumothorax conveys significant morbidity in older patients, with prolonged hospital stays and a risk of developing infections. To reduce the risk of pneumothorax, a traditional ‘blind’ subclavian puncture should be avoided wherever possible. Implantation using the cephalic vein, the use of ultrasound-guided punctures or extra-thoracic punctures with fluoroscopic guidance have been shown to reduce the risk of pneumothorax and should be used when possible.14,15 The higher incidence of lead dislodgement in the elderly is often related to an increase in venous tortuosity as well as reduced cardiac mass for lead attachment.13 Additional redundancy should be left on the lead during the implant. Data from the Pacemaker Selection in the Elderly (PASE) trial demonstrated that older age is a risk factor for lead perforation.15 Furthermore, a study by Sterlinski et al. demonstrated that – compared with passive leads – active leads were more likely to result in perforation.16 Therefore, to minimise the risk of perforation we recommend either using a passive fixation lead or an active fixation lead to the interventricular septum avoiding the right ventricular apex. While there are data demonstrating that dual-chamber may be superior to single-chamber pacemakers in the elderly regarding symptoms related to the pacemaker syndrome,17 there may be circumstances when a single-chamber system is appropriate. In frail,

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It is important to offer an individual, tailored approach when pacing is considered in the elderly. These patients are more likely to have multiple co-morbidities that could affect the decision-making process. For example, in a bed-bound patient with an incidental finding of sinus node disease who is having fleeting dizzy spells, any benefit may not outweigh the risk and inconvenience of pacemaker implantation. Therefore, when discussing therapy with any patient – but particularly the elderly where the trauma of intervention may have a bigger impact than the existing symptoms – it is important to provide clear information as to why the procedure may help so that they can weigh this up against the downsides. A decision aid for monitoring and pacing options is shown in Figure 1.

Lead selection

Cephalic

144

unstable, agitated patients presenting in complete heart block, it would be reasonable to reduce the procedure time and implant a singlelead device to render the patient safe and to avoid a more prolonged procedure that could be distressing.

ICDs are implanted either for secondary prevention in patients who have a survived cardiac arrest or as primary prevention therapy.5,6 The evidence for the use of ICDs in these situations is well established but, as in many clinical trials, the elderly (>75 years) are poorly represented in these studies with a mean age of 63 in published randomised controlled trials (RCTs).18 Healey et al. first highlighted the issue on the overall benefit of ICDs as secondary prevention by pooling data from published RCTs. They found that elderly patients had a higher incidence of non-arrhythmic deaths, minimising the benefit of an ICD. However, the modest sample of 252 elderly patients (aged ≥75 years) in this study may not reflect modern-day practice.19 Other observational studies from the Ontario database highlighted that age alone cannot be the sole predictor of mortality but rather that other co-morbidities like chronic renal failure, heart failure and chronic obstructive pulmonary disease are significant predictors of mortality.20 An analysis of real-world data on the impact on ICD for secondary prevention involving over 12,000 patients over the age of 65 years showed that, while the rates of death increased with age, four in five older patients survived beyond 2 years. However, the study did not demonstrate the mode of death. Interestingly, beyond mortality, older patients have significant morbidity following an ICD implantation with higher rates of admission to special nursing facilities and re-admission to hospitals.21 While offering an ICD as secondary prevention seems like a logical choice and in line with current guidelines, it should be noted that – although it can prolong life – ICD implantation carries certain risk of increased morbidity. In the elderly population, some patients would value quality of life rather than longevity and therefore an open and honest discussion needs to take place prior to embarking on an implant. It is important to recognise that the ICD may simply change the mode of death from a sudden one to a longer, protracted and ultimately more distressing one, with no impact upon quality of life in the intervening period. This is likely in conflict with the end-of-life expectations of most – if not all – patients. Primary prevention ICDs are indicated in patients with heart failure with a left ventricular EF <35% except those in New York Heart Association

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Implantable Cardiac Electronic Devices (NYHA) class IV and who have been on optimal medical therapy for a minimum of 3 months and expected to live more than a year.5,6 Mode of death in patients with heart failure can either be driven by a life-threatening arrhythmia or pump failure. Data from the ALTITUDE registry showed that the frequency of ICD therapy in the older age group is lower and other observational studies show that the mode of death in the elderly is more likely to be pump failure.22 Elderly patients are also more likely to have multiple co-morbidities that could impact on 1-year survival. Ferretto et al. studied patients aged >75 years who had an ICD implanted for primary prevention. The authors concluded that age alone was not a predictor of 1-year mortality but rather EF <25% and moderate to severe renal failure predicted a high 1-year non-arrhythmia death of up to 45.5%.23

Figure 2: Decision Aid for the Use of Complex Devices

Heart failure EF <35% Survival >1 year Optimal medical therapy 3 months LBBB QRSD >130 ms Non-LBBB QRSD >150 ms

Cardiac Resynchronisation Therapy Cardiac resynchronisation therapy (CRT) either alone (CRT-P) or in combination with a defibrillator (CRT-D) is well established in the treatment of patients with heart failure. Its use in the elderly is increasing, with up to 40% of CRT being implanted in patients over the age of 80 years.24 Although clinical trials do not exclude elderly patients, the major trials that influence our clinical practice have a predominantly younger population making results derived from these trials unrepresentative of the older age group. Killu et al. conducted a retrospective analysis to determine the outcomes of CRT in patients aged >80 years. They demonstrated that although overall survival was worse when compared to their younger counterparts, CRT resulted in improvement in NYHA class, EF and mitral regurgitation severity.25 Martens et al. investigated the impact of CRT on both morbidity and mortality. Their findings were similar to those of Killu et al., with improvements in NYHA class and EF compared with younger counterparts. They also showed that elderly patients had higher allcause mortality but this was no different to age-matched controls who had no heart failure. In addition, they demonstrated that elderly patients had a similar rate of heart-failure-related admissions compared to younger patients. The mode of death in octogenarians was mainly non-cardiac. When a death had a cardiac cause it was because of worsening heart failure rather than malignant arrhythmia.24 Aktas et al. analysed data from the multicentre automatic defibrillator trial and

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Not NYHA IV Offer ICD with counselling

Meets criteria for CRT

YES Non-ischaemic cardiomyopathy

Favour

The use of ICDs in heart failure patients changes the mode of death from an arrhythmia cause to one of progressive pump failure. Furthermore, although older patients have been found to be less likely to have ICD shocks, both appropriate and inappropriate shocks are likely to have a significant impact on physical and mental wellbeing.22 A clear plan for disabling anti-tachycardia therapy when approaching end-of-life care should be discussed with all patients having an ICD implanted so that they are able to make their wishes clear, ideally well in advance of any potential incapacity. It is important to ensure that the patient understands the distinction between bradycardia and tachycardia therapies when having this discussion. Generally, if one has not had the potentially uncomfortable, albeit necessary discussion with the elderly patient about how they ‘want to die’ then it is likely that one has not really given them all the information they need to decide whether an ICD is right for them.

NO

YES

YES

Ischaemic cardiomyopathy >80 years old with significant co-morbidities

CRT-D

ICD implant

NO YES

Meets CRT criteria

NO

CRT-P Previous cardiac arrest

Offer ICD with counselling

CRT = cardiac resynchronisation therapy; CRT-D = CRT in combination with defibrillator; CRT-P = CRT alone; EF = ejection fraction; LBBB = left bundle branch block; NYHA = New York Heart Association.

showed that elderly patients (>75 years) had a lower risk of ventricular tachy-arrhythmias compared with their younger counterparts (<75 years) providing further evidence to support the notion that malignant arrhythmias are less frequent in the elderly.26 The publication of the Danish Randomized, Controlled, Multicenter Study to Assess the Efficacy of Implantable Cardioverter Defibrillator in Patients With Non-ischemic Systolic Heart Failure on Mortality (DANISH) generated intense debate on whether ICD has any added value in the elderly non-ischaemic cardiomyopathy population because in the pre-specified subgroup analysis, ICDs did show benefit in younger but not older (>70 years) patients and sudden death rates in the elderly were much lower than their younger counterparts.27,28 Real-world data from a large, single-centre series29 have suggested that CRT-D does not provide additional survival benefit in patients with non-ischaemic cardiomyopathy. Recent data from two centres in the UK with a median long-term follow up of 4.7 years showed CRT-D only had mortality benefit over CRT-P in patients with ischaemic aetiology.30 Given a lack of robust RCTs, international guidelines do not advise on prescription of CRT-P or CRT-D. Data from the CeRtiTuDe cohort showed that CRT-P patients selected in routine clinical practice did not benefit from adding a defibrillator. CRT-P patients in this cohort tended to be older and mainly had a non-ischaemic aetiology.31 In addition, while there are emerging data suggesting that addition of an ICD in elderly patients (>75 years) undergoing CRT implant does not impact on survival,32 it is worth remembering CRT-P alone is an excellent treatment option, as demonstrated in the CArdiac REsynchronisation in Heart Failure (CARE-HF) study.33 The final decision on CRT-D versus CRT-P should not only be guided by heart failure aetiology but, more importantly, our patients’ expectations and desires. A decision aid guiding the use of complex devices is shown in Figure 2.

Remote Monitoring Remote monitoring has been shown to be easy to use and well accepted in the elderly population. There are two areas where this could have a significant impact in this population group. The first is

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Drugs and Devices in AF detection as elderly patients tend to have a high CHA2DS2-VASc score and remote monitoring could prevent delay in appropriate anticoagulation. The second area is in heart failure monitoring to allow for early intervention and avoid hospitalisation. Hospital admission in elderly patients can be prolonged, often leaving them deconditioned even after discharge from hospital.34

Conclusion To quote the French author Jules Renard, “it is not how old you are, but how you are old”. It is not age itself that affects the decision process but the co-morbidities that come with age that are important. Thunes et al. demonstrated that patients who underwent CRT-D implant who had more co-morbidities (high Charlson co-morbidity index) had a poorer survival.35 Risk stratification using validated scores can help guide the consultation by providing patients with objective data that could impact on their ultimate decision.36 Decision making for device implantation in elderly people should not be driven by guidelines alone. These patients may have complex co-morbidities and personal wishes that cannot be accommodated by guidelines. It is important to have a clear, open discussion

1.

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 indricks G, Camm J, Merkely B, et al. The EHRA White Book H 2017. The current status of cardiac electrophysiology in ESC Member Countries. Available at: www.escardio.org/static_file/ Escardio/Subspecialty/EHRA/Publications/Documents/2017/ ehra-white-book-2017.pdf (accessed 10 April 2019). Seshamani M, Gray A. The impact of ageing on expenditures in the National Health Service. Age Ageing 2002;31:287–94. PMID: 12147567. National Institute for Health and Care Excellence. Dual chamber pacemaker for symptomatic bradycardia due to sick sinus syndrome without atrioventricular block. London: NICE, 2014. Available at: www.nice.org.uk/guidance/ta324 (accessed 10 April 2019). National Institute for Health and Care Excellence. Implantable cardioverter defibrillators and cardiac resynchronisation therapy for arrhythmia and heart failure. London: NICE, 2014. Available at: https://www.nice.org.uk/guidance/ta314 (accessed 10 April 2019). Brignole M, Auricchio A, Baron-Esquivias G, et al. 2013 ESC guidelines on cardiac pacing and cardiac resynchronisation therapy: the Task Force on cardiac pacing and resynchronization therapy of the European Society of Cardiology (ESC). Developed in collaboration with the European Heart Rhythm Association (EHRA). Eur Heart J 2013;34:2281–329. https://doi.org/10.1093/eurheartj/eht150; PMID: 23801822. Priori S, Blomström-Lundqvist C, Mazzanti A et al. 2015 ESC guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The task force for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Eur Heart J 2015;36:2793–867. https://doi.org/10.1093/eurheartj/ ehv316; PMID: 26320108. Gale CR, Cooper C, Sayer AA. Prevalence and risk factor for falls in older men and woman: The English Longitudinal Study of Ageing. Age Aging 2016;45;789–94. https://doi.org/10.1093/ ageing/afw129; PMID: 27496938. Al-Aama T. Falls in the elderly. Can Fam Physician 2011;57:771–6. PMID: 21753098. Furukawa T, Maggi R, Bertolone C, et al. Additional diagnostic value of very prolonged observation by implantable loop recorder in observation by implantable loop recorder in patients with unexplained syncope. J Cardiovasc Electrophysiol 2012;23:67–71. https://doi.org/10.1111/j.15408167.2011.02133.x; PMID: 21777327. Bringole M, Moya A, De Lange FJ, et al. 2018 ESC guidelines for the diagnosis and management of syncope. Eur Heart J 2018:39:1883–948. https://doi.org/10.1093/eurheartj/ehy037; PMID: 29562304. Sanna T, Diener HC, Passman RS, et al. CRYSTALAF Investigators. Cryptogenic stroke and underlying atrial fibrillation. N Eng J Med 2014;370:2478–86. https://doi. org.10.1056/NEJMoa1313600; PMID: 24963567. Bradshaw PJ, Stobie P, Knuiman MW, et al. Trends in the incidence and prevalence of cardiac pacemaker insertion in an aging population. Open Heart 2014;1:e000177. https://doi. org/10.1136/openhrt-2014-000177; PMID: 25512875. Armaganijan LV, Toff WD, Nielsen JC, et al. Are elderly patients at increased risk of complications

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with patients about the reasons for device therapy and to ensure this meets their expectations and wishes. This sometimes can be challenging in the presence of other family members where their wishes and views may not be aligned with the patient’s. Therefore there may be times when one has to ensure that the patient has a genuine opportunity to individually assess their treatment options, albeit keeping in mind that having the family engaged and involved is crucial.

Clinical Perspective • Prolonged cardiac monitoring is useful in making a diagnosis but often a pragmatic approach is recommended in the elderly. • Peri-procedural complications can have a drastic impact on elderly patients and our approach should be adapted to reduce such risk. • ICDs save lives but can impact on long-term morbidity. • CRT confers functional and mortality benefits in the elderly and should not be withheld. • A holistic, patient-centred approach is essential in care delivery.

following pacemaker implantation? A meta-analysis of randomised trials. Pacing Clin Electrophysiol 2012;35:131–4. https://doi.org/10.1111/j.1540-8159.2011.03240.x; PMID: 22040168. Kirkfeldt RE, Johansen JB, Nohr EA, et al. Pneumothorax in cardiac pacing: a population based cohort study of 28,860 Danish patients. Europace 2012;14:1132–8. https://doi. org/10.1093/europace/eus054; PMID: 22431443. Link MS, Estes NA 3rd, Griffin JJ, et al. Complication of dual chamber pacemaker implantation in the elderly. Pacemaker selection in the elderly (PASE) investigators. J Interv Card Electrophysiol 1998;2:175–9. https://doi. org/10.1023/A:1009707700412; PMID: 9870010. Sterlinski M, Przybylski A, Maciag A, et al. Subacute cardiac perforation associated with active fixation leads. Europace 2009;11:206–12. https://doi.org/10.1093/europace/eun363; PMID: 19109359. 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. Pacemaker Selection in the Elderly Investigators. N Engl J Med 1998;338:1097–104. https://doi.org/10.1056/ NEJM199804163381602; PMID: 9545357. Connolly SJ, Hallstrom AP, Cappato R, et al. Meta‐analysis of the implantable cardioverter defibrillator secondary prevention trials. AVID, CASH, and CIDS studies. Eur Heart J 2000;21:2071–8. https://doi.org/10.1053/euhj.2000.2476; PMID: 11102258. Healey JS, Hallstrom AP, Kuck KH, et al. Role of the implantable defibrillator among elderly patients with a history of life-threatening ventricular arrhythmias. Eur Heart J 2007 28;1746–9. https://doi.org/10.1093/eurheartj/ehl438; PMID: 17283003. Yung D, Birnie D, Dorian P, et al. Survival after implantable cardioverter‐defibrillator implantation in the elderly. Circulation 2013;127:2383–92. https://doi.org/10.1161/ CIRCULATIONAHA.113.001442; PMID: 23775193. Betz JK, Katz DF, Peterson PN, et al. Outcomes among older patients receiving implantable cardioverter-defibrillators for secondary prevention: From the NCDR ICD Registry. J Am Coll Cardiol 2017;69:265–74. https://doi.org/10.1016/j. jacc.2016.10.062; PMID: 28104069. Saxon LA, Hayes DL, Gilliam FR, et al. Long-term outcome after ICD and CRT implantation and influence of remote device follow-up: the ALTITUDE survival study. Circulation 2010;122:2359–67. https://doi.org/10.1161/ CIRCULATIONAHA.110.960633; PMID: 21098452. Ferretto S, Zorzi A, Dalla Valle C, et al. Implantable cardioverter defibrillator in the elderly: predictors of appropriate interventions and mortality at 12 months follow up. Pacing Clin Electrophysiol 2017;40:1368–73. https://doi. org/10.1111/pace.13215; PMID: 28994461. Martens P, Verbrugge FH, Nijst P, et al. Mode of death in octogenarians treated with cardiac resynchronisation therapy. J Card Fail 2016;22:970–7. https://doi.org/10.1016/j. cardfail.2016.09.023; PMID: 27717763. Killu AM, Wu JH, Friedman PA, et al. Outcomes of cardiac resynchronisation therapy in the elderly. Pacing Clin

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Electrophysiol 2013;36:664–72. https://doi.org/10.1111/ pace.12048; PMID: 23252710. Aktas MK, Goldenberg I, Moss AJ, et al. Comparison of age (<75 years versus >75 years) to risk of ventricular tachyarrhythmias and implantable cardioverter defibrillator shocks (from the Multicentre Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy). Am J Cardiol;2014:114:1855–60. https://doi.org/10.1016/j. amjcard.2014.09.026; PMID: 25438913. Køber L, Thune JJ, Nielsen JC, et al. Defibrillator implantation in patients with nonischaemic systolic heart failure. N Eng J Med 2016;375:1211–30. https://doi.org/10.1056/NEJMoa1608029; PMID: 27571011. Elming MB, Nielsen JC, Haarbo J, et al. Age and outcome of primary prevention implantable cardioverter defibrillators in patients with nonischaemic systolic heart failure. Circulation 2017;136:1772–80. https://doi.org/10.1161/ CIRCULATIONAHA.117.028829; PMID: 28877914. Kutyifa V, Geller L, Bogyi P, et al. Effects of cardiac resynchronistion therapy with implantable cardioverter defibrillator versus cardiac resynchroisation therapy with pacemaker on mortality in heart failure pateints: Results of a high volume, single centre experience. Eur J Heart Fail 2014;16:1323–30. https://doi.org/10.1002/ejhf.185; PMID: 25379962. Leyva F, Zegard A, Umar F, et al. Long-term clinical outcomes of cardiac resynchronisation therapy with or without defibrillation: impact of the aetiology of cardiomyopathy. Europace 2018;20:1804–12. https://doi.org/10.1093/europace/ eux357; PMID: 29697764. Marijon E, Leclercq C, Narayanan K, et al. Causes of death analysis of patients with cardiac resynchronisation therapy: An analysis of the CeRtiTuDe cohort study. Eur Heart J 2015;36:2767–76. https://doi.org/10.1093/eurheartj/ehv455; PMID: 26330420. Döring M, Ebert M, Dagres N, et al. Cardiac resynchronisation therapy in the ageing population – with of without an implantable defibrillator? Int J Cardiol 2018:263:48–53. https:// doi.org/10.1016/j.ijcard.2018.03.087; PMID: 29754922. Cleland JG, Daubert JC, Ermann E, et al. The effect of cardiac resynchronisation on morbidity and mortality in heart failure. N Eng J Med 2005;352:1539–49. https://doi.org/10.1056/ NEJMoa050496; PMID: 15753115. Ricci RP, Morichelli L, Varma N. Remote monitoring for follow-up patients with cardiac implantable electronic devices. Arrhythm Electrophysiol Rev 2014;3:123–8. https://doi. org10.15420/aer.2014.3.2.123; PMID: 26835079. Theuns DA, Schaer BA, Soliman OI, et al. The prognosis of implantable defibrillator patients treated with cardiac resynchronisation therapy: comorbity burden as predictor of mortality. Europace 2011;13:62–9. https://doi.org/10.1093/europace/euq328; PMID: 20833692. Goldenberg I, Vyas AK, Hall WJ, et al. Risk stratification for primary implantation of cardioverter-defibrillator in patients with ischemic left ventricular dysfunction. J Am Coll Cardiol 2008:51:288–96. https://doi.org/10.1016/j.jacc.2007.08.058; PMID: 18206738.

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Arrhythmia & Electrophysiology Review Volume 8 Issue 2 Spring 2019