AER 8.4 by Radcliffe Cardiology

Arrhythmia & Electrophysiology Review Volume 8 • Issue 4 • Winter 2019

Volume 8 • Issue 4 • Winter 2019

www.AERjournal.com

Unmasking Adenosine: The Purinergic Signalling Molecule Critical to Arrhythmia Pathophysiology and Management Gareth DK Matthews and Andrew A Grace

Idiopathic Left Ventricular Tachycardia Originating in the Left Posterior Fascicle Hongwu Chen, Kit Chan, Sunny S Po and Minglong Chen

Multimodality Imaging to Guide Ventricular Tachycardia Ablation in Patients with Non-ischaemic Cardiomyopathy Ling Kuo, Jackson J Liang, Saman Nazarian and Francis E Marchlinski

High-power, Short-duration Radiofrequency Ablation for the Treatment of AF Irum D Kotadia, Steven E Williams and Mark O’Neill

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Association Between Anteroseptal scar of basal LV on CMRMultimodality

Treatment Double Potential Planning Required for Idiopathic dilated cardiomyopathy with Intramural Late Cardiac SBRT Gadolinium Enhancement and Termination of Ventricular Tachycardia

Use of ICE to Incorporate the Moderator Band and Associated Intracardiac Structures Into the Electroanatomic Map to Facilitate Ablation

ISSN – 2050-3369

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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

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

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Volume 8 • Issue 4 • Winter 2020

www.AERjournal.com Official journal of

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

Section Editor – Arrhythmia Mechanisms / Basic Science

Section Editor – Implantable Devices

Section Editor – Arrhythmia Risk Stratification

University of Cambridge, Cambridge

Virginia Commonwealth University School of Medicine, Richmond, VA

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

Section Editor – Clinical Electrophysiology and Ablation

Section Editor – Atrial Fibrillation Gregory YH Lip

Section Editor – Imaging in Electrophysiology

Johns Hopkins Medicine, Baltimore, MD

Liverpool Centre for Cardiovascular Science, University of Liverpool

Sanjiv M Narayan

Stanford University Medical Center, CA

Angelo Auricchio

Carsten W Israel

Douglas Packer

Fondazione Cardiocentro Ticino, Lugano

JW Goethe University, Frankfurt

Mayo Clinic, St Mary’s Campus, Rochester, MN

Charles Antzelevitch

Warren Jackman

Carlo Pappone

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

IRCCS Policlinico San Donato, Milan

Sunny Po

Pierre Jaïs

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

Andrew Grace

Hugh Calkins

Ken Ellenbogen

Pier D Lambiase

Editorial Board

Lankenau Institute for Medical Research, Pennsylvania, PA

Joseph G Akar Yale University School of Medicine, New Haven, CT

Carina Blomström-Lundqvist Uppsala University, Uppsala

Johannes Brachmann Klinikum Coburg, II Med Klinik, Coburg

Josep Brugada

Hospital Sant Joan de Déu, University of Barcelona, Barcelona

Pedro Brugada

Roy John Northshore University Hospital, New York, NY

Prapa Kanagaratnam

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

Frédéric Sacher

Imperial College Healthcare NHS Trust, London

Bordeaux University Hospital, Electrophysiology and Heart Modelling Institute, Bordeaux

Josef Kautzner

Richard Schilling

Institute for Clinical and Experimental Medicine, Prague

Barts Health NHS Trust, London

University of Brussels, UZ-Brussel-VUB

Roberto Keegan

Alfred Buxton

Afzal Sohaib

Hospital Privado del Sur, Bahia Blanca, Argentina

Imperial College London, London

Beth Israel Deaconess Medical Center, Boston, MA

Karl-Heinz Kuck

William Stevenson

Asklepios Klinik St Georg, Hamburg

Vanderbilt School of Medicine, Nashville, TN

Cecilia Linde

Richard Sutton

David J Callans University of Pennsylvania, Philadelphia, PA

A John Camm St George’s University of London, London

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

Harry Crijns Maastricht University Medical Center, Maastricht

Sabine Ernst

Cover image © AdobeStock

University of Bordeaux, CHU Bordeaux

National Heart and Lung Institute, Imperial College London, London

Karolinska University, Stockholm

Francis Marchlinski University of Pennsylvania Health System, Philadelphia, PA

John Miller Indiana University School of Medicine, Indiana, IN

Fred Morady Cardiovascular Center, University of Michigan, MI

Royal Brompton & Harefield NHS Foundation Trust, London

Andrea Natale

Hein Heidbuchel Antwerp University and University Hospital, Antwerp

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

Gerhard Hindricks

Mark O’Neill

University of Leipzig, Leipzig

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

Panos Vardas Heraklion University Hospital, Heraklion

Marc A Vos University Medical Center Utrecht, Utrecht

Hein Wellens University of Maastricht, Maastricht

Katja Zeppenfeld Leiden University Medical Center, Leiden

Douglas P Zipes Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapoli, IN

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Managing Editor Ashlynne Merrifield | Production Editor Aashni Shah Publishing Director Leiah Norcott | Senior Designer Tatiana Losinska Contact ashlynne.merrifield@radcliffe-group.com

Key Account Directors Rob Barclay, David Bradbury, Gary Swanston Accounts Team William Cadden, Bradley Wilson Contact rob.barclay@radcliffe-group.com

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Marketing Manager Gabriela Montoya Contact gabriela.montoya@radcliffe-group.com

Chief Executive Officer David Ramsey Chief Operations Officer Liam O’Neill

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: Winter 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

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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 Medical Media retains 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 charges 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. Waivers are available. For further details, please visit: https://www.aerjournal.com/aer-information-authors.

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 Foreword

238

Demosthenes G Katritsis DOI: https://doi.org/10.15420/aer.8.4.FO1

Drugs and Devices Unmasking Adenosine: The Purinergic Signalling Molecule Critical to Arrhythmia Pathophysiology and Management

240

Gareth DK Matthews and Andrew A Grace DOI: https://doi.org/10.15420/aer.2019.05

Clinical Arrhythmias Idiopathic Left Ventricular Tachycardia Originating in the Left Posterior Fascicle

249

Hongwu Chen, Kit Chan, Sunny S Po and Minglong Chen DOI: https://doi.org/10.15420/aer.2019.07

Electrophysiology and Ablation Multimodality Imaging to Guide Ventricular Tachycardia Ablation in Patients with Non-ischaemic Cardiomyopathy

255

Ling Kuo, Jackson J Liang, Saman Nazarian and Francis E Marchlinski DOI: https://doi.org/10.15420/aer.2019.37.3

High-power, Short-duration Radiofrequency Ablation for the Treatment of AF

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Irum D Kotadia, Steven E Williams and Mark O’Neill DOI: https://doi.org/10.15420/aer.2019.09

Challenges Associated with Interpreting Mechanisms of AF

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Caroline H Roney, Andrew L Wit and Nicholas S Peters DOI: https://doi.org/10.15420/aer.2019.08

Non-invasive Stereotactic Radioablation: A New Option for the Treatment of Ventricular Arrhythmias

285

Chen Wei, Pierre Qian, Usha Tedrow, Raymond Mak and Paul C Zei DOI: https://doi.org/10.15420/aer.2019.04

Arrhythmias from the Right Ventricular Moderator Band: Diagnosis and Management

294

Megan Barber, Jason Chinitz and Roy John DOI: https://doi.org/10.15420/aer.2019.18

Ivabradine and AF: Coincidence, Correlation or a New Treatment? A Review Article

300

Mahmoud Abdelnabi, Ashraf Ahmed, Abdallah Almaghraby, Yehia Saleh and Haitham Badran DOI: https://doi.org/10.15420/aer.2019.30.2

Corrigendum Corrigendum to: Preventive Ventricular Tachycardia Ablation in Patients with Ischaemic Cardiomyopathy: Meta-analysis of Randomised Trials

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Roland R Tilz, Charlotte Eitel, Evgeny Lyan, Kivanc Yalin,Spyridon Liosis, Julia Vogler, Ben Brueggemann, Ingo Eitel, Christian Heeger, Ahmed AlTurki and Riccardo Proietti DOI: https://doi.org/10.154210/aer.2019.8.4.CG1

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Foreword

Evolution of the Editorial Board Underpins a Commitment to Change and Innovation

“It is not the strongest of the species that survives, nor the most intelligent that survives. It is the one that is most adaptable to change.”

his famous quotation from the great Charles Darwin has always guided Arrhythmia & Electrophysiology Review and its editorial staff. One of the journal’s foundations is an unconditional commitment to change and innovation. This principle is not only a prerequisite for intellectual motivation and excitement, but it is also essential for survival in a rapidly evolving digital era. Changes in our editorial board and section editing in part reflect this attitude. We are happy to announce a restructure of our focused sections, with new section editors: • Ken Ellenbogen Section Editor (Implantable Devices) Virginia Commonwealth University School of Medicine, Richmond, VA, US • Gregory YH Lip Section Editor (Atrial Fibrillation) Liverpool Centre for Cardiovascular Science, University of Liverpool, Liverpool, UK • Pier D Lambiase Section Editor (Arrhythmia Risk Stratification) Institute of Cardiovascular Science, University College London, and Barts Heart Centre, London, UK • Sanjiv M Narayan Section Editor (Imaging in Electrophysiology) Stanford University Medical Center, CA, US These distinguished colleagues, together with Andrew Grace and Hugh Calkins, will undoubtedly upgrade our publishing of highquality, focused articles that relate to their area of expertise. Angelo Auricchio has stepped down as Section Editor because this conflicts with his Europace editorial role, but remains on our editorial board. His contribution has been exemplary, and I am personally indebted. I am sure Angelo will continue his great job as an editorial board member. In the continued evolution of our editorial board, we are happy to welcome new members: • Douglas Packer Mayo Clinic, Rochester, MN, US • Harry Crijns Maastricht University Medical Center, the Netherlands • Shih-Ann Chen National Yang Ming University School of Medicine and Taipei Veterans General Hospital, Taipei, Taiwan

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Access at: www.AERjournal.com

Foreword • Roberto Keegan Hospital Privado del Sur, Bahia Blanca, Argentina • Joseph G Akar Yale University School of Medicine, New Haven, CT, US • Roy John North Shore University Hospital, New York, NY, US I am sure none of these experts needs an introduction to the electrophysiology community. Their wholehearted willingness to participate attests to the international appeal of the journal and is, indeed, hugely encouraging to all of us to continue with more determination than ever. Finally, I would like to express my sincerest thanks and deepest appreciation to the board members who have stepped down: • Riccardo Cappato • Samuel Lévy • Antonio Raviele Their assistance and support have been vital for the success of the journal so far. I am sure that they will continute to be involved as authors and reviewers for Arrhythmia & Electrophysiology Review. Demosthenes G Katritsis Editor-in-Chief, Arrhythmia & Electrophysiology Review Hygeia Hospital, Athens, Greece

DOI: https://doi.org/10.15420/aer.8.4.FO1

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

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Drugs and Devices

Unmasking Adenosine: The Purinergic Signalling Molecule Critical to Arrhythmia Pathophysiology and Management Gareth DK Matthews 1,2 and Andrew A Grace 2,3 1. Cambridge University NHS Foundation Trust, Cambridge, UK; 2. Royal Papworth Hospital NHS Foundation Trust, Cambridge, UK; 3. Department of Biochemistry, University of Cambridge, Cambridge, UK

Abstract Adenosine was identified in 1929 and immediately recognised as having a potential role in therapy for arrhythmia because of its negative chronotropic and dromotropic effects. Adenosine entered mainstream use in the 1980s as a highly effective agent for the termination of supraventricular tachycardia (SVT) involving the atrioventricular node, as well as for its ability to unmask the underlying rhythm in other SVTs. Adenosine has subsequently been found to have applications in interventional electrophysiology. While considered a safe agent because of its short half-life, adenosine may provoke arrhythmias in the form of AF, bradyarrhythmia and ventricular tachyarrhythmia. Adenosine is also associated with bronchospasm, although this may reflect irritant-induced dyspnoea rather than true obstruction. Adenosine is linked to numerous pathologies relevant to arrhythmia predisposition, including heart failure, obesity, ischaemia and the ageing process itself. This article examines 90 years of experience with adenosine in the light of new European Society of Cardiology guidelines for the management of SVT.

Keywords Adenosine, supraventricular, tachycardia, purine, bradycardia, heart block, European Society of Cardiology, guidelines, ageing, obesity, heart failure Disclosure: The authors have no conflicts of interest to declare. Received: 27 July 2019 Accepted: 8 November 2019 Citation: Arrhythmia & Electrophysiology Review 2019;8(4):240–8. DOI: https://doi.org/10.15420/aer.2019.05 Correspondence: Gareth Matthews, Murray Edwards College, University of Cambridge, Huntingdon Road, Cambridge CB3 0DF, UK. E: gdkm2@cam.ac.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 use of adenosine in cardiology is ubiquitous. From arrhythmia to coronary intervention to cardiac imaging, adenosine is an essential part of everyday practice because of its widespread effects on electrophysiology and the coronary vasculature. Electrophysiologists will be most familiar with adenosine for its use in terminating supraventricular tachycardias (SVTs) that are dependent on the atrioventricular node (AVN) and in unmasking underlying rhythms. Decades of clinical experience in the use of adenosine in SVT have refined its clinical applications as reflected in the 2019 update of European Society of Cardiology guidelines for this condition.1 The role of adenosine in disorders encountered in cardiac electrophysiology is set to expand as patients increasingly survive ischaemic heart disease, populations become older and the burden of metabolic syndrome manifests. Adenosine signalling also has roles in atrial flutter, AF and ventricular arrhythmia. New research strongly implicates adenosine in other conditions associated with cardiac consequences, such as obesity, diabetes and pulmonary disease. This article provides an updated and encompassing review of the role of exogenous and endogenous adenosine on cardiac electrophysiology, and provides insights into its potential future therapeutic uses.2,3

Adenosine Discovery and Early Characterisation Sir Alan Nigel Drury and Sir Albert Szent-Györgyi (Figure 1), who worked at the University of Cambridge in the departments of pathology and

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biochemistry respectively, are widely acknowledged as being the first to identify the actions of adenosine on the heart in 1929.4 In the same year this work was published, Karl Lohmann was accredited with the discovery of adenosine triphosphate (ATP); these combined works heralded the beginnings of purinergic science.5 Szent-Györgyi later received the Nobel Prize in 1937 for his work on vitamin C and components of the citric acid cycle. Drury, who had previously worked closely with ECG pioneer Sir Thomas Lewis, had been responsible for seminal observations on the re-entrant mechanism of atrial flutter, vagal stimulation and the mechanism of quinidine in AF.6–9 Drury and Szent-Györgyi found that injecting extracts from bullock heart into small animals resulted in transient bradycardia, which was recorded using ECGs (Figure 2A). This was not antagonised by atropine, suggesting a mechanism independent of vagal stimulation. The extract was purified and shown to be composed of adenine, a pentose sugar and phosphoric acid, and was chemically similar to adenosine monophosphate (AMP). Adenosine and adenosine diphosphate (ADP) had similar cardiac effects, whereas other nucleoside products, such as guanosine, did not. The mechanism of the bradycardia was highgrade atrioventricular (AV) block, although sinus bradycardia was observed at higher doses. The effect typically occurred 10–12 seconds following administration, with the maximal effect at 15–30 seconds. Adenosine was also shown to reduce the refractory period and augment conduction velocity during pacing at high heart rates. They

Unmasking Adenosine hypothesised a role for adenosine in terminating atrial flutter and AF, attributed to its effect on the atrial refractory period. The translation of adenosine use from animal studies into humans was swift, with broadly similar results found a year later.10

Figure 1: Sir Alan Drury and Sir Albert Szent-Györgyi

Pharmacology of Adenosine Adenosine is an endogenous purine formed by adenine and D-ribose produced from the degradation of ATP, ADP and AMP by ectoenzymes (predominantly CD39 and CD73) which is a process universal to most mammalian cells.11 The production of adenosine is widely employed in cellular signalling as an indication of ATP turnover. Extracellular adenosine levels may be elevated by additional release from cardiomyocytes, platelets, endothelium and nerves induced by ischaemia/hypoxia, catecholamines and calcium.12,13 There are four G-protein coupled adenosine receptor subtypes present in cardiac tissue: A1 (Galphai), A2A(Galphas), A2B(Galphas) and A3(Galphai), which critically affect three main aspects of cardiac physiology. First, adenosine induces coronary vasodilatation, increasing blood flow according to tissue demand.14,15 This is mediated by A2 receptor signalling, especially A2A, with high potency due to large receptor reserves.16,17 Second, adenosine has negative inotropic effects via antagonism of sympathetic pathways.18,19 Third, adenosine exerts major electrophysiological effects, predominantly mediated by the A1 receptors with AMP and adenosine being 10-fold more efficacious in direct actions on downstream currents than ATP in pharmacological studies.20,21 Abrogation of electrophysiological effects by inhibiting conversion of AMP to adenosine or accelerating the metabolism of adenosine to inosine suggest that adenosine is the primary mediator of endogenous signalling at the A1 receptor.21 The cardiac expression of A1 receptors and associated G-proteincoupled, inward-rectifying potassium (GIRK) channels is concentrated in the right atrium; this is three times higher than it is in the left atrium, especially in superolateral regions. This regional heterogeneity in expression results in greater reduction in right atrial action potential duration (APD) in response to adenosine.22 Adenosine has a short half-life of less than 10 seconds, typically being cleared from the plasma within 30 seconds either by adenosine deaminase, which is present in erythrocytes and vascular endothelium, or by phosphorylation to AMP. A short half-life, as in many applications, can be advantageous because effects are short lived, which limits the potential for adverse events. However, this means both direct oral administration and long-term therapy are precluded. It can also result in drug delivery issues because a peripherally administered adenosine bolus is subject to significant dispersion and longer transit times. This allows greater metabolism and results in higher and more variable dosages. Therefore, it is advocated that adenosine should be delivered either via a central line or a large-bore cannula placed, for example, in the antecubital fossa.1,23 Methylxanthines, such as caffeine and theophylline, are adenosine antagonists, reducing its effect. Caffeine ingested within 4–6 hours, but not 6–8 hours, may mean a higher dose is required.24 Dipyridamole, an antiplatelet and vasodilatory agent, accentuates the actions of adenosine by inhibiting metabolism by adenosine deaminase; it does this both directly and, more importantly, indirectly by preventing erythrocyte uptake of adenosine where it is subsequently deaminated by inhibition of adenosine transporters.25–27

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Sir Alan Drury (left) and Sir Albert Szent-Györgyi (right) are accredited with the discovery of adenosine’s cardiac action. Sources: Drury: Walter Stoneman. Reproduced with permission from the National Portrait Gallery, London. Szent-Györgyi: JW McGuire, National Institutes of Health. Reproduced with permission from the National Library of Medicine.

Figure 2: Effects of Adenosine Administration A

1 sec

Onset of atrioventricular block

A: From the original work of Drury and Szent-Györgyi; the first ECG record showing the negative chronotropic effects of IV adenosine administration.4 Bovine cardiac extract was injected into an anaesthetised guinea pig via the jugular vein and an ECG trace recorded. Within 3 seconds, there was complete atrioventricular dissociation followed by full conduction recovery within 9–12 seconds. The reaction could be “repeatedly obtained by re-injection”. B: The striking clinical translation with the unmasking of human atrial flutter following IV administration of adenosine. Sources: A: Drury and Szent-Györgyi, 1929.4 Reproduced with permission from Wiley. B: Camm and Garratt, 1991.169 Reproduced with permission from Massachusetts Medical Society.

Electrophysiological Effects of Adenosine Adenosine exerts its electrophysiological effects via the A1 receptor, which couples with GIRK channels, similar to the mechanism of the muscarinic acetylcholine receptor.28 There may also be interactions with the KATP channel.29 GIRK channels are responsible for the IKAdo current, which causes membrane hyperpolarisation. In addition, the Galphai subunit of the A1 receptor inhibits cyclic AMP (cAMP) production, therefore reducing the beta1-adrenoreceptor response to catecholamines and reducing L-type Ca2+ channel currents, again paralleling muscarinic pathways.30 Increased IKAdo results in a reduced APD and therefore a shorter refractory period.21 Because of a greater receptor reserve and therefore downstream amplifying signalling pathways, adenosine is 11 times more efficacious at inhibiting beta1adrenoreceptor response than activating IKAdo.31,32 Regional variations in cardiac adenosine response are dependent on the density of adenosine receptors as well as site-specific variations in function, other receptor expression and ion channel distributions. Membrane hyperpolarisation and reduction in cAMP levels in the

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Drugs and Devices sinoatrial node result in negative chronotropy via reduced pacemaker currents (If), with effects being more pronounced in conditions of higher sympathetic drive.33,34 Additional negative chronotropic effects might be mediated by reductions in cytosolic Ca2+ release and subsequent decreases in repolarising K+ channels that regulate automaticity.35 In the AVN, which shows high A1 receptor density in the nodal region, the inhibitory effects of adenosine result in negative dromotropy and reduced gradient of the cardiac upstroke.20 In atrial myocardium, shortening of the APD and reduced cAMP result in reduced inotropy and refractory period.36 His-Purkinje automaticity is reduced by adenosine in the basal state but more markedly in the presence of catecholamines.37,38 The ventricular myocardium is relatively unaffected by adenosine at rest; however, ventricular APD and inotropy are reduced by adenosine in the presence of increased sympathetic tone.39 The effects of ATP are broadly similar to those of adenosine, reflecting the rapid metabolism of ATP to adenosine that likely exerts direct cardiac actions with high potency at a molecular level.21 However, ATP has the additional effects of increasing vagal tone via P2X receptor stimulation, which potentially explains the more potent in vivo bradycardic effects of ATP on a mole-for-mole basis.40,41

Role of Adenosine in Supraventricular Tachycardia Presentation with SVT in the emergency department is common and accounts for significant repeat attendance. SVT usually results in unpleasant symptoms of palpitations and pre-syncope, but is rarely life-threatening in isolation and often spontaneously selfterminates. Guideline-based management of SVT suggests a trial of vagal manoeuvres in the first instance, because these may be effective in up to 43% of patients, particularly modified Valsalva techniques.1,42 Valsalva techniques may be contraindicated in recent MI or stroke, glaucoma, retinopathy, carotid artery stenosis, aortic stenosis or the third trimester of pregnancy.43 Adenosine is then recommended if vagal manoeuvres fail or are inappropriate, and is successful in approximately 90% of cases. Direct current cardioversion is indicated if the patient is haemodynamically compromised.

Atrioventricular Node-dependent Supraventricular Tachycardia The first published reports of purinergic compounds employed to terminate tachycardias were in 1955 and used ATP.44 However, purinergic compounds did not enter widespread clinical use until the 1980s, when DiMarco et al. first demonstrated the clinical efficacy of adenosine and Greco et al. showed the efficacy of ATP in the termination of SVT.45–47 These case series showed adenosine to be efficacious in SVTs where the re-entrant circuit involved the AVN, particularly atrioventricular re-entrant tachycardia and atrioventricular node re-entrant tachycardia. Adenosine and ATP are thought to have similar efficacy at terminating SVT.48 Side-effects were noted to be minor and transient, but doses required were variable. This was accounted for by rapid clearance, variable rates of injection through different cannula sizes and the patient’s degree of intrinsic sympathetic tone. In SVTs that were not AVN-dependent, adenosine was established to be useful in unmasking underlying rhythms when these were obscured by rapid ventricular capture. Adenosine can also be used off label to elucidate dual AVN physiology or concealed accessory pathways to facilitate ablation procedures.49,50

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While adenosine is effective at terminating AVN-dependent SVT, other pharmacological agents are also useful.1 Calcium channel antagonists (CCAs), of which verapamil is the best studied, are often reluctantly prescribed by general physicians in the emergency department. The potentially mortal risks of verapamil in patients with ventricular arrhythmia misdiagnosed as SVT have earned it the unfortunate epithet of ‘verapakill’. However, when used appropriately in SVT, CCAs are as clinically effective as adenosine.51 The time to cardioversion with CCAs is slightly longer and the risk of hypotension is slightly greater, although the latter is rare and is mitigated by slower infusions.42 The rates of minor side-effects were higher with adenosine. CCAs may therefore be a good alternative to adenosine where patients are haemodynamically stable and in whom adenosine is contraindicated. The longer half-life of verapamil may also make it more cost effective as a single administration than repeated doses of adenosine, and it may be more suitable for longerterm administration. However, CCAs should be avoided in heart failure, concomitant beta-blocker use and in broad complex tachycardias that might represent ventricular tachycardia (VT). Both adenosine and CCAs are superior to beta-blockers in SVT termination, and beta-blockers are associated with an increased risk of hypotension, which makes them a third-line therapy.1 The exception to this is in pregnancy, where adenosine (which does not cross the placenta) is used as first-line therapy and beta-blockers might be considered before CCAs because the latter pose an increased risk to the fetus.42 Attempts to reduce the burden of SVTs on emergency departments have included examining paramedic-led adenosine administration in the community when the patient has a narrow complex tachycardia without a history of structural or ischaemic heart disease.52 Successful adenosine cardioversion at the scene of presentation allows immediate discharge of certain patients with follow-up arranged by the primary care physician. In this study, 81% of adenosine-treated patients cardioverted to sinus rhythm and 77% of these could be directly discharged, accounting for more than half of the patients treated. Paramedic-led care was associated with faster treatment times, higher patient satisfaction and a significant cost reduction of about one third. Follow-up rates were similar for paramedic and hospital treated patients. This is important because, while adenosine is effective in the termination of AVN-dependent SVT in the short term, ablation should be considered as the gold-standard, long-term treatment.1 Healthcare use analysis shows that patients seen by an electrophysiologist have a reduced need for emergency services for future episodes and that 78% of the patients referred to an electrophysiologist were subsequently ablated, with a 91% success rate.53 Adenosine sensitivity identified patients who were more likely to respond to ablation therapy. SVTs are the most commonly encountered arrhythmias in children and may precipitate heart failure in infants.54 Vagal manoeuvres terminate 25% of paediatric cases, with adenosine success in 79% of cases.55 SVT refractory to adenosine is encountered in 15% and is more likely in younger infants; higher doses may be required in these circumstances.54 The reasons for this are not clear but contributors might include the smaller calibre of paediatric cannulae, relative AVN insensitivity or late presentation after which decompensation has already occurred. Verapamil is contraindicated in infants, making

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Unmasking Adenosine adenosine the preferred agent, although digoxin, propranolol, amiodarone and procainamide have been used.

Atrioventricular Node-independent Supraventricular Tachycardia The circuit in atrial flutter is not AVN dependent so adenosine will not reliably terminate this rhythm. However, the dromotropic effect of adenosine results in ventricular slowing so it is frequently used in the emergency department to evaluate the underlying rhythm in narrow complex tachycardia (Figure 2B). While this is perceived as a low-risk manoeuvre, some case reports suggest haemodynamic instability can occasionally be induced by conversion to 1:1 AVN conduction, induction of AF or increased catecholaminergic drive with paradoxical worsening of tachycardia.56,57 It is therefore advisable that adenosine be avoided if the underlying rhythm is clear from the 12-lead ECG without need for unmasking manoeuvres.58 In the context of a broad complex tachycardia, where atrial flutter with aberrant conduction is suspected, adenosine is safer to use than a CCA.59 Several mechanistic studies suggest that atrial flutter is critically dependent on antecedent AF to produce a line of block between the superior and inferior vena cava, allowing re-entry around the cavotricuspid isthmus (CTI).60,61 This is supported by the results of the Impact of Different Ablation Approaches on Outcome In Coexistent Atrial Fibrillation and Flutter (APPROVAL) study, where ablation outcomes were improved by concomitant flutter and AF ablations, compared to flutter ablation alone. Animal models investigating this mechanism have shown that purine administration may reduce the refractory period of this line of block, preventing it from being sustained and thus converting flutter to AF.62 The implications of this are important for unmasking the underlying rhythm in a narrow, complex tachycardia because adenosine might convert an underlying flutter into AF, therefore misleading the interpretation of the culprit rhythm. Adenosine has been advocated in ablation procedures for the assessment of dormant connection. Injury currents set up as a result of ablation result in membrane depolarisation, which in turn inactivates voltage-gated Na+ channels preventing initiation of excitation. Over time, these injury currents dissipate and the membrane potential may recover, allowing previously isolated regions to propagate. Adenosine transiently hyperpolarises injured regions, which may become electrically excitable following a recovery period, thus unmasking dormant connections.63 Some clinical studies demonstrate an increased detection of dormant connections of the pulmonary veins during AF ablation following adenosine testing, while others have not shown longterm improvements in outcome. 64â&#x20AC;&#x201C;66 This discrepancy might be due to differences in study protocol.63 Adenosine has also been advocated in CTI-dependent atrial flutter ablations to assess for dormant connections.67,68 A negative adenosine provocation test with bi-directional block after CTI ablation is strongly predictive that reconnection will not occur and may be used to reduce procedure duration by decreasing assessment time for reconnection.69

Role of Adenosine in Other Electrical Cardiac Pathology Ventricular Arrhythmia In contrast to the sinoatrial node, AVN and atrial structures, previous animal studies have suggested that the ventricular

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myocardium has negligible GIRK channels, and therefore the direct electrophysiological effects of adenosine in reducing refractory period are absent.39,70 More recent human studies, however, have demonstrated GIRK expression in the ventricle at approximately half the level of the atrium and this is involved in ventricular repolarisation, including in response to adenosine.71,72 Adenosine exerts indirect effects on ventricular myocytes via inhibition of cAMP and therefore attenuation of sympathetic actions. 73 Paradoxically, adenosine may also increase sympathetic drive at the neuronal level via A 2-mediated chemoreceptor pathways, though cellular mediated mechanisms are usually dominant.74 Junctional ectopic tachycardias arising from the His-Purkinje system or ventricular myocardium result from either abnormal automaticity or triggered activity, which are often catecholamine driven. Adenosine has been used to differentiate between abnormal automaticity, which is adenosine insensitive, and triggered activity, which is adenosine sensitive.75 There may be a role for adenosine in distinguishing VT whose origin is triggered activity from delayed afterdepolarisations (DADs). DADs are reported to arise when there is Ca2+ overload in the cardiomyocyte that activates the electrogenic Na+/Ca2+ exchanger. Adenosine has been shown to abolish DADs by decreasing Ca2+ influx, thereby reducing triggered activity that might be stimulated by catecholaminergic activity.76

Sick Sinus Syndrome Some have suggested that sick sinus syndrome might be an adenosinemediated disease, given its cardioinhibitory effects.77 However, the adenosine antagonist theophylline does not improve sinus node function, which suggests it is not a central mediator in this condition.78 Patients with sick sinus syndrome may have an exaggerated response to adenosine, particularly when challenged in the context of syncope or presyncope, possibly suggesting a role for adenosine as a noninvasive test.79 This may result from an increased expression of adenosine receptors, particularly in the elderly. Similar results have been found for ATP administration.80,81 The antiplatelet agent ticagrelor has been implicated in sinus node dysfunction and ventricular pauses, potentially via increased production of adenosine.82

Syncope Neurally mediated syncope is thought to arise from paradoxical cardioinhibitory reflexes secondary to reductions in preload. Adenosine may be useful in the diagnosis of neurally mediated and unexplained syncope in combination with tilt table testing, particularly in the under 40s, by identifying patients susceptible to transient AV block.83â&#x20AC;&#x201C;85 Pulmonary embolism results in syncope in approximately 10% of cases and may represent a significant proportion of syncope presentations to the emergency department.86,87 Purinergic signalling resulting from the release of ATP by activated platelets following pulmonary embolism has been suggested to result in transient bradycardia and syncope in these cases.88

Role of Adenosine in Other Pathology Related to Arrhythmia Obesity and Diabetes The prevalence of obesity has doubled since 1980, with current estimates suggesting that one in three adults is now obese, which has significant costs to healthcare services and the wider economy.89,90

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Drugs and Devices Obesity is an independent risk factor for the development of AF with a 3–7% increased risk of AF per unit increase in BMI.91 Obesity also confers an increased risk of sudden cardiac death (SCD) from ventricular arrhythmia, particularly in middle-aged people and in patients with ischaemic cardiomyopathy.92–94 Suggested mechanisms proposed for increased arrhythmogenicity in obesity include increased pro-inflammatory cytokines, oxidative stress and fibrosis. Changes in electrical properties of the myocardium are also observed with shorter atrial and pulmonary vein refractory periods, impaired repolarisation in the ventricles and conduction abnormalities.95–97 Adenosine shows generally protective actions in the pathophysiology of obesity, the complex metabolic pathways of which have been extensively reviewed. 98 Plasma adenosine concentrations are increased in obesity and are typically 1.5 times higher than in lean individuals; tissue levels can be higher still.99 Activation of A1 receptors facilitate insulin-dependent glucose uptake and reduces obesityrelated systemic insulin resistance.100,101 Activation of A1 receptors increases plasma leptin and reduces adiponectin levels, both of which would have anti-obesogenic effects.102,103 Activation of the A2B receptors results in the secretion of anti-inflammatory cytokines such as IL–10 and IL–4.104 No studies directly link obesity, adenosine and arrhythmia; however, common pathophysiological pathways are involved. Adenosine may therefore be a significant area for future research and therapy in obesity-related arrhythmia.

Heart Failure Worldwide, 26 million people have heart failure and estimates predict the prevalence of heart failure will have risen by 46% by 2030 in the US.105,106 The prognosis of heart failure remains worse than that for most cancers and a major contributor is a markedly increased risk of SCD, presumed secondary to ventricular arrhythmia.107 The proportion of deaths related to SCD ranges between 33% and 64%.108 Patients with heart failure also have increased risks of both SVTs and AF, which increase morbidity and mortality.13 Catheter ablation of AF in patients with heart failure may reduce mortality.109 Disruption of cardiac energetics is well established in the pathophysiology of heart failure, particularly a reduced utilisation of free fatty acids in preference to glucose as a metabolic substrate, mitochondrial dysfunction and reduced intracellular ATP levels.110–112 In later stages, insulin resistance might be responsible for reducing glucose supply to the failing heart, further switching metabolism to ketones.113 Purinergic receptors are upregulated in heart failure and plasma levels of adenosine also increase.114,115 Therapy with adenosine may have a cardioprotective role in heart failure via A1 and A3 receptors by reducing cardiac hypertrophy, improving glucose homeostasis, reducing acidosis, improving calcium handling, improving mitochondrial function, reducing sympathetic stimulation and increasing natriuretic peptide release.116–119 However, increased circulating adenosine levels may have deleterious effects on the kidneys via A1 receptor-mediated vasoconstriction of the afferent arterioles, resulting in a decrease in glomerular filtration rate as well as sodium retention via the reninangiotensin-aldosterone system.120 Therefore, raised adenosine levels may worsen volume overload and precipitate cardiorenal syndrome, although this may be ameliorated to some extent by A2 receptormediated vasodilatation.

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Ageing Population ageing is one of the most significant epidemiological pressures facing healthcare systems. During the century between 1900 and 2000, there was a 3.1-fold increase in the proportion of the population above 65 in the US.121 In Europe, where the population is the oldest worldwide, it is estimated that 25% of people will be over the age of 65 by 2030 – an approximate doubling.122 Ageing brings problems of an increased risk of pathology (especially ischaemic heart disease and heart failure), greater comorbidity, polypharmacy, impaired renal function, frailty and cognitive decline, as well as social complexities. The prevalence of AF increases markedly from age 65 and 10% of individuals over the age of 80 have clinically overt AF; the number with unrecognised AF is likely greater.123 It has been suggested that AF itself contributes to the ageing process through to increased cerebral infarcts, tissue hypoperfusion and systemic inflammation.124 AF has been associated with dementia even in the absence of overt stroke.125 SCD also increases with age, with the annual risk seven times greater in 80-year-olds than in 40-year-olds.126 The elderly may gain less benefit from ICD therapy than younger patients.127 Aged myocardium is less tolerant to ischaemia and may show a blunted response to preconditioning.128 It has been suggested that adenosine is a key determinant of enhanced ischaemia tolerance. Aged hearts have greater interstitial levels of adenosine, potentially due to decreased cellular uptake, but produce less adenosine in response to adrenergic stimulation than young hearts.129 Age-related decline in cardioprotective adenosine response might be secondary to reduced downstream signalling from the A1 receptor and, in animal models, ageing lowers the anti-adrenergic effects of adenosine.130,131 However, adenosine remains safe and effective for the use of SVT management in the elderly.132

Adverse Effects and Contraindications of Adenosine The short half-life of adenosine is advantageous when considering potential adverse effects. The side-effects of adenosine are unpleasant, but usually transient and tolerable. Chest pain, dyspnoea, cutaneous flushing and a sense of impending doom are well known. The most significant adverse effects are bronchospasm and arrhythmogenesis.

Bronchospasm and Pulmonary Effects Caution has traditionally been exercised with adenosine regarding its propensity to cause bronchospasm in people with asthma or chronic obstructive pulmonary disease (COPD); recently, this practice has been questioned. Original reports suggested that inhaled adenosine, but not other nucleosides, could cause bronchoconstriction in patients with asthma but not in those with normal airway physiology. This appeared to have a maximal effect at 5 minutes after administration with partial recovery after 30 minutes.133 The mechanism proposed was a disturbance in the balance of the autonomic nervous system, which might favour bronchoconstriction, although other studies around that time had demonstrated increased sympathetic outflow without bronchoconstriction.74 A large, multicentre study of adenosine administration in patients undergoing nuclear imaging assessment of coronary perfusion reported that the incidence of bronchospasm was rare, occurring in only seven cases in more than 9,000 patients.134 Other later studies have somewhat refuted these claims. IV adenosine was shown to stimulate minute ventilation and the sensation of

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Unmasking Adenosine dyspnoea in patients with normal airways physiology, which is thought to arise from the activation of vagal C-fibres (J-receptors) and accounts for the well-documented sensation of dyspnoea.135 A study of IV adenosine in patients with asthma showed a similar but augmented response. Importantly, dyspnoeic sensations were not associated with objective spirometry measurements of airways obstruction.136 Animal studies in the rat, where small C-fibres of the vagus nerve were inhibited using capsaicin treatment, showed this eliminated adenosine-induced dyspnoea. 137 Furthermore, blockade of the adenosine A1 receptor but not the A2 receptor prevented the response.138

Figure 3: Summary of the Contributions of Adenosine to Arrhythmia Ageing

Obesity and diabetes

Additionally, no cross-sectional imaging or pulmonary function tests were presented to exclude underlying airways disease.

Ischaemia and pre-conditioning Increased levels

Adenosine

The implication of such studies is that adenosine-induced dyspnoea, a C-fibre mediated response, might have been misinterpreted as bronchospasm in earlier reports, and therefore adenosine is likely to be safer in obstructive airways disease than previously supposed. Nevertheless, case reports suggestive of bronchospasm continue to be published, mostly in patients with asthma or COPD.139,140 In the latter case, bronchoconstriction was sufficiently severe to cause respiratory failure requiring intubation; however, this was in the context of longterm theophylline use, suggesting that bronchoconstriction might have been a response to rapid theophylline antagonism. Another case report suggests an episode of profound bronchospasm in a young patient with apparently normal airways physiology, although the patient had a BMI of 40, which raises the possibility of obesity-related hypoventilation syndrome, obstructive sleep apnoea and obesity-related asthma.141

A 1AR G α(i) βγ ↑GIRK Negative chronotropy

↓Sympathetic actions

It is rare that adenosine causes bronchoconstriction in patients with normal airways physiology. However, there are accounts of plausible harm caused in people with asthma and chronic lung disease, and those dependent on methylxanthines. Asthma is prevalent in children, where the most common arrhythmia is SVT. Adenosine should therefore be used with caution in these cases.1

↓Sympathetic activity ↓cAMP ↓APD ↑Membrane hyperpolarisation ↓Refractoriness ↓lnotropy

Negative dromotropy C b

AF AV node-dependent SVT termination

B Unmasking other SVTs

Furthermore, adenosine has recently been associated in the pathophysiology of severe COPD and idiopathic pulmonary fibrosis. In these conditions, CD73 (an enzyme involved in extracellular adenosine production) and adenosine A2 receptors are upregulated, with a particular preponderance in pulmonary macrophages. Adenosine is produced in response to cell damage, and upregulation of production and receptors allows for purinergic remodelling, which ultimately causes fibrosis.142 Similar findings have been reported in cystic fibrosis.143

Heart failure

Anti-arrhythmic effects

D Ventricular arrhythmia

Pro-arrhythmic effects

A: AVN dependent SVT terminated by adenosine; B: atrial flutter unmasked by adenosine; C: AF induced during adenosine administration in a nuclear perfusion study; D: VT precipitated by adenosine in a patient treated for narrow complex tachycardia secondary to AF. APD = action potential duration; AV = atrioventricular; cAMP = cyclic adenosine monophosphate; GIRK = G-protein-coupled, inward-rectifying potassium; SVT = supraventricular tachycardia. Sources: A: Watt et al. 1986.170 Reproduced with permission from Wiley. B: Znojkiewicz et al. 2013.171 C: Kanei et al. 2008.172 D: Knight et al. 1998.173 B–D: Reproduced with permission from Elsevier.

Significant tachyarrhythmias have also been encountered in the form of torsades de pointes, sustained VT and VF.153–159 The risk of VF may be increased when adenosine is used in stable VT, preexcitation or in patients with a prolonged QT interval.160–162 Several case series highlight the risk of inducing ventricular arrhythmia during fractional flow reserve measurements following intracoronary adenosine administration, suggesting that IV is a safer route or that lower doses are needed.163–166

Pro-arrhythmic Effects of Adenosine Studies in emergency departments suggest adenosine induces arrhythmia in approximately 13% of those treated for SVT.42 These are mostly transient and benign, such as pauses, ventricular ectopy and non-sustained VT; however, major arrhythmias are also encountered, albeit rarely.144 Significant bradyarrhythmia in the form of sinus arrest, heart block and asystole have been reported.145–148 Adenosine-induced bradyarrhythmia may be more common when it is given concomitantly with other rate control medications and in patients with orthotopic liver transplantation, sepsis or heart failure.147,149–151 Adenosine administration has been associated with anoxic seizure in the context of bradyarrhythmia.152

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Adenosine Following Cardiac Transplant Concerns regarding adenosine in patients receiving a cardiac transplant have been raised because adenosine receptors are upregulated following parasympathetic denervation, potentially making adenosine more likely to cause asystole. This is of potential concern as up to 50% of cardiac transplant patients develop SVT, which reduces cardiac output and may result in invasive investigations for acute rejection. Alternatives such as CCAs may cause drug interactions with immunosuppressants and are contraindicated in infants. However, a recent case series of patients in sinus rhythm following cardiac transplant given adenosine showed no major adverse events, including asystole, or need for pacing, which calls these views into question.167

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Drugs and Devices Transplant patients may require reduced doses, especially when the PR interval is prolonged. However, it should be noted that these studies were in young patients who did not have manifest SVT at the time of administration, so it remains to be shown if findings are translatable to the different neurohumoral circumstances present during SVT or in older populations.

Conclusion Adenosine celebrates its ninth decade of recognition this year. It continues to be a crucial member of the armamentarium in the management of arrhythmia (Figure 3), particularly SVT.1 Advances in metabolomics and receptor biology are now elucidating the critical role of adenosine in numerous common conditions related to arrhythmogenesis. In most cases, endogenous adenosine appears to play an anti-arrhythmic role, particularly in the context of ischaemia.168 Purinergic signalling pathways are likely to be future targets in the management of arrhythmia, both directly by actions on cardiac electrophysiology and indirectly in the treatment of its associated risk factors.

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Clinical Perspective • Adenosine is the first-line pharmacological therapy, following vagal manoeuvres where these are appropriate, in the treatment of acute atrioventricular node-dependent tachycardias, particularly atrioventricular re-entrant tachycardia and atrioventricular nodal re-entrant tachycardia, and has a termination rate of approximately 90%. • Although administration is frequently associated with transient unpleasant symptoms, in the majority of cases adenosine is safe to use because of its short half-life. However, patients must be monitored for rare major adverse events, including arrhythmia, bronchospasm and severe dyspnoea. • Calcium-channel antagonists are a good alternative to adenosine and have similar termination efficacy. They should be considered in patients with contraindications to adenosine or where a longer-acting pharmacological strategy is required.

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138. Hong JL, Ho CY, Kwong K, et al. Activation of pulmonary C fibres by adenosine in anaesthetized rats: role of adenosine A1 receptors. J Physiol 1998;508:109–18. https://doi. org/10.1111/j.1469-7793.1998.109br.x; PMID: 9490825. 139. DeGroff CG, Silka MJ. Bronchospasm after intravenous administration of adenosine in a patient with asthma. J Pediatr 1994;125:822–23. https://doi.org/10.1016/s00223476(94)70085-0; PMID: 7965442. 140. Burkhart KK. Respiratory failure following adenosine administration. Am J Emerg Med 1993;11:249–50. https://doi. org/10.1016/0735-6757(93)90138-2; PMID: 8489671. 141. Coli S, Mantovani F, Ferro J, et al. Adenosine-induced severe bronchospasm in a patient without pulmonary disease. Am J Emerg Med 2012;30:2082.e3–5. https://doi.org/10.1016/j. ajem.2011.11.005; PMID: 22177587. 142. Zhou Y, Murthy JN, Zeng D, et al. Alterations in adenosine metabolism and signaling in patients with chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. PloS One 2010;5:e9224. https://doi.org/10.1371/journal.pone.0009224; PMID: 20169073. 143. Picher M, Burch LH, Boucher RC. Metabolism of P2 receptor agonists in human airways: implications for mucociliary clearance and cystic fibrosis. J Biol Chem 2004;279:20234–41. https://doi.org/10.1074/jbc.M400305200; PMID: 14993227. 144. Pelleg A, Pennock RS, Kutalek SP. Proarrhythmic effects of adenosine: one decade of clinical data. Am J Ther 2002;9:141– 7. https://doi.org/10.1097/00045391-200203000-00008; PMID: 11897928. 145. Reed R, Falk JL, O’Brien J. Untoward reaction to adenosine therapy for supraventricular tachycardia. Am J Emerg Med 1991;9:566–70. https://doi.org/10.1016/0735-6757(91)90117-3; PMID: 1930402. 146. Tomcsányi J, Tenczer J, Horváth L. Unusual effect of adenosine. Int J Cardiol 1995;49:89–91. https://doi. org/10.1016/0167-5273(95)02274-Z; PMID: 7607771. 147. Brodsky MA, Hwang C, Hunter D, et al. Life-threatening alterations in heart rate after the use of adenosine in atrial flutter. Am Heart J 1995;130:564–71. https://doi. org/10.1016/0002-8703(95)90367-4; PMID: 7661076. 148. McCollam PL, Uber WE, Van Bakel AB. Adenosine-related ventricular asystole. Ann Intern Med 1993;118:315–6. https://doi. org/10.7326/0003-4819-118-4-199302150-00023; PMID: 8420457. 149. Giedd KN, Bokhari S, Daniele TP, et al. Sinus arrest during adenosine stress testing in liver transplant recipients with graft failure: three case reports and a review of the literature. J Nucl Cardiol 2005;12:696–702. https://doi.org/10.1016/j. nuclcard.2005.07.007; PMID: 16344232. 150. Dierkes S, Hennersdorf MG, Perings C, et al. Enlarged effects of adenosine in a septic patient with multiple myeloma and atrial flutter. Acta Cardiol 2003;58:363-6. https://doi. org/10.2143/AC.58.4.2005296; PMID: 12948044. 151. Belloni FL, Wang J, Hintze TH. Adenosine causes bradycardia in pacing-induced cardiac failure. Circulation 1992;85:1118–24. https://doi.org/10.1161/01.cir.85.3.1118; PMID: 1531622. 152. Webster DP, Daar AA. Prolonged bradyasystole and seizures following intravenous adenosine for supraventricular tachycardia. Am J Emerg Med 1993;11:192–4. https://doi. org/10.1016/0735-6757(93)90121-Q; PMID: 8476467. 153. Harrington GR, Froelich EG. Adenosine-induced torsades de pointes. Chest 1993;103:1299–301. https://doi.org/10.1378/ chest.103.4.1299; PMID: 8131497. 154. Wesley RC, Turnquest P. Torsades de pointe after intravenous adenosine in the presence of prolonged QT syndrome. Am Heart J 1992;123:794–6. https://doi.org/10.1016/00028703(92)90525-z; PMID: 1539535. 155. Teodorovich N, Margolin E, Kogan Y, et al. Torsades de pointes after adenosine administration. J Electrocardiol 2016;49:171–3. https://doi.org/10.1016/j.jelectrocard.2015.12.013; PMID: 26850499. 156. Frank R, Marty H. Polymorphic ventricular tachycardia after intravenous adenosine. Schweiz Med Wochenschr 2000;130:1576 [in German]. PMID: 11092061.

157. Kaplan IV, Kaplan AV, Fisher JD. Adenosine induced atrial fibrillation precipitating polymorphic ventricular tachycardia. Pacing Clin Electrophysiol 2000;23:140–1. https://doi. org/10.1111/j.1540-8159.2000.tb00662.x; PMID: 10666766. 158. Huemer M, Boldt L-H, Rolf S, et al. Sustained monomorphic ventricular tachycardia after adenosine infusion. Int J Cardiol 2009;131:e97–100. https://doi.org/10.1016/j. ijcard.2007.07.068; PMID: 18006091. 159. Pella J, Stancák B, Komanová E, et al. Ventricular fibrillation after administration of adenosine. Vnitr Lek 1995;41:832–5 [in Slovak]. PMID: 8600655. 160. Parham WA, Mehdirad AA, Biermann KM, et al. Case report: adenosine induced ventricular fibrillation in a patient with stable ventricular tachycardia. J Interv Card Electrophysiol 2001;5:71–4. https://doi.org/10.1023/A:1009810025584; PMID: 11248777. 161. Gupta AK, Shah CP, Maheshwari A, et al. Adenosine induced ventricular fibrillation in Wolff-Parkinson-White syndrome. Pacing Clin Electrophysiol 2002;25:477–80. https://doi. org/10.1046/j.1460-9592.2002.00477.x; PMID: 11991373. 162. Celiker A, Tokel K, Cil E, et al. Adenosine induced torsades de pointes in a child with congenital long QT syndrome. Pacing Clin Electrophysiol 1994;17:1814–7. https://doi. org/10.1111/j.1540-8159.1994.tb03752.x; PMID: 7838793. 163. Piccolo R, Niglio T, Di Gioia G, et al. Adenosine-induced torsade de pointes complicating a fractional flow reserve measurement in a right coronary artery intermediate stenosis. Cardiovasc Revasc Med 2013;14:118–20. https://doi. org/10.1016/j.carrev.2012.12.010; PMID: 23433828. 164. Shah AH, Chan W, Seidelin PH. Ventricular fibrillation precipitated by intracoronary adenosine during fractional flow reserve assessment – a cautionary tale. Heart Lung Circ 2015;24:e173–5. https://doi.org/10.1016/j.hlc.2015.05.012; PMID: 26166173. 165. Khan ZA, Akbar G, Saeed W, et al. Ventricular fibrillation with intracoronary adenosine during fractional flow reserve assessment. Cardiovasc Revasc Med 2016;17:487–9. https://doi. org/10.1016/j.carrev.2016.07.004; PMID: 27477304. 166. Patel HR, Shah P, Bajaj S, et al. Intracoronary adenosineinduced ventricular arrhythmias during fractional flow reserve (FFR) measurement: case series and literature review. Cardiovasc Interv Ther 2017;32:374–80. https://doi.org/10.1007/ s12928-016-0427-8; PMID: 27577946. 167. Flyer JN, Zuckerman WA, Richmond ME, et al. Prospective study of adenosine on atrioventricular nodal conduction in pediatric and young adult patients after heart transplantation. Circulation 2017;135:2485–93. https://doi.org/10.1161/ CIRCULATIONAHA.117.028087; PMID: 28450351. 168. Conti JB, Belardinelli L, Utterback DB, et al. Endogenous adenosine is an antiarrhythmic agent. Circulation 1995;91:1761–7. https://doi.org/10.1161/01.cir.91.6.1761; PMID: 7882485. 169. Camm AJ, Garratt CJ. Adenosine and supraventricular tachycardia. N Engl J Med 1991;325:1621–9. https://doi. org/10.1056/NEJM199112053252306; PMID: 1944450. 170. Watt AH, Bernard MS, Webster J, et al. Intravenous adenosine in the treatment of supraventricular tachycardia: a dose-ranging study and interaction with dipyridamole. Br J Clin Pharmacol 1986;21:227–30. https://doi. org/10.1111/j.1365-2125.1986.tb05180.x; PMID: 3954939. 171. Znojkiewicz P, Spector PS. Dysrhythmias and tachyarrhythmias. In: Parsons PE, Wiener-Kronish JP, eds. Critical Care Secrets. 5th ed. Philadelphia, PA: Mosby, 2013:197– 203. https://doi.org/10.1016/B978-0-323-08500-7.00030-8. 172. Kanei Y, Hanon S, Van-Tosh A, et al. Adenosine-induced atrial fibrillation during pharmacologic stress testing: Report of eight cases and review of the literature. Int J Cardiol 2008;129:e15–7. https://doi.org/10.1016/j.ijcard.2007.05.090; PMID: 17689721. 173. Knight BP, Zivin A, Souza J, et al. Use of adenosine in patients hospitalized in a university medical center. Am J Med 1998;105:275–80. https://doi.org/10.1016/S00029343(98)00261-7; PMID: 9809687.

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Clinical Arrhythmias

Idiopathic Left Ventricular Tachycardia Originating in the Left Posterior Fascicle Hongwu Chen, 1 Kit Chan, 2 Sunny S Po 3 and Minglong Chen 1 1. Division of Cardiology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China; 2. Division of Cardiology, University of Hong Kong Shenzhen Hospital, Shenzhen, China; 3. Section of Cardiovascular Diseases and Heart Rhythm Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK, US

Abstract Ventricular tachycardias originating from the Purkinje system are the most common type of idiopathic left ventricular tachycardia. The majority if not all of the reentrant circuit involved in this type of tachycardia is formed by the Purkinje fibres of the left bundle branch, particularly the left posterior fascicle. In general, slowly conducting Purkinje fibres (P1) form the antegrade limb, and normally conducting Purkinje fibres (P2) form the retrograde limb of the reentrant circuit of the ventricular tachycardia originating from the left posterior fascicle. Elimination of the critical Purkinje elements in the reentrant circuit is the route to successful ablation. While the reentrant circuit identified by activation mapping provides the roadmap to ablation targets, comparing the difference in the His-ventricular interval during sinus rhythm and tachycardia also helps to identify the critical site in the reentrant circuit.

Keywords Idiopathic ventricular tachycardia, Purkinje system, left posterior fascicle Disclosure: The authors have no conflicts of interest to declare. Received: 30 July 2019 Accepted: 26 November 2019 Citation: Arrhythmia & Electrophysiology Review 2019;8(4):249â&#x20AC;&#x201C;54. DOI: https://doi.org/10.15420/aer.2019.07 Correspondence: Minglong Chen, Cardiology Division, First Affiliated Hospital of Nanjing Medical University, 300#, Guangzhou Road, Nanjing, 210029, Jiangsu, China. E: chenminglong@njmu.edu.cn 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 tachycardia (VT) originating from the Purkinje system is the most common type of idiopathic left ventricular tachycardia (ILVT), especially among young Asians.1,2 It usually has a benign course. Research over the past two decades has deepened our understanding of the anatomy of the Purkinje system and the mechanisms of ILVT. This review focuses on the research history and anatomy of the Purkinje system, as well as its clinical features, electrocardiographic characteristics and mechanisms, and the management of Purkinje-related ILVT.

History of Purkinje-related Idiopathic Left Ventricular Tachycardia In 1845, a fibre bundle was discovered by Purkinje.3 In 1906, Tawara described the details of the Purkinje fibres as a conduction system.4 In 1972, Cohen et al. first reported that ILVT originated in the left posterior fascicular region.5 It was characterised by relatively narrow QRS complexes with right bundle branch block (RBBB) morphology and left axis deviation. In 1979, Zipes described three characteristics of a specific form of ILVT: atrial pacing induction; RBBB with left axis deviation; and absence of structural heart disease.6 Two years later, Belhassen et al. proposed the fourth characteristic of this type of ILVT.7 They found that this type of ILVT could be terminated by verapamil and named it verapamilsensitive ventricular tachycardia. Ohe et al. reported another form of ILVT with RBBB and right-axis deviation in 1988.8 In 1993, Nakagawa et al. found that presystolic Purkinje potentials could be recorded in

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the left posterior fascicular region and catheter ablation targeting the earliest Purkinje potential successfully eliminated the tachycardia.9

Anatomy of the Purkinje System In the normal human heart, the atrioventricular node is located in the triangle of Koch. It gives rise to the penetrating His bundle, which is situated at the fibrous commissure formed by the right coronary cusp, the non-coronary cusp and the anterior and septal leaflets of tricuspid valve. It branches into the left and right bundles.10 The left bundle branch (LBB) is wider than the right bundle branch (RBB). In theory, the LBB divides into the left anterior and posterior fascicles, with or without the left septal branch. However, histopathological studies have demonstrated marked anatomic variation of LBB (Figure 1).11 Unlike the penetrating His bundle, which is encased in an insulating fibrous sheath, the LBB system consists of a complex network of conducting fibres.11 The density of distal Purkinje fibres depends on their anatomical distribution, with the highest density near the base of papillary muscles and the middle of the left ventricle. The distal Purkinje fibres can penetrate the endocardium and reach one third the thickness of myocardium.12

Cellular Electrophysiological Properties of the Purkinje System and Mechanism of Purkinje-related Left Ventricular Tachycardia At the Purkinje-myocyte junction, the Purkinje cells are coupled to ventricular myocytes via the transitional cells, which possess specific

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Clinical Arrhythmias Figure 1: Histopathological Examination of Left Purkinje System 1

The left septal branch has four patterns of origin: from the main left bundle (cases 1–4); from the left anterior branch (cases 5–7); from the left posterior branch (cases 8–14); and from both the left anterior branch and the left posterior branch to form either a septal branch or a septal fibre (cases 15–20). Source: Demoulin and Kulbertus et al. 1972.11 Reproduced with permission from BMJ Publishing Group.

Figure 2: Typical QRS Morphology of Idiopathic Left Ventricular Tachycardia Originating from the Left Posterior Fascicular

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The QRS pattern shows right bundle branch block morphology with left axis deviation.

electrical properties. The transitional cells contribute to the electrical coupling and conduction at the Purkinje-myocardial junction at some sites; they also lead to electrical uncoupling from neighboring Purkinje cells at other locations. Electrical uncoupling of transitional cells from Purkinje cells could facilitate retrograde conduction and re-entry arrhythmia within the Purkinje network. Studies have shown that false tendons, which contain a high density of Purkinje fibres, may contribute to Purkinje-related ILVT, which is evidenced by elimination of ILVT after

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surgical resection of false tendons and partial cryo-coagulation of their adjacent ventricular myocardium.13,14

Clinical and Electrocardiogram Characteristics Purkinje-related VT is the most common type of ILVT; 60–70% of those with Purkinje-related VT are identified in young Asian men.1,2 Common symptoms include palpitations, fatigue, dyspnoea and dizziness. Syncope and sudden death are rare.15 While it can be triggered by exercise, it can also occur at rest.9,16 This type of VT is usually verapamil sensitive and can be classified into three subtypes according to the QRS morphology: left posterior fascicular VT, with RBBB morphology and left axis deviation (due to myocardial exit from the left posterior fascicle) (Figure 2); left anterior fascicular VT, with RBBB morphology and right axis deviation; and left upper fascicular VT, with narrow QRS complexes and normal electrical axis or right axis deviation.17,18 ILVT originating from the left posterior fascicle is the most common form, accounting for more than 90% of all cases.

Re-entry as the Mechanism of Purkinje-related Idiopathic Left Ventricular Tachycardia Studies have shown that the mechanism of Purkinje-related ILVT is re-entry, as atrial or ventricular stimulation can induce, entrain and terminate the tachycardia. Echocardiography studies have demonstrated a higher prevalence of false tendons or fibromuscular band extension to the basal septum in patients with Purkinje-related ILVT.19–21 This suggests that the false tendons and fibromuscular bands may be involved in a reentrant mechanism in ILVT.13,14 Zhan et al. performed high-density, three-dimensional electro-anatomical mapping of the left ventricular septum in patients with Purkinjerelated ILVT.22 In that study, the prevalence of fragmented potentials preceding the local ventricular activation in the left ventricular septum was higher than it was in the control group, which supports the hypothesis of re-entry. Nogami et al. performed a study to demonstrate the mechanism of posterior fascicle-related ILVT (LPF-ILVT) by entrainment and resetting, using multipolar electrode catheters in the left ventricle.23 In 15 of the 20 patients, two distinct potentials (P1 and P2) were recorded at the left mid-septum of left ventricle. During VT, there was orthodromic activation of the P1 and retrograde activation of P2. During VT, P1 and P2 were activated in the reverse direction and converged at the distal recording site near the LV apex (Figure 3). Entrainment pacing at the apex of the left ventricle captured P1 orthodromically and produced QRS configurations similar to that of the clinical VT. The post-pacing intervals were similar to the tachycardia cycle length (Figure 4). Intravenous verapamil prolonged the tachycardia cycle length as well as the P1–P2 and P2–P1 intervals, with no effect on the P2–QRS interval. During sinus rhythm, only P2 was recorded at the same site, while the retrograde P1 was obscured by the larger ventricular potentials (Figure 3). Ablation at the site of the earliest retrograde Purkinje potential eliminated the conduction between P1 and P2. After successful ablation, P1 could be recorded after each QRS in sinus rhythm, with a base-to-apex activation pattern. The investigators demonstrated a macro-re-entry circuit with the antegrade limb involving specialised verapamil-sensitive Purkinje tissue (P1) with decremental conduction property, and the retrograde limb involving the left posterior fascicle (P2). Ouyang et al. speculated that the reentrant circuit of LPF-ILVT may consist of antegrade and retrograde Purkinje potentials, bridged

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Idiopathic Left Ventricular Tachycardia Figure 3: Potentials in Idiopathic Left Ventricular Tachycardia

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During idiopathic left ventricular tachycardia, a diastolic potential (P1) and a presystolic Purkinje potential (P2) were recorded. P1 potentials showed antegrade activation from proximal to distal electrodes; P2 potentials were activated retrogradely from distal to proximal electrodes. During normal sinus rhythm, recording at the same site showed that P2 potentials were activated antegradely before the onset of QRS; P1 potentials were obscured by the larger ventricular signals. Source: Nogami et al. 2000.23 Reproduced with permission from Elsevier.

Figure 4: Entrainment Pacing at the Apex of the Left Ventricle A I II

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A: Pacing from the distal electrodes, starting with a coupling interval of 400 ms, captured P1 orthodromically and produced QRS configurations similar to that of the clinical VT. The postpacing interval was equal to the tachycardia cycle length. B: Schematic representation of the concealed entrainment during tachycardia. Source: Nogami et al. 2000.23 Reproduced with permission from Elsevier.

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Clinical Arrhythmias Figure 5: Schematic Representation of the Left Posterior Fascicular Ventricular Tachycardia Re-entry Circuit

Figure 7: Retrograde Purkinje Potential 26 ms

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The re-entry circuit includes ventricular myocardium, part of the left posterior fascicle (LPF), a P1 fibre and a slow conduction zone connecting the ventricular myocardium and proximal P1. A. In patients with a recordable P1 and a more negative His-ventricular (HV) interval during left posterior fascicle-related ventricular tachycardia (LPF-VT), the P1 fibre is probably in parallel and adjacent to the LPF; the connection between P1 and the LPF (P2) is located at a more distal portion of the LPF. B. In patients with a recordable P1 and a slightly negative HV interval during LPF-VT, the P1 fibre is in parallel and adjacent to the LPF; the connection between P1 and the LPF (P2) is located at the middle or proximal portion of the LPF. C. In patients without a recordable P1 and a slightly negative HV interval, the P1 fibre may be shorter in length and or have a nonparallel orientation to the LPF. Source: Liu et al. 2016.25 Reproduced with permission from Wolters Kluwer Health.

Figure 6: Re-entry Circuit of Idiopathic Ventricular Tachycardia

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Identification of the retrograde Purkinje potential during normal sinus rhythm in a patient with posterior fascicle-related idiopathic ventricular tachycardia. Note a short, sharp, late high-frequency and low-amplitude potential following the local ventricular activation in the left posterior fascicle region. Note that retrograde Purkinje potential was synonymous with P2. Source: Ouyang et al. 2002.24 Reproduced with permission from Wolters Kluwer Health.

they proved that the slowly conducting myocardial tissue between P2 and P1 makes up the slow conduction zone of the tachycardia circuit (Figure 5). Moreover, they demonstrated that the site of the P1–P2 connection can be predicted by the HV interval during VT. A more negative HV interval predicted a more distal left posterior fascicular connection between the P1 and P2 potentials.

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Komatsu et al. also demonstrated that the reentrant circuit of LPFILVT may involve the Purkinje system as well as neighboring papillary muscles; this was characterised by distinctive electrocardiographic features (Figure 6).26

Mapping and ablation

Mapping P1 and P2 Potential During Tachycardia

In patients with recordable P1 and P2 signals, the ablation target should be the P1 diastolic potential because it is a critical component of the tachycardia circuit. It should be ablated at the apical third of the septum, with a shift toward a basal site until successful ablation is achieved to avoid inadvertent injury to the LBB or the His bundle.23,27 In patients without a recordable P1 potential, the earliest retrograde Purkinje potential (P1) during tachycardia is the target of ablation.

Pace Mapping

1. Typical IVLT 2. PM-related IVLT

Using QRS morphology and the site of successful ablation, left posterior fascicle-related idiopathic ventricular tachycardia (LPF-ILVT) can be classified into two subtypes: (1) typical LPF-ILVT involving P1 and P2 bridged by septal ventricular myocardium; and (2) LPF-ILVT originating from the Purkinje network around the posterior papillary muscle. IVLT = idiopathic ventricular tachycardia; PM = papillary muscle. Source: Komatsu et al. 2017.26 Adapted with permission from Wolters Kluwer Health.

by ventricular myocardium.24 Recently, further investigation of the mechanism of LPF-ILVT was reported by Liu et al. 25 In that study, multipolar electrode catheters were used to continuously record the P1 and P2 potentials. Both the P1 and P2 potentials could be recorded in 64% of patients, which is consistent with the findings of Nogami’s study.23 Using the entrainment and resetting responses,

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As the Purkinje network may have multiple myocardial exits, pace mapping is not reliable in guiding ablation. Sites with perfect pace mapping can be remote from the critical component of the circuit as this involves the downstream Purkinje network or adjacent ventricular myocardium. Successful ablation site may produce a poor match with the tachycardia, pace mapping is not a preferred approach.

Electroanatomical Mapping in Sinus Rhythm Ouyang et al. . found that the sharp retrograde Purkinje potential (PP) following the local ventricular ECG could be recorded at the left posterior fascicular region during normal sinus rhythm in patients with LPF-ILVT.25 They also demonstrated that the retrograde PP during normal sinus rhythm correlated with the diastolic PP

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Idiopathic Left Ventricular Tachycardia during tachycardia. Ablation at the retrograde PP sites rendered tachycardia non-inducible (Figure 7).

Figure 8: Identification of the Left His-Purkinje System During Normal Sinus Rhythm

In contrast, Zhan et al.22 discovered a short, fragmented and highfrequency potential preceding the local ventricular activation in the LPF region in patients with ILVT (Figure 8). These fragmented signals could not be recorded in control patients. They speculated that the fragmented antegrade PP may represent an arrhythmogenic substrate in LPF-ILVT and may guide successful ablation.

His-ventricular Interval Mapping in Sinus Rhythm Ma et al. found that the HV interval and surface ECG morphology of LPF-ILVT may help clinicians to identify the successful ablation site.28 They demonstrated that the more negative the HV interval is during VT, the further the breakthrough site is far from the paroxysmal HisPurkinje system. They also found that lead I and V6 QRS morphology can predict the origin of LPF-ILVT. In lead V6, an R/S ratio ≤0.3 predicted a distal exit of LPF-VT with 83% sensitivity and 91% specificity, while R/S ratio ≥0.6 predicted a proximal exit of LPF-VT with 88% sensitivity and 97% specificity. In lead I, the R/S ≤0.5 predicted a distal exit of LPF-VT with 83% sensitivity and 91% specificity, while the R/S ≥1.0 predicted a proximal exit of LPF-VT with 88% sensitivity and 81% specificity. Chen et al.. demonstrated that the earliest retrograde Purkinje potential (P2) site can be calculated by measuring the HV interval during tachycardia and the normal sinus rhythm.29 The successful ablation site was half of the HV interval between the normal sinus rhythm (A+B) and tachycardia (B-A) (Figure 9). They also found that the target site of P-V interval (B) during tachycardia was identical to that of during NSR (B). This method is especially useful in cases of LPF-ILVT that can be induced in the baseline and become non-inducible during mapping and ablation.

Note that a fragmented potential (white arrow) preceding the local ventricular activation posterior to the left posterior fascicle. Note that antegrade Purkinje potential was synonymous with P1. Source: Zhan et al. 2016.22 Reproduced with permission from Heart Rhythm Society.

Figure 9: Predicted Earliest Retrograde Purkinje Potentials from Left Posterior Fascicles

AVN

LAF HB

RBB

LPF B

AVN

LAF HB

RBB

LPF B

Anatomical Linear Ablation When the tachycardia cannot be induced during the procedure but the operator is certain that LPF-VT is the correct diagnosis, empirical linear ablation transecting the LPF can be an effective strategy, as reported by Chen et al.30 According to those studies, radiofrequency energy could be delivered during normal sinus rhythm or during tachycardia; both of these ablation strategies might make the tachycardia non-inducible. Recently, Creta et al.. reported a meta-analysis to assess the efficacy of the two ablation strategies.31 They found that ablation performed in tachycardia had a similar success rate after multiple procedures to with ablation in sinus rhythm only (95.1%, 95% CI [92.2–97%]; I2=0% versus 94.8%, 95% CI [87.6–97.9%], I2 = 0% respectively).

Recurrence After Ablation Most cases of LPF-ILVT recurrence are the reappearance of the tachycardia that was treated in the index ablation procedure. Recurrence secondary to new onset left upper septal VT is rare.32–34 The mechanism of upper septal VT remains controversial. One study demonstrated that the mechanism may be macrore-entry since reversed diastolic potential (P1) and pre-systolic potential (P2) could be recorded. During LPF-ILVT, the P1 potentials recorded at multipolar electrodes showed antegrade activation from the proximal to distal, while P2 potentials showed retrograde conduction. During upper septal VT in the second procedure, the P1 and P2 activation sequences were reversed. 32 In contrast,

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

HIS +A

+B V

Sinus HV=A+B

HIS –A

+B V

Tachy HV=B-A

Schematic demonstrations of the predicted earliest retrograde Purkinje potential (PP) from left fascicles during sinus rhythm and left posterior fascicle-related idiopathic ventricular tachycardia (LPF-ILVT). The conduction interval from the earliest retrograde PP to the His bundle was defined as time A, and that from the earliest retrograde PP to the onset of surface ECG as time B. Therefore, the HV interval during normal sinus rhythm (NSR) is A+B (left panel), while the HV during LFTAs is B–A (right panel). The earliest retrograde PP time (B) can be calculated from these two intervals [(HVNSR + HVLFTA )/2]. Note that retrograde Purkinje potential was synonymous to P2. PP = Purkinje potential; tachy = tachycardia. Source: Chen et al. 2016.29 Reproduced with permission from Elsevier.

Guo et al. did not reliably record diastolic potential using threedimensional mapping system.33 They argued for a mechanism of macro-re-entry or micro-re-entry in the upper septum where the circuit was unmappable. Regardless of the mechanism involved, the tachycardia can be ablated successfully by focal ablation in the proximal LV septum with titrated power from 10W to 25W to avoid injuring the His bundle.

Conclusion LPF-ILVT is the most common type of arrhythmia, and originates from the Purkinje system, especially in young Asian men. The mechanism of the tachycardia is re-entry, involving both the Purkinje system and ventricular myocardium in most cases. Radiofrequency ablation is the first-line treatment. An understanding of the anatomy of Purkinje system and mechanism of ILVT helps clinicians to devise a comprehensive approach to successful radiofrequency ablation.

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Clinical Arrhythmias Clinical Perspective • The slowly conducting Purkinje fibres (P1) and normally conducting Purkinje fibres (P2) form the antegrade and retrograde limb of the reentrant circuit of ventricular tachycardia (VT) originating from the left posterior fascicle. • Ablation that targets the P1 or early P2 potential can eliminate this type of VT. • The difference between the His-ventricular interval in sinus rhythm and during VT can also help target ablation.

10.

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12.

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ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Electrophysiology and Ablation

Multimodality Imaging to Guide Ventricular Tachycardia Ablation in Patients with Non-ischaemic Cardiomyopathy Ling Kuo, 1,2,3 Jackson J Liang, 3 Saman Nazarian 3 and Francis E Marchlinski 3 1. Heart Rhythm Center, Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; 2. Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; 3. Electrophysiology Section, Cardiovascular Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, US

Abstract Catheter ablation is an effective treatment option for ventricular tachycardia (VT) in patients with non-ischaemic cardiomyopathy (NICM). The heterogeneous nature of NICM aetiologies and VT substrate in patients with NICM play a role in long-term ablation outcomes in this population. Over the past decades, more precise identification of NICM aetiologies and better characterisation of various substrates have been made. Application of multimodal imaging has greatly contributed to the accurate diagnosis of NICM subtypes and improved VT ablation strategies. This article summarises the current knowledge of multimodal imaging used in the characterisation of non-ischaemic NICM substrates, procedural planning and image integration for the optimisation of VT ablation.

Keywords Ventricular tachycardia, catheter ablation, non-ischaemic cardiomyopathy, late gadolinium enhancement, cardiac MRI, CT, PET, nuclear imaging Disclosure: LK is supported by Taipei Veterans General Hospital-National Yang-Ming University Excellent Physician Scientists Cultivation Program, No 106-V-A-009. Additional support was provided by the Mark S Marchlinski Fund in Cardiac Electrophysiology. SN serves as PI for research funding from Biosense Webster, Imricor and Siemens, is a consultant to CardioSolv and is funded by US NIH NHLBI grants R01HL116280 and R01HL142893. FEM serves as consultant for Abbott Medical, Biosense Webster, Biotronik and Medtronic. The University of Pennsylvania Conflict of Interest Committee manages all commercial arrangements. JJL has no conflicts of interest to declare. Received: 9 May 2019 Accepted: 19 September 2019 Citation: Arrhythmia & Electrophysiology Review 2019;8(4):255–64. DOI: https://doi.org/10.15420/aer.2019.37.3 Correspondence: Francis E Marchlinski, Electrophysiology Section, Cardiovascular Division, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce St, Philadelphia, PA 19104, US. E: francis.marchlinski@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.

Catheter ablation has been increasingly used as a treatment for refractory ventricular tachycardia (VT) in patients with non-ischaemic cardiomyopathy (NICM). However, ablation outcomes tend to be quite variable because of the heterogeneity of the aetiology for the NICM and associated VT substrate in these patients.1–3 Patients with NICM can be sub-classified based on specific genotypic and phenotypic findings, including dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy (ARVC), hypertrophic cardiomyopathy, restrictive cardiomyopathy, lamin A/C (LMNA) cardiomyopathy, sarcoid cardiomyopathy, amyloid cardiomyopathy, post-myocarditis cardiomyopathy and left ventricular (LV) non-compaction cardiomyopathy (LVNC).4 While one recent multicentre study reported VT ablation outcomes of all NICM aetiologies, including myocarditis, sarcoidosis and valvular disease,5 most VT ablation studies in NICM have focused on patients with the dilated cardiomyopathy phenotype and exclude patients with ARVC, hypertrophic cardiomyopathy, LVNC, restrictive cardiomyopathy, cardiac sarcoidosis (CS), valvular disease and acute myocarditis.1,6,7 The different NICM aetiologies exhibit discrete substrate patterns. Unlike the distinct dense scar, which exhibits subendocardial to transmural features in patients with prior MI and ischaemic cardiomyopathy (ICM), progression of myocardial fibrosis with predominantly perivalvular and/or intramural/subepicardial patterns is more commonly observed

in NICM. This pattern of involvement can be demonstrated on cardiac MRI (CMR), electroanatomical voltage mapping (EAVM) and histology.8–10 Because of the presence of heterogeneous substrate in patients with different types of NICM, cardiac imaging is especially helpful to define the location and extent VT substrate and guide pre-procedural planning. This review will provide a summary of the current understanding of substrate characteristics identified by multimodal imaging and EAVM, the practicality of image integration during ablation procedures, as well as the impact of imaging modality utilisation on VT ablation outcome in various NICM aetiologies.

Value of Pre-procedural Imaging and Image Integration to Guide Refractory VT Ablation in Non-ischaemic Cardiomyopathy Pre-procedural imaging is helpful to guide VT ablation in patients with healed MI and ICM. In these patients, multimodality imaging can help to identify arrhythmogenic substrate and critical components of VT circuits, leading to decreased radiofrequency ablation time, total procedure time, and improved acute and long-term ablation success rates.11–17 In contrast, the impact of pre-procedural imaging to guide VT ablation in NICM differs based on the underlying NICM aetiology. Pre-procedural imaging can visualise the presence of epicardial substrates and predict when epicardial mapping may be

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Electrophysiology and Ablation warranted.18–20 Moreover, it localises important structures such as the phrenic nerve and epicardial coronary arteries which can be integrated into the electroanatomical map to avoid complications during ablation.20,21

the time of the procedure. The landmarks and registration distances between CMR or CT-segmented images and electroanatomical maps as well as their impact on outcome in different studies are summarised in Table 1.

CMR is the most well-studied imaging modality used to guide VT ablation in patients with NICM. Andreu et al. showed no difference in core scar detection between regular resolution (1.4–2.0 × 1.4–2.0 × 5.0 mm) and 3D high spatial resolution (1.4 × 1.4 × 1.4 mm) late gadolinium enhancement (LGE)-CMR, but more accurate characterisation of the border zone scar region using high spatial resolution CMR with thresholds set at 40–60% of maximal signal intensity (SI).22 The border zone scar region on 3D LGE-CMR correlated with scar on EAVM in 79.2% of patients, compared with only 37.7–61.8% with 2D regular resolution CMR. However, there were only seven NICM patients in this 30-patient cohort referred for VT ablation.22

VT Substrate Patterns in Different Non-ischaemic Cardiomyopathy Aetiologies

The feasibility of delineating small VT isthmuses on LGE-CMR in NICM requires further investigation. Siontis et al. compared acute and longterm ablation outcomes in idiopathic dilated cardiomyopathy (IDCM) patients with and without pre-procedural LGE-CMR and found that patients in whom pre-procedural LGE-CMR was performed and areas of possible VT substrate were defined, had higher acute procedural success (63% versus 24%; OR 7.86; p<0.001) and improved survival free of the composite endpoint of VT recurrence, heart transplantation or death (27% versus 60%; p=0.02).23

While acute ablation success rates are similar between these two scar patterns, patients with anteroseptal as opposed to inferolateral scar pattern are more likely to have long-term VT recurrence and require repeat ablation.27 In addition, the anteroseptal scar pattern often predicts VT circuit location near the conduction system, prompting preprocedural discussion about the possibility of atrioventricular block and need for permanent pacing strategies. Frequently, anteroseptal scar patterns extend to involve extensive areas of the endocardial and epicardial perivalvular LV.

Cardiac CT imaging is another helpful imaging modality to guide NICM VT ablation. Esposito et al. identified arrhythmogenic substrate in 39 of 42 patients utilising CT with delayed enhancement.24 Piers et al. integrated CT and LGE-CMR images simultaneously in 10 NICM patients and proposed an algorithm to detect epicardial and intramural arrhythmogenic substrate.25 They found that in areas with fat thickness >2.8 mm, bipolar or unipolar voltage were attenuated and electrogram duration was lengthened, leading to failure of scar delineation from normal myocardium. In contrast, abnormal electrogram morphologies (late potentials, double potential, fragmented or >4 sharp spikes) could identify the substrate even with the existence of thick fat. In their study, a unipolar voltage cut-off value ≤7.95 mV was able to detect intramural scar. In a study by Yamashita et al., in which image-integration was used to guide VT ablation in 116 patients, 89% of critical VT isthmuses and 85% of local abnormal ventricular activities (LAVA) sites could be identified.21 The efficiency in identifying LAVA with imaging was higher in ICM (90%) and ARVC (90%) than in NICM (72%).

Oloriz et al. have previously characterised electrogram abnormalities correlating with CMR substrate and reported that late potentials were more frequently seen on the epicardium in patients with an inferolateral (80%) versus anteroseptal (7%) scar pattern.27 Differences

Figure 1 shows an LV wall thickness shell with reconstruction of the aorta, coronary arteries and septal aneurysm generated from CT. Figure 2 shows a pre-procedural LGE-CMR image depicting anteroseptal patchy scar and inferolateral transmural scar. Registration of the CMR-segmented LV shell to endocardial and epicardial EAVM by using landmarks of aorta, LV apex and mitral annulus is successfully accomplished. Pre-procedural images can be segmented and displayed as 3D shells and integrated into the electroanatomical map for intraprocedural use. Since critical VT circuits can be quite small, accurate registration of the CT or CMR-segmented 3D models with the EAVMs is crucial to permit precise evaluation of structural as well as electrical abnormalities. Utilisation of intracardiac echo for identification of the cusps and true LV/right ventricle (RV) apices, and their use as landmarks can be extremely helpful for accurate image registration at

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Idiopathic Dilated Cardiomyopathy There are two predominant substrate patterns in patients with IDCM as identified by unipolar voltage on EAVM and LGE-CMR.26–28 the first is a basal, anteroseptal scar pattern, which frequently extends to the perivalvular region, as well as subepicardial, and the second is an inferolateral or true posterior scar pattern. Identifying the scar pattern in IDCM with pre-procedural imaging allows one to anticipate acute and long-term ablation success, and provide valuable information to share with patients prior to their procedure.

in ablation success between these two groups are likely to be a result of difficulties in targeting VT substrate in the anteroseptal group, as well as the higher prevalence of septal hypertrophy. While patients with inferolateral substrate are more likely to have epicardial late potentials that may be amenable to ablation from the epicardium or coronary venous system, those with anteroseptal substrate frequently have deep intramyocardial substrate within the interventricular septum or LV summit, where effective energy delivery and substrate elimination is difficult with currently available tools. Our group have also reported a strong association between electrogram characteristics and the transmural extent and intramural types (endocardial, mid-wall, epicardial, patchytransmural) of scar as measured on LGE-CMR in IDCM. Myocardial wall thickness, scar transmurality, and intramural scar types were independently associated with electrogram amplitude, duration, and deflections. Fractionated and isolated potentials were more likely to be observed in regions with higher scar transmurality (p<0.0001 by ANOVA) and in regions with patchy scar (versus endocardial, mid-wall, epicardial scar; p<0.05 by ANOVA). Most VT circuit sites were located in scar with >25% scar transmurality.18 Figure 3 shows a patient with NICM in whom VT was terminated with ablation at a site from LV endocardium that correlated with intramural scar identified by low unipolar voltage of EAVM and LGE-CMR. In addition to LGE-CMR, fludeoxyglucose (FDG)-PET imaging holds promise for dissecting the role of active inflammation in NICM VT patients.

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Multimodality Imaging to Guide Ventricular Tachycardia Ablation Figure 1: Left Ventricular Wall Thickness Shell with Reconstruction of the Aorta, Coronary Arteries and Septal Aneurysm Generated from CT

PA view

0.5 mV

1.5 mV

2 5 mm Min

AP view Max

Wall thickness

Septal aneurysm The 3D left ventricle shell, aorta, coronary arteries and septal aneurysm (arrow) are generated from CT imaging. Wall thickness of the left ventricle can be displayed, which defines wall thinning <5 mm as abnormal according to previous ischaemic cardiomyopathy scar. AP = anteroposterior; PA = posteroanterior.

Figure 2: Pre-procedural Late Gadolinium Enhancement-Cardiac MRI Depicting Anteroseptal Patchy Scar and Inferolateral Transmural Scar

Anteroseptal patchy scar Inferolateral transmural scar

Idiopathic dilated cardiomyopathy

A: Anteroseptal patchy scar and inferolateral transmural scar on late gadolinium enhancement-cardiac MRI (CMR); B: Endocardial and epicardial contouring of the left ventricle (LV) and scar detection based on 6 standard deviations from remote normal myocardium; C: 3D right ventricle, LV endocardial and epicardial shell generated from CMR; D: Registration of electroanatomical voltage mapping and CMR-segmented LV shell utilising Carto Merge module by using landmarks of aorta, mitral annulus and LV apex; E: Electroanatomical voltage mapping points projected to late gadolinium enhancement-CMR can associate electrograms with signal intensity based on CMR. Courtesy of Dr Jae-Seok Park, Electrophysiology, Division of Cardiology, Department of Medicine, Mediplex Sejong General Hospital, South Korea.

Tung et al. showed that nearly half of patients referred with unexplained cardiomyopathy and ventricular arrhythmia have focal myocardial inflammation on PET, suggesting an occult arrhythmogenic inflammatory cardiomyopathy in these ‘idiopathic’ NICM patients.29 The potential benefit of immunosuppressive medical therapy is unclear. One review suggested that identification of arrhythmogenic inflammatory cardiomyopathy, may prompt the usage of the antiinflammatory medical therapy in early stage of arrhythmia before catheter ablation.30 Further efforts on establishing optimal diagnostic and treatment paradigms for NICM VT and premature ventricular contraction patients are warranted.

substrate in patients undergoing VT ablation.31–33 The distribution of LGE in patients with CS is variable and frequently patchy, often involving the interventricular septum (predominantly involving the basal and/or mid-ventricular septum, with or without RV involvement) and inferolateral wall.34,35 Additionally, LGE is more frequently seen in subepicardial layers.36 Muser et al. reported that approximately one-third of all affected cardiac segments revealed transmural LGE with preserved wall thickness in patients with CS and VT undergoing ablation.37 The presence of LGE on CMR identifies areas with inflammation, granuloma and scar on necropsy.38,39

Cardiac Sarcoidosis Cardiac sarcoidosis (CS) is an under-diagnosed aetiology of NICM. Cardiac imaging modalities, including LGE-CMR and PET, have dramatically improved the diagnosis of CS and can define the

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Interestingly, compared to patients with IDCM, those with CS tend to have more abnormal electrograms. 37 Whether fibrosis or active inflammation represents the main culprit contributing to

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Electrophysiology and Ablation Table 1: Studies of Non-ischaemic Cardiomyopathy Ventricular Tachycardia Ablation with Image Integration Using Pre-procedural CT and Cardiac MRI Images Studies

Patient

Image Modalities

EAVM and

Registration

Registration Anatomical

Population

and Resolution

Mapping

Method

Accuracy

(mm)

Catheter

Outcome

Landmark

(mm)

Bogun et al. 200919

NICM (n=29)

CMR: 1.4 × 2.2 × 8.0

Carto 3.5 mm catheter

Landmark + surface; CartoMerge

4.8 ± 3.6

Aorta, LV apex, mitral annulus

Identify arrhythmogenic substrate in NICM and strategy

Spears et al. 201287

NICM (n=10)

CMR: 1.3 × 1.3 × 6.0

Carto 3.5 mm catheter

Landmark + surface; CartoMerge

3.6 ± 2.9

Aorta, His bundle, mitral valve annulus, LV apex

BV >1.9 mV and UV <6.7 mV had a NPV of 91% for detecting non-endocardial scar from no scar or endocardial scar

Cochet et al. 201362

ICM (n=3) NICM (n=3) Myocarditis (n=2) IDCM (n=1)

CMR: 1.25 × 1.25 × 2.5

Carto and NavX, PentaRay and 3.5 mm catheter

Landmark + surface; CartoMerge

N/R

Coronary sinus, aortic root, left atrium, LV, mitral annulus

In myocarditis, sub-epicardial LGE matched areas of epicardial low voltage.

Desjardins et al. 201360

NICM (n=15) • 11: IDCM • 4: sarcoidosis

CMR: 1.4 × 2.2 × 8.0

Carto 3.5 mm catheter or 4 mm catheter

Landmark + surface; CartoMerge

<5.0

Aorta, mitral annulus, LV apex

Define best cutoff values of BV <1.55 mV and UV <6.78 mV to separate endocardial measurements overlying scar as compared with areas not overlying a scar.

Piers et al. 201325

NICM (n=10)

CMR: N/R CT: 0.5 × 0.5 × 2.0

Carto 3.5 mm catheter

Landmark + visual alignment; CartoMerge

3.2 ± 0.4

Left main coronary artery

BV, UV and electrogram duration >50 ms Can distinguish scar from normal myocardium in areas <2.8 mm fat

Piers et al. 2014.7

ICM (n=23) NICM (n=21)

CMR: N/R

Carto 3.5 mm catheter

Landmark + visual alignment; CartoMerge

3.8 ± 0.6

Left main coronary artery

Critical isthmus sites located in close proximity to CMRderived core-border zone transition and in regions with >75% transmural scar

Yamashita et al. 201621

NICM (n=30) ARVC (n=19)

CMR: 1.25 × 1.25 × 2.5; CT angiography: thickness 0.6

Carto and NavX, multielectrode (1-2-1 mm) or 4 mm catheter

Landmark + surface; CartoMerge or field scaling of NavX

3.9 ± 1.0

N/R

Integration motivated additional mapping; 43% modified epicardial ablation strategy owing to the localisation of vessels and nerve

Esposito et al. 201624

NICM (n=19) • 12: IDCM • 1: LMNA • 5: myocarditis • 1: other

CT: N/R

Carto: N/R

Landmark + surface; CartoMerge

2.9 ± 2.1

Aorta, LV

Delayed enhancement segments on CT correlated with low voltage area

ARVC = arrhythmogenic right ventricular cardiomyopathy; BV = bipolar voltage; CMR = cardiac magnetic resonance; EAVM = electroanatomical voltage mapping; ICM = ischaemic cardiomyopathy; IDCM = idiopathic dilated cardiomyopathy; LGE = late gadolinium enhancement; LMNA = lamin A/C; LV = left ventricle; N/R = not reported; NICM = non-ischaemic cardiomyopathy; NPV = negative predictive value; UV = unipolar voltage.

sustained monomorphic VT remains unclear.37,40,41 Blankstein et al. demonstrated that the presence of focal perfusion defects with 82rubidium nuclear scanning and FDG uptake on cardiac PET identified patients at higher risk of VT or death.40 In contrast, Muser et al. found that the abnormal electrograms were more correlated with LGE on CMR rather than inflammation identified by PET.37 Figure 4 shows an example of fractionated electrograms located in the LGE region on CMR, with good pace-mapping QRS morphology similar to clinical VT morphology. While there is no definite benefit of immunosuppressive therapy in patients with monomorphic VT and NICM, this strategy is a reasonable approach in patients with CS and VT, particularly in the acute inflammatory phase of the disease when polymorphic VT may be manifest. VT characteristics and ablation outcomes can

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differ based on the degree of active inflammation with CS, and VT ablation outcomes in patients with CS tends to be worse than other aetiologies of NICM.1,5,42

Lamin A/C Cardiomyopathy LMNA cardiomyopathy can present in a similar manner to CS, with conduction abnormalities, ventricular arrhythmias and heart failure. The diagnosis can be confirmed with advanced genetic testing. Consideration of the diagnosis of LMNA cardiomyopathy should be made in all patients with suspected CS who do not respond to anti-inflammatory treatment or who do not have evidence of active inflammation on PET imaging. The specific substrate pattern in LMNA cardiomyopathy, as characterised by CMR, predominantly involves the basal and anteroseptal segments with preserved wall thickness.

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Multimodality Imaging to Guide Ventricular Tachycardia Ablation Figure 3: Example of the Association Between Double Potential with Intramural Late Gadolinium Enhancement and Termination of Ventricular Tachycardia 0.5 mV

1.5 mV

0 mV

8.3 mV

40%

60% max SI

VT termination site at sub-right coronary cusp I II III aVR aVL aVF V1 V2 V3 V4 V5 V6

BV: 1.6 mV UV: 4.7 mV Double potential

Pre-procedural segmented CMR Mid-septum of LV shell

Anteroseptal scar of basal LV on CMR Idiopathic dilated cardiomyopathy

Normal bipolar voltage but abnormal unipolar voltage around the perivalvular area extending to anteroseptal wall are noted on electroanatomical voltage mapping (EAVM). Pre-procedural late gadolinium enhancement (LGE)-CMR segmented LV shell displays perivalvular to anteroseptal scar involving mid-septum. After registration of EAVM and LGE-segmented LV shell, the VT termination point on EAVM is projected to LGE region on CMR. BV = bipolar voltage; CMR = cardiac magnetic resonance; LV = left ventricle; RV = right ventricle; SI = signal intensity; UV = unipolar voltage; VT = ventricular tachycardia.

Figure 4: Example of Fractionated Electrograms Located in the Late Gadolinium Enhancement Region on Cardiac MRI

0.5 mV

1.5 mV

0 mV

8.3 mV

40%

60% max SI Pace mapping: 99.4% I II III aVR aVL aVF V1 V2 V3 V4 V5 V6

BV: 0.7 mV UV: 4.9 mV Duration: 122 ms

Pre-procedural segmented CMR Mid-septum of LV shell

Inferoseptal scar of mid LV on CMR Cardiac sarcoidosis

Small area of abnormal bipolar voltage at septum of mid-LV and extensive abnormal unipolar voltage from basal, perivalvular, inferoseptal wall to mid-LV are noted on electroanatomical voltage mapping. Pre-procedural late gadolinium enhancement-CMR segmented LV shell displays inferoseptal scar at mid-septum of mid LV. The good pace-mapping point on electroanatomical voltage mapping is projected to late gadolinium enhancement region on CMR. BV = bipolar voltage; CMR = cardiac magnetic resonance; LV = left ventricle; SI = signal intensity; UV = unipolar voltage.

Importantly, VT ablation outcomes in patients with LMNA cardiomyopathy tend to be among the worst of all NICM subgroups.43,44 One study reported a dismal 25% success rate despite multiple ablations, and frequently requiring supplementary techniques such as ethanol injection or surgical ablation. Furthermore, nearly all (91%) patients had â&#x2030;Ľ1 VT recurrence after the last procedure, and the disease process tended to rapidly progress, with a mortality rate of 26% of patients, and a high rate of heart transplantation because of end-stage

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heart failure.44 Reasons for poor success with VT ablation in patients with LMNA cardiomyopathy include poor accessibility of the substrate which tends to be basal septal and intramural.

Myocarditis Myocarditis is an important cause of dilated cardiomyopathy worldwide. LGE-CMR and T2-weighted sequences are useful imaging methods for diagnosis of myocarditis.45 The pattern of VT substrate in patients with post myocarditis cardiomyopathy typically involves the sub-epicardium

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Electrophysiology and Ablation and lateral basal LV, and a combined endocardial and epicardial approach is frequently necessary to achieve durable VT elimination.46,47 A recent multicentre study of 50 patients with myocarditis-related VT reported 1-year VT recurrence rate of 23%.5

on CMRI in patients with IDCM and VT but noted that VT electrogram substrate and origin of VT can occur in approximately 10–20% of patients in the absence of LGE in regions with low unipolar voltage using the higher cut-off value of 8.3 mV.61

Left Ventricular Non-compaction

In a series that included 15 patients (10 with IDCM and five with CS), we determined that voltage thresholds of 1.78 mV and 5.64 mV for bipolar and unipolar scar, respectively, maximise both sensitivity and specificity for identification of LGE on CMR.18 Piers, et al. identified LV endocardial bipolar and unipolar voltage cut-offs of 2.04 mV and 9.84 mV to define scar correlating with LGE-CMR (modified FWHM, ternary method set SI thresholds at 35% and 50% of maximal SI).28 During epicardial voltage mapping, Piers et al. identified bipolar and unipolar voltage cut-offs of 1.81 mV and 7.95 mV, respectively, to correlate with LGE-CMR in 10 NICM patients with VT.25

LVNC is a rare genetic cardiomyopathy, which results from the cessation of embryogenesis of endocardium and mesocardium, generating twolayered structure of the myocardium with a compacted, thin epicardial layer and a non-compacted, thickened endocardial layer with deep intertrabecular recesses. This process mostly affects the inferior and lateral wall from mid to apical LV.48–51 Muser et al. showed that areas with abnormal electroanatomical substrates and low bipolar voltage in patients with VT and LVNC correlate well with non-compacted segments seen on CMR or echocardiography in the majority (75%) of patients.52 Wan et al. found that LGE was detected on CMR in 19 of 57 patients with LVNC, with variable distribution and frequently involving the septum.53 The mechanisms by which LGE develops in patients with LVNC are not understood.

Arrhythmogenic Right Ventricular Cardiomyopathy ARVC is an inherited cardiomyopathy, which is characterised by cardiac myocyte degeneration and fibro-fatty replacement. Akdis et al. suggested that typical ARVC is the right-dominant subtype of arrhythmogenic cardiomyopathy, which is predominantly associated with mutations in genes encoding proteins of the intercalated disc.54 The other two subtypes, including biventricular form and left-dominant form, are mimics of other NICM including sarcoidosis. ARVC can also occur without evidence of desmosomal protein abnormalities suggesting a predominant role for a triggering mechanism and not a genetically determined degenerative disease. The exact triggering mechanism for disease manifestation and progression is poorly understood but the absence of rapid scar progression appears to be the rule rather than the exception.55 Fibrofatty tissue infiltration typically extends from the epicardial surface or mid-myocardium, and may involve the entire thickness of the myocardium.56 CT can identify arrhythmogenic substrate for ARVC patients. Komatsu et al. demonstrated that the majority of LAVAs were located in segments with extensive intramyocardial fat (80%).57 Yamashita et al. also demonstrated a 90% agreement between LAVAs and hypo-attenuated areas identified on multi-detector CT.21

Correlation Between Substrate Derived with Electroanatomical Voltage Mapping and Cardiac MRI/CT/PET Prior electroanatomical voltage mapping studies have defined normal endocardial and epicardial bipolar voltage cut-offs of >1.5 mV and >1 mV, respectively, and normal unipolar voltage cutoff of >8.3 mV.58,59 Different voltage cut-off values have been proposed to identify scar based on correlation with multimodality imaging. Desjardins et al. evaluated 11 IDCM and four sarcoidosis patients with intramural scar detected on LGE-CMR utilising full width at half maximum (FWHM) method, and identified bipolar and unipolar voltage cut-offs of 1.55 mV and 6.78 mV, respectively, to define intramural scar.60 Meanwhile, Liang, et al. identified a unipolar voltage cut-off of 4.8 mV to best correlate with interventricular septal scar defined by FWHM

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Maccabelli et al. showed that 95% of patients with myocarditis-related VT had subepicardial LGE on CMR that correlated with areas of unipolar voltage <8 mV.46 Of note, the above-mentioned studies utilised a 3.5 mm tip open-irrigated catheter with 2 mm ring electrode and 1 mm inter-electrode spacing, or a solid-tip 4 mm catheter for EAVM sampling. Importantly, the validity of different voltage cut-off values for deﬁning abnormal substrate should be conﬁrmed/established for maps created using catheters with different interelectrode spacing and specifically when using small electrode size recording tools. The utility of CT imaging to define VT substrate in patients with NICM has been less well defined. In a small study of 12 patients with IDCM, Esposito et al. demonstrated good correlation between CT-defined substrate (wall thinning <5 mm on CT angiography or visually defined enhanced segments on delayed-enhanced CT) with areas of bipolar and unipolar scar detected with EAVM.24 Cochet et al. acquired high-density endocardial and epicardial EAVM and registered to CMR/multi-detector CT, and found that LGE on CMR and wall-thinning <5 mm at CT corresponded to low voltage areas with bipolar voltage <1.5 mV and LAVA.62 On the contrary, Yamashita et al. demonstrated a poor correlation between wall thinning and EAVM scar (13 ± 16% agreement) in 28 NICM patients with multidetector CT imaging.21 To date, no studies have investigated the correlation between the substrate on EAVM and LGE on CMR or delayed perfusion area on CT in hypertrophic cardiomyopathy patients, and the effect of ventricular hypertrophy on scar voltage cut-offs with EAVM remains unclear. Bazan et al. demonstrated that the myocardial wall thickness or distance from the normal tissue to the abnormal substrate is one of the key factors that can influence the interpretation of abnormal unipolar voltage cutoff value.63 In patients with hypertrophy, the applicable unipolar cut-off value when using a 3.5 mm electrode tip may be greater than the standard 8.3 mV cut-off.64,65 Titrating the slider bar up to 10 mV, or even higher, in the setting of LV hypertrophy may permit identification of areas with layered midmyocardial or epicardial scar. Glashan et al. confirmed the linear association of wall thickness with both unipolar or bipolar voltage in the myocardium without fibrosis detected by histology.66 In these scenarios, certain regions that ‘ghost in’ when adjusting the slider bar upwards may represent areas of intramural and epicardial substrate in patients with LV hypertrophy.

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Multimodality Imaging to Guide Ventricular Tachycardia Ablation Table 2: The Identification of Arrhythmogenic Substrate by Different Image Modalities Studies

Patient

Image

Population

Modalities

Dickfeld et al. 200888

ICM (n=12) NICM (n=2)

PET-CT Thallium scan or rubidium PET

Bogun et al. 200919

NICM (n=29)

Santangeli et al. 201169

Multimodal Imaging Substrate

Electroanatomical

Correlation of Images and

Substrate

Electroanatomical Substrate

Scar: FDG to blood flow match pattern Diseased/hibernating myocardium: FDG to blood flow mismatch pattern

BV <0.5 mV: scar; 0.5–1.5 mV: abnormal myocardium

PET/CT-derived scar maps correlate with voltage map (r=0.89; p<0.05) Scar size, location and border zone predict high resolution voltage map channels (r=0.87; p<0.05).

CMR

Two blinded observers identify LV scar and manually contoured for quantification

BV <1.5 mV: scar (LVA)

CMR-derived scar size correlates with endocardial scar size (BV <1 mV: r=0.96; p<0.0001; BV <1.5mV: r=0.94, p<0.0001)

ARVC (n=18) Myocarditis (n=13) Idiopathic RV outflow tract (n=5)

CMR

Experienced radiologist blindly identifies RV scar

BV <0.5 mV: scar; 0.5–1.5 mV: border zone

Scar ≥20% of the RV area is the best cutoff value to detect LGE (Sen: 83%, Spe: 92%)

Spears et al. 201287

NICM (n=10)

CMR

Core scar: SI ≥50% of maximal myocardial SI Grey scar: SI > the maximum remote myocardial SI, but <50% of the maximal SI (full width at halfmaximum)

N/R

BV >1.9 mV and UV <6.7 mV: 91% NPV for detecting non-endocardial scar from no scar or endocardial scar

Cochet et al. 201362

ICM (n=3) NICM (n=3) Myocarditis (n=2) IDCM (n=1)

CMR CT

Scar: 50–100% of maximal myocardial SI Grey zone: 35–50% of maximal myocardial SI Wall-thinning: LV end-diastolic wall thickness <5 mm

BV <1.5 mV as LVA and LAVA

NICM: poor overlap of LGE CMR-defined substrate with EAVM LVA Wall-thinning matched areas of LVA with an overlap of 63 ± 21% Myocarditis: good overlap of sub-epicardial LGE with LVA (scar: 83 ± 24%; grey zone: 92 ± 12%) Wall-thinning was not found despite the presence of LV epicardial low voltage.

Desjardins et al. 201360

NICM (n=15)

CMR

Two blinded observers identified scar

BV <1.5 mV: LVA

1.55 mV for BV (AUC=0.69, Sen: 61%, Spe: 66%) and 6.78 mV for UV (AUC=0.78, Sen: 76%, Spe: 69%) are best cutoff values for the identification of intramural substrate

Piers et al. 201325

NICM (n=10)

CMR CT

Scar: >35% maximal myocardial SI Fat thickness

BV <1.5 mV: LVA

1.81 mV for BV (AUC: 0.73, Sen: 59%, Spe: 78%) and 7.95 mV for UV (AUC: 0.79, Sen: 80%, Spe: 72%) enables to distinguish scar from normal myocardium in areas <2.8 mm fat

Esposito et al. 201624

NICM (n=19)

Visually defined delayed enhanced segments as scar and the scar transmurality

BV ≤1.5 mV UV ≤8 mV (for LV) Late potentials

Delayed enhancement segments on CT correlated with low voltage area (Sen: 76%, Spe: 86%, NPV: 95%)

Liang et al. 201861

NICM (n=95)

CMR

Scar: full width at half-maximum method

BV ≤1.5 mV UV ≤8.3 mV

4.8 mV for UV cutoff value provides best correlation with LGE on CMR (AUC: 0.75, Sen: 75%, Spe: 70%)

Xie et al. 201870

ARVC (n=10)

CMR

N/R

Epicardium: BV ≤0.5 mV: dense scar BV >1 mV: normal myocardium

SI Z score >0.05 correlates with BV <0.5 mV and <−0.16 correlates with BV >1 mV SI Z score >0.05 identifies delayed potentials in the RV epicardium (Sen: 72%, Spe: 56%)

ARVC = arrhythmogenic right ventricular cardiomyopathy; BV = bipolar voltage; CMR = cardiac MRI; FDG = fludeoxyglucose; ICM = ischaemic cardiomyopathy; IDCM = idiopathic dilated cardiomyopathy; LAVA = local abnormal ventricular activities; LGE = late gadolinium enhancement; LV = left ventricle; LVA = low-voltage area; N/R = not reported; NICM = non-ischaemic cardiomyopathy; NPV = negative predictive value; RV = right ventricle; Sen = Sensitivity; SI = signal intensity; Spe = Specificity; UV = unipolar voltage.

Several important issues must be considered when evaluating RV substrate. First, the RV free wall is thin and normal voltage cut-offs differ from the RV septum. Second, the aortic root, which overlaps the RV septum to RV outflow tract (RVOT), can influence the normal voltage cut-off. Finally, in addition to scar, fat can be arrhythmogenic in patients with ARVC. Normal RV endocardial voltage cut-offs, based on studies examining patients with normal ventricles without evidence of EAVM or CMRI scar, have been identified to be >1.5 mV (bipolar) and >5.5 mV (unipolar, free wall).58,64,67 However, we have shown that unipolar voltage correlating

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

with CMR scar along the posterior RVOT opposite the aortic root tends to be lower than the rest of the posterior septal area, and the authors calculated optimal unipolar voltage cut-off values of 6 mV for the posterior aspect of the RVOT opposite to the aortic root and 7.5 mV for the remainder of the septal aspect of the RV.68 Santangeli et al. reported in a mixed cohort of 18 patients with ARVC, 13 patients with myocarditis and five with idiopathic RVOT arrhythmias that the distribution of LGE correlated well with the distribution of EAVM scar defined as bipolar voltage of <1.5 mV, including free wall, posterior/inferior wall as well as RVOT. However,

261

Electrophysiology and Ablation the existence of LGE on CMR missed 91% of EAVM substrates when the RV EAVM scar area was <20%, indicating that EAVM is much more sensitive for substrate identification than CMRI when the scar burden is low.69 Recently, we reported the association of regional LGE-CMR standardised intensity with 3,205 epicardial electrogram map points in 10 ARVC patients. Bipolar (−1.43 mV/z-score; p<0.001) and unipolar voltage amplitude (−1.22 mV/z-score; p<0.001) were associated with regional signal intensity standardised by z-scores. Signal intensity z-score thresholds >0.05 (95% CI [−0.05–0.15]) and <−0.16 (95% CI [−0.26–0.06]) corresponded to bipolar voltage measures <0.5 and >1.0 mV, respectively. 70 The characterisation of different image modalities in association with arrhythmogenic substrates are summarised in Table 2.

Innovative Image-guided Treatments Recently, innovative imaging-guided treatments have been utilised for refractory VT patients. For patients with severe adhesions post cardiac surgery or repeated epicardial ablations limiting standard percutaneous epicardial access, Aksu et al. described a minimally invasive surgical approach to achieve epicardial access via videoassisted thoracoscopy.71 Stereotactic body radiation therapy (SBRT) is an increasingly utilised non-invasive therapy for patients with refractory VT. Cuculich et al. performed SBRT in five high-risk refractory VT patients and demonstrated dramatic reduction of VT burden over long-term follow-up.72 The recent Phase I/II Study of EP-guided Noninvasive Cardiac Radioablation for Treatment of Ventricular Tachycardia (ENCORE-VT), was a single-arm prospective study that demonstrated SBRT to be associated with marked reduction of VT burden, and as such may be a viable alternative treatment option for patients with VT refractory to ablation.73 Sympathetic hyperactivity clearly plays a vital role in the genesis and maintenance of ventricular arrhythmias, and cardiac sympathetic denervation has been reported as the effective VT treatment which can reduce the burden of ICD shocks.74-76 Vaseghi et al. demonstrated that bilateral cardiac sympathetic denervation is more beneficial than left cardiac sympathetic denervation in VT storm patients.77 Of note, PET imaging can be helpful in assessing cardiac sympathetic innervation.78

Limitations of Cardiac Imaging Assessment and Image Integration

3D in-plane resolution of wideband sequences is limited to 1.5 × 1.5 mm with slice thicknesses ranging from 4–8 mm, which may not be sufficient to clearly delineate critical VT isthmuses.80,81 One advantage of CT compared with delayed enhancement (DE)-CMR is that devicerelated artifact can be quantified logically: each voxel with a value >20% of the maximum density can be considered as hyperdense artifacts, while voxels with values less than −150 HU can be considered as hypodense artifacts.82 Furthermore, although evolving evidence indicates that CMR can be safely performed in patients with devices, including those who are pacemaker dependent, and even in those with abandoned leads or non-MRI conditional systems,CMR may not be universally offered by all centres for patients with ICDs at the current time.83,84

Functional Ventricular Tachycardia Isthmus Assessment The above-mentioned imaging modalities focus on the detection of structural abnormalities and their association with demonstrated EAVM substrates in non-ischaemic VT patients. Few studies have correlated the imaging detected abnormalities to the functional VT isthmuses in NICM patients.7 Anter et al. identified the VT critical isthmus zone, corresponding to the location of a steep activation gradient and very low voltage amplitude during sinus rhythm in the post-infarction swine model.85 The functional electroanatomical high-density mapping allows identification of VT reentrant circuits whilst the EAVM or electrograms during sinus rhythm have limited specificity to identify VT circuits. Ciaccio et al. proposed the source-sink mismatch model to explain how the ischaemic VT re-entrant circuits form and become sustained.86 Of note, it is typically challenging to precisely identify non-ischaemic VT circuits and correlate circuit components with imaging structural abnormalities due to the haemodynamic instability and multiple VT morphologies.

Lack of Evidence Associating Histology and Non-ischaemic Scar Detected by Cardiac MRI or CT There is no agreement on the optimal method and SI thresholds, as well as CT attenuation thresholds to delineate fibrosis/scar or border zone area within scars validated by histology in the setting of prior infarction. Prior studies have utilised various methods to identify fibrosis/scar on the LGE-CMR and CT angiography. By LGE-CMR, the thresholds can be defined using standardised myocardial SI.

Image Resolution and Presence of ICDs It is challenging to delineate the border zone substrate using partial volume averaging with LGE. Schelbert et al. acquired CMR imaging utilising 7 Telsa scanner to identify post-infarction myocardial fibrosis in the ex vivo rat heart and demonstrated that the intermediate signal intensity is resolution dependent.79 Of note, high resolution images can identify intermediate signal intensity voxels correlating with histological fibrosis and a possible VT isthmus, but blur with normal myocardium when image resolution declines due to partial volume effect. In patients with pacemakers and ICDs, imaging artifact from the pulse generator and leads can limit the interpretation of substrate from CMR or CT. The application of a wideband LGE sequence has reduced the hyper-enhanced CMR artifact, however, the dark magnetic susceptibility artifacts remain problematic. Additionally, the current

262

One methodology sets thresholds at 35%, 50% or 40% and 60%7,28,22 to distinguish scar core and border zone area from normal myocardium. For NICM patients, 6 standard deviations above the average SI of healthy remote myocardium has been utilised to define scar.18 In CT, scar may be estimated as hypo-attenuation regions on immediate first pass imaging, or as hyper-attenuation regions on DE imaging acquired 10 minutes after contrast agent injection. Similar to CMR, the extent of scar based upon CT attenuation can be assessed visually or quantitatively using specialised software. Wall thinning <5 mm with LV bulging or aneurysmal dilation can also be used to estimate scar distribution.24 Compared to CMR, CT offers exceptional spatial resolution. However, CMR offers improved temporal and contrast resolution. The optimal method to identify scar employing

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Multimodality Imaging to Guide Ventricular Tachycardia Ablation either LGE-CMR or CT imaging remains to be definitively elucidated and will likely depend upon the patient condition, renal function, ability to breath hold, and institutional resources. The current evidence for scar delineation by imaging in NICM is primarily based on the association with electroanatomical mapping and abnormal electrograms.

Conclusion The underlying VT substrate in patients with NICM can be quite variable, depending on the underlying NICM aetiology. Pre-procedural multimodality imaging and intra-procedural image integration can be helpful to delineate VT substrate and facilitate safe and effective VT ablation in patients with NICM.

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user D, Santangeli P, Castro SA, et al. Long-term outcome M after catheter ablation of ventricular tachycardia in patients with nonischemic dilated cardiomyopathy. Circ Arrhythm Electrophysiol 2016;9:e004328. https://doi.org/10.1161/ CIRCEP.116.004328; PMID: 27733494. Kumar S, Barbhaiya C, Nagashima K, et al. Ventricular tachycardia in cardiac sarcoidosis: characterization of ventricular substrate and outcomes of catheter ablation. Circ Arrhythm Electrophysiol 2015;8:87–93. https://doi.org/10.1161/ CIRCEP.114.002145; PMID: 25527825. Dinov B, Fiedler L, Schonbauer R, et al. Outcomes in catheter ablation of ventricular tachycardia in dilated nonischemic cardiomyopathy compared with ischemic cardiomyopathy: results from the Prospective Heart Centre of Leipzig VT (HELP-VT) study. Circulation 2014;129:728–36. https://doi. org/10.1161/CIRCULATIONAHA.113.003063; PMID: 24211823. Elliott P, Andersson B, Arbustini E, et al. Classification of the cardiomyopathies: a position statement from the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J 2008;29:270–6. https://doi. org/10.1161/CIRCULATIONAHA.113.003063; PMID: 24211823. 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; PMID: 30236386. Piers SR, Leong DP, van Huls van Taxis CF, et al. Outcome of ventricular tachycardia ablation in patients with nonischemic cardiomyopathy: the impact of noninducibility. Circ Arrhythm Electrophysiol 2013;6:513–21. https://doi.org/10.1161/ CIRCEP.113.000089; PMID: 23619893. Piers SR, Tao Q, de Riva Silva M, et al. CMR-based identification of critical isthmus sites of ischemic and nonischemic ventricular tachycardia. JACC Cardiovasc Imaging 2014;7:774–84. https://doi.org/10.1016/j.jcmg.2014.03.013; PMID: 25051947. Kapelko VI. Extracellular matrix alterations in cardiomyopathy: The possible crucial role in the dilative form. Exp Clin Cardiol 2001;6:41–9. PMID: 20428444. Liuba I, Frankel DS, Riley MP, et al. Scar progression in patients with nonischemic cardiomyopathy and ventricular arrhythmias. Heart Rhythm 2014;11:755–62. https://doi. org/10.1016/j.hrthm.2014.02.012; PMID: 24561162. Karamitsos TD, Francis JM, Myerson S, et al. The role of cardiovascular magnetic resonance imaging in heart failure. J Am Coll Cardiol 2009;54:1407–24. https://doi.org /10.1016/j.jacc.2009.04.094; PMID: 19796734. Tao Q, Piers SR, Lamb HJ, et al. Preprocedural magnetic resonance imaging for image-guided catheter ablation of scar-related ventricular tachycardia. Int J Cardiovasc Imaging 2015;31:369–77. https://doi.org/10.1007/s10554-014-0558-x; PMID: 25341408. Gupta S, Desjardins B, Baman T, et al. Delayed-enhanced MR scar imaging and intraprocedural registration into an electroanatomical mapping system in post-infarction patients. JACC Cardiovasc Imaging 2012;5:207–10. https://doi.org/10.1016/j. jcmg.2011.08.021; PMID: 22340829. Desjardins B, Crawford T, Good E, et al. Infarct architecture and characteristics on delayed enhanced magnetic resonance imaging and electroanatomic mapping in patients with postinfarction ventricular arrhythmia. Heart Rhythm 2009;6:644–51. https://doi.org/10.1016/j.hrthm.2009.02.018; PMID: 19389653. Andreu D, Berruezo A, Ortiz-Perez JT, et al. Integration of 3D electroanatomic maps and magnetic resonance scar characterization into the navigation system to guide ventricular tachycardia ablation. Circ Arrhythm Electrophysiol 2011;4:674–83. https://doi.org/10.1161/CIRCEP.111.961946; PMID: 21880674. Ghannam M, Cochet H, Jais P, et al. Correlation between computer tomography-derived scar topography and critical ablation sites in postinfarction ventricular tachycardia. J Cardiovasc Electrophysiol 2018;29:438–45. https://doi. org/10.1111/jce.13441; PMID: 29380921. Copie X, Blankoff I, Hnatkova K, et al. Influence of the duration of recording in the reproducibility of the signal

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Clinical Perspective • The arrhythmogenic substrate can differ, depending on the aetiology of non-ischaemic cardiomyopathy (NICM). • Multimodality imaging is helpful to characterise the substrate in patients with NICM prior to ventricular tachycardia (VT) ablation. • Image integration, although not yet characterising detailed histology, can delineate the location and extent of the VT substrate and appears to facilitate safe and effective VT ablation.

averaged electrocardiogram. Arch Mal Coeur Vaiss 1996;89:723–7 [in French]. PMID: 8760658. Cedilnik N, Duchateau J, Dubois R, et al. Fast personalized electrophysiological models from computed tomography images for ventricular tachycardia ablation planning. Europace 2018;20(Suppl 3):iii94–101. https://doi.org/10.1093/europace/ euy228; PMID: 30476056. Sasaki T, Miller CF, Hansford R, et al. Impact of nonischemic scar features on local ventricular electrograms and scarrelated ventricular tachycardia circuits in patients with nonischemic cardiomyopathy. Circ Arrhythm Electrophysiol 2013;6:1139–47. https://doi.org/10.1161/CIRCEP.113.000159; PMID: 24235267. Bogun FM, Desjardins B, Good E, et al. Delayed-enhanced magnetic resonance imaging in nonischemic cardiomyopathy: utility for identifying the ventricular arrhythmia substrate. J Am Coll Cardiol 2009;53:1138–45. https://doi.org/10.1016/j. jacc.2008.11.052; PMID: 19324259. Yamashita S, Sacher F, Mahida S, et al. Role of high-resolution image integration to visualize left phrenic nerve and coronary arteries during epicardial ventricular tachycardia ablation. Circ Arrhythm Electrophysiol 2015;8:371–80. https://doi.org/10.1161/ CIRCEP.114.002420; PMID: 25713213. Yamashita S, Sacher F, Mahida S, et al. Image integration to guide catheter ablation in scar-related ventricular tachycardia. J Cardiovasc Electrophysiol. 2016;27:699–708. https:// doi.org/10.1111/jce.12963; PMID: 26918883. Andreu D, Ortiz-Perez JT, Fernandez-Armenta J, et al. 3D delayed-enhanced magnetic resonance sequences improve conducting channel delineation prior to ventricular tachycardia ablation. Europace 2015;17:938–45. https://doi. org/10.1093/europace/euu310; PMID: 25616406. Siontis KC, Kim HM, Sharaf Dabbagh G, et al. Association of preprocedural cardiac magnetic resonance imaging with outcomes of ventricular tachycardia ablation in patients with idiopathic dilated cardiomyopathy. Heart Rhythm 2017;14:1487– 93. https://doi.org/10.1016/j.hrthm.2017.06.003; PMID: 28603002. Esposito A, Palmisano A, Antunes S, et al. Cardiac CT with delayed enhancement in the characterization of ventricular tachycardia structural substrate: relationship between CT-segmented scar and electro-anatomic mapping. JACC Cardiovasc Imaging 2016;9:822–32. https://doi.org/10.1016/j. jcmg.2015.10.024; PMID: 26897692. Piers SR, van Huls van Taxis CF, Tao Q, et al. Epicardial substrate mapping for ventricular tachycardia ablation in patients with non-ischaemic cardiomyopathy: a new algorithm to differentiate between scar and viable myocardium developed by simultaneous integration of computed tomography and contrast-enhanced magnetic resonance imaging. Eur Heart J 2013;34:586–96. https://doi. org/10.1093/eurheartj/ehs382; PMID: 23161702. Hsia HH, Callans DJ, Marchlinski FE. Characterization of endocardial electrophysiological substrate in patients with nonischemic cardiomyopathy and monomorphic ventricular tachycardia. Circulation 2003;108:704–10. https://doi. org/10.1161/01.CIR.0000083725.72693.EA; PMID: 12885746. Oloriz T, Silberbauer J, Maccabelli G, et al. Catheter ablation of ventricular arrhythmia in nonischemic cardiomyopathy: anteroseptal versus inferolateral scar sub-types. Circ Arrhythm Electrophysiol 2014;7:414–23. https://doi.org/10.1161/ CIRCEP.114.001568; PMID: 24785410. Piers SR, Tao Q, van Huls van Taxis CF, et al. Contrastenhanced MRI-derived scar patterns and associated ventricular tachycardias in nonischemic cardiomyopathy: implications for the ablation strategy. Circ Arrhythm Electrophysiol 2013;6:875–83. https://doi.org/10.1161/CIRCEP.113.000537; PMID: 24036134. Tung R, Bauer B, Schelbert H, et al. Incidence of abnormal positron emission tomography in patients with unexplained cardiomyopathy and ventricular arrhythmias: The potential role of occult inflammation in arrhythmogenesis. Heart Rhythm 2015;12:2488–98. https://doi.org/10.1016/j.hrthm.2015.08.014; PMID: 26272522. Bauer BS, Li A, Bradfield JS. arrhythmogenic inflammatory cardiomyopathy: a review. Arrhythm Electrophysiol Rev 2018;7: 181–6. https://doi.org/10.15420/aer.2018.26.2; PMID: 30416731.

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75. V aseghi M, Shivkumar K. The role of the autonomic nervous system in sudden cardiac death. Prog Cardiovasc Dis 2008;50:404–19. https://doi.org/10.1016/j.pcad.2008.01.003; PMID: 18474284. 76. Vaseghi M, Barwad P, Malavassi Corrales FJ, et al. Cardiac sympathetic denervation for refractory ventricular arrhythmias. J Am Coll Cardiol 2017;69:3070–80. https://doi. org/10.1016/j.jacc.2017.04.035; PMID: 28641796. 77. Vaseghi M, Gima J, Kanaan C, et al. Cardiac sympathetic denervation in patients with refractory ventricular arrhythmias or electrical storm: intermediate and longterm follow-up. Heart Rhythm 2014;11:360–6. https://doi. org/10.1016/j.hrthm.2013.11.028; PMID: 24291775. 78. Sasano T, Abraham MR, Chang KC, et al. Abnormal sympathetic innervation of viable myocardium and the substrate of ventricular tachycardia after myocardial infarction. J Am Coll Cardiol 2008;51:2266–75. https://doi. org/10.1016/j.jacc.2008.02.062; PMID: 18534275. 79. Schelbert EB, Hsu LY, Anderson SA, et al. Late gadoliniumenhancement cardiac magnetic resonance identifies postinfarction myocardial fibrosis and the border zone at the near cellular level in ex vivo rat heart. Circ Cardiovasc Imaging 2010;3:743–52. https://doi.org/10.1161/ CIRCIMAGING.108.835793; PMID: 20847191. 80. Ranjan R, McGann CJ, Jeong EK, et al. Wideband late gadolinium enhanced magnetic resonance imaging for imaging myocardial scar without image artefacts induced by implantable cardioverter-defibrillator: a feasibility study at 3 T. Europace 2015;17:483–8. https://doi.org/10.1093/europace/ euu263; PMID: 25336666. 81. Rashid S, Rapacchi S, Shivkumar K, et al. Modified wideband three-dimensional late gadolinium enhancement MRI for patients with implantable cardiac devices. Magn Reson Med 2016;75:572–84. https://doi.org/10.1002/mrm.25601; PMID: 25772155. 82. Prell D, Kalender WA, Kyriakou Y. Development, implementation and evaluation of a dedicated metal artefact reduction method for interventional flat-detector CT. Br J Radiol 2010;83:1052–62. https://doi.org/10.1259/bjr/19113084; PMID: 20858662. 83. Nazarian S, Hansford R, Rahsepar AA, et al. Safety of magnetic resonance imaging in patients with cardiac devices. N Engl J Med 2017;377:2555–64. https://doi.org/10.1056/ NEJMoa1604267; PMID: 29281579. 84. Russo RJ, Costa HS, Silva PD, et al. Assessing the risks associated with MRI in patients with a pacemaker or defibrillator. N Engl J Med 2017;376:755–64. https://doi. org/10.1056/NEJMoa1603265; PMID: 28225684. 85. Anter E, Kleber AG, Rottmann M, et al. Infarct-related ventricular tachycardia: redefining the electrophysiological substrate of the isthmus during sinus rhythm. JACC Clin Electrophysiol 2018;4:1033–48. https://doi.org/10.1016/j. jacep.2018.04.007; PMID: 30139485. 86. Ciaccio EJ, Coromilas J, Wit AL, et al. Source-sink mismatch causing functional conduction block in re-entrant ventricular tachycardia. JACC Clin Electrophysiol 2018;4:1–16. https://doi. org/10.1016/j.jacep.2017.08.019; PMID: 29600773. 87. Spears DA, Suszko AM, Dalvi R, et al. Relationship of bipolar and unipolar electrogram voltage to scar transmurality and composition derived by magnetic resonance imaging in patients with nonischemic cardiomyopathy undergoing VT ablation. Heart Rhythm 2012;9:1837–46. https://doi. org/10.1016/j.hrthm.2012.07.022; PMID: 22846338. 88. Dickfeld T, Lei P, Dilsizian V, et al. Integration of threedimensional scar maps for ventricular tachycardia ablation with positron emission tomography-computed tomography. JACC Cardiovasc Imaging 2008;1:73–82. https://doi.org/10.1016/j. jcmg.2007.10.001; PMID: 19356409.

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Electrophysiology and Ablation

High-power, Short-duration Radiofrequency Ablation for the Treatment of AF Irum D Kotadia, 1 Steven E Williams 2 and Mark O’Neill 1 1. Guy’s and St Thomas’ NHS Foundation Trust, London, UK; 2. King’s College London, UK

Abstract High-power, short-duration (HPSD) ablation for the treatment of AF is emerging as an alternative to ablation using conventional ablation generator settings characterised by lower power and longer duration. Although the reported potential advantages of HPSD ablation include less tissue oedema and collateral tissue damage, a reduction in procedural time and superior ablation lesion formation, clinical studies of HPSD ablation validating these observations are limited. One of the main challenges for HPSD ablation has been the inability to adequately assess temperature and lesion formation in real time. Novel catheter designs may improve the accuracy of intra-ablation temperature recording and correspondingly may improve the safety profile of HPSD ablation. Clinical studies of HPSD ablation are on-going and interpretation of the data from these and other studies will be required to ascertain the clinical value of HPSD ablation.

Keywords High-power, short-duration ablation, radiofrequency ablation lesion formation, AF Disclosure: MO has received research support and honoraria from Biosense Webster and consultation fees from Medtronic, Biosense Webster, St Jude/Abbott and Siemens. SEW has received research support from Biosense Webster. IDK has no conflicts of interest to declare. Received: 10 August 2019 Accepted: 9 December 2019 Citation: Arrhythmia & Electrophysiology Review 2019;8(4):265–72. DOI: https://doi.org/10.15420/aer.2019.09 Correspondence: Irum D Kotadia, Division of Imaging Sciences and Biomedical Engineering, King’s College London, 4th Floor North Wing, St Thomas’ Hospital, 249 Westminster Bridge Rd, London SE1 7EH, UK. E: irum.kotadia@kcl.ac.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.

AF is the most common sustained cardiac arrhythmia and radio frequency is the dominant energy source used for atrial ablation. Owing to an ageing population and the increasing burden of cardiovascular disease, the prevalence of AF, particularly in developed countries, is increasing.1,2 With increasing prevalence comes additional financial burden.3 It is paramount that AF therapy is effective in reducing morbidity and improving quality of life. Evidence that AF is frequently triggered by ectopy arising from within the pulmonary veins led to the development of pulmonary vein isolation as a widely practised therapy and circumferential pulmonary vein isolation is now fundamental to the vast majority of AF ablation procedures.4–6 Success in AF ablation requires the creation of a contiguous, transmural and electrically isolating ablation scar that surrounds the pulmonary veins while avoiding collateral tissue injury.2,7,8 Radiofrequency ablation lesion formation is dependent on several key variables, including power and current delivery, duration of energy application, catheter contact, orientation and stability.7,9,10 Conventionally, pulmonary vein isolation radiofrequency ablation has employed low-power, longduration (LPLD) generator settings with the aim of producing mature ablation lesions while minimising complications including steam pops, cardiac tamponade, pulmonary vein stenosis and collateral tissue damage.3,11 Conventional settings at most ablation centres are usually in the region of 25–35 W for 30–60 seconds per lesion.12,13 As an alternative, ablation using high-power, short-duration (HPSD) generator settings was originally suggested in 2006, yet relatively few trials have assessed its performance and comparability to conventional settings.14 Nevertheless, recent simulation studies and small clinical

trials have shown potential advantages of high-power short duration ablation as a viable alternative treatment strategy. Definitions of what constitutes high power shows considerable variability within the literature, which suggests this in a range of 50–90 W. While there have been a number of computer simulation and experimental studies delivering power at the upper range, far fewer clinical trials have adopted this approach because of concerns regarding patient safety. For the purpose of this article, high power is defined as the use of an ablation generator power output of 50 W or above. This article reviews the data on HPSD ablation as an alternative to conventional radiofrequency ablation. After briefly describing the fundamental principles underlying ablation lesion formation, the potential advantages of HPSD ablation are explored. The function of a new ablation catheter aiming to improve the safety of HPSD ablation is described and gaps in knowledge together with suggestions for future research in this area are identified.

Radiofrequency Ablation Lesion Formation During radiofrequency ablation, electromagnetic energy is converted to thermal energy, resulting in tissue heating and destruction.15 Tissue heating occurs via two mechanisms: resistive (direct) and conductive (indirect) heating (Figure 1). Resistive heating is an active process and generated when the radiofrequency energy applied encounters an impedance at the catheter electrode/myocardium interface and within the myocardium itself. Resistive heating is rapid, beginning and ending immediately with the initiation and cessation of radiofrequency energy application. Conductive heating is a passive process as heat is transferred away from the ablation lesion core. Conductive heating

Access at: www.AERjournal.com

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Electrophysiology and Ablation Figure 1: Heat Sources and Heat Sinks During Cardiac Radiofrequency Ablation

Convective cooling

Blood perfusion cooling Blood flow

Resistive heating

Conductive heating

Figure 2: Radiofrequency Ablation Circuit

R_myocardium

Key to understanding how this energy delivery results in tissue heating is the distinction between power (measured in watts) and energy (measured in joules). While power describes the rate at which energy is consumed per unit time, it is the quantitative property of energy that must be conferred on an object to perform work on that object. Power and energy are therefore linked by the following formula: Energy (J) = power (W) × time (s) Therefore, for a typical LPLD atrial ablation lesion, the energy delivered may be in the order of 900 J (30 W × 30 s), with around 90 J delivered to the myocardium. Energy applied in a high-power, short-duration lesion may actually be significantly less, in the order of 450 J (90 W × 5s), with around 45 J delivered to the myocardium.

R_blood

Radiofrequency generator R_body

Radiofrequency ablation circuit representing parallel impedance circuits of blood and myocardium, connected through a large third impedance back to the radiofrequency generator. R_blood = myocardial/catheter interface; R_body = rest of body × return electrode; R_myocardium = myocardial tissue.

takes anywhere from 30 seconds to 2 minutes to reach a stable state of thermal equilibrium.7,16 If radiofrequency delivery is halted before this, conductive heating will continue after the termination of radiofrequency energy delivery. The radiofrequency circuit can be thought of as two impedances in parallel (that of blood and that of myocardium), connected through a large third impedance (the body) back to the radiofrequency generator (Figure 2). Much of the energy delivered during radiofrequency application does not heat myocardium, but is dissipated within blood, which is a superior conductor to tissue due to not only its lower impedance but also increased catheter contact given its liquid state.16 Energy delivery can be further altered by the degree of catheter contact at the tissue interface. Total circuit impedance has been shown to rise in vitro as the catheter is progressively pressed into myocardium; less of the ablation electrode is then in contact with the highly conductive blood pool, increasing Rmyocardium and decreasing Rblood (Figure 3A). Data from the authors’ laboratory has shown these observations reproduced during in vivo atrial ablation (Figure 3B, unpublished data). As the distance between the catheter and the target ablation site increases, energy delivery is reduced by as much as 75%.15 Further energy is absorbed in large nearby structures, such as the left lung, which is

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wrapped around the left atrial wall and may account for some of the conflicting evidence between in vitro and in vivo findings.14 Subsequent ex vivo and computational modelling studies have attempted to simulate a similar environment to that seen in vivo to recreate a realistic heat dispersion model of a beating heart.17 With general assumptions made regarding catheter contact, typical blood flow and impedance of surrounding structures, only 9% of total energy delivered will contribute to the creation of a standard lesion.16

Consider next how this energy is converted into heat. Temperatures above 50°C result in irreversible cell death, while those in the range of 45–50°C have been shown to create lesions with reversible injury and therefore the ability to recover excitability.15,18,19 The specific heat capacity of a substance is the amount of energy that must be added to 1 g of that substance to increase its temperature by 1°C, and is a physical constant that varies depending on the physical properties of the substance, in this case atrial myocardium. Temperature change is therefore related to applied energy, mass and specific heat by the following equation: ΔT =

Q mc

Q is the energy added (measured in joules), m is the mass of the substance being heated (measured in grams) and c is the specific heat capacity of the substance (measured in Jg−1K−1). Specific heat capacity for myocardium is temperature dependent but values around 3.111 Jg−1K−1 have previously been used in simulation studies of cardiac radiofrequency ablation.20,21 Taking the density of myocardium as 1.053 g/cm3, and modelling a typical lesion as a truncated sphere with a depth of 5 mm and a width of 8 mm (volume 0.18 cm3 ; Figure 4), it can be shown that around only ~14 J would be required to raise the temperature of myocardium within the ablation lesion from 37°C to 60°C, which is well within the energy delivered by both typical LPLD and new high-power, high-duration settings.22 Put another way, at generator power outputs of 60 W, where around 6 W is delivered to the tissue, an effective 5 × 8 mm lesion could be formed in around only 2–3 seconds, which is consistent for example with the time taken to eliminate conduction in an accessory pathway that has been accurately located. Therefore, it is the total quantity of energy delivered to the tissue, not the duration of energy application per se, that is important in achieving tissue heating and ablation lesion formation. Nevertheless, simulation studies show that multiple other factors including electric conductivity,

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High-power, Short-duration Ablation

a trend towards wider lesions with increasing power. In most of these studies, lesion diameters were generally measured histologically under direct visualisation. Only one study measured the distance from the endocardial surface to the 53°C isotherm, previously shown to indicate irreversible tissue injury, and could therefore include a comment on the contributions of conductive and resistive heating with HPSD ablation.14 A further study performed in vitro on porcine left ventricular myocardium compared lesion geometry at irrigation rates of 2 ml/min and 17 ml/min.26 At a lower irrigation flow, application of higher powers led to steam pops. The higher irrigation flow allowed delivery of higher powers of 40 W for up to 30 seconds compared with 10 seconds at a lower irrigation flow. Although the surface width was reduced with higher irrigation rates, there was little difference in lesion depth. At this time, there is no consensus definition for what constitutes HPSD ablation, making it challenging to describe the clinical settings required to achieve the increased efficacy and improved safety reported. Figure 5 shows the relationship between total energy delivery (J), lesion depth (mm) and lesion width (mm) based on published in silico, ex vivo and in vivo studies. Data points are coloured, based on arbitrary definitions of ablation category as lower power, long duration (mean power 20–39 W, mean duration >20 seconds), HPSD (mean power >50 W, mean duration 0–9 seconds) or other (mean power 40–49 W, mean duration 10–19 seconds). As predicted on the basic principles described above, there is a linear relationship between total energy and lesion depth, regardless of the classification of ablation type. However, the relationship between total energy and lesion width is more complicated, with HPSD ablation resulting in a greater lesion width than lower-power, long-duration ablation for the same energy delivered. This difference likely results from a combination of an increased contribution of conductive heating to lesion formation in lower-power, long-duration ablation combined with increased duration

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Resistance (ohm)

110 90 70 50 −10

−5

Depth (mm) 1 kHz

10 kHz

100 kHz

500 kHz

0.2

0.1

45–50

40–45

35–40

30–35

25–30

20–25

Source: Cao et al.

2002.56

15–20

0.0 10–15

Studies of lesion geometry at different power and duration settings demonstrate a clear correlation between total energy delivery and lesion depth, and suggest that the total energy delivered is the key variable rather than the rate at which it is delivered.14,17,26,28 There is also

130

5–10

Lesion Geometry

Resistance versus depth 150

0–5

Characteristics of High-power, Short-duration Ablation

Figure 3: Relationship Between Catheter-myocardium Contact Force and Circuit Impedance

∆ Impedance (%/100)

thermal conductivity, current density, electric field intensity and heat loss due to blood perfusion in the myocardial wall all influence ablation lesion formation.21 Although the effects of perfusion in the myocardial wall are minimal, the effects of cooling from myocardial blood flow and catheter irrigation are not negligible, with the result of cooling the tissue surface within the immediate vicinity of the electrode and reducing the lesion size at the tissue surface.23–25 In HPSD ablation, the majority of tissue death occurs via resistive heating and, as a result, theoretical advantages have been proposed, including optimised lesion geometry, reduced collateral tissue damage and increased durability of electrical isolation, in addition to obvious benefits in procedural duration.8,14,17,26 These characteristics are explored in more detail below. However, to understand the optimal duration of high-power energy delivery, it is also necessary to predict the degree of conductive heating that might occur when the duration of energy application is altered. Although there are numerous reports describing the advantages of HPSD ablation, no currently available technology can provide adequate real-time assessment of lesion formation and recommendations for HPSD ablation are based on trial and error experience from highly expert centres.8,14,17,27

Contact force (g) Reproduced with permission from IEEE.

Figure 4: Ablation Lesion Volume Model r Spherical cap 3 mm

Blood Myocardium Volume of ablation lesion = volume of sphere − volume of spherical cap Volume of sphere = 4/3 π3 Volume of spherical cap = 1/3 πh2(3r−h)

8 mm

5 mm

Ablation lesion

of delivery to permit the cooling effect of endocardial blood flow and/ or catheter irrigation to confine lesion width.

Complication Rates and Collateral Damage Major complications occur in approximately 3.5% of AF ablation procedures because of direct and collateral injury among other factors.29 While there is a vast worldwide experience with conventional ablation settings, the safety profile of HPSD ablation is much less well established. A single retrospective study of almost 14,000 ablations demonstrated low complication rates, but procedure technique varied, with duration of application in a range of 2–15 seconds. There are concerns that high power could increase complications, including steam pops, charring and cardiac perforation, leading to tamponade. Steam pops in particular instigate thrombus formation, which can embolise, causing cerebral ischaemic events. A loose correlation has been illustrated in previous studies between procedure length and risk of developing asymptomatic cerebral ischaemia identifiable on brain magnetic resonance imaging, although there are no current

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Electrophysiology and Ablation Figure 5: Lesion Geometry and Radiofrequency Energy Relationships for High-power, Short-duration and Low-power, Long-duration Ablation A

Lesion Depth Versus Total Power Delivered 6.5

5.5

4.5

Lesion width (mm)

Lesion depth (mm)

Lesion Width Versus Total Power Delivered 12

4 3.5 3 2.5 2

8 7 6 5 4

1.5

0.5

100 200 300 400 500 600 700 800 900 1,000 1,100 1,200 1,300

100 200 300 400 500 600 700 800 900 1,000 1,100 1,2001,300 Energy (J)

Energy (J) HPSD

LPLD

Other

HPSD

LPLD

Other

A shows lesion depth compared with change in total power delivered (power [W] × time [seconds]). Data compiled from several published studies assessing change in lesion depth with variable power and duration of delivery. B shows lesion width compared with change in total power delivered (power [W] × time [seconds]). Data compiled from several published studies assessing change in lesion depth with variable power and duration of delivery.14,17,26,28 LPLD = low power, long duration; HPSD = high power, short duration.

robust data to explore an association between HPSD and the risk of cerebral lesions.30,31 In vitro ablation has previously been performed using a myocardial phantom set-up, comparing conventional settings of 40 W/30 s against several HPSD settings in a range of 40–80 W/5 s. At 70 W/5 s and 80 W/5 s applications, catheter tip temperature sensors measuring above 80°C were shown to have potential for serious complications.32 This was reinforced in vivo by steam pops occurring at both settings. Interestingly, collateral thermal injury to the lungs was observed in conventional settings as well as at 80 W/5 s and the optimal setting found to minimise collateral damage while creating durable lesions was 50–60 W/5 s.14 The relationship between thermal latency and lesion depth using identical radiofrequency energy but over shorter time periods (1 second, 5 seconds, or 30 seconds) has been tested using a computer model. Tissue becomes overheated with temperatures over 100°C at 1 second and 5 second durations and could lead to collateral damage and complications in the clinical setting.33 These findings were correlated in vivo whereby lesions created without temperature limitation resulted in a 1.7% incidence of steam pops, all of which occurred at temperatures over 85°C.17 For this reason, all studies advocating HPSD ablation strongly recommend the use of an automatic temperature cut-off. The exact cut-off varies between studies between 50°C and 80°C.8,14,34–36 Small animal studies have shown safety and efficacy in using high powers between 50 W and 90 W with contact forces of 10–20 g and using irrigated catheters to maintain a catheter tip-tissue temperature of less than 55–65°C during lesion formation.8,14,17,37 Atrio-oesophageal fistula as a consequence of left atrial ablation is a rare but life-threatening complication with a mortality rate of at least 50%. The oesophagus can lie within 2 mm of the posterior left atrial wall, placing it in danger of injury with changes in lesion depth.38 The combined experience to date is too limited to define the risk of oesophageal injury with HPSD ablation. However, late gadolinium enhancement MRI of the oesophagus in 574 patients

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following AF ablation using user-defined HPSD settings of 50 W for 5 seconds reported a 14.3% incidence of moderate to severe thermal oesophageal late gadolinium enhancement, although no fistulas were reported.35 The patterns of severity were similar between HPSD and LPLD groups despite a marginal increase in comorbidities in the study group, a larger left atrial volume based on volume index and more central positioning of the oesophagus in relation to the posterior left atrial wall. These findings are in keeping with a previous retrospective study of more than 10,000 patients where atrio-oesophageal fistulas were recorded in four patients who underwent HPSD ablation. In three of these patients, power was reduced from 45–50 W to 35 W on the posterior wall and ablation performed for a longer duration.9 From a biophysical perspective, it is conceivable that HPSD ablation may be safer for patients because it causes less collateral damage. Initial computer simulation studies generated concern that delivering a similar amount of energy over a shorter duration would result in lesions of greater depth due to thermal latency after the ablation had been halted.33 This strategy led to significant elevation in catheter tip temperature of up to 100°C when total energy was delivered over 1 second and 5 seconds and remained above 80°C for up to 7–10 seconds after termination of delivery, well within the tissue overheating range. Further simulations have demonstrated that HPSD lesions require less total energy delivery to achieve wider but shallower lesions which may somewhat mitigate this risk.28 In line with the theoretical predictions described above, experimental data confirms that, with HPSD ablation, the ratio of endocardial heating to irrigation-mediated cooling is higher, reducing convective cooling, mitigating subendocardial sparing and including the endocardium within the maximum zone of heating.17 Furthermore, the shorter duration restricts conductive heating and therefore thermal latency, creating a shallower lesion.28 In fact, earlier studies show a discrepancy in the rates of complications, such as steam pops and charring, with conventional generator settings between in vitro and in vivo experiments, with higher complication rates in

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High-power, Short-duration Ablation Table 1. Overview of High-power, Short-duration Studies Author

Study

Power

Duration

Number of patients

Main findings

Retrospective study

45–50 W

2–15 s

13,974

HPSD has a low complication rate, shorter procedural and total radiofrequency time and more localised and durable lesions than LPLD

Rozen et al. 2017;17 201834

In vivo

50–90 W

90 W for 4 s + N/A 50 W for 6 s (10 s in total)

Use of QDOT Micro Catheter to deliver HPSD ablation is feasible and safe, with effective lesion formation

Barkagan et al. 201857

In vivo

90 W

4 s

N/A

HPSD results in shorter procedural time, more predictable lesion formation and non-inferior safety profile compared with LPLD

Nilsson et al. 200637

Cohort study

45 W

40 s

90 (45 in study group, 45 in control group)

HPSD results in shorter procedural and total radiofrequency time and is both safe and effective compared with LPLD

Bourier et al. 201828

In silico

50–80 W

6–13 s

N/A

HPSD results in similar lesion volumes but different lesion geometry to LPLD

Bhaskaran et al. 201714

In vitro In vivo

40–80 W 50–80 W

5 s 5 s

N/A N/A

HPSD creates transmural lesions and is as safe and effective as LPLD

Ali-Ahmed et al. 201926

In vitro

20–50 W

5–40 s

N/A

HPSD results in effective lesion formation with less collateral damage than LPLD

Irastorza et al. 201833

In silico

Power adjusted to pulse duration ensuring delivery of 140 J total energy

1–10 s

N/A

Increased thermal latency phenomenon with HPSD. Maintaining constant delivery of energy with variable pulse duration is not the optimal strategy as short pulses results in overheating

Leshem et al. 201817

In vitro In vivo

90 W 90 W

4–8 s 4 s

N/A N/A

HPSD results in improved lesion contiguity and predictable lesion formation with a non-inferior safety profile when compared with LPLD

Reddy et al. 201936

In vivo

90 W

4 s

52 patients

HPSD results in shorter procedural times, shorter fluoroscopy time and reduced fluid volume for irrigation. Feasibility and safety demonstrated

Winkle et al. 2019

These studies shows the significant variation in ablation settings investigated. HPSD = high-power, short-duration; LPLD = lower-power, long-duration; N/A = not available.

vivo. This was thought to be a consequence of poor heat dispersion, which is accentuated by a longer duration of ablation in vivo.14 The suggestion of reduced collateral damage was further demonstrated during an in vivo study where conventional settings showed lung injury and temporary phrenic nerve palsy that was absent in HPSD ablation. However, given the infrequency of such complications, these results must be interpreted with caution until larger, multicentre trials can corroborate or refute these findings.17

Clinical Outcomes and Lesion Characteristics Several trials reaffirm that the clinical outcomes of AF ablation remain modest.5,39–41 The Catheter Ablation vs Anti-arrhythmic Drug Therapy for Atrial Fibrillation Trial (CABANA) demonstrated that only 50% of all patients undergoing AF ablation remain free of AF at 3 years after the procedure, with up to 17% requiring further ablation procedures.42 One mechanism for the recurrence of AF following pulmonary vein isolation is the reconnection of the pulmonary veins to the left atrium, which may be because of gaps in the pulmonary vein encirclement or non-transmural lesions within the encirclement.43–45 Incomplete lesion formation can result in reversible conduction block due to transient oedema creating temporary electrical isolation at the time of the procedure.46 Recurrence of arrhythmia may accompany recovery of left atrium to pulmonary vein conduction in the weeks following ablation once inflammation has resolved.47 Anatomical studies have measured the maximum wall thickness of the sleeves surrounding the pulmonary veins at less than 4 mm, with an average thickness of 2 mm.48,49 Durable lines therefore require contiguous thermal injury to this depth to create permanent pulmonary vein isolation.

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As described earlier, conventional ablation at LPLD settings relies on a combination of resistive and conductive heating to produce transmural lesions. Mathematical modelling shows resistive heating to achieve a lesion depth of only 1–1.5 mm during LPLD ablation, requiring conductive heating to create deeper transmural lesions.16,18 In contrast, HPSD ablation studies using computer modelling, static tissue and in vivo have demonstrated lesions of greater depth being generated due to resistive heating with minimal conductive heating, a biophysical lesion profile that may result in more predictable lesion formation in the thin-walled atrium (Table 1).14,17,26,28,33,34 When compared with conventional ablation settings, HPSD (90 W/4 s) linear ablation and pulmonary vein isolation therefore resulted in more predictable lesion formation, contiguous lines and transmural lesions in beating pig hearts.17 In comparison, conventional ablation settings resulted in gaps visible to the naked eye, variable lesion sizes and non-transmural lesions on histology.17 Catheter stability is also an important determinant of lesion formation.10 Longer-duration energy applications may be associated with compromised stability of catheter contact. Lesion characteristics determined in ex vivo stationary tissue preparations do not accurately capture the range of movement seen in the beating heart, where increased variability between lesions and an overall smaller lesion size are seen compared to ablation in a stationary muscle tissue preparation.17 Longer application times as a result of reduced catheter contact and stability could conceivably lead to increased local tissue oedema, reversible atrial injury and therefore only temporary pulmonary vein isolation.8 For these reasons, HPSD ablation may result

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Electrophysiology and Ablation in improved permanent pulmonary vein isolation although this requires investigation in further clinical studies.

Procedural Duration AF catheter ablation procedure durations vary between operators and centres but typically last between 90 and 180 minutes with point-bypoint radiofrequency energy application techniques.9,14 In an era of increasing disease burden, the demand for AF ablations continues to rise with greater numbers of patients of increasing complexity being referred for intervention.1,2,47 With the costs of AF care estimated to amount already to 1% of the UK’s NHS budget, methods of reducing costs and improving resource allocation must be considered.2,3 Against this background, one potential benefit of HPSD ablation might be a reduction in procedure time. In a porcine study, radiofrequency delivery for 5 seconds at 50 W achieved a mean lesion depth of 3 mm, while at 30 W a duration of 2–4 times longer (10–20 seconds) was required to achieve lesions of a similar depth.26 In early clinical studies dating back to 2006, cautiously attempted HPSD ablation with settings of 45 W/20 s was compared with a control group of 30 W/120 s, and published results indicated ablation time was reduced by as much as 80%. This was accompanied by a more modest 26% reduction in overall procedure time.8,37 More recently, the Clinical Study for Safety and Acute Performance Evaluation of the THERMOCOOL SMARTTOUCH SF-5D System Used With Fast Ablation Mode in Treatment of Patients With Paroxysmal Atrial Fibrillation (QDOT FAST) trial was the first prospective clinical multicentre trial of HPSD ablation, performed as a feasibility study. The total procedure time was 105 ± 25 minutes with an average fluoroscopy time of 6.6 ± 8.2 minutes and included a 20-minute waiting period after pulmonary vein isolation and an adenosine/ isoproterenol challenge.36 Although there was no comparative control group within the study, this does compare favourably with previous reports on procedure duration using radiofrequency technology. Particular patient groups such as those with heart failure may benefit from shorter procedural and ablation times. Since both LPLD and HPSD ablation lesions are delivered with irrigation, the duration of radiofrequency energy application is directly linked to the volume of intravenous fluid delivered intraprocedurally. In the QDOT FAST trial, average periprocedure fluid volume delivery was 382 ± 299 ml compared with 898–1,880 ml previously demonstrated in the NAVISTAR THERMOCOOL Catheter for the Radiofrequency Ablation of Symptomatic Paroxysmal Atrial Fibrillation (THERMOCOOL AF), SMART-AF and THERMOCOOL SMARTTOUCH Catheter for the Treatment of Symptomatic Paroxysmal Atrial Fibrillation (SMART-SF) Radiofrequency Ablation Safety Study trials.50–52 Despite this theoretical advantage, however, a clinical benefit of reduced irrigation fluid delivery has not yet been demonstrated. Furthermore, the study size of QDOT FAST Trial (n=52) lacked power to provide conclusive results other than to demonstrate feasibility and the need for further studies. A larger, on-going clinical trial of 185 patients is in progress, the Evaluation of QDOT MICRO™ Catheter for Pulmonary Vein Isolation (PVI) in Subjects With PAF study (Q-FFECIENCY; NCT03775512).

Further Trials One of the main challenges in radiofrequency ablation is the inability to reliably assess tissue temperature in real time as a marker of lesion formation. The vast majority of published studies describing HPSD

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ablation involve catheters containing a single thermocouple; however, the catheter irrigation system negates the utility of this thermocouple for the estimation of tissue temperature. Catheter stability and orientation can further confound temperature readings, which are made from a single point of contact. A novel irrigated tip catheter, the QDOT Micro Catheter (Biosense Webster), has been designed. It contains six thermocouples, three of which are positioned distally and embedded more superficially than previously at 75 μm below a metallic tip that acts as a highquality conductor between the tissue-catheter interface and the thermocouples. The remaining three thermocouples are 3 mm more proximal enabling accurate temperature recording in real time that is independent of catheter orientation.8,17,27,34 In addition, the catheter retains the SmartTouch (Biosense Webster) technology for contact force sensing and has an improved cooling irrigation system with backward flow towards the most proximal thermocouple. This is designed to reduce temperature-sensing inaccuracies and to increase temperature sensitivity in the parallel catheter orientation, which has previously been challenging.17 The catheter can be used alongside a proprietary radiofrequency generator that has a short ramp-up time of <0.5 seconds, which, when combined with temperature feedback every 33 milliseconds, allows finer control of delivery during applications.53 Further work is needed to determine optimal ablation settings for HPSD ablation. A mathematical model has been proposed incorporating temperature measurements, contact force sensing, impedance and catheter orientation, which aims to enable accurate lesion size prediction with the use of the QDOT Micro Catheter. In a swine study, this model demonstrated a strong correlation with lesion depth with a prediction error of 1.5 mm between lesion depth estimates and those measured with histology.27 Considering the theoretical predictions discussed above, it is unsurprising that lesion depth is predictable given the direct correlation between energy delivery and lesion depth. However, it is expected that there could be a different relationship with lesion width in view of other variables that affect ablation lesion formation, including blood flow and tissue surface cooling. Such phenomena may be especially important to lesion contiguity during HPSD ablation and require further study, as has been done for conventional ablation.54 The QDOT Micro Catheter was subsequently trialled using a thigh muscle tissue preparation to simulate cardiac ablation. A generator output of 90 W delivered for 4 seconds was identified as the optimum setting that would provide high power at short duration and with low risks of steam pop or thrombus formation. These settings were subsequently used to perform cardiac ablation in 15 swine to assess safety and lesion durability, which were respectively found to be superior and equal to conventional settings.17 A further small study by the same group found that all posterior lines created in the right atrium with HPSD ablation were wider and remained intact after 30 days while none of the lines performed at conventional settings remained intact.8 Despite seemingly encouraging results, it must be acknowledged that these studies may not be directly transferable to clinical use, particularly given the narrow window between therapy and safety at high power. The QDOT FAST trial is the only trial to have attempted very high power in clinical use and, despite a small cohort, a significant adverse event did occur, with one patient diagnosed with a haemorrhage from an oesophageal ulcer that occurred one day after the procedure which was managed medically.

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

High-power, Short-duration Ablation Gaps in Knowledge Much of the literature to date shows promise for the use of HPSD ablation but there is no consensus on the precise power and duration that conveys the maximum potential clinical benefit with the least possible risk. Current definitions for HPSD ablation vary from 50 W to 90 W for durations of 2–20 seconds. The majority of human trials to date have used a maximum power of 50 W for perceived patient safety reasons, but recent findings suggest that it might be possible to use higher generator power outputs in patients. Further research is therefore required to ascertain the optimal generator settings for human AF. A clinical trial of HPSD ablation using the QDOT Micro catheter is on-going in a cohort of 185 patients. Outcome measures include procedure efficacy measured at the time of the procedure, within 7 days and up to 12 months after ablation and early adverse events within 7 days of the procedure or significant adverse events within 30 days. The results of this trial will be informative in clarifying the safety profile of HPSD ablation in patients. A better understanding of lesion geometry created using HPSD ablation is also required to understand the balance between resistive heating and conductive heating as power applied is increased. This will aid in predicting changes in lesion formation with variable power delivery and duration of individual lesions. At a time when there is an increasing shift towards individualised patient therapies, more in-depth knowledge of lesion geometry may allow titration of ablation settings to the target, for example based on atrial wall thickness or areas of low voltage.55

o AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed G atrial fibrillation in adults. JAMA 2001;285:2370–5. https://doi. org/10.1001/jama.285.18.2370; PMID: 11343485. 2. Chugh SS, Havmoeller R, Narayanan K, et al. Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 study. Circulation 2014;129:837–47. https://doi. org/10.1161/CIRCULATIONAHA.113.005119; PMID: 24345399. 3. Stewart S, Murphy N, Walker A, et al. Cost of an emerging epidemic: an economic analysis of atrial fibrillation in the UK. Heart 2004;90:286–92. https://doi.org/10.1136/hrt.2002.008748. 4. Haïssaguerre M, Jaïs P, Shah DC, et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med 1998;339:659–66. https://doi. org/10.1056/NEJM199809033391003; PMID: 9725923. 5. Verma A. Atrial-fibrillation ablation should be considered first-line therapy for some patients. Curr Opin Cardiol 2008;23:1–8. https://doi.org/10.1097/HCO.0b013e3282f2e27c; PMID: 18281820. 6. Fuster V, Rydén LE, Cannom DS, et al. 2011 ACCF/AHA/ HRS focused updates incorporated into the ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation. J Am Coll Cardiol 2011;57:e101–98. https://doi. org/10.1161/CIR.0b013e318214876d; PMID: 21382897. 7. Kumar S, Barbhaiya CR, Balindger S, et al. Better lesion creation and assessment during catheter ablation. J Atr Fibrillation 2015;8:1189. https://doi.org/10.4022/jafib.1189 27957200;8:1189; PMID: 27957200. 8. Barkagan M, Contreras-Valdes FM, Leshem E, et al. Highpower and short-duration ablation for pulmonary vein isolation: safety, efficacy, and long-term durability. J Cardiovasc Electrophysiol 2018;29:1287–96. https://doi.org/10.1111/ jce.13651; PMID: 29846987. 9. Winkle RA, Mohanty S, Patrawala RA, et al. Low complication rates using high power (45–50 W) for short duration for atrial fibrillation ablations. Heart Rhythm 2019;16:165–9. https://doi. org/10.1016/j.hrthm.2018.11.031; PMID: 30712645. 10. Williams SE, Harrison J, Chubb H, et al. The effect of contact force in atrial radiofrequency ablation: electroanatomical, cardiovascular magnetic resonance, and histological assessment in a chronic porcine model. JACC Clin Electrophysiol 2015;1:421–31. https://doi.org/10.1016/j.jacep.2015.06.003; PMID: 29759471. 11. Mujovic N, Marinkovic M, Lenarczyk R, et al. Catheter ablation of atrial fibrillation: an overview for clinicians. Adv Ther 2017;34:1897–917. https://doi.org/10.1007/s12325-0170590-z; PMID: 28733782. 12. Reddy VY, Dukkipati SR, Neuzil P, et al. Randomized, controlled trial of the safety and effectiveness of a contact

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13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

Of note, sample numbers from trial data so far are small. There have been few prospective or multicentre trials, and no randomised trials at this time. Larger, randomised controlled trials assessing high and very high power delivery will be essential to determine the efficacy and safety of these settings. Given the infrequency of major complications such as stroke, pulmonary vein stenosis and atrio-oesophageal fistula formation, it is likely that a true understanding of patient safety will be difficult to fully delineate from small randomised trials. A clear advantage in safety, efficacy and cost must be indisputable to advocate a change to HPSD ablation given the vast quantity of data collected from hundreds of thousands of patients worldwide that has formed current ablation techniques.

Clinical Perspective • Successful AF ablation therapy is contingent on the creation of durable, contiguous transmural lesions that result in permanent pulmonary vein isolation. • High-power, short-duration (HPSD) ablation demonstrates promise as an alternative approach to radiofrequency energy delivery, potentially contributing to superior lesion formation, non-inferior complication rates and shorter procedural times. • On-going clinical trials using the novel QDOT Micro Catheter will gather data to assess the safety and efficacy of HPSD ablation. At present, QDOT-FAST is the only prospective, multicentre trial assessing HPSD ablation. • Much more extensive validation of the use of HPSD ablation will be required before widespread uptake can be recommended.

force-sensing irrigated catheter for ablation of paroxysmal atrial fibrillation: results of the TactiCath Contact Force Ablation Catheter Study for Atrial Fibrillation (TOCCASTAR) study. Circulation 2015;132:907–15. https://doi.org/10.1161/ CIRCULATIONAHA.114.014092; PMID: 26260733. Reddy VY, Shah D, Kautzner J, et al. The relationship between contact force and clinical outcome during radiofrequency catheter ablation of atrial fibrillation in the TOCCATA study. Heart Rhythm 2012;9:1789–95. https://doi.org/10.1016/j. hrthm.2012.07.016; PMID: 22820056. Bhaskaran A, Chik W, Pouliopoulos J, et al. Five seconds of 50–60 W radio frequency atrial ablations were transmural and safe: an in vitro mechanistic assessment and force-controlled in vivo validation. Europace 2017;19:874–880. https://doi. org/10.1093/europace/euw077; PMID: 27207815. Simmers TA, de Bakker JM, Wittkampf FH, Hauer RN. Effects of heating with radiofrequency power on myocardial impulse conduction: is radiofrequency ablation exclusively thermally mediated? J Cardiovasc Electrophysiol 1996;7:243–7. https://doi. org/10.1111/j.1540–8167.1996.tb00521.x; PMID: 8867298. Wittkampf FHM, Nakagawa H. RF catheter ablation: lessons on lesions. Pacing Clin Electrophysiol 2006;29:1285–97. https:// doi.org/10.1111/j.1540-8159.2006.00533.x; PMID: 17100685. Leshem E, Zilberman I, Tschabrunn CM, et al. Highpower and short-duration ablation for pulmonary vein isolation: biophysical characterization. JACC Clin Electrophysiol 2018;4:467–79. https://doi.org/10.1016/j.jacep.2017.11.018; PMID: 30067486. Nath S, DiMarco JP, Haines DE. Basic aspects of radiofrequency catheter ablation. J Cardiovasc Electrophysiol 1994;5:863–876. https://doi.org/10.1111/j.1540-8167.1994. tb01125.x; PMID: 7874332. Haines D. Biophysics of ablation: application to technology. J Cardiovasc Electrophysiol 2004;15(s10 Suppl):S2–11. https://doi. org/10.1046/j.1540-8167.2004.15102.x; PMID: 15482456. Bhavaraju NC, Valvano JW. Thermophysical properties of swine myocardium. Int J Thermophys 1999;20:665–76. https:// doi.org/10.1023/A:1022673524963. Tungjitkusolmun S, Woo EJ, Cao H, et al. Thermal-electrical finite element modelling for radio frequency cardiac ablation: effects of changes in myocardial properties. Med Biol Eng Comput 2000;38:562–8. https://doi.org/10.1007/BF02345754; PMID: 11094815. Vinnakota KC, Bassingthwaighte JB. Myocardial density and composition: a basis for calculating intracellular metabolite concentrations. Am J Physiol Heart Circ Physiol 2004;286:H1742–9. https://doi.org/10.1152/ajpheart.00478.2003; PMID: 14693681. Haines DE, Watson DD. Tissue heating during radiofrequency

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Electrophysiology and Ablation PMID: 16380552. 33. I rastorza RM, d’Avila A, Berjano E. Thermal latency adds to lesion depth after application of high-power short-duration radiofrequency energy: Results of a computer-modeling study. J Cardiovasc Electrophysiol 2018;29:322–7. https://doi. org/10.1111/jce.13363; PMID: 28988468. 34. Rozen G, Ptaszek LM, Zilberman I, et al. Safety and efficacy of delivering high-power short-duration radiofrequency ablation lesions utilizing a novel temperature sensing technology. Europace 2018;20:f444–50. https://doi.org/10.1093/europace/ euy031; PMID: 29579196. 35. Baher A, Kheirkhahan M, Rechenmacher SJ, et al. High-power radiofrequency catheter ablation of atrial fibrillation: using late gadolinium enhancement magnetic resonance imaging as a novel index of esophageal injury. JACC Clin Electrophysiol 2018;4:1583–94. https://doi.org/10.1016/j.jacep.2018.07.017; PMID: 30573123. 36. Reddy VY, Grimaldi M, De Potter T, et al. Pulmonary vein isolation with very high power, short duration, temperaturecontrolled lesions: the QDOT-FAST trial. JACC Clin Electrophysiol 2019;5:778–86. https://doi.org/10.1016/j.jacep.2019.04.009; PMID: 31320006. 37. Nilsson B, Chen X, Pehrson S, Svendsen JH. The effectiveness of a high output/short duration radiofrequency current application technique in segmental pulmonary vein isolation for atrial fibrillation. Europace 2006;8:962–5. https://doi. org/10.1093/europace/eul100; PMID: 17043070. 38. Simmers TA, Wittkampf FH, Hauer RN, Medina EO. In vivo ventricular lesion growth in radiofrequency catheter ablation. Pacing Clin Electrophysiol 1994;17:523–31. https://doi. org/10.1111/j.1540-8159.1994.tb01421.x; PMID: 7513882. 39. Brooks AG, Stiles MK, Laborderie J, et al. Outcomes of longstanding persistent atrial fibrillation ablation: a systematic review. Heart Rhythm 2010;7:835–46. https://doi.org/10.1016/j. hrthm.2010.01.017; PMID: 20206320. 40. Bertaglia E, Tondo C, De Simone A, et al. Does catheter ablation cure atrial fibrillation? Single-procedure outcome of drug-refractory atrial fibrillation ablation: a 6-year multicentre experience. Europace 2010;12:181–7. https://doi.org/10.1093/ europace/eup349; PMID: 19887458.

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41. T eunissen C, Kassenberg W, van der Heijden JF, et al. Fiveyear efficacy of pulmonary vein antrum isolation as a primary ablation strategy for atrial fibrillation: a single-centre cohort study. Europace 2016;18:1335–42. https://doi.org/10.1093/ europace/euv439; PMID: 26838694. 42. 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;321:1261–74. https://doi.org/10.1001/jama.2019.0693; PMID: 30874766. 43. Verma A, Kilicaslan F, Pisano E, et al. Response of atrial fibrillation to pulmonary vein antrum isolation is directly related to resumption and delay of pulmonary vein conduction. Circulation 2005;112:627–35. https://doi. org/10.1161/CIRCULATIONAHA.104.533190; PMID: 16061753. 44. Ouyang F, Antz M, Ernst S, et al. Recovered pulmonary vein conduction as a dominant factor for recurrent atrial tachyarrhythmias after complete circular isolation of the pulmonary veins: lessons from double Lasso technique. Circulation 2005;111:127–35. https://doi.org/10.1161/01. CIR.0000151289.73085.36; PMID: 15623542. 45. Kowalski M, Grimes MM, Perez FJ, et al. Histopathologic characterization of chronic radiofrequency ablation lesions for pulmonary vein isolation. J Am Coll Cardiol 2012;59:930–8. https://doi.org/10.1016/j.jacc.2011.09.076; PMID: 22381429. 46. Wood MA, Fuller IA. Acute and chronic electrophysiologic changes surrounding radiofrequency lesions. J Cardiovasc Electrophysiol 2002;13:56–61. https://doi.org/10.1046/j.15408167.2002.00056.x; PMID: 11843484. 47. Lip GY, Kakar P, Watson T. Atrial fibrillation – the growing epidemic. Heart 2007;93:542–3. https://doi.org/10.1136/ hrt.2006.110791; PMID: 17435064. 48. Ho SY, Sanchez-Quintana D, Cabrera JA, Anderson RH. Anatomy of the left atrium: implications for radiofrequency ablation of atrial fibrillation. J Cardiovasc Electrophysiol 1999;10:1525–33. https://doi.org/10.1111/j.1540-8167.1999. tb00211.x; PMID: 10571372. 49. Hall B, Jeevanantham V, Simon R, et al. Variation in left atrial transmural wall thickness at sites commonly targeted

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Electrophysiology and Ablation

Challenges Associated with Interpreting Mechanisms of AF Caroline H Roney 1,2 , Andrew L Wit 2,3 and Nicholas S Peters 2,4 1. School of Biomedical Engineering and Imaging Sciences, King’s College London, London, UK; 2. Imperial Centre for Cardiac Engineering, Imperial College London, London, UK; 3. Department of Pharmacology, Columbia University College of Physicians and Surgeons, New York, NY, US; 4. National Heart and Lung Institute, Imperial College London, London, UK

Abstract Determining optimal treatment strategies for complex arrhythmogenesis in AF is confounded by the lack of consensus regarding the mechanisms causing AF. Studies report different mechanisms for AF, ranging from hierarchical drivers to anarchical multiple activation wavelets. Differences in the assessment of AF mechanisms are likely due to AF being recorded across diverse models using different investigational tools, spatial scales and clinical populations. The authors review different AF mechanisms, including anatomical and functional re-entry, hierarchical drivers and anarchical multiple wavelets. They then describe different cardiac mapping techniques and analysis tools, including activation mapping, phase mapping and fibrosis identification. They explain and review different data challenges, including differences between recording devices in spatial and temporal resolutions, spatial coverage and recording surface, and report clinical outcomes using different data modalities. They suggest future research directions for investigating the mechanisms underlying human AF.

Keywords AF, cardiac arrhythmia mechanisms, anatomical re-entry, functional re-entry, hierarchical drivers, triggered activity, anarchical multiple wavelets Disclosure: CHR received a Medical Research Council Skills Development Fellowship (MR/S015086/1) and was supported by the Wellcome/EPSRC Centre for Medical Engineering (T203148/Z/16/Z). NSP was funded by the BRC Programme of National Institute of Health Research, UK. All other authors have no conflicts of interest to declare. Received: 5 August 2019 Accepted: 18 November 2019 Citation: Arrhythmia & Electrophysiology Review 2019;8(4):273–84. DOI: https://doi.org/10.15420/aer.2019.08 Correspondence: Caroline Roney, School of Biomedical Engineering and Imaging Sciences, Rayne Institute, 4th Floor, Lambeth Wing, St Thomas’ Hospital, Westminster Bridge Rd, London SE1 7EH, UK. E: caroline.roney@kcl.ac.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.

Determining optimal treatment strategies for complex arrhythmogenesis in AF is confounded by the lack of consensus on the mechanisms causing AF. Fundamental to defining arrhythmogenic mechanisms of AF are the distinctions and interplay between functional features (determined by the electrophysiology of a cell) and structural features (determined by whether a structural or anatomical feature is critical to the existence and location of a source), as well as between hierarchical and anarchical mechanisms (determined by whether an arrhythmia is perpetuated by discrete drivers or a universally distributed random phenomenon, respectively). Current discussions focus on whether myocardial activation in AF exhibits any organisation and, if it does, whether this organisation is due to functional or structural properties of the tissue. The hierarchical theory of AF proposes a degree of organisation in AF, sustained by discrete electrical drivers, whereas the anarchical theory proposes that AF is sustained by a large number of randomly propagating, self-perpetuating activation wavelets without the presence of discrete electrical drivers.1–3 Differences in reported AF mechanisms may be because AF is recorded across diverse models, investigational tools, spatial scales and clinical populations, ranging from paroxysmal to permanent AF. With this motivation, what follows is a series of definitions of the key mechanistic phenomena and classifications. This article outlines the proposed potential mechanisms of AF, describes the different data

modalities and analysis techniques used, indicates the challenges associated with interpretation of AF mechanisms and how these may be overcome and suggests areas of future research. Throughout this review, possible explanations for divergent findings between studies are suggested.

Mechanisms of AF Here we briefly describe some of the concepts that are proposed to underlie AF, which is defined as a high-frequency turbulent electrical activity in the atria. Sustained AF requires the presence of both a driver initiating the arrhythmia (consisting of either impulse initiation by automaticity or triggered activity, or re-entrant activity) and a substrate that causes fibrillatory conduction. AF mechanisms depend on the degree of electrical and structural remodelling, which changes as AF progresses from paroxysmal to persistent to permanent AF. This is described in detail in the review by Schotten et al.1 Proposed AF mechanisms include automaticity and triggered activity, both of which are examples of abnormal impulse formation, as well as re-entrant mechanisms. Both automaticity and triggered activity may initiate re-entry and manifest as waves emanating centrifugally from a focal source. Although a single focus of automaticity is likely to be too slow to drive AF, recurrent triggered activity may maintain AF by continuously causing fibrillatory activity in the atria.4 During paroxysmal

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Electrophysiology and Ablation Figure 1: Mechanisms of AF

perfused HF sheep atria.10 Hansen et al. used late gadolinium enhanced

(LGE) MRI and dual optical mapping to show that re-entrant drivers anchor to micro-anatomical tracks maintaining AF.11,12

Classical AF Mechanisms

a. Ectopic focus

b. Single circuit re-entry

c. Multiple wave re-entry

Novel Mechanistic Concepts

All re-entrant circuits, whether anatomical or functional (see below), must have an excitable gap, which is the short time interval during the re-entry cycle when excitation by an external impulse is possible. This gap can be partially or fully excitable. Anatomical circuits can have a partially excitable gap when the wavelength just fits the path length or a fully excitable gap when the wavelength is significantly shorter than the path length. Figure 2A shows a schematic re-entry with a fully excitable gap.

Functional Re-entry

a. Stable rotors

b. Unstable fibrosislinked rotors

c. Epi-endo dissociation

A: Classical AF mechanisms include: initiation from an ectopic focus (a); automatic or triggered activity), single circuit re-entry (b) and multiple wavelet re-entry (c). B: More recently proposed AF mechanisms include stable rotors (a); unstable fibrosis-linked rotors (b, with areas of fibrosis shown in grey) and epicardial–endocardial dissociation (c). Source: Nattel et al.6 Reproduced with permission from Wolters Kluwer Health.

AF, these electrical triggers and ectopic beats are frequently located in the pulmonary veins.5 In this review, we focus on re-entrant mechanisms, where ‘re-entry’ is defined as the repetitive excitation of tissue by a recirculating wavefronts. Figure 1 shows several of the proposed mechanisms involved in the initiation and maintenance of AF. These mechanisms include the classical AF mechanisms of a single ectopic focus, single circuit re-entry and multiple wavelet re-entry, as well as more recent mechanistic concepts of stable rotors, unstable fibrosis-linked rotors and epicardial–endocardial dissociation.6 Arrhythmia initiation and maintenance, by mechanisms including re-entry, depends on the arrhythmia substrate, which we define as the electrophysiological and structural properties that underlie arrhythmia initiation and maintenance. Features of this substrate may be anatomical or functional.

Anatomical Re-entry Anatomical re-entry occurs when a wavefront of excitation propagates around an anatomical obstacle and re-excites myocardium that it has previously excited to form a re-entrant circuit. Following on from Mayer’s experiments in 1906,7 Mines suggested a model of fixed anatomical re-entry in 1913 based on experiments in atrial and ventricular ring-like preparations that could be responsible for tachyarrhythmias in humans.8 Mines showed that re-entry around such a circuit required the product of the wave conduction velocity and refractory period (the wavelength) to be smaller than the length of the circuit (the path length). For example, macro re-entry around cardiac structures, such as the tricuspid annulus (a cause of atrial flutter), occurs when this condition is satisfied, and the length of the path and the conduction velocity determine the cycle length of the activity.9 Anatomical re-entry may also occur at the micro scale with the movement of a wavefront around a small anatomical obstacle such as a small region of fibrosis sustaining fibrillatory conduction. As such, micro-anatomical obstacles anchor re-entrant wavefronts; Tanaka et al. demonstrated that fibrosis in heart failure (HF) determines AF dynamics as re-entrant sources anchor to areas of fibrosis in Langendorff-

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Following on from Garrey’s suggestion in 1914 that re-entry could be initiated without an anatomic obstacle, in 1973 Allessie et al. provided the first direct experimental evidence that the presence of an anatomical obstacle is not necessary for re-entry, demonstrating the existence of functional re-entry.13,14 We define functional re-entry as re-entrant activity in the absence of a predetermined anatomical obstacle or circuit. Functional conduction block occurs when cardiac activation fails due to source–sink mismatch.

Leading Circle Mechanism In 1973, Allesie et al. proposed the ‘leading circle’ theory in which a unidirectional block (due to a heterogeneous distribution of refractory period) causes an excitation wavefront to travel in a circular pathway.14 In this theory, wavefronts also travel centripetally (towards the centre of the circle) and centrifugally (away from the centre). This theory is called ‘leading circle’ because there is a main circle that takes the path corresponding to the smallest possible circuit for which the path length equals the wavelength (approximately equal to the conduction velocity multiplied by the effective refractory period); centripetal wavefronts travelling over shorter circuits hit refractory tissue, whereas centrifugal wavefronts are dominated by the faster rate of the leading circle (Figure 2B).15 The leading circle theory does not have a fully excitable gap but must have a partially excitable gap. The leading circle wavefront travels through partially refractory tissue, which reduces the conduction velocity, in turn reducing the wavelength.16 The central area is refractory because it is stimulated twice as fast as the leading circle activation by the centripetal wavefronts, leading to an unexcitable region. The inclusion of centripetal wavefronts in this model was motivated by the presence of low-amplitude, short-duration deflections; however, this observation is also compatible with contemporary spiral wave theory. The leading circle theory does not take into account the role of wavefront curvature, which is a very important component of rotors and the spiral wave mechanism.

Spiral Wave Theory Spiral waves are ubiquitous in nature and excitable media; for example, spiral waves occur in chemical reactions (e.g. the Belousov– Zhabotinsky reaction), morphogenesis of amoeba,17 mitochondrial calcium waves in frog eggs18 and chicken retina.19 Spiral wave theory for cardiac arrhythmias was developed in theoretical studies performed by Krinsky in the USSR in the 1960s and by Winfree in the US.20,21 The first experimental evidence for the existence of spiral waves in cardiac tissue was from Davidenko et al. in sheep ventricular muscle.22 A rotor is a classification of functional re-entry where wavefront curvature

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Interpreting Mechanisms of AF Figure 2: Re-entry, Leading Circle and Spiral Mechanisms

itable gap Exc

0 1

–20

Wave lengh

Wa v

ele n gt

Voltage (mV)

–60 –80

3 CORE

–40

0.8

hj ‘excitable gap’

0.6 0.4 0.2

Wave front

Wave tail

Velocity vector

Phase singularity

A: Re-entry around a ring (created by an anatomic obstacle). The wavelength, shown in black, is shorter than the path length and there is a fully excitable gap (white). B: Leading circle re-entry around a functional obstacle with a refractory centre. Arrows indicate centripetal wavefronts. C: Example of a 2D spiral wave where the rotor tip is indicated by the white asterisk. D: Diagram showing a 3D scroll wave. E: Spiral wave conduction velocity (arrows), action potential duration and wavelength decrease towards the spiral wave core because of electrotonic effects. Example action potential traces are shown with a shorter action potential duration close to the core. Wavefront curvature becomes more pronounced near the centre of the spiral wave, or rotor, and there is a phase singularity where the wavefront and wavetail meet. F: Transmembrane voltage (top) and an estimation of the excitable gap (bottom) calculated as a product of the sodium current inactivation variables for a computational simulation. Source: Pandit et al.137 Reproduced with permission from Wolters Kluwer Health.

is the cause of the wavelength being shorter than the path length. The wave of excitation emitted by the rotor is a spiral wave in two dimensions or a scroll wave in three dimensions.23 Figure 2C shows a spiral wave and Figure 2D shows a schematic scroll wave. The convex curvature of the wavefront increases towards and attains a critical value at the centre, and conduction velocity slows such that the wavefront cannot propagate into the core. The decrease in conduction velocity, action potential duration and wavelength due to electrotonic effects is illustrated in Figure 2e. At the centre, the wavefront curvature is so high that the wavefront source cannot provide enough current to depolarise the resting sink tissue ahead of it, causing rotation. As such, this core area is excitable but not excited, in contrast with the full refractory centre of the leading circle theory. The centre of rotation, or core, is the organising centre of the spiral or scroll wave. The activation and repolarisation wavefronts meet each other at a nonexcited point known as a phase singularity (PS), at which the phase of activation is undefined, and all excitation–recovery phases converge. Figure 2E shows the PS point where the wavefront and wave tail meet. A stationary rotor will have a PS that follows a circular trajectory, whereas meandering rotors have more complex trajectories. The trajectory of the PS path determines the diameter of the spiral wave core. The spiral wave theory has no fixed wavelength; wavelength also likely changes in the leading circle model as the re-entrant wavefront moves from transverse to longitudinal conduction in anisotropic tissue. The mother rotor hypothesis proposes that AF is not entirely random, but that hierarchical periodic rotors drive the AF, acting as sources of high-frequency wavefronts.24 The leading circle theory and spiral wave theory are different models to explain functional re-entry. One of the key differences between the models is that they predict different responses to sodium channel blockade, with the leading circle theory predicting that re-entry is promoted by reducing the wavelength and the spiral wave theory predicting an antiarrhythmic action because

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of increased meander, increased core size and decreased critical curvature, which is consistent with experimental findings.15 In addition, the leading circle theory does not explain the observation that wavelength is not reduced in several experimental models and many AF patients.25 Kléber and Rudy state that a freely rotating wavefront in an excitation– diffusion system has to be spiral shaped because velocity must decrease from the edge to the centre of the wave to satisfy a constant period of rotation and because the velocity of a convex wavefront is less than that of the linear wavefront at the edge.16 As such, leading circle theory was a historically considered mechanism, whereas spiral wave theory is a useful contemporary concept. Wavefronts from a mother rotor may break into multiple wavefronts: wavebreak occurs when a wavefront encounters an obstacle (e.g. scar tissue), leading to the formation of daughter wavefronts, or wavelets, and fibrillatory conduction. Many studies report that AF re-entrant circuits are unstable13,26,27 and of short duration,28,29 which challenges the theory that discrete drivers sustain AF. An emerging novel hypothesis to explain how unstable re-entrant circuits may sustain AF is the idea of continuous phase singularity regeneration or ‘renewal’, which was initially proposed by Dharmaprani et al.30

Multiple Wavelets The multiple wavelet hypothesis, initially proposed by Moe and Abildskov in 1959, states that AF is a disorganised anarchical atrial rhythm in which there are multiple random activation wavelets sustaining the activity, independent of the initiating event.31 Moe et al. developed a computational model and predicted that at least 26 wavelets are required to sustain the arrhythmia.32 Experimental support for this hypothesis came from the Allessie group, who found that between four

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Electrophysiology and Ablation and six wavelets were required to sustain turbulent atrial arrhythmia with the application of acetylcholine to dog hearts.33 However, the multiple wavelet hypothesis does not explain the origin of the activity that causes the wavelets; if there were a small number of wavelets, then one would expect them to coalescence and annihilate AF.24 The Cox–Maze surgical procedure aims to terminate AF by using surgical incisions to reduce the atrial tissue mass below the critical circuit size required by multiple wavelet re-entry.34 In addition, computational modelling studies have investigated potential approaches for ablating multiple wavelet activation. For example, Carrick et al. simulated different ablation lesion sets to test the effects of ablation lesion length and multiple wavelet circuit density on ablation outcome, finding that applying ablation at regions of high circuit density most efficiently decreased re-entry duration.35 Carrick et al. then extended this to predict the most efficient distribution of ablation lesions for multiple wavelet activation.36

Breakthrough Activation Allessie et al. found no evidence for the presence of stable focal sources or rotors in a human epicardial mapping study using a high-resolution mapping catheter (interelectrode distance 2.25 mm) during cardiac surgery.37 Instead, they proposed a novel theory for the development of AF in structural heart disease, where the endocardium and epicardium of the atrium become electrically dissociated and epicardial breakthrough leads to fibrillatory waves.38 Electrical activation arising on the endocardial or epicardial cardiac tissue surface from transmural propagation through the cardiac tissue is termed breakthrough activation. This breakthrough could be focal from the other surface of the heart or due to transmural re-entry. This represents a limitation of the endo–epicardial dissociation theory because it is difficult to determine whether it is a unique mechanism or a manifestation of transmural scroll waves.21 Although how best to treat an AF substrate with endocardial–epicardial dissociation is an open question, recent studies by Jiang et al. and Piorkowski et al. demonstrate the feasibility of AF catheter ablation based on epicardial and endocardial substrate mapping.39–41

according to its definition; adding an obstacle will anchor a rotor but is not a necessary component of its mechanisms. Conversely, micro re-entry around an anatomical obstacle need not be a rotor.

Cardiac Mapping Techniques Some of the divergence in mechanisms observed across studies may be due to the different analytical techniques used; as such, we review commonly used methodologies here.

Activation Time Mapping Charting local activation time from extracellular recordings (electrograms) on anatomical maps (electroanatomical mapping) are key to determining mechanisms of atrial flutters, tachycardias and slower regular rhythms because they indicate the pattern of activation, including electrical circuits and focal sources. However, activation time mapping for AF data is much more challenging because fractionation in the electrogram signals makes activation time assignment difficult, signals change continuously over time and it is difficult to select a suitable time window in which to display these maps. The local activation time of a unipolar electrogram is defined as the time of the maximum downslope because this has been shown to correspond to the time of maximum upstroke of the action potential and maximum sodium conductance, providing a biophysical basis for this choice of marker.46 In contrast, the choice of marker for the activation time of bipolar electrograms does not have a biophysical basis and varies between studies, with choices including the maximum absolute amplitude and the maximum derivative.47 Unipolar electrograms represent a more local signal, but are often contaminated by artefacts from the ventricles; bipolar electrograms typically eliminate the ventricular signal, but their amplitude depends on wavefront direction.48,49 The Schotten laboratory developed a technique to automatically assign activation times and reconstruct wavefronts from unipolar AF data.50 Activation time mapping analysis groups together similar local activation times into fibrillation waves. Activation time maps can be post-processed to calculate conduction velocity maps.51–53

Electrogram Features Classification of Mechanisms Different studies group together different functional and anatomical mechanisms for the presentation and interpretation of their findings. For example, Weiss et al. classify the leading circle and spiral wave theories as functional re-entrant mechanisms, separate from anatomical re-entry even when the rotor is anchored by an anatomical (fibrous tissue) core.4 Richter et al. differentiate between anatomically anchored spiral waves and functional spiral waves, which may meander.42 In contrast, Nattel et al. do not make this distinction and consider that the spiral wave theory also explains rotors anchored to anatomical obstacles, effectively considering all re-entrant mechanisms together.43 A rotor that is anchored to an anatomical obstacle that is large enough to become its centre of rotation cannot be distinguished from anatomical re-entry. Similarly, Krogh-Madsen et al. classify re-entry in their model as a mother rotor, even though it is anchored.44 We suggest dividing mechanisms into abnormal impulse initiation and abnormal impulse conduction, following Hoffman and Rosen.45 Using this classification, re-entry is then a general subheading under abnormal impulse conduction that includes anatomical and functional re-entry. Importantly, a rotor does not require an anatomical obstacle

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Techniques to analyse fibrillatory electrogram data include frequency analysis, such as dominant frequency or organisational index calculations, fractionation scoring analysis, continuous electrical activity calculation, gradient of activation calculation, Shannon entropy analysis and peak-to-peak voltage calculation.54–59 Features of the electrogram indicating properties of the underlying atrial structure may be identified and targeted during ablation with the aim of eliminating electrical drivers. Clinical mapping studies have used different measures to target electrical drivers, including identifying sites of high dominant frequency (DF; the frequency with the highest power in the power spectrum obtained by applying the fast Fourier transform). DF analysis may be performed on invasive or non-invasive recordings; for example, Guillem et al. identified sites of maximal DF from non-invasive body surface potential mapping data.60 Areas of high DF are thought to indicate areas of driver activity, and some clinical studies have targeted these areas.61 Sanders et al. demonstrated that ablating areas of high DF prolonged AF cycle length and increased AF termination for paroxysmal but not persistent AF.54 In advanced forms of AF, areas of slow activity are also important, and targeting areas of high DF is unlikely to provide sufficient

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Interpreting Mechanisms of AF ablation therapy. Jarman et al. found that areas of high DF are not spatiotemporally stable, suggesting that they do not represent a fixed driver.62 Salinet et al. suggest instead targeting areas that are repeatedly of high DF.63 Shariat et al. propose using regional DF analysis to identify regions of wavebreak.64 The Radiofrequency Ablation of Drivers of Atrial Fibrillation (RADAR-AF) trial showed that ablating high-frequency sources, identified using DF analysis, together with pulmonary vein isolation (PVI) is not significantly different to using PVI alone.65 This highlights that the usefulness of DF for targeting ablation is questionable because the arrhythmia mechanism is unstable.66,67 A key technical challenge for frequency mapping that needs to be taken into consideration is that the temporal resolution is limited by the short duration of cardiac recordings compared with the sampling rate. Nademanee et al. proposed that fragmented electrograms represent areas where AF is perpetuated.55 Ablation of complex fractionated atrial electrograms (CFAE) terminated AF in 95% of patients in their study.53 However, other groups have failed to replicate this success.68,69 One confounding factor is that there are different definitions of fractionated electrograms, with the clinically used electroanatomical mapping software using different algorithms to calculate CFAE scores, which have been shown to correlate poorly with each other and with conduction velocity and the number of waves per AF cycle.70 In addition, it is difficult to separate the mechanisms underlying electrogram morphology. Narayan et al. mapped local refractoriness of atrial tissue using monophasic action potential (MAP) catheters to classify the fractionation of bipolar electrograms, finding that far field signals account for 67% of fractionation and that other CFAE types include rapid localised AF sites (8%), spatial disorganisation (17%) and CFAE following AF acceleration, which is often accompanied by MAP alternans (8%).71 A high-density mapping study of patients during AF, sinus rhythm and paced rhythms showed that CFAE distribution is highly variable and often caused by wave collision.72 Electroanatomical mapping data may be processed to calculate the peakto-peak amplitude of each bipolar electrogram signal across the atrium to construct a spatial map of voltage. Areas of low voltage may identify regions of fibrotic tissue. Marcus et al. investigated the spatial distribution of voltage, demonstrating that AF patients exhibit more low-voltage areas on the septal and posterior walls.59 Jadidi et al. combined PVI ablation with ablation guided by electrogram voltage to show improved outcomes for persistent AF compared with PVI alone.73 Box isolation of fibrotic areas is an ablation approach that applies patient-specific lesions surrounding areas of low-voltage tissue.74 One challenge associated with voltage mapping of bipolar electrogram signals is that the amplitude of bipolar electrogram signals depends on wavefront direction. Omnipolar mapping technology has the potential to overcome this limitation by providing an orientation-independent measure of voltage.75

Phase Mapping Despite fibrillation being a seemingly random process, Gray et al. developed a technique to analyse fibrillatory signals to translate periodicity in the signals into loops in a two-variable-state space that represents the system.76 For phase mapping, the two-variable system consists of the signal at a particular location plotted against a timedelayed version of the signal. The phase angle is then measured as the angle around this trajectory for each point in the domain, and a spatial singularity in phase then corresponds to the centre of a rotating wave.76 The landmark paper of Gray et al. revealed a degree

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of spatiotemporal organisation in fibrillation, and the technique used to reveal this organisation is one method that can be used to locate the tip of spiral waves and analyse their dynamics. More recently, the Hilbert transform has been used to create a time-delayed signal, and techniques have been developed for phase mapping of unipolar and bipolar electrogram data.77,78 Topological rules enforce that the ends of wavefronts must be connected either to each other, to boundaries or to phase singularities.79 Phase mapping has been used by several clinical centres to guide ablation therapy. For example, the focal impulse and rotor modulation (FIRM) software applies phase mapping to basket electrode catheters to identify electrical drivers as ablation targets.80 Non-invasive ECG imaging (ECGi) technologies consist of a vest of body surface electrodes for electrical recordings together with an imaging scan to provide anatomical information, with these being combined to construct detailed electroanatomical maps.81 Phase mapping has been applied to ECGi recordings to identify the spatiotemporal distribution of electrical drivers during AF, with ablation focused on the high-density regions.81 Recent clinical review papers provide more details on electrical driver determination in AF.82,83

Activation Versus Phase Mapping A potential advantage of phase mapping over activation mapping is that phase mapping does not assign particular importance to an activation point, which is advantageous for fractionated signals in which it is difficult to assign an activation time. Methodologies for constructing phase maps consist of both pre- and post-processing algorithms. Preprocessing steps may be used to construct sinusoidal signals from atrial recordings prior to the application of the Hilbert transform to calculate phase. For example, Kuklik et al. developed a sinusoidal recomposition technique for unipolar electrograms in which an electrogram signal is expressed as a sum of sinusoidal wavelets of one period length.78 Although this technique does not explicitly require activation times to be assigned to the signal, it assumes a constant cycle length for the signal to define the sinusoidal wavelets. Kuklik et al. compared cycle lengths calculated from times assigned to the unipolar signals to those calculated from the times of phase inversions and showed a good correlation.78 Roney et al. developed a technique for phase mapping of unipolar or bipolar electrograms that uses a sequence of filters and a variation of a pseudoempirical mode decomposition technique to preprocess the signals prior to phase analysis.77 Filtering the electrogram signals removes highfrequency components of the signal, which may represent activation for fractionated signals. Post-processing steps include interpolation and extrapolation of activation time recordings or phase values measured at a sparse arrangement of points either to a regular grid or to the entire atrial surface. We previously demonstrated that the spatial resolution of AF data can significantly affect the interpretation of the underlying AF mechanism,84 which is a particularly important consideration when interpreting findings from low-resolution recording devices.85 Jacquemet investigated the effects of different phase interpolation techniques on false-positive and -negative phase singularity detections.86 Clinically, both activation time and phase mapping techniques are challenging to apply to sequentially acquired AF recordings due to

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Electrophysiology and Ablation the temporal instability of AF. For globally acquired data, activation mapping is feasible but challenging due to electrogram fractionation and because it requires the choice of a time window in which to display activation wavefronts. Phase mapping has been successfully used to guide clinical ablation approaches,81 but requires specialist analysis techniques. It is important to ensure that differences in findings between clinical centres are not because of differences in analysis techniques. Consequently, we recommend applying multiple analysis techniques to the same electrical dataset to increase confidence in the findings; for example, using both activation and phase mapping or using alternative phase mapping techniques.3,87

Fibrosis Mapping Previous studies have demonstrated an association between AF driver location and fibrosis distribution: rotors are observed at the borders of patchy scar in clinical non-invasive ECGi studies88 and in modelling studies.89 As such, fibrotic areas represent an alternative target for catheter ablation. One of the challenges associated with clinical implementation of atrial LGE imaging is the requirement for standardised image processing techniques and, as such, Sim et al. published a standardised, reproducible open-source platform for AF assessment.90 Areas of fibrosis may be identified as areas of low voltage and ablated (box isolation of fibrotic areas74) or imaging data may be used to identify areas of high LGE intensity. Kircher et al. compared applying PVI together with either linear ablation or ablation of low-voltage areas to find that ablating low-voltage areas increased arrhythmia-free survival rate.91 The Delayed-Enhancement MRI (DE-MRI) Determinant of Successful Radiofrequency Catheter Ablation of Atrial Fibrillation (DECAAF) study showed that atrial fibrosis detected on LGE-MRI was independently associated with AF recurrence. 92 However, other studies found no correlation between LGE and rotors.93 Efficacy of Delayed Enhancement MRI-Guided Ablation vs Conventional Catheter Ablation of Atrial Fibrillation (DECAAFII; NCT02529319) is a current clinical study investigating whether ablation guided by LGE-MRI is superior to PVI.94 Chen et al. compared identifying arrhythmogenic areas as sites with spatiotemporal dispersion or continuous activity to low-voltage areas and areas of increased intensity on LGE-MRI to find that most arrhythmogenic activities colocalised with low-voltage areas, but there was less colocalisation with fibrosis identified using LGE-MRI.95 Modelling studies may aim to select regions of fibrosis most likely to harbour re-entrant drivers.96

92.85 cm2) and showed that wavefronts from foci or breakthrough maintained AF, with no evidence of re-entry.26 High-density mapping catheters offer high-fidelity signals at good spatial resolution (2–6 mm), but are limited in their coverage (diameter 2–3.5 cm), and so data have to be collected sequentially to construct a global map. These electrogram recordings may be processed to construct global maps of electrogram features, including DF values and fractionation indices. Both the Biosense Webster Carto and the Abbott EnSite Precision electroanatomical mapping systems offer toolboxes to assess electrogram fractionation using different algorithms,70 which may inform ablation strategies. Constructing activation maps from AF data in which activation patterns may be complex and continuously changing is challenging. To address these challenges, Mann et al. developed an algorithm called RETRO-Mapping to detect wavefront propagation from sequential AF recordings.97 The Rhythmia system (Boston Scientific) has been used with the Orion mini-basket catheter (Boston Scientific) to map atrial tachycardia to identify entrance and exit gaps at high resolution.98 High-density catheters can be used to identify missed pulmonary vein–atrial connections after pulmonary vein ablation. Recently, an omnipolar mapping technology, which provides orientation-independent measurements of cardiac activation and voltage, has been developed and integrated in the Abbott EnSite Precision electroanatomical mapping system. 99 The system uses a high-density grid of 16 equidistant electrodes (HD Grid Mapping Catheter Sensor Enabled; Abbott Technologies), with 3-3-3-mm spacing to provide improved localisation of scar, lesion gaps and wavefront collision.100 Hong et al. used this catheter for mapping of the atria to differentiate between far- and near-field signals and to assess bidirectional conduction block after PVI.101

For catheter ablation cases, different clinical centres use different catheters and electroanatomical mapping systems, each of which has its own advantages and disadvantages, which must be considered in data interpretation.

Basket catheters record endocardial electrograms and offer a more global coverage; however, this coverage is limited to the atrial body and reduced by bunching of splines. For example, Laughner et al. measured interspline distances in the LA ranging from 1.5 to 121.2 mm, with one-third of mapping electrodes exhibiting poor contact.85 FIRM is a clinical mapping system that uses a basket catheter and phase mapping technology to identify rotors and focal sources in patients undergoing ablation for AF.102 Using the technology revealed that AF was sustained by an average of two to three rotors or focal sources, within a mean (± s.d.) area of 2.2 ± 1.4 cm2, which were then ablated.103 The technology has shown an improved clinical outcome compared with conventional ablation in many studies; however, a recent study showed that catheter ablation of sites identified by FIRM mapping terminated AF in only a minority of patients.104 The CARTOFINDER software (Biosense Webster) within Carto may be used with basket mapping catheters to identify rotational and focal activation areas.105

Contact Mapping Systems

Non-contact Mapping Systems

Multiple high-density electrode plaques have been used to map the epicardial atrial surface during surgery. For example, de Groot et al. used a spoon-shaped device with 244 unipolar electrodes (diameter 3.6 cm; interelectrode distance 2.25 mm), as well as a rectangular array of 8 × 8 electrodes (interelectrode distance 2.5 mm) to demonstrate the presence of focal fibrillation waves due to epicardial breakthrough.38 In addition, Lee et al. collected simultaneous data from three epicardial electrode arrays with a total of 510–512 electrodes (total area

Non-contact electrode mapping systems, such as the dipole density mapping AcQMap system (Acutus Medical), which is used together with ultrasound imaging, offer a global coverage at a high resolution. The Utilizing Novel Dipole Density Capabilities to Objectively Visualize the Etiology of Rhythms in Atrial Fibrillation (UNCOVERAF) 127-patient trial used AcQMap technology together with other ablation technologies to show promising results for freedom from AF at 1 year.106

Data Challenges Data Modality

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Interpreting Mechanisms of AF Body surface ECGi mapping has the advantage that it reconstructs signals from the epicardium of most of the left and right atria; however, it may not map the atrial septum and the pulmonary veins, and signals are smoothed during the inverse calculation. In addition, the technology does not map the endocardium.81

Endocardial Versus Epicardial Surface Recordings The choice of endocardial or epicardial mapping will affect recordings and may explain differences between, for example, findings from ECGi and basket mapping studies. For instance, the electrical activity on the endocardium and epicardium of the atrium during AF has been shown to exhibit degrees of discordance, in which there are periods where the surfaces show the same wavefront pattern and times when they have different wavefront patterns.107 Hansen et al. found that intramural drivers were seen on subendocardial optical mapping, but these manifested as either re-entry or breakthrough patterns on subepicardial mapping.11

Differences Between Studies Recent clinical studies have published disparate findings on the mechanisms underlying AF. For example, the Signal Transfer of Atrial Fibrillation Data to Guide Human Treatment (STARLIGHT) clinical trial found no evidence of sustained rotational drivers; instead, persistent AF in these patients was sustained by multiple wavelets of activation.3 Navara et al. demonstrated the existence of rotational and focal activation in pulmonary vein antral regions for cases in which ablation terminated AF before complete PVI.87 Honarbakhsh et al. used the CARTOFINDER technology together with a basket catheter to identify transient but repetitive focal or rotational drivers.108

Ablation Approaches AF ablation approaches differ in their anatomical or electrical targets, as well as in the methodologies and recording devices used to identify these targets. PVI remains the cornerstone of AF ablation, and ablation approaches for persistent AF typically include PVI together with other ablation lesions. Ablation approaches may target features of the electrogram signal; for example, Nademanee et al. pioneered the ablation of CFAE signals, demonstrating a high success rate.55 However, other clinical centres using CFAE ablation failed to replicate these outcomes, possibly due to the different aetiologies of fractionation.72 An alternative ablation approach is to target areas of high frequency identified using DF analysis. However, the RADAR-AF trial showed that ablating high-frequency sources, identified using DF analysis, together with PVI was not significantly different to using PVI alone.65 Ablation techniques that target specific electrogram features, including the degree of fractionation, spatiotemporal dispersion57 or areas of DF, have the advantage that they can be applied to sequentially acquired recordings, from readily available catheters. The Substrate and Trigger Ablation for Reduction of Atrial Fibrillation Trial – Star AF II Study (Star AF II) found no improvement in ablation outcome with the addition of linear ablation or CFAE ablation to PVI for persistent AF patients.109 Globally acquired recordings may be post-processed using phase mapping to identify electrical drivers that are targeted during ablation. This approach demonstrated promising success rates using basket catheters in the Conventional Ablation for Atrial Fibrillation With or Without Focal Impulse and Rotor Modulation (CONFIRM) trial, but other clinical centres showed varied outcomes using the technique.102,103 Phase mapping has also been applied to non-invasive

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ECGi recordings to identify and target electrical drivers during AF.81 These techniques require recording devices with global coverage and specialist analytical techniques. Alternatively, some ablation approaches target areas of fibrotic remodelling. These may be identified as regions of low voltage using sequential electrical mapping and isolated electrically using box isolation of fibrotic areas74 or imaging techniques; for example, DECAAFII is a clinical study investigating whether ablation guided by LGE-MRI is superior to PVI.92 Ablation approaches may also aim to modify the electrical size of the atria or target specific anatomical structures.110,111

Spatial and Temporal Resolution Recording modalities are typically limited in either resolution or coverage, as explained in the previous section. We investigated how spatial resolution affects interpretation of AF recordings, expressing spatial resolution requirements as a linear function of the spatial wavelength, and found that high-density multipolar catheters provide sufficient resolution for rotor and focal source detection, but that the basket catheter is prone to false rotor detections.84 Aronis and Ashikaga considered the effects of multiple coexisting rotors on resolution requirements and found that including more than one rotor increased errors 10-fold, suggesting higher resolution requirements for cases with multiple drivers.112

Data Processing Correct processing of unipolar electrograms requires careful QRS subtraction.113 Spatial interpolation of voltage will create problems if electrograms have different degrees of contact, and bipolar amplitude is direction dependent. Interpolation of phase does not have these problems; however, phase must be interpolated as a circular variable.84,86 Pathik et al. analysed basket catheter electrograms and reported 2D rotors that are not present in 3D, suggesting that correctly incorporating distance between splines in 2D analysis is important.114 Reliable detection of activation times for atrial electrograms during AF is challenging, particularly for fractionated signals.

Differentiating Between Mechanisms Using Limited Data and Interpolation Phase mapping including data interpolation will not be able to differentiate between a leading circle and spiral way mechanism because both will appear as a spiral wave with a phase singularity after analysis. The interpretation of phase mapping of conduction block requires particular care. Podziemski et al. demonstrated that analysis of conduction block data may result in phase singularities that are not due to rotational wavefronts;115 an example is shown in Figure 3 in which phase singularity locations coincide with lines of conduction block. Spiral waves with linear cores have been observed in both computational and experimental studies (core size 1–2 cm), which may appear similar to conduction along a line of block. Topologically, wavefronts must end on either a boundary or PS, so there will be a PS at the end of a wavefront moving along a line of block. Considering the rate of change of phase around a PS point, or the magnitude of conduction delay, may indicate whether the PS is at a fixed rotor core or a conduction block line (which may be a linear core). In addition, using computational simulations, Martínez-Mateu et al. showed that far-field components of unipolar electrograms make it difficult to distinguish between functional and anatomical re-entry.116 An alternative interpretation of

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Electrophysiology and Ablation Figure 3: Phase Singularities May Occur at Lines of Conduction Block

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A: A phase map corresponding to the isochrone wave map in B. Circles indicate phase singularity locations, white arrows show propagation direction, black arrows show the phase singularity trajectory and dashed lines indicate conduction block. C: Electrograms around a phase singularity. D: Examples of phase singularity detections for which corresponding isochrone maps show the phase singularity locations coinciding with lines of conduction block. PS = phase singularity. Source: Podziemski et al.115 Reproduced with permission from Wolters Kluwer Health.

the findings of Podiziemski et al. is motivated by the work of Arthur Winfree, who states that rotors are seldom symmetric;21 the core of a rotor is often elongated because of the anisotropic properties of conduction (the long axis of the ellipse would be in the longitudinal direction of fast conduction) and described as an arc of functional conduction block. Luther et al. investigated re-entry during atrial tachycardia using the Rhythmia system and showed that pseudo re-entrant circuits often appear as stable rotational activation.117 This is shown in Figure 4, in which a secondary wavefront colliding with a partial rotational circuit gives the appearance of a complete rotational circuit. To correctly interpret arrhythmia mechanisms and to determine appropriate ablation approaches, it is important to differentiate between stable rotational activation and pseudo re-entrant circuits. This distinction is important for determining how ablation lines affect individual wavefronts during arrhythmia. During AF there will be more wavefront collisions and conduction around lines of block, making correct interpretation even more complex.

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Future Perspectives There are differences in opinion over how to classify re-entrant mechanisms, for example whether leading circle and spiral re-entries should be classified separately and whether a re-entry anchored to a small structural obstacle should be considered an anatomical re-entry or a functional spiral wave. We recommend following Hoffman and Rosen, dividing mechanisms into abnormal impulse initiation and abnormal impulse conduction.45 Re-entry is then a general subheading under abnormal impulse conduction that includes anatomical and functional re-entry, with anatomical re-entry around a central anatomical obstacle. A rotor does not require an obstacle according to its definition; adding an obstacle will anchor a rotor but is not a necessary component of its mechanisms. Conversely, micro re-entry around an anatomical obstacle need not be a rotor. Interestingly, anchors caused by fibrotic remodelling could be anatomical (including micro-anatomical re-entry caused by insulating collagen) or functional, due to the action potential duration and conduction velocity properties of tissue in the presence of fibrosis (Figure 5).118 An ablation

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Interpreting Mechanisms of AF line from the centre of the re-entrant circuit to a boundary of the tissue theoretically works for both anatomical and functional cases. As the same ablation approach may work in either case and we cannot differentiate between these mechanisms clinically, considering these mechanisms as hierarchical, as opposed to anarchical, could be a beneficial classification.

Figure 4: Pseudo Re-entrant Circuits Composed of Multiple Wavefronts May Appear as Stable Rotational Activity 150 ms 1

Ensuring the correct classification of phase singularities may prove crucial in their use for targeting ablations because wavefront break up does not represent an equal target to a stable rotor. Targeting regions of the atria with a high probability of drivers may be a promising ablation strategy in the instance that drivers are an important AF mechanism. Increased understanding of the reason for this is warranted, including the development of methodologies for determining the relative importance of different drivers in the case of multiple drivers.119 Perhaps, uncovering a degree of order in anarchical AF paves the way for the identification of ablation targets. Thus, future studies into anarchical AF, to investigate whether any order exists, are paramount. Ablation strategies for AF either target anatomical structures, use information on the structural substrate from imaging data or use information on the electrical substrate from electroanatomical mapping. For example, Pambrun et al. systematically targeted the coronary sinus and the vein of Marshall, the pulmonary veins and any anatomical isthmus block regions, showing that this lesion set provides good short-term outcomes.111 The DECAAFII clinical trial ablation strategy is to isolate areas of fibrotic tissue identified using LGE-MRI.92 Recent ablation approaches using electroanatomical mapping data include the stochastic trajectory analysis of ranked signals (STAR) mapping approach, which identified early sites of activation and ablated these to produce a favourable clinical outcome.120 Future research directions include how best to combine anatomical, structural and electrical measures to guide ablation therapy and to assess the additional benefit of mapping AF to provide patient-specific ablation approaches. Understanding the tissue properties underlying AF is important for designing treatments aimed at limiting disease progression. Further studies linking the atrial substrate and arrhythmia, similar to that of Zhao et al., will advance the mechanistic understanding of AF and its ablation.12 The degree of re-entrant driver meander may be decreased by both anatomical and electrophysiological properties (e.g. by application of acetylcholine). Re-entry anchor location and driver formation may also depend on electrophysiology, conduction velocity dynamics, cardiac wavelength and anisotropy.52,121–124 These tissue and electrophysiological properties each affect the electrogram signal, but inferring these individual properties from the electrogram signal is challenging. Simultaneous optical and electrical mapping will enable increased understanding of the relationship between electrogram and transmembrane voltage features.125 In addition, detailed cellular-level mapping of the electrical properties of the centre of re-entrant activity, extending the study of Houston et al., will enable identification of arrhythmia mechanisms and will bridge the cellular and tissue levels.126 Further clinical, basic science and computational studies investigating optimal ablation approaches for these different arrhythmia mechanisms are required. For example, Bayer et al. used computational modelling studies to suggest an alternative ablation

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This example shows a carousel of activation on the posterior mitral annulus, mapped using the Rhythmia system, which appears to be stable rotational activity. However, closely examining the activity shows there is a primary activation wavefront (marked 1) travelling through an area of slow conduction (sites 1–3), which exhibit electrogram fractionation (right). A secondary wavefront (marked 2) collided with the primary wavefront, which is indicated by the split potentials at sites 6 and 7. This secondary wavefront then propagated to site 9, resulting in the appearance of complete rotation. LAA = left atrial appendage; LLPV = left lower pulmonary vein; MA = mitral annulus; RLPV = right lower pulmonary vein. Source: Luther et al.117 Reproduced with permission from Wolters Kluwer Health.

Figure 5: Type of Fibrotic Remodelling Affects Phase Singularity Locations, Where Anchors Could be Anatomical or Functional A

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A: A model incorporating interstitial fibrosis, conduction slowing and ionic changes due to paracrine effects shows a large number of phase singularities (purple circles). Some of these are due to wavefront break up close to the left inferior pulmonary vein. B: A model incorporating the same distribution of fibrotic remodelling, but modelled as replacement fibrosis and conduction slowing, shows fewer phase singularities with more stable re-entry. Source: Roney et al.118 Reproduced with permission from Oxford University Press.

approach that aims to streamline activation patterns.127 Roney et al. performed a virtual pilot clinical study to use simulations to predict whether an extreme ablation approach of ablating interatrial connections would return the right atrium to sinus rhythm.128 In addition, Weiss et al. examined the effects of ablation lesions on mother rotor activity,

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Electrophysiology and Ablation showing that ablation at the core may convert the functional re-entry to a slower anatomical re-entry, whereas ablating from the core to a border interrupts the circuit and terminates the arrhythmia.4 Finally, we recommend the design of new mapping catheters based on the resolution, data type and analysis methods discussed here. Computational models of atrial arrhythmia have been used to offer important insights into arrhythmia mechanisms.128–130 A recent pioneering study from the Trayanova laboratory identified patientspecific targets for AF for patients with a fibrotic substrate.131 However, patient-specific modelling of AF is challenging due to the anatomical and structural complexity of the atria and the dynamic nature of the electrical substrate. Future research into improved methodologies for model construction, calibration and uncertainty quantification is required for aspects including segmentation,90 anatomical structures,128 electrical and structural anisotropy,52,132,133 repolarisation heterogeneity and restitution,134 conduction heterogeneity,51 registration,135 fibrotic remodelling118 and performing predictions on clinical timescales.136 Identifying the properties of the atrial substrate responsible for sustaining the arrhythmia (e.g. critical areas of fibrosis) may

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potentially be important for understanding the arrhythmia. Electrical mapping results need to be interpreted carefully, alongside other measures of the substrate, to identify the sustaining mechanisms of the arrhythmia.

Clinical Perspective • AF mechanisms include anatomical and functional re-entry, hierarchical drivers that include re-entry and triggered activity, and anarchical multiple wavelets. • Data challenges, including differences between recording devices in spatial and temporal resolutions, spatial coverage and recording surface, may account for differences in reported AF mechanisms. • Identifying the properties of the atrial substrate responsible for sustaining an arrhythmia (e.g. critical areas of fibrosis) may potentially be important for understanding the arrhythmia. • Electrical mapping results need to be interpreted carefully, alongside other measures of the substrate, to identify the sustaining mechanisms of the arrhythmia.

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Treatment of atrial fibrillation by the ablation of localized sources: CONFIRM (Conventional Ablation for Atrial Fibrillation With or Without Focal Impulse and Rotor Modulation) trial. Am J Coll Cardiol 2012;60:628–36. https://doi.org/10.1016/j. jacc.2012.05.022; PMID: 22818076. 103. Baykaner T, Lalani GG, Schricker A, et al. Mapping and ablating stable sources for atrial fibrillation: summary of the literature on Focal Impulse and Rotor Modulation (FIRM). J Interv Card Electrophysiol 2014;40:237–44. https://doi.org/10.1007/s10840014-9889-8; PMID: 24647673. 104. Benharash P, Buch E, Frank P, et al. Quantitative analysis of localized sources identified by focal impulse and rotor modulation mapping in atrial fibrillation. Circ Arrhythm Electrophysiol 2015;8:554–61. https://doi.org/10.1161/ CIRCEP.115.002721; PMID: 25873718. 105. Daoud EG, Zeidan Z, Hummel JD, et al. Identification of repetitive activation patterns using novel computational analysis of multielectrode recordings during atrial fibrillation and flutter in humans. JACC Clin Electrophysiol 2017;3:207–16. https://doi.org/10.1016/j.jacep.2016.08.001; PMID: 29759514. 106. Grace A, Willems S, Meyer C, et al. High-resolution noncontact charge-density mapping of endocardial activation. JCI Insight 2019;4:pii:126422. https://doi.org/10.1172/jci.insight.126422; PMID: 30895945. 107. Gutbrod SR, Walton R, Gilbert S, et al. Quantification of the transmural dynamics of atrial fibrillation by simultaneous endocardial and epicardial optical mapping in an acute sheep model. Circ Arrhythm Electrophysiol 2015;8:456–65. https://doi. org/10.1161/CIRCEP.114.002545; PMID: 25713215. 108. Honarbakhsh S, Schilling RJ, Dhillon G, et al. A novel mapping

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Electrophysiology and Ablation system for panoramic mapping of the left atrium. JACC Clin Electrophysiol 2017;4:124–34. https://doi.org/10.1016/j. jacep.2017.09.177; PMID: 29387810. 109. Verma A, Jiang C-Y, Betts TR, et al. Approaches to catheter ablation for persistent atrial fibrillation. N Engl J Med 2015;372:1812–22. https://doi.org/10.1056/NEJMoa1408288; PMID: 25946280. 110. Williams SE, O’Neill L, Roney CH, et al. Left atrial effective conducting size predicts atrial fibrillation vulnerability in persistent but not paroxysmal atrial fibrillation. J Cardiovasc Electrophysiol 2019;30:1416–27. https://doi.org/10.1111/ jce.13990; PMID: 31111557. 111. Pambrun T, Denis A, Duchateau J, et al. MARSHALL bundles elimination, Pulmonary veins isolation and Lines completion for ANatomical ablation of persistent atrial fibrillation: MARSHALL-PLAN case series. J Cardiovasc Electrophysiol 2019;30:7–15. https://doi.org/10.1111/jce.13797; PMID: 30461121. 112. Aronis KN, Ashikaga H. Impact of number of co-existing rotors and inter-electrode distance on accuracy of rotor localization. J Electrocardiol 2018;51:82–91. https://doi.org/10.1016/j. jelectrocard.2017.08.032; PMID: 28988690. 113. Handa BS, Roney CH, Houston C, et al. Analytical approaches for myocardial fibrillation signals. Comput Biol Med 2018;102:315–26. https://doi.org/10.1016/j. compbiomed.2018.07.008; PMID: 30025847. 114. Pathik B, Kalman JM, Walters T, et al. Absence of rotational activity detected using 2-dimensional phase mapping in the corresponding 3-dimensional phase maps in human persistent atrial fibrillation. Heart Rhythm 2018;15:182–92. https://doi.org/10.1016/j.hrthm.2017.09.010; PMID: 28917553. 115. Podziemski P, Zeemering S, Kuklik P, et al. Rotors detected by phase analysis of filtered, epicardial atrial fibrillation electrograms colocalize with regions of conduction block. Circ Arrhythm Electrophysiol 2018;11:e005858. https://doi. org/10.1161/CIRCEP.117.005858; PMID: 30354409. 116. Martínez-Mateu L, Romero L, Saiz J, Berenfeld O. Far-field contributions in multi-electrodes atrial recordings blur distinction between anatomical and functional reentries and may cause imaginary phase singularities – a computational study. Comput Biol Med 2019;108:276–87. https://doi. org/10.1016/j.compbiomed.2019.02.022; PMID: 31015048. 117. Luther V, Sikkel M, Bennett N, et al. Visualizing localized re-entry with ultra-high density mapping in iatrogenic atrial tachycardia. Circ Arrhythm Electrophysiol 2017;10:e004724.

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https://doi.org/10.1161/CIRCEP.116.004724; PMID: 28356307. 118. Roney CH, Bayer JD, Zahid S, et al. Modelling methodology of atrial fibrosis affects rotor dynamics and electrograms. Europace 2016;18(Suppl 4):iv146–55. https://doi.org/10.1093/ europace/euw365; PMID: 28011842. 119. Bellmann B, Lin T, Ruppersberg P, et al. Identification of active atrial fibrillation sources and their discrimination from passive rotors using electrographical flow mapping. Clin Res Cardiol 2018;107:1021–32. https://doi.org/10.1007/s00392-018-12747; PMID: 29744616. 120. Honarbakhsh S, Hunter RJ, Ullah W, et al. Ablation in persistent atrial fibrillation using stochastic trajectory analysis of ranked signals (STAR) mapping method. JACC Clin Electrophysiol 2019;5:817–29. https://doi.org/10.1016/j.jacep.2019.04.007; PMID: 31320010. 121. Roney CH, Bayer JD, Cochet H, et al. Variability in pulmonary vein electrophysiology and fibrosis determines arrhythmia susceptibility and dynamics. PLoS Comput Biol 2018;14:e1006166. https://doi.org/10.1371/journal. pcbi.1006166; PMID: 29795549. 122. Avula UMR, Abrams J, Katchman A, et al. Heterogeneity of the action potential duration is required for sustained atrial fibrillation. JCI Insight 2019;5:128765. https://doi.org/10.1172/ jci.insight.128765; PMID: 31021331. 123. Honarbakhsh S, Schilling RJ, Orini M, et al. Structural remodeling and conduction velocity dynamics in the human left atrium: relationship with reentrant mechanisms sustaining atrial fibrillation. Heart Rhythm 2019;16:18–25. https://doi.org/10.1016/j.hrthm.2018.07.019; PMID: 30026014. 124. Saha M, Roney CH, Bayer JD, et al. Wavelength and fibrosis affect phase singularity locations during atrial fibrillation. Front Physiol 2018;9:1207. https://doi.org/10.3389/fphys.2018.01207; PMID: 30246796. 125. Chowdhury RA, Tzortzis KN, Dupont E, et al. Concurrent micro- to macro-cardiac electrophysiology in myocyte cultures and human heart slices. Sci Rep 2018;8:6947. https://doi.org/10.1038/s41598-018-25170-9; PMID: 29720607. 126. Houston C, Tzortzis KN, Roney C, et al. Characterisation of re-entrant circuit (or rotational activity) in vitro using the HL1-6 myocyte cell line. J Mol Cell Cardiol 2018;119:155–64. https://doi. org/10.1016/j.yjmcc.2018.05.002; PMID: 29746849. 127. Bayer JD, Roney CH, Pashaei A, et al. Novel radiofrequency ablation strategies for terminating atrial fibrillation in the left atrium: a simulation study. Front Physiol 2016;7:108. https:// doi.org/10.3389/fphys.2016.00108; PMID: 27148061.

128. Roney CH, Williams SE, Cochet H, et al. Patient-specific simulations predict efficacy of ablation of interatrial connections for treatment of persistent atrial fibrillation. Europace 2018;20(Suppl 3):iii55–68. https://doi.org/10.1093/ europace/euy232; PMID: 30476055. 129. Aslanidi OV, Colman MA, Varela M, et al. Heterogeneous and anisotropic integrative model of pulmonary veins: computational study of arrhythmogenic substrate for atrial fibrillation. Interface Focus 2013;3:20120069. https:// doi.org/10.1098/rsfs.2012.0069; PMID: 24427522. 130. Loewe A, Poremba E, Oesterlein T, et al. Patient-specific identification of atrial flutter vulnerability – a computational approach to reveal latent re-entry pathways. Front Physiol. 2019;9:1910. https://doi.org/10.3389/fphys.2018.01910; PMID: 30692934. 131. Boyle PM, Zghaib T, Zahid S, et al. Computationally guided personalized targeted ablation of persistent atrial fibrillation. Nat Biomed Eng 2019;3:870–9. https://doi.org/10.1038/s41551019-0437-9; PMID: 31427780. 132. Fastl TE, Tobon-Gomez C, Crozier A, et al. Personalized computational modeling of left atrial geometry and transmural myofiber architecture. Med Image Anal 2018;47:180– 90. https://doi.org/10.1016/j.media.2018.04.001; PMID: 29753182. 133. Pashakhanloo F, Herzka DA, Ashikaga H, et al. Myofiber architecture of the human atria as revealed by submillimeter diffusion tensor imaging. Circ Arrhythm Electrophysiol 2016;9:e004133. https://doi.org/10.1161/CIRCEP.116.004133; PMID: 27071829. 134. Corrado C, Williams S, Karim R, et al. A work flow to build and validate patient specific left atrium electrophysiology models from catheter measurements. Med Image Anal 2018;47:153–63. https://doi.org/10.1016/j.media.2018.04.005; PMID: 29753180. 135. Roney CH, Pashaei A, Meo M, et al. Universal atrial coordinates applied to visualisation, registration and construction of patient specific meshes. Med Image Anal 2019;55:65–75. https://doi.org/10.1016/j.media.2019.04.004; PMID: 31026761. 136. Cantwell CD, Mohamied Y, Tzortzis KN, et al. Rethinking multiscale cardiac electrophysiology with machine learning and predictive modelling. Comput Biol Med 2019;104:339–51. https://doi.org/10.1016/j.compbiomed.2018.10.015; PMID: 30442428. 137. Pandit SV, Jalife J. Rotors and the dynamics of cardiac fibrillation. Circ Res 2013;112:849–62. https://doi.org/10.1161/ CIRCRESAHA.111.300158; PMID: 23449547.

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Electrophysiology and Ablation

Non-invasive Stereotactic Radioablation: A New Option for the Treatment of Ventricular Arrhythmias Chen Wei, 1,2 Pierre Qian, 2 Usha Tedrow, 2 Raymond Mak 3 and Paul C Zei 2 1. Harvard Medical School, Boston, MA, US; 2. Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, MA, US; 3. Department of Radiation Oncology, Brigham and Women’s Hospital/Dana-Farber Cancer Institute, Boston, MA, US

Abstract Ventricular tachycardia (VT) is associated with significant morbidity and mortality. Radiofrequency catheter ablation can be effective for the treatment of VT but it carries a high rate of recurrence often attributable to insufficient depth of penetration for reaching critical arrhythmogenic substrates. Stereotactic body radioablation (SBRT) is a commonly used technology developed for the non-invasive treatment of solid tumours. Recent evidence suggests that it can also be effective for the treatment of VT. It is a non-invasive procedure and it has the unique advantage of delivering ablative energy to any desired volume within the body to reach sites that are inaccessible with catheter ablation. This article summarises the pre-clinical studies that have formed the evidence base for SBRT in the heart, describes the clinical approaches for SBRT VT ablation and provides perspective on next steps for this new treatment modality.

Keywords Ablation, cardiac arrhythmias, noninvasive, radiosurgery, radiotherapy, stereotactic, ventricular tachycardia Disclosure: PQ was supported by a Bushell Travelling Fellowship from the Royal Australasian College of Physicians. UT has received personal fees from Abbott, personal fees from Biosense Webster and Thermedical. RM has received personal fees from AstraZeneca and NewRT. PCZ has received personal fees from Cyberheart, grants and personal fees from Biosense Webster during the conduct of the study, is on the advisory board for Varian and provides research support to Biosense Webster. Acknowledgements: The representative cardiac imaging and electroanatomical map were provided by PCZ, UT, and RM. RM provided the target treatment plan and dose volume histogram. Received: 25 July 2019 Accepted: 18 November 2019 Citation: Arrhythmia & Electrophysiology Review 2019;8(4):285–93. DOI: https://doi.org/10.15420/aer.2019.04 Correspondence: Paul Zei, Department of Cardiac Electrophysiology and Cardiovascular Medicine, Brigham and Women’s Hospital, 70 Francis St, Boston, MA 02115, US. E: pzei@bwh.harvard.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.

Ventricular tachycardia (VT) is a life-threatening sequela found in patients with cardiomyopathy. ICDs can terminate ventricular arrhythmias, but recurrent device shocks lead to reduced quality of life and are associated with higher mortality.1–5 Radiofrequency catheter ablation has emerged as an effective treatment for VT refractory to anti-arrhythmic therapy and has also been shown to reduce ICD shocks.6,7 However, in the presence of structural heart disease, the long-term recurrence rate of ventricular arrhythmias has been shown to be greater than 50% across multiple trials, with complication rates ranging from 6 to 10%.7–15 In addition, the cost to the healthcare system of initial ablation and hospitalisation per patient has been estimated at C$20,642 (£11,920); 995% CI C$11,773–44,741 [£6,798–£25,836]). Taken together, these numbers signal a need for treatments that are more efficacious and cost-effective.16 Treatment failure is likely the result of multiple potential factors. Endocardial radiofrequency ablation has limited ability to penetrate deeper arrhythmogenic substrates in the ventricular myocardium, particularly when disease processes alter the myocardial composition with replacement fibrosis, fat, calcification, or overlying chronic thrombus. Even when percutaneous epicardial access can be safely obtained in patients without prior cardiac surgery, ablation energy delivery is

often limited by epicardial fat and risk of coronary and phrenic nerve injury.9,17–19 While various alternative techniques have been devised to allow greater access, including transcoronary ethanol ablation, needle catheter ablation and bipolar ablation, these methods still rely on invasive techniques to achieve a permanent and sufficiently transmural lesion that encompasses critical VT circuitry.17,20–22 The clinical VT may also be too unstable to adequately map and delineate during catheter ablation, and there may be multiple VT circuits and substrates that preclude adequate mapping and treatment. These factors point to the complex architecture that often underlies VT substrate. Stereotactic body radiotherapy (SBRT) is a non-invasive ablation modality, originally developed for the focal treatment of solid malignancies. It is now being applied to cardiac arrhythmias with promising early results. This widely used technology uses high-energy photons generated from many radiation beams directed at different angles to concentrate ablative energy in any pre-defined zone within the body.11 SBRT should overcome many of the limitations of catheter ablation, as it can target substrates that are too extensive or inaccessible using catheter ablation. However, the freedom to non-invasively designate and deliver treatment volumetrically and the use of SBRT as the ablation energy source brings new challenges and considerations.

Access at: www.AERjournal.com

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Electrophysiology and Ablation Historical Background to Stereotactic Radioablation Stereotactic radiotherapy was first conceived by the neurosurgeon Lars Leksell in the 1950s as a non-invasive method for treating inaccessible lesions deep in the brain, particularly arteriovenous malformations (AVMs).23 Termed stereotactic radiosurgery (SRS), the technology was rapidly adopted for the treatment of brain tumours and was used as a non-invasive outpatient procedure with short recovery times.24 While initially restricted to the brain by limited technological capability to accurately target and account for physiologic motion, advancements in imaging, treatment planning and radiation delivery systems have allowed the same technology to be adapted for treatment of tumours throughout the body in a technique called stereotactic body radiation therapy (SBRT).25 SBRT has also been used clinically to treat numerous benign conditions, including keloids, heterotopic ossification and trigeminal neuralgia.26,27 Non-malignant diseases that may benefit from the therapy are being investigated, including hypertension treated via renal arterial denervation.28

Mechanism of Tissue Injury and Pre-clinical Validation During SBRT, high-dose radiation is delivered via numerous noncoplanar beams that converge on a single target with sub-millimetre accuracy.29,30 In contrast, conventional radiotherapy uses no more than several beams at one time and the radiation is fractionated into small dosages delivered over weeks to months to avoid collateral injury to adjacent organs. Because SBRT distributes radiation across many beams at different angles, the dose delivered to any one region of healthy tissue is minimised, which allows for treatment to be given in either one or several fractions. The primary mechanism of radiation-induced cell death is from ionisation and free radical production, which leads to the accumulation of double-strand breaks in DNA that trigger cell cycle arrest and cell death. There is growing evidence that SBRT also works through additional indirect mechanisms owing to the higher dose, mainly through damage to tissue vasculature, leading to cell hypoxia and necrosis.24,31 To this end, radiation-induced vascular changes in tumours have been observed in the hours or days after treatment, and pre-clinical studies have shown additional cell death aside from the direct effects of radiation.31,32 These mechanisms have not been fully elucidated and there remains controversy over their exact role in SBRT. Most of the literature has focused on tumour biology, and less is known about mechanisms of injury in normal tissue and especially arrhythmogenic cardiac tissue. Since radiation in cardiac SBRT is directed at non-dividing myocytes, the mechanism of action is likely to be different than that for tumours. However, there have been studies that have investigated single-fraction whole heart irradiation in animal models, and these demonstrated dose-dependent myocardial degeneration and fibrosis progressing from epicardial tissue to full transmurality in the months after irradiation at doses of 20 Gy and higher.33–35 Evidence of a reduction in capillary density was shown to precede that of myocardial degeneration, suggesting the early and prominent role of vascular injury in radiation-induced damage.34 Though not entirely translatable given differences in treatment delivery, these findings are similar to those observed in the proof-of-principle animal studies that have demonstrated successful AV nodal and

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pulmonary vein ablation following SBRT.36–39 In these studies, treatment effect was associated with myocyte necrosis and microvascular injury and, in particular, target histology (obtained after 3–6 months) consistently demonstrated radiation-induced fibrosis at the site of treatment with minimal effects outside of the target volume and no evidence of injury to surrounding tissues, including the trachea, oesophagus, lungs and phrenic nerves. Tissue sections were notable for severe myocyte architectural disruption and necrosis, along with severe vasculitis in intramyocardial vessels. However, these assessments of complications were still within a relatively short posttreatment timeframe, as radiation effects may not manifest for years. Dose-finding across these studies supported a threshold of 25 Gy delivered as a single fraction, as effective at creating myocardial fibrosis and associated conduction block, but dosages of up to 35 to 40 Gy had no complications associated with radiation.36,39,40 The timeline of measured electrophysiologic effect, specifically conduction block, varied but was typically months, though shorter durations were observed for higher dosages of 35 to 40 Gy. In contrast, as will be discussed, clinical electrophysiologic effects appear to occur significantly sooner. Based on these results and experience gleaned from other applications of SBRT in oncology, clinical studies have used 25 Gy for treatment. Nonetheless, the optimal dose regimen has yet to be elucidated. Additionally, the pre-clinical studies described were done on normal cardiac tissue; therefore, the effect of SBRT on myocardial scar biology and electrophysiology remains poorly understood.

Clinical Application to Treatment of Ventricular Tachycardia Clinical experience with cardiac SBRT as a treatment for ventricular tachycardia has focused on patients who have failed anti-arrhythmic and conventional catheter ablation therapy. To date, more than 50 patients have been treated worldwide, with published data including a total of 43 patients.41–49 The first reported use of SBRT for treatment of VT was published by Loo et al. in 2014. It demonstrated a transient decrease in VT episodes for 7 months after a 2-month blanking period after irradiation with 25 Gy.41 No acute or late complications were observed, but at 9 months, recurrent VT occurred in the context of and exacerbation of chronic obstructive pulmonary disease (COPD), ending in death. This seminal study was followed by several more case reports detailing the efficacy of cardiac SBRT, with details summarised in Table 1.42,43,45 The next representative study was a case series conducted by Cuculich et al. involving five patients treated for refractory VT, with a resulting 99.9% reduction in VT episodes from baseline, again without complications through a total follow-up period of 46 person-months.44 The largest study to date, a Phase I/II clinical trial that enrolled 19 patients, was published by Robinson et al. in 2019, and demonstrated a reduction from baseline in median VT episodes for 15 out of 16 patients followed for a median time of 13 months, with associated improvement in quality-of-life measures.46 Most recently, Neuwirth et al. published a case series of 10 patients with structural heart disease and refractory VT, and observed a 87.6% reduction in total VT burden after a 90-day blanking period.49 In this cohort, two patients showed no response to SBRT, two had late response at 3 and 6 months, and eight of the 10 patients had

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Non-invasive Ablation of Ventricular Tachycardia Table 1: Clinical Experience with Cardiac Stereotactic Body Radioablation for Ventricular Tachycardia Author, journal,

Type of study

date

Patient

Follow-up

Outcomes

Safety

Significance

characteristics

Loo et al. 201541

Case report

1 patient with refractory VT

9 months with a 2-month blanking period

Decrease in total VT from 562 to 52 episodes/month from months 2â&#x20AC;&#x201C;9, VT cycle length slowing

No acute or late complications. Patient died after 9 months from COPD exacerbation and recurrent VT

First human patient treated

Neuwirth et al. 201949

Case report

1 patient with refractory VT

4 months

No malignant arrhythmia detected during follow-up

No complications during follow-up

Second case report

Zei et al. 201763

Abstract

4 patients with refractory VT

12 months

One patient did not undergo ablation due to issues with fiducial. One patient as described in Loo et al.41 Two patients arrhythmia-free for >12 months

No complications during follow-up

Two new patients with VT treated

Cuculich et al. 201744

Case series

5 patients with structural heart disease and refractory VT

12 months, 6-week blanking period

99.9% reduction in total VT episodes from baseline over 46 patient months. 1 patient underwent additional invasive CA at 4 weeks.

One patient with fatal stroke 3 weeks posttreatment, unclear if related to SBRT. No other acute or late complications. Serial CT at 4 months with inflammatory changes, resolution at 12 months

First case series

Jumeau et al. 201845

Case report

1 patient in an ICU admitted for incessant VT storm

4 months

No sustained VT observed after SBRT. Patient discharged after 2 months

No complications during follow-up

First rescue treatment of ICU patient with VT storm

Robinson et al. 201946

Single-arm phase I/II prospective clinical trial

17 patients with refractory VT

13 months, 6-week blanking period

94% reduction in total VT episodes (median 119 to 3) in 15/16 evaluable patients. QOL improvement at 6 months. OS 89% at 6 months 72% at 12 months 69% with recurrence by 6 months, resulting in three deaths

No acute toxicities. Delayed pericarditis/ effusion (28%) and pneumonitis (11.1%) response to medical therapy. One patient died from an unrelated accident 17 days post therapy

First single-centre prospective Phase I/II trial

Haskova et al. 201847

Case report

1 patient with refractory VT secondary to unresectable cardiac fibroma

8 months

Gradual elimination of VT post-SBRT (unclear timeline)

No reported complications during follow-up

First use of SBRT for cardiac fibroma

Zeng et al. 201948

Case report

1 patient with refractory VT secondary to unresectable cardiac lipoma

4 months

100% reduction in VT episodes (129/24 hours before SBRT to 0 by second month)

No complications during follow-up

First use of SBRT for cardiac lipoma

Neuwirth et al. 201949

Case series

10 patients with structural heart disease and refractory VT

28 months, 90-day blanking period

87.6% reduction in total VT burden. Recurrence in 8/10 patients, mean time to first anti-tachycadia pacing and shock 6.5 and 21 months respectively. 2 patients with no response, 2 patients with late effect (3 and 6 months).

Only acute toxicity was nausea (n=4). 1 possible grade 3 late toxicity: progression of mitral regurgitation at 17 months 3 non-arrhythmic deaths (1 dementia, 2 HF)

Longest follow-up times compared with other studies

CA = catheter ablation; COPD = coronary obstructive pulmonary disease; HF = heart failure; QOL = quality of life; SBRT = Stereotactic body radioablation; VT = ventricular tachycardia.

recurrence with mean time to anti-tachycardia pacing and shock at 6.5 and 21 months respectively. Collectively, these studies appear to show a dramatic reduction in device-detected VT burden following therapy after a set blanking period. In general, side-effects were mostly mild, with the most significant events involving one report of pericarditis which was

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

managed conservatively with anti-inflammatories, one case of valvular disease progression, two patients with self-resolving pneumonitis, and five with delayed pericardial effusions.46,49 No deaths resulted from the treatment itself, though many patients later experienced recurrence, with some resulting in death.46 Histology was obtained for one patient who suffered from stroke unrelated to the treatment during follow-up, which demonstrated prominent ectatic blood vessels at the interface

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Electrophysiology and Ablation Table 2: Cardiac Stereotactic Body Radioablation Treatment Parameters Publication

Substrate Assessment Modalities

Treatment

Dose

Procedure

Platform

Delivered

Length

Motion Compensation

Loo et al. 201541

Echocardiogram, PET, 12-lead ECG

CyberKnife

25 Gy/ 1 fraction

90 min

Dynamic tracking (Synchrony) with temporary pacing wire as fiducial for respiratory. Fluoroscopy during transient breath holds for cardiac.

Neuwirth et al. 201949

Diagnostic CT, EAM studies

CyberKnife

25 Gy/ 1 fraction

114 min

Dynamic tracking (Synchrony) with LV electrode as fiducial. No additional safety margin.

Zei et al. 201763

Cardiac CT, CMR, PET, 12-lead ECG, prior EAM studies

CyberKnife

25 Gy/ 1 fraction

Not reported

Dynamic tracking (Synchrony) with fiducial tracking as available.

Cuculich et al. 201744

SPECT, CMR, cardiac CT, echocardiogram, ECGi (Cardioinsight Noninvasive 3D Mapping System), prior EAM studies

TrueBeam

25 Gy/ 1 fraction

11â&#x20AC;&#x201C;18 min

4D respiratory-gated CT to determine target volume plus cardiac and respiratory motion, plus safety margin of 5 mm.

Jumeau et al. 201845

Planning CT, CMR, prior EAM studies

CyberKnife

25 Gy/ 1 fraction

45 min

Dynamic tracking (Synchrony) with RV ICD lead as fiducial. No additional safety margin.

Robinson et al. 201946

SPECT, CMR, cardiac CT, echocardiogram, ECGi (Cardioinsight Noninvasive 3D Mapping System), prior EAM studies

TrueBeam

25 Gy/ 1 fraction

15.3 min

4D respiratory-gated CT to determine target volume plus cardiac and respiratory motion, plus safety margin of 5 mm.

Haskova et al. 201847

Planning CT, intracardiac echo, prior EAM

CyberKnife

25 Gy/ 1 fraction

Not reported

Not reported.

Zeng et al. 201948

Planning CT, 12-lead echocardiogram, prior EAM

CyberKnife

24 Gy/ 3 fractions

Not reported

Dynamic tracking (Synchrony) with fluoroscopically implanted fiducial (pacemaker lead) for respiratory, fluoroscopy for cardiac.

Neuwirth et al. 201949

Planning CT, ECG-gated CT, prior endocardial +/- epicardial EAM

CyberKnife

25 Gy/ 1 fraction

68 min

ECG-gated CT for cardiac motion. Dynamic tracking (Synchrony) with existing ICD leads as surrogate fiducials for respiratory motion. No additional safety margin.

CA = catheter ablation; CMR = cardiac MRI; COPD = coronary obstructive pulmonary disease; EAM = electroanatomical mapping; HF = heart failure; LV = left ventricular; QOL = quality of life; RV = right ventricular; SBRT = stereotactic body radioablation; SPECT = single-photon emission CT; VT = ventricular tachycardia.

of dense scar and viable myocardium, as has been described in pre-clinical studies, though without evidence of acute vasculitis or tissue oedema.44 There was no evidence of acute myocyte necrosis, haemorrhage, or acute inflammation. The results of the published data are summarised in Table 1.

care unit setting, with no recurrence of sustained VT after treatment, as did Neuwirth et al. in select patients.45,49 Robinson et al. also noted treatment efficacy in most patients within 6 weeks, prior to the several-month time window observed in the aforementioned pre-clinical studies.46

SBRT has been associated with a remarkable reduction of VT burden. However, a small proportion of patients failed to demonstrate this. Further study to understand the mechanisms behind a lack of response will be critical. Furthermore, it is plausible that further understanding of the mechanism of action and optimisation of the treatment protocol will extend the duration of treatment effect.46 It should also be emphasised that these findings were limited to patients who had already failed conventional therapy, and it is not known how effective cardiac SBRT is for patients with less refractory disease.

Conversely, Neuwirth et al. reported a lack of response in two patients and delayed treatment effect in two more patients, which they attributed to smaller target volume and discontinuation of antiarrhythmics before SBRT.49 Additional studies providing more clinical data may help delineate the best treatment parameters as well as the optimal medical management strategy peri-ablation. Further research is also needed to characterise the progression of fibrosis in relation to treatment effect, as well as contributions from vascular injury, which has been shown to occur more acutely following radiation in the preclinical setting.

In addition, the timescale of initial treatment effect and the parameters that modulate it are not well understood. Investigators have generally incorporated a multi-week blanking period postSBRT to allow for late radiation fibrosis to take effect in accordance with the suggested mechanism of action. However, several notable discrepancies in the clinical experience point towards additional mechanisms at play. For example, Jumeau et al. used cardiac SBRT to induce successful resolution of VT storm in the acute intensive

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In terms of safety, acute and subacute toxicities appear uncommon and have been limited to several cases of pericarditis, pneumonitis and delayed pericardial effusions which were managed conservatively. However, the long-term side-effects of treatment are still under investigation. Another potential concern, though not yet seen clinically with cardiac SBRT, is cardiac device malfunction after radiotherapy, with estimates that range from 3â&#x20AC;&#x201C;7% of cases and correlating with

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Non-invasive Ablation of Ventricular Tachycardia Figure 1: Representative Imaging

A: Section of the patient’s cardiac CT with scar-associated fat (green shading) and wall thinning. The cardiac CT was processed with proprietary wall thickness segmentation software with the resultant 3D reconstruction shown. B: The areas corresponding to fatty infiltration did not have consistent endocardial pace-capture (grey dots). More basally, pace-capture with long stim-QRS duration and exit septal to the posteromedial papillary muscle was observed, matching the clinical VT morphology. This indicated the presence of a deep channel of slow conduction through the region of intramyocardial fat which was included in the radioablation planning target volume.

radiation beam energy.50,51 Given that cardiac SBRT involves high-dose ablative radiotherapy, device malfunction is a concern; nonetheless, the disturbances that have been described typically manifest as transient device interferences occurring only during irradiation or resets to back up settings. Given the need for further delineation of the risk profile of cardiac SBRT, we recommend careful peri-SBRT monitoring of device function.

SBRT Treatment Planning and Delivery Successful implementation of SBRT hinges on numerous factors, including correct identification of the intended target, design of a radiotherapy plan that prioritises dosing to the target while sparing adjacent critical organs, and accurate radiation delivery, which requires collaboration from a multidisciplinary team of radiation oncologists, cardiac electrophysiologists, physicists, dosimetrists and therapists. Pre-treatment imaging, including CT or MRI, is required to delineate the arrhythmogenic substrate, after which an individualised treatment plan is generated using target contours drawn by a physician followed by computerised dosimetry planning.17–18 During planning and treatment delivery, compensation for cardiorespiratory motion is a unique consideration for cardiac applications of SBRT.

Patient Selection While early results have been promising, cardiac SBRT remains under investigation and is indicated in patients who have intractable arrhythmia refractory to drug escalation and catheter ablation. As a non-invasive outpatient procedure that is not limited by substrate geography, it is particularly suited to patients with significant comorbidities who are unlikely to tolerate prolonged general anaesthesia or hospitalisation or have inaccessible arrhythmogenic substrate.

Determining the Arrhythmogenic Substrate Cardiac SBRT depends on characterisation of both the anatomic and electrophysiologic topology of the arrhythmogenic substrate to inform the creation of an accurate 3D target volume. Cardiac imaging with CT, MRI and ECG provide an assessment of the structural correlate for VT circuits while 12-lead ECG, electroanatomic mapping (EAM) and

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multi-electrode electrocardiographic imaging (ECGI) provide valuable information on VT exit sites and isthmuses. Most patients who have received cardiac SBRT have undergone prior ablation and previous EAM studies provide important information for SBRT treatment planning. If EAM was able to define an ablation target, but technical reasons precluded effective delivery of ablative energy, the mapping information may be quite helpful. ECGI or 12-lead ECG during non-invasive programmed stimulation can be useful where available, comprising a surface-based multi-electrode system that can record and reconstruct the heart’s electrical activity onto a CT-generated 3D anatomic model. In conjunction with noninvasive programmed stimulation through patient implanted devices, it has been used to map activation in VT.44 Currently, ECGI provides data primarily pertaining to epicardial electrical activity; in cases of endocardial or intramural substrate, substrate location may still be accurately inferred from epicardial mapping data, but this remains an area that is being researched.25 In patients with structural heart disease, options for imaging anatomic scar include MRI, cardiac CT, and radionuclide imaging. Cardiac MRI is the current gold standard for assessing ventricular scar (as identified by late gadolinium enhancement), but usage may be limited in patients with non-compatible ICDs and in situations where image quality is perturbed by device artifacts.52,53 In these situations, cardiac CT can be a valuable alternative, as it is not only effective at characterising detailed cardiac anatomy due to its high spatial resolution, but can also define putative arrhythmogenic substrates, which often localise to sites of significant wall thinning, fibrosis, fat, and calcium.54–6 Radionuclide imaging can also be obtained using single photon emission CT (SPECT) or PET, both of which are commonly used to detect silent ischaemia, although these modalities have poor spatial resolution and often require integration with other imaging modalities.

Creation of the Treatment Volume After target delineation, the next step in planning involves creating the target volume and determining the patient set-up required for

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Electrophysiology and Ablation Figure 2: The Representative Treatment Plan

is to minimise motion as much as possible (using immobilisation and compression devices) and to contour a larger target volume to encompass the entire target location as seen on a respiratory-gated 4D CT and where available, a cardiac-gated CT.57 Another approach is to use a system capable of tracking motion and delivering radiation based on gating. In this method, a fiducial marker – which can be an existing device component or an implanted gold seed – is used to orient the radiation beam, serving as a trigger to switch the beam on and off as it moves in and out of a preset location. Another way is to use a linear accelerator mounted on a roving robotic arm that can move freely and synchronise with the target in real-time using an internal respiratory tracking system. The roving robotic arm allows the linear accelerator to access more oblique angles and the respiratory tracking system uses continual imaging of fiducials to align the radiation beam with the motion of the target.58 This latter approach is provided by the CyberKnife (Accuray) delivery platform. A summary of the motion compensation approaches that have been used is shown in Table 2.

A visualisation of the representative treatment plan. The planning target volume was dosed to 25 Gy. The maximum target isodose reached was 31 Gy with rapid dose-fall off to critical structures at risk, including coronary arteries, valves, ICD lead insertions, phrenic nerve, lungs, ribs, oesophagus, stomach and bowel.

treatment delivery. The patient is brought to a radiation oncology suite to undergo simulation, during which they are immobilised in the position they will be in when they receive radiation, and imaging is performed to simulate their anatomy during treatment. Several devices may be used to fix the patient in a reproducible position, including a vacuum-assisted cushion shaped to the patient’s body. Once the patient is positioned appropriately, a free-breathing planning CT is obtained, which serves as the anatomic reference upon which a 3D target is contoured. Where available, a respiratory-gated 4D CT may also be obtained, which comprises a series of reconstructed CT scans corresponding to different phases of breathing and provides information about target excursion throughout the respiratory cycle. A composite of these scans is fused with the free-breathing planning CT to create an adjusted planning image set. Following the simulation, the electrical and anatomical information must be registered with the planning CT. The radiation oncologist, in consultation with the electrophysiologist, uses anatomic scar characterisation using MRI, CT, SPECT, and/or echocardiogram together with electrophysiologic data derived from EAM, ECGI, and/or 12-lead ECG as a guide for contouring the target on the planning CT. This is done on a separate software platform. The contouring process can be time-consuming owing to factors such as the manual comparison of imaging studies and mapping data, and consideration of adjacent radiosensitive organs, device lead insertion sites, valvular structures, conduction systems and the phrenic nerve.

Cardiorespiratory Motion Compensation It is important to ensure that the treatment volume encompasses the target during cardiorespiratory motion. Since the heart contracts with a ‘wringing’ action with limited positional displacement, most of the heart’s translational movement can be attributed to the respiratory cycle, particularly at sites where myocardial contractility is reduced due to scarring.17 Specific cardiorespiratory compensation methods depend on the treatment device used and fall broadly into two categories. One strategy

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Figure 1 shows a representative example of the multimodality treatment planning required for cardiac SBRT. In this example, the patient presented with recurrent VT in the setting of ischaemic cardiomyopathy that was unresponsive to quinidine and amiodarone as well as three attempts at endocardial catheter ablation. Cardiacgated CT was obtained to define detailed cardiac anatomy, particularly areas of wall thinning and myocardial scar components, as well as critical collateral structures (Figure 1A). Wall thickness segmentation was subsequently performed on the cardiac-gated CT, with image processing done using MUSIC software (Liryc-Université de Bordeaux/ Inria Sophia Antipolis), which has been shown to accurately colocalise regions of wall thinning with voltage-defined scar.59 Also shown is the 3D reconstruction that was created using this method. The patient’s previous EAM is shown for side-by-side comparison. It demonstrates areas of dense and patchy scar in the basal to mid inferoseptal left ventricle, corresponding to fatty infiltration (Figure 1B). The radiation treatment plan and target volume were constructed by manually superimposing this information onto a treatment planning CT (fused to a respiratory-gated 4D-CT; Figure 2). The radiation was calculated to a target isodose of 25 Gy with a rapid dose fall-off.

Treatment Delivery On the day of treatment, the patient only needs to spend a few hours at the centre. After check-in, the patient is assessed by the radiation oncologist and electrophysiologist and is then positioned according to the parameters determined at the time of the simulation. Treatment typically takes 10–15 minutes, after which the patient undergoes a period of post-treatment monitoring before they are discharged. Depending on the institution, a variety of radiation delivery platforms are available. The treatment systems that have been used thus far include the CyberKnife and the Varian TrueBeam/Edge (Varian) (Table 2). Some platforms use dynamic target tracking, although it is unclear how much this improves targeting accuracy.42,45,49 Undoubtedly, treatment times with these platforms are significantly longer.60 In comparison, systems for which continuous fiducial imaging has not been applied, such as the Varian TrueBeam/Edge, are comparably more time efficient and instead use X-rays taken at regular intervals throughout treatment to ensure correct patient alignment.60 In fact, the increased treatment time necessitated by a motion tracking approach

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Non-invasive Ablation of Ventricular Tachycardia Figure 3: Workflow Schematic for Cardiac Stereotactic Body Radioablation

Pre-treatment evaluation 2–3 weeks prior

Treatment planning 1–2 weeks prior

Treatment

Patient selection and consent Radiation oncologist, electrophysiologist

Imaging of ablation target Cardiac CT and/or cMRI Prior EP studies Electroanatomic mapping

Target generation Radiation oncologist, electrophysiologist, dosimetrist

Assessment and set-up (60 minutes)

Radiation oncologist, radiation therapist, dosimetrist, nursing

Quality assurance and collision check Radiation oncologist, dosimetrist, physicist, radiation therapist

Ablation (10–15 minutes) Radiation oncologist, electrophysiologist, dosimetrist, radiation therapist, nursing

Outpatient day procedure

Radiation oncologist, electrophysiologist, nursing, radiation therapist

Follow-up

ICD checks

Outpatient visits

Weekly

2 months, 4 months, 8 months, 1 year

Months to years

Stimulation (planning CT plus 4D CT)

Post-treatment monitoring Nursing

CT scans 4 months, 12 months

may introduce treatment inaccuracies and/or reduced treatment efficacy. Further investigation is needed for this.

Follow-up Follow-up consists of regular surveillance by the electrophysiologist and radiation oncologist. These include ICD checks and posttreatment imaging with transthoracic ECG and cardiac CT to monitor efficacy and safety.

Our Approach Our approach to treatment planning, delivery, and follow-up is summarised in Figure 3. In general, target definition is achieved using a combination of cardiac-gated CT and EAM. Cardiac and respiratory motion is visualised on both cardiac-gated CT and respiratory-gated 4D CT. Motion compensation is done by targeting the substrate throughout the combined motion envelope during treatment planning, and then by checking consistent alignment of anatomy with fiducials via serial imaging (on cone-beam CT and periodic triggered kV images) on the day of treatment. Target definition is done jointly by radiation oncology and electrophysiology and the full treatment planning takes 1–2 weeks. Patients are monitored after treatment for any complications and then followed with sequential ICD checks, imaging and clinic appointments.

publicly funded healthcare system. Regardless, because cardiac SBRT is an outpatient treatment that obviates the need for anaesthesia or hospitalisation, its adoption may lead to significant cost savings compared with catheter ablation. Although there is no data on cardiac SBRT, the charges associated with lung SBRT have been estimated at $10,616 and $8,042 (£8,150 and £ 6,174) over 3–5 fractions in US and Canadian studies respectively; those for cardiac SBRT may be lower given that it is administered in one fraction.61,62 Additionally, SBRT is widely available worldwide, with recent data confirming a total of 11,568 radioablation devices installed and in active use, which may arguably present a lower barrier for patient access than treatment in electrophysiology labs capable of performing complex VT ablation.17 Nevertheless, a direct comparison of charges as well as true cost between cardiac SBRT and catheter ablation is not yet available and the patient population for which this novel procedure is indicated is limited to those who have not responded to conventional therapy. As we gain more clinical experience and data from longer clinical follow-up that can help assess efficacy and safety, such a comparison of cost-effectiveness may become possible.

Future Directions Cost-effectiveness There are an estimated 4 million–5 million cases of sudden cardiac death per year worldwide, of which a substantial proportion result from ventricular arrhythmias.60 Little data exists regarding the costeffectiveness of available VT treatments, but the charges associated with initial catheter ablation and the subsequent hospital stay have been estimated at C$20,642 (£11,920).16 The relationship between charges, which reflect the cost to the healthcare system and true cost has not been explored, but it would not be unreasonable to assume that the two are closely associated, particularly in Canada’s

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Although cardiac SBRT is a promising novel treatment modality for medically refractory VT, significant clinical and technical questions need to be addressed. For the former, these include elucidating the underlying mechanism of radiation-associated treatment effect and its long-term durability. For the latter, further work needs to be directed towards identifying the best protocol for treatment planning, including substrate characterisation, multimodality integration, motion compensation, as well as treatment delivery. The ideal standardised approach should improve efficiency and efficacy, with an overall goal of extending the duration of treatment effect.

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Electrophysiology and Ablation Future studies would benefit from more detailed follow-up to examine the time course for anti-arrhythmic effect in the blanking period. Similarly, an improved understanding of the pathophysiology of radiation-induced conduction block and tissue injury in normal myocardium and myocardial scar is greatly needed. Standard ICD programming should also be used (particularly if an endpoint of device-detected VT burden or ICD therapies is used). A registry to enable follow-up beyond enrolment in a clinical trial and to standardise approaches for treatment delivery would be helpful in this emerging therapy. An additional benefit that a registry would provide is tracking of real-world safety and efficacy data. Ongoing collaboration among radiation oncologists, electrophysiologists, cardiac imaging specialists, as well as basic science researchers will help drive this progress.

Conclusion While early results have been promising, cardiac SBRT remains an investigational protocol that is indicated in patients who have intractable arrhythmia that does not respond to drug escalation and catheter ablation. As a non-invasive outpatient procedure that is not limited by substrate geography, it is particularly well-suited to patients who would not tolerate anaesthesia or prolonged hospitalisation and have poorly accessible substrate that is still well-defined. Clinical experience has demonstrated good short-term efficacy with minimal adverse effects; however, additional studies are needed to investigate its long-term efficacy and side-effects, its mechanism of effect and its cost-effectiveness.

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Clinical Perspective • The use of stereotactic body radioablation for treatment of medically refractory ventricular tachycardia provides distinct advantages which include non-invasive ablation, outpatient treatment and the ability to target larger substrates and sites otherwise inaccessible by radiofrequency catheter ablation. • The mechanism of action is not well understood, but may be due to a combination of subacute vascular damage and late radiation fibrosis with a timeline of treatment effect that typically ranges from weeks to months but has been observed in the acute setting. • The clinical experience includes more than 50 treated patients and collectively demonstrates dramatic short-term reduction in device-detected VT burden with minimal acute to subacute side-effects but unclear long-term safety and efficacy. • Successful treatment planning requires close multidisciplinary collaboration to integrate anatomic and electrophysiologic target delineation, creation of the target volume and treatment plan, delivery of ionising radiation and follow up in the outpatient setting. • Future research should aim to further elucidate the pathophysiology and timeline of radiation-induced antiarrhythmic effect, define the ideal parameters of treatment, provide data on long-term safety and efficacy, and determine the cost-effectiveness of this novel treatment modality.

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45. J umeau R, Ozsahin M, Schwitter J, et al. Rescue procedure for an electrical storm using robotic non-invasive cardiac radio-ablation. Radiother Oncol 2018;128:189–91. https://doi. org/10.1016/j.radonc.2018.04.025; PMID: 29753550. 46. Robinson CG, Samson PP, Moore KMS, 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. 47. Haskova J, Peichl P, Pirk J, et al. Stereotactic radiosurgery as a treatment for recurrent ventricular tachycardia associated with cardiac fibroma. HeartRhythm Case Rep 2019;5:44–7. https:// doi.org/10.1016/j.hrcr.2018.10.007; PMID: 30693205. 48. Zeng LJ, Huang LH, Tan H, et al. Stereotactic body radiation therapy for refractory ventricular tachycardia secondary to cardiac lipoma: a case report. Pacing Clin Electrophysiol 2019; 42:1276–9. https://doi.org/10.1111/pace.13731; PMID: 31116434. 49. Neuwirth R, Cvek J, Knybel L, et al. Stereotactic radiosurgery for ablation of ventricular tachycardia. Europace 2019;21:1088–95. https://doi.org/10.1093/europace/euz133; PMID: 31121018. 50. Bagur R, Chamula M, Brouillard E, et al. Radiotherapyinduced cardiac implantable electronic device dysfunction in patients with cancer. Am J Cardiol 2017;119:284–9. https://doi. org/10.1016/j.amjcard.2016.09.036; PMID: 27823600. 51. Zaremba T, Jakobsen AR, Søgaard M, et al. Radiotherapy in patients with pacemakers and implantable cardioverter defibrillators: a literature review. Europace 2016;18:479–91. https://doi.org/10.1093/europace/euv135; PMID: 26041870. 52. Kim RJ, Wu E, Rafael A, et al. The use of contrast-enhanced magnetic resonance imaging to identify reversible myocardial dysfunction. N Engl J Med 2000,343:1445–53. https://doi. org/10.1056/NEJM200011163432003; PMID: 11078769. 53. Dickfeld T, Lei P, Dilsizian V, et al. Integration of threedimensional scar maps for ventricular tachycardia ablation with positron emission tomography-computed tomography. JACC Cardiovasc Imaging 2008;1:73–82. https://doi.org/10.1016/j. jcmg.2007.10.001; PMID: 19356409. 54. Mahida S, Sacher F, Dubois R, et al. Cardiac imaging in patients with ventricular tachycardia. Circulation 2017;136:2491–507. https://doi.org/10.1161/ CIRCULATIONAHA.117.029349; PMID: 29255125.

55. S asaki T, Calkins H, Miller CF, et al. New insight into scar-related ventricular tachycardia circuits in ischemic cardiomyopathy: Fat deposition after myocardial infarction on computed tomography – a pilot study. Heart Rhythm 2015;12:1508–18. https://doi.org/10.1016/j.hrthm.2015.03.041; PMID: 25814415. 56. Alyesh DM, Siontis KC, Sharaf Dabbagh G, et al. Postinfarction myocardial calcifications on cardiac computed tomography. Circ Arrhythm Electrophysiol 2019;12:e007023. https://doi. org/10.1161/CIRCEP.118.007023; PMID: 31006314. 57. Tong Y, Yin Y, Lu J, et al. Quantification of heart, pericardium, and left ventricular myocardium movements during the cardiac cycle for thoracic tumor radiotherapy. OncoTargets Ther 2018;11:547–54. https://doi.org/10.2147/OTT.S155680; PMID: 29416355. 58. Wang L, Fahimian B, Soltys SG, et al. Stereotactic arrhythmia radioablation (STAR) of ventricular tachycardia: a treatment planning study. Cureus 2016;8:e694. https://doi.org/10.7759/ cureus.694; PMID: 27570715. 59. Takigawa M, Martin R, Cheniti G, et al. Detailed comparison between the wall thickness and voltages in chronic myocardial infarction. J Cardiovasc Electrophysiol 2019;30:195– 204. https://doi.org/10.1111/jce.13767; PMID: 30288836. 60. Chugh SS, Reinier K, Teodorescu C, et al. Epidemiology of sudden cardiac death: clinical and research implications. Prog Cardiovasc Dis 2008;51:213–28. https://doi.org/10.1016/j. pcad.2008.06.003; PMID: 19026856. 61. Mitera G, Swaminath A, Rudoler D, et al. Cost-effectiveness analysis comparing conventional versus stereotactic body radiotherapy for surgically ineligible stage I non-smallcell lung cancer. J Oncol Pract 2014;10:e130–6. https://doi. org/10.1200/JOP.2013.001206; PMID: 24643574. 62. Lanni TB, Grills IS, Kestin LL, Robertson JM. Stereotactic radiotherapy reduces treatment cost while improving overall survival and local control over standard fractionated radiation therapy for medically inoperable non-small-cell lung cancer. Am J Clin Oncol 2011;34:494–8. https://doi.org/10.1097/ COC.0b013e3181ec63ae; PMID: 20805737. 63. Zei PC, Gardner E, Maguire P. Non-invasive cardiac radiosurgery: clinical experience for treatment of refractory ventricular tachycardia. Heart Rhythm 2017;14(Suppl 1):S119. https://doi.org/10.1016/j.hrthm.2017.04.005.

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Electrophysiology and Ablation

Arrhythmias from the Right Ventricular Moderator Band: Diagnosis and Management Megan Barber, 1 Jason Chinitz 2 and Roy John 2 1. Nassau University Medical Center, Zucker School of Medicine at Hofstra/Northwell, NY, US; 2. Department of Medicine and Cardiology, Northshore University Hospital, NY, US

Abstract The moderator band in the right ventricle is being increasingly recognised as a source for arrhythmias in the absence of identifiable structural heart disease. Because it carries part of the conduction system from the right ventricle septum to the free wall, it is a source of Purkinje-mediated ventricular arrhythmias that manifest as premature ventricular contractions (PVC) or repetitive ventricular tachycardia. More importantly, short coupled PVCs triggering polymorphic ventricular tachycardia and VF have been localised to the moderator band and ablation of these Purkinje mediated PVCs can effectively prevent recurrent VF. The exact mechanism of arrhythmogenesis is still debated but stretch, fibrosis and ion channel alterations might be responsible. Arrhythmias originating in this region of the right ventricle may thus be another cause for idiopathic VF that is potentially treatable with catheter-based ablation techniques. Recognition of the typical PVC morphology can point to the moderator band as the source of idiopathic VF and an opportunity for timely intervention. The available data on the anatomy, electrophysiology and management options are reviewed.

Keywords Moderator band, premature ventricular contractions, ventricular arrhythmia, ventricular tachycardia, idiopathic VF Disclosure: The authors have no conflicts of interest to declare. Received: 5 December 2019 Accepted: 16 December 2019 Citation: Arrhythmia & Electrophysiology Review 2019;8(4):294–9. DOI: https://doi.org/10.15420/aer.2019.18 Correspondence: Roy M John, Cohen 1, Northshore University Hospital, 300 Community Drive, Manhasset, NY 11030, US. E: rjohn7@northwell.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.

Ventricular arrhythmias are designated idiopathic when demonstrable structural heart disease, significant coronary disease including coronary spasm or genetic arrhythmia syndromes are absent.1 These arrhythmias may be benign but are also a recognised cause of sudden cardiac death. The common form of idiopathic ventricular tachycardia (VT) originates in the ventricular outflow tracts, manifest with extra-systoles with long coupling intervals or runs of repetitive VT, and is generally not associated with increased mortality.2 However, more malignant ventricular arrhythmias may also be idiopathic, but frequently originate with short-coupled ventricular extra-systoles that result in polymorphic VT and may degenerate into VF.3,4,5 Idiopathic ventricular arrhythmias may have variable sites of origin. In addition to the common sites of origin from the right and left ventricular outflow tracts, the fascicles of the conduction tissue, perivalvular tissue and papillary muscles are other sources of origin.6 Less often they originate from the epicardium, free-running Purkinje fibres and intra-cavitary structures such as the moderator band (MB).7 Short-coupled premature ventricular contractions (PVCs) originating within the Purkinje network specifically have been identified as a source of triggered malignant VF.4,5,8 Haïssaguerre et al. described VF initiated by triggers within the Purkinje system.4,5 Nakamura et al. identified PVC triggers in thirteen patients presenting with VF without structural heart disease, four of whom had origination from Purkinje potentials or MB. Ablation of the triggering PVC was successful

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in suppressing recurrence of VF.9 Many primary VF events were initially regarded idiopathic until specific phenotypic and genotypic patterns eventually became evident to classify them as disease entities with distinct pathophysiological mechanisms (e.g. Brugada syndrome, early repolarisation syndrome). Until the use of intracardiac echocardiography (ICE) became common place in VT ablations, the MB as a source of short coupled PVCs and VF was not well recognised 7,10–12 The MB is a right ventricular structure composed of Purkinje and myocardial tissue and an important target for potentially curative ablation, but ablation at this location has certain important considerations. The aetiology, diagnosis and management of arrhythmias originating from the MB are reviewed herein.

Anatomy and Electrophysiology of the Moderator Band The MB is present, with varying prominence, in all human hearts and in other primates. It is an intra-cavitary structure in the right ventricle (RV) spanning from the lower limit of the inflow tract of the RV anterior septum to the base of the anterior papillary muscle of the RV free wall. It is part of the septo-marginal trabeculation that provides support to the anterior papillary muscle of the tricuspid valve (Figure 1).13 Its name originates from a traditional description that the structure ‘moderated’ the RV by preventing excessive distention. In addition to this postulated function, it is now known that it carries within it a fascicle of the right bundle that allows for rapid activation

Arrhythmias from the Right Ventricular Moderator Band Figure 1: Location and Structure of the Moderator Band

Subpulmonary infundibulum

*Groups of specialised conducting myocytes Fibrous sheath

Endocardium AO

Moderator band RA

Myocardium RV

20 m

Fibrous sheath

Anterior papillary muscle

RV anterior free wall

50 m

A: Reconstructed ventricular endocardial view with the parietal walls of the right atrium and ventricle removed to show the septal surface. The atrioventricular conduction axis (green) and the right bundle and its ramifications (purple) have been reconstructed and superimposed. The moderator band can be seen inserting at anterior free wall at base of anterior papillary muscle. Ramifications from the right bundle branch extend to the infundibulum (white star) and to the supraventricular crest (asterisk). Dashed square shows the area where histology shown in right panel was obtained; B: Haematoxylin and eosin staining of myocardium at junction of the moderator band with the anterior papillary muscle. Bundles of specialised conduction tissue are seen encased in fibrous sheaths; C: Masson trichrome staining showing a section of tendinous cord of the moderator band with specialised conduction tissue. AO = aorta; RA = right atrium; RV = right ventricle. Source: De Almeida et al. 2019.14 Reproduced with permission from Elsevier.

of the RV free wall (Figure 1).14 Transection of the MB often results in a distal right bundle branch block pattern. The morphology of the MB is highly variable, ranging from short and thick (the commonest variant) to long narrow bands of muscle. Additionally, its location along the length of the RV from the tricuspid valve to the apex is variable, with the majority being in the apical half of the RV cavity. Vascular supply to the MB originates from the anterior interventricular branch of the left coronary artery with anastomotic contribution from the right coronary artery at the base of the RV anterior papillary muscle, which forms an important collateral circulation between the left and right coronary arteries.13 Structurally the MB is highly organised, composed of rapidly conducting specialised Purkinje fibres surrounded by ventricular myocytes.14,15 The Purkinje fibres are insulated from surrounding ventricular myocardium by collagen and adipose tissue until peripheral arborisation along the RV-free wall (Figure 1).14,16 There is considerable inter-individual variability in thickness and the ratio of muscle to Purkinje fibre that is likely a determinant of the proarrhythmic potential of the MB.15 There are multiple mechanisms by which the MB participates in arrhythmias (Figure 2).16 In most ventricular arrhythmias implicating the MB, Purkinje potentials are often demonstrable preceding the onset of arrhythmia and dissociation or abolition of the potential is a marker for successful suppression of arrhythmias.4,10,11 Purkinje fibres have been shown to initiate arrhythmias by several mechanisms including enhanced automaticity, triggered activity and re-entry.16

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In the genesis of PVCs, triggered activity is the likely mechanism. Afterdepolarisations can be initiated by traveling Ca++ waves and alteration in balance of inward and outward currents.16 Ca++ waves can initiate membrane depolarisation in a well polarised aggregate of Purkinje cells in the absence of a specific stimulus.17 In addition, the transient outward current (Ito) has been implicated in Purkinje early afterdepolarisation.18 Genome-wide haplotype-sharing analysis of Dutch families with idiopathic VF identified over-expression of the DPP6 gene. Upregulation of DPP6 in the Purkinje fibre was subsequently shown to enhance Ito in cardiac Purkinje fibres relative to ventricular muscle. This strong repolarisation gradient between the Purkinje fibre and the surrounding ventricular myocardium can result in short-coupled PVCs possibly because of phase 2 re-entry.19 The mechanism for conduction and perpetuation of an afterdepolarisation from the Purkinje fibres to the surrounding myocyte is a matter of debate as the Purkinje fibre source is small compared to the larger myocardial sink. In a computational modelling study by Xie et al., the presence of fibrosis or downregulation of IK1 and ICaL, lowered the number of source cells required for early or delayed afterdepolarisation induced triggered action potentials.20 This may explain why some patients develop arrhythmias related to Purkinje firing while others do not. Once repetitive stimulation occurs, sustained ventricular arrhythmias can be due to re-entry or spiral wave break up into fibrillation. In the sheep and human wedge preparations Walton et al. demonstrated shorter refractory periods in the Purkinje fibres of the MB compared to surrounding myocardium and were able to demonstrate macro-re-entry between the RV free wall and the

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Electrophysiology and Ablation Figure 2: Potential Mechanisms of Pro-arrhythmia of the Moderator Band

Prolongation of the action potential associated with its higher degree of mechanical stretch

Repolarisation gradient between Purkinje fibre and surrounding myocardium result in phase 2 re-entry

Short coupled PVCs trigger polymorphic VT and VF by spiral wave re-entry

Right bundle branch Tricuspid valve

Anterior papillary muscle Propagation of spontaneous impulses from Purkinje fibre to myocardium facilitated by fibrosis and downregulation of ion channels

Subendocardial ventricular plexus

Moderator band

Macro re-entry circuit involving the moderator band acting as a bridge between the RV free wall and interventricular septum

PVC = premature ventricular contraction; VF = ventricular fibrillation; RV = right ventricle; VT = ventricular tachycardia. Source: Sadek et al. 2015.10 Adapted with permission from Elsevier.

Figure 3: Onset of VF Triggered by Monomorphic Premature Ventricular Contraction

VT triggering ICD shocks and that was ablated successfully in region between the MB and free wall insertion.10 The MB is also subject to stretch-related arrhythmia because of its position spanning the septum and RV free wall. Mechanical stimulation of the ventricular myocardium is known to generate membrane depolarisation, prolongation of action potential duration and triggered activity.21 A more benign arrhythmia related to the MB is via atrio-fascicular accessory pathways that are known to insert into the Purkinje system of the MB making it part of atrioventricular reciprocating tachycardias in patients with the Mahaim accessory pathway.13 Although the MB might be part of the circuit, ablation for a Mahaim tachycardia is usually targeted at the atrio-fascicular pathway adjacent to the tricuspid annulus.

Clinical features of Patients with Moderator Band-related Arrhythmias

A: A 12-lead ECG rhythm strip (25 mm/s) depicting a premature ventricular contraction (PVC) originating from the moderator band. The PVC is short coupled (360 ms), has an left bundle branch block morphology with left superior axis; B: Frequent short coupled PVCs and couplets occur in clusters; C: A short coupled PVC provokes sustained polymorphic ventricular tachycardia that degenerated to VF. Source: Chinitz, et al. 2019.12 Reproduced with permission from Elsevier.

interventricular septum.15 Whether such a macro-re-entrant mechanism is operative in the clinical arrhythmias involving the MB is unclear. In the series by Sadek et al., one patient has recurrent monomorphic

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The arrhythmias of MB origin described in the literature range from monomorphic PVCs to VF with electrical storm.7,10–12 There is little information on the MB related PVC or repetitive VTs. Clinical series and case reports provide more information on patients who present with idiopathic VF, usually provoked by monomorphic PVCs. The patients who manifest VF often present with cardiac arrest as their initial symptom and frequently have electrical storm. The mean age of patients in the published series is the mid-40s (range 27–61 years) with probable higher propensity in males.7,10–12 Cardiac testing including coronary angiography, transthoracic echocardiography and contrast enhanced cardiac MRI are negative for structural heart disease. All episodes of VF in the hitherto published reports appear to be triggered by short coupled PVCs with coupling interval less

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Arrhythmias from the Right Ventricular Moderator Band than 400 ms. In some cases, an underlying bradycardia and pause dependency is present.7 Arrhythmias tend to occur in clusters with bigeminal PVCs that may lead to triggering of VF.

Figure 4: Pacing from the Moderator Band 200 ms

S1: 550 I II

Electrocardiographic Diagnosis Consistent with their origin from within the apical RV, PVCs from the MB typically have a left bundle branch block (LBBB) pattern and a left superior axis with positive QRS in leads I and aVL (Figure 3).10 Sadek et al. described the PVCs as being relatively narrow with a mean QRS duration of 152.77 ± 15.2 ms with an intrinscoid deflection in the precordial leads <100 ms.10 Precordial QRS transition is typically later than V4 and always later than that of the sinus QRS in keeping with an apical lateral origin of the PVC. However, ectopy may exit the MB from its insertion points, predominantly at the septum or in the anterior papillary muscle, and may therefore result in variable precordial transition and frontal plane axis (Figure 4).22 This variability may complicate differentiation of PVCs originating from the MB from those originating from other RV regions.

Management of Moderator Band-related Arrhythmias The exact incidence of PVCs or monomorphic VT of MB origin is unknown as early reports of ablation for these benign arrhythmias rarely used intracardiac echocardiography to define exact sources. Most recent reports of MB related arrhythmias refer to PVC-mediated VF. There are very little data on the medical therapy of VF triggered by MB PVCs but as the Purkinje fibres are the likely trigger for the arrhythmia, acute medical therapy for VF suppression appear to follow the general principles of management of idiopathic VT. In one of the early reports of MB-triggered VF, pause dependency was evident and atrial pacing was effective for acute suppression.7 The use of isoproterenol that is highly effective for suppression of electrical storm in the early repolarisation syndrome23, 24 has not been reported in MB related VF but is a consideration when conventional drugs such as lidocaine, procainamide or amiodarone fail to control the arrhythmia. The ability to suppress the Ito with quinidine, disopyramide and bepridil has proven useful for suppression of idiopathic VF. Belhassen et al. reported effective chronic suppression of inducible VT and VF in patients with idiopathic VF treated with high doses of quinidine (1,000 to 2,000 mg/day).25 However, quinidine in such high doses is seldom well tolerated and the drug is no longer widely available. Its effect on PVC triggered VF of MB origin is not well described but therapy with quinidine is worth attempting in cases where conventional antiarrhythmics prove ineffective. It should be borne in mind that quinidine has the potential for QT prolongation and torsade de pointes VT in susceptible patients.

Ablation of Moderator Band-associated Arrhythmias Several case reports and case series indicate that ablation of ventricular arrhythmias originating from the MB is an effective form of therapy especially in PVC-mediated VF and electrical storm.7,10–12 Early reports of successful ablation of idiopathic VF targeting Purkinje mediated PVCs must have included the MB but not recognised as such because ICE was not in common use. In one multicentre study of 27 patients with idiopathic PVC, the Purkinje system in the anterior RV was involved in nine of them.4 At least some of these were likely of MB origin based on ECG examples in the report. In this series, ablation was successful in suppressing recurrent VF in the majority (89%) with some of the patients able to avoid a defibrillator implant after prolonged

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III aVR aVL aVF V1 V2 V3 V4 V5 V6

2:40:08 PM

2:40:09 PM

2:40:10 PM

A 12-lead ECG recording (100 mm/s) obtained with pacing from a single position on the lateral aspect of the moderator band. Note the change in QRS axis and morphology that occurred indicating variable exit sites of the elicited ventricular complex. Source: Chinitz et al. 2019.12 Reproduced with permission from Elsevier.

Figure 5: Mapping of Purkinje Potentials on the Moderator Band in a Patient with Premature Ventricular Contractiontriggered VF

I I II III V6

AbI d

Abl p

His d Purkinje potentials are seen on the ablation catheter during sinus beats (black arrow). During premature ventricular contraction (PVC), the Purkinje potentials (blue arrows) are seen preceding the surface QRS by >100 ms. Catheter pressure in the area triggered polymorphic ventricular tachycardia that degenerated to VF and required external shock. Ablation at this site of earliest Purkinje recording suppressed PVC and further VF.

in-hospital monitoring showed no further arrhythmia.4 In the series by Sadek et al., 10 of 394 patients with idiopathic ventricular arrhythmias had an MB origin.10 Seven of these presented with VF. Ablation was performed targeting Purkinje potential either at the septal or free wall insertion and guided by intracardiac echocardiography. Six of the 10 patients needed a second ablation (three had already undergone prior ablation attempts). Arrhythmia suppression was achieved without drug use in nine of 10 patients during a mean follow up of 21 months.10 These reports confirm the efficacy of ablation for Purkinje mediated recurrent VF in general and in relation to the MB although multiple ablation attempts may be required. Typically, ablation for MB related arrhythmia require the use of an electroanatomic mapping system preferably with the ability to incorporate ultrasound images (see below). In the absence of an intracardiac echocardiography, the use of a transthoracic echo to visualise the location of the MB has been reported.26 Earliest activation during PVCs is targeted and typically a Purkinje potential is evident preceding the QRS by 30–100 ms (Figure 5). Pacing at the site usually replicates QRS morphology although it is possible that varying exits between the septum and free wall can alter morphology (Figure 4). RF application may trigger repetitive PVCs or rarely, provoke VF (Figure 5). MB ablation poses several challenges. Identification of the causative Purkinje potentials can be difficult, and effective ablation may be hindered by surrounding myocardial tissue of variable thickness and

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Electrophysiology and Ablation Figure 6: Use of Intracardiac Echocardiography to Incorporate the Moderator Band and Associated Intracardiac Structures Into the Electroanatomic Map to Facilitate Ablation A

A: Intracardiac Echocardiography (ICE) of the right ventricle obtained by placing the ICE probe at the tricuspid valve annulus. The moderator band is traced in purple and the right ventricle (RV) trabecular and anterior papillary muscle is traced in green; B: The moderator band (purple) and RV anterior papillary muscle (green) are incorporated into the electro-anatomic map based on their positions identified on ICE; C: Electro-anatomic map after ICE integration demonstrating the ablation catheter making contact on the moderator band within the right ventricular cavity (white arrow).

Figure 7: Adjuvant Use of a Cryoballoon for Ablation of Moderator Band Arrhythmia A

Tricuspid valve

ICD lead ICD lead Inflated cryoballoon Moderator band

Inflated cryoballoon Moderator band

Use of a 24 mm Arctic Front II Cryoballoon (Medtronic) for ablation on the moderator band in a patient with recurrent premature ventricular contraction-triggered VF after four prior attempts at radiofrequency ablation failed to suppress the arrhythmia. A: Intracardiac echocardiography (ICE) image demonstrating an inflated cryoballoon in contact with the moderator band; B:Â Illustration depicting intracardiac right ventricle structures, including position of the inflated cryoballoon positioned along the moderator band, as seen on ICE.

length thereby resulting in need for more aggressive ablation.13,15 In addition, as the MB is a suspended intracavitary structure, ablation is frequently limited by difficulty with catheter stability and inability to maintain consistent contact.6,10,12 Also, Purkinje-associated arrhythmias may be particularly susceptible to suppression with sedation. Nakamura et al. described the reduction of identifiable PVC targets from 92% to 63% when general anaesthesia was used as opposed to conscious sedation.9 We have used isoproterenol, epinephrine, ventricular and atrial stimulation to provoke PVCs during the procedure. Finally, the variable morphology of the MB supports different PVC-exit sites that may need to be targeted at multiple points along its length from the lateral RV wall to the anterior RV papillary muscle and interventricular septum.22,26 Interestingly, ablation at the earliest Purkinje potential on the MB usually suppresses all PVC morphologies in keeping with the concept of a common origin and varying exits.

can be identified on ICE and incorporated into the electro-anatomic map to guide and verify catheter contact along the MB (Figure 6).6 However, ICE alone may not sufficiently facilitate effective ablation in all necessary sites owing to the variable and complex structure of the MB. Effective ablation along the MB therefore may be facilitated by contact force-sensing catheters with vector analysis in addition to ICE to verify catheter position, as well as higher energy delivery to compensate for the difficulty applying steady contact. Appreciation of an impedance decrease by at least 10 ohms may be beneficial to confirm tissue heating. In one report, a cryoballoon was successfully used to facilitate consistent contact and create broad based lesions along the entire length of the MB in a patient in whom multiple prior catheter-based RF ablations had failed to suppress PVC mediated VF (Figure 7).12

ICE is essential for visualisation and identification of intracardiac structures, such as the MB. The MB and associated papillary muscles

As data on long-term results of ablation for MB arrhythmias are sparse, one has to rely on success rates for ablation of idiopathic VF

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Outcome in Patients with Moderator Bandassociated Arrhythmias

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Arrhythmias from the Right Ventricular Moderator Band as a surrogate. The long-term success rate for ablation of Purkinje mediated VF is 80% during follow up to 5 years.27 Regardless of the suppression of arrhythmias, most of these patients will need an ICD to protect against recurrent VF and sudden death as the long-term prognosis and nature of progression of these patients is unknown. Some of these patients may have associated occult endomyocardial fibrosis that facilitates the propagation of PVCs and development of fibrillation (see above). Continued follow up is essential as manifest phenotypes of known diseases may become apparent with time. Some advocate the use of genetic testing to exclude known genetic arrhythmia syndromes. However, the yield from genetic testing for a known disease specific genetic mutation in idiopathic VF is very limited, ranging from 0–9%.1

Conclusion The RV MB is increasingly being identified as a common source for idiopathic VF. The arrhythmias that occur in association with the MB follow a course similar to other Purkinje-mediated arrhythmias. Short

Visser M, van der Haijden JF, Doevendans PA, et al. Idiopathic ventricular fibrillation: the struggle for definition, diagnosis and follow up. Cir Arrhythm Electrophysiol 2016;9:e003817. https://doi.org/10.1161/CIRCEP.115.003817; PMID: 27103090. 2. John RM, Stevenson WG. Outflow tract premature ventricular contractions and ventricular tachycardia: the typical and the challenging. Card Electrophysiol Clin 2016;8:545–54. https://doi. org/10.1016/j.ccep.2016.04.004; PMID: 27521088. 3. Viskin S, Rosso R, Rogowski O, Belhassen B. The “shortcoupled” variant of right ventricular outflow ventricular tachycardia: a not-so-benign form of benign ventricular tachycardia. J Cardiovasc Electrophysiol 2005;16:912–16. https:// doi.org/10.1111/j.1540-8167.2005.50040.x; PMID: 16101636. 4. Haïssaguerre M, Shoda M, Jaïs P, et al. Mapping and ablation of idiopathic ventricular fibrillation. Circulation 2002;106:962–7. https://doi.org/10.1161/01.CIR.0000027564.55739.B1; PMID: 12186801. 5. Haïssaguerre M, Shah DC, Jaïs P, et al. Role of Purkinje conducting system in triggering of idiopathic ventricular fibrillation. Lancet 2002;359:677–8. https://doi.org/10.1016/ S0140-6736(02)07807-8; PMID: 11879868. 6. Yamada T, Kay GN. Anatomical consideration in catheter ablation of idiopathic ventricular arrhythmias. Arrhythm Electrophysiol Rev 2016;5:203–9. https://doi.org/10.15420/ aer.2016:31:2; PMID: 28116086. 7. Anter E, Buxton AE, Silverstein JR, Josephson ME. Idiopathic ventricular fibrillation originating from the moderator band. J Cardiovasc Electrophysiol 2013;24:97–100. https://doi. org/10.1111/j.1540-8167.2012.02374.x; PMID: 22882745. 8. Nogami A, Sugiyasu A, Kutoba S, Kato K. Mapping and ablation of idiopathic ventricular fibrillation from the Purkinje system. Heart Rhythm 2005;2:646–9. https://doi.org/10.1016/j. hrthm.2005.02.006; PMID: 15922276. 9. Nakamura T, Schaeffer B, Tanigawa S, et al. Catheter ablation of polymorphic ventricular tachycardia/fibrillation in patient with and without structural heart disease. Heart Rhythm 2019;16:1021–27. https://doi.org/10.1016/j.hrthm.2019.01.032; PMID: 30710740. 10. Sadek MM, Benhayon D, Sureddi R, et al. Idiopathic ventricular arrhythmias originating from the moderator

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11.

12.

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16.

17.

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coupled PVCs with LBBB left superior axis morphology should alert to the possibility of the MB as a source. Mapping and ablation guided by intracardiac echocardiography can be lifesaving and highly successful in preventing recurrence. The technical difficulties of stable catheter positioning on the MB, the differential impulse exits along the septum and free wall and the importance of locating and dissociating Purkinje potential during ablation are features to be recognised for successful management of these arrhythmias.

Clinical Perspective • The RV moderator band is a source for Purkinje-mediated arrhythmias. • PVCs and VT from the moderator band have typical morphological features that point to it as source. • The RV moderator band is a source of idiopathic VF triggered by PVCs that is potentially treated with catheter ablation.

band: Electrocardiographic characteristics and treatment by catheter ablation. Heart Rhythm. 2015;12:67–75. https://doi. org/10.1016/j.hrthm.2014.08.029; PMID: 25240695. Ho RT, Frisch DR, Greenspon AJ. Idiopathic ventricular fibrillation ablation facilitated by Pentaray mapping of the moderator band. JACC Clin Electrophysiol 2017;3:313–4. https:// doi.org/10.1016/j.jacep.2016.08.006; PMID: 29759527. Chinitz JS, Sedaghat D, Harding M, et al. Adjuvant use of a cryoballoon to facilitate ablation of premature ventricular contraction-triggered ventricular fibrillation originating from the moderator band. HeartRhythm Case Rep 2019;5:578–81. https://doi.org/10.1016/j.hrcr.2019.09.001; PMID: 31890580. Loukas M, Klaassen Z, Tubbs RS, et al. Anatomical observations of the moderator band. Clin Anat 2010;23:443–50. https://doi.org/10.1002/ca.20968; PMID: 20235167. De Almeida MC, Stephenson RS, Anderson RH, et al. Human subpulmonary infundibulum has an endocardial network of specialized conducting cardiomyocytes. Heart Rhythm 2019. https://doi.org/10.1016/j.hrthm.2019.07.033; PMID: 31377422; epub ahead of press. Walton, RD, Pashaei A, Martinez ME, et al. Compartmentalized structure of the moderator band provides a unique substrate for macroreentrant ventricular tachycardia. Circ Arrhythm Electrophysiol 2018;11:e005913. https://doi.org/10.1161/ CIRCEP.117.005913; PMID: 30354313. Boyden PA, Dun W, Robinson RB. Cardiac Purkinje fibres and arrhythmias: the GK Moe award lecture 2015. Heart Rhythm 2016;13:1172–81. https://doi.org/10.1016/j.hrthm.2016.01.011; PMID: 26775142. Boyden PA, Hirose M, Dun W. Cardiac Purkinje cells. Heart Rhythm 2010;7:127–35. https://doi.org/10.1016/j. hrthm.2009.09.017; PMID: 19939742. Zhao A, Xie Y, Wen H. et al. Role of transient outward potassium current in the genesis of early afterdepolarization in cardiac cells. Cardiovasc Res 2012;95:308–16. https://doi. org/10.1093/cvr/cvs183; PMID: 22660482. Xiao L, Koopman TT, Ordog B. et al. Unique cardiac Purkinje fiber transient outward current β-subunit composition: a potential molecular link to idiopathic ventricular fibrillation.

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Circ Res 2013;112:1310–22. https://doi.org/10.1161/ CIRCRESAHA.112.300227; PMID: 23532596. Xie Y, Sato D, Garfinker A, et al. So little source, so much sink: requirements for afterdepolarizations to propagate in tissue. Biophys J 2010;99:1408–15. https://doi.org/10.1016/j. bpj.2010.06.042; PMID: 20816052. Kamkin A, Kiseleva I, Isenberg G. Stretch-activated currents in ventricular myocytes: amplitude and arrhythmogenic effects increase with hypertrophy. Cardiovasc Res 2000; 48:409–20. https://doi.org/10.1016/S0008-6363(00)00208-X; PMID: 11090836. Li YQ, Wang YX, Que DD. Et al. Successful ablation of moderator band-originated ventricular tachycardia at its ventricle insertion sites. Chin Med J (Engl) 2018; 131:1371–2. https://doi.org/10.4103/0366-6999.232807; PMID: 29786055. Aizawa Y, Chinushi M, Hasegawa K. et al. Electrical storm in idiopathic ventricular fibrillation is associated with early repolarization. J Am Coll Cardiol 2013;62:1015–9. https://doi. org/10.1016/j.jacc.2013.05.030; PMID: 23747791. Haissaguerre M, Sacher F, Nogami A, et al. Characteristics of recurrent ventricular fibrillation associated with inferolateral early repolarization: role of drug therapy. J Am Coll Cardiol 2009;53:612–9. https://doi.org/10.1016/j.jacc.2008.10.044; PMID: 19215837. Bellhassen B, Viskin S, Fish R. et al. Effects of electrophysiologic guided therapy with class 1A antiarrhythmic drugs on the long term outcome of patients with idiopathic ventricular fibrillation with or without the Brugada syndrome. J Cardiovasc Electrophysiol 1999;10:1301–12. https://doi.org/10.1111/j.1540-8167.1999.tb00183.x; PMID: 10515552. Li JY, Jiang JB, He Y, et al. Ventricular tachycardia originating from moderator band: new perspective on catheter ablation. Case Rep Cardiol 2017; 2017:3414360. https://doi. org/10.1155/2017/3414360; PMID: 28197345. Knecht S, Sacher F, Wright M, Hocini M, et al. Long-term follow up of idiopathic ventricular fibrillation ablation: a multicenter study. J Am Coll Cardiol 2009;54:522–8. https://doi.org/10.1016/j. jacc.2009.03.065; PMID: 19643313.

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Electrophysiology and Ablation

Ivabradine and AF: Coincidence, Correlation or a New Treatment? Mahmoud Abdelnabi, 1 Ashraf Ahmed, 2 Abdallah Almaghraby, 2 Yehia Saleh 2,3 and Haitham Badran 4 1. Cardiology and Angiology Unit, Department of Clinical and Experimental Internal Medicine, Medical Research Institute, University of Alexandria, Egypt; 2. Department of Cardiology, Faculty of Medicine, University of Alexandria, Egypt; 3. Michigan State University, East Lansing, MI, US; 4. Department of Cardiology, Faculty of Medicine, Ain Shams University, Cairo, Egypt

Abstract Ivabradine is a heart rate-lowering agent that inhibits pacemaker funny current (If). It has been approved by the European Medicines Agency and the US Food and Drug Administration for patients with stable angina and heart failure (HF). AF is a common issue especially in ischaemic heart disease and HF patients. In contrast to experimental findings and a limited number of clinical trials that demonstrate the emerging role of ivabradine for heart rate control in AF or maintenance of sinus rhythm, there is accumulating contradictory data indicating that there is, in fact, an increased incidence of new-onset AF among people who are taking ivabradine in clinical practice. This article reviews the most recent evidence highlighting the diversity of data in relation to the use of ivabradine and the onset of AF and whether it has a legitimate role in AF treatment and the maintenance of sinus rhythm.

Keywords Ivabradine, heart rate, angina, If current, If channels, heart failure, acute coronary syndromes, AF Disclosure: The authors have no conflicts of interest to declare. Received: 9 March 2019 Accepted: 8 January 2020 Citation: Arrhythmia & Electrophysiology Review 2019;8(4):300–3. DOI: https://doi.org/10.15420/aer.2019.30.2 Correspondence: Mahmoud Hassan Abdelnabi, Cardiology and Angiology Unit, Department of Clinical and Experimental Internal Medicine, Medical Research Institute, University of Alexandria, Egypt. E: Mahmoud.hassan.abdelnabi@outlook.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.

Ivabradine is a pure heart rate-lowering agent best characterised by its negative chronotropic effect on the sinoatrial node. 1 Its unique mechanism selectively blocks the pacemaker funny (If) channels, which are responsible for spontaneous depolarisation in the sinoatrial node that regulates heart rate during sinus rhythm (Figure 1). 2 Since 1980, it has been well established that controlling the heart rate is the main target when treating coronary artery disease (CAD) and heart failure (HF) and is associated with a beneficial effect on mortality and morbidity.3,4

According to the 2017 update to the American College of Cardiology/ American Heart Association and the Heart Failure Society of America guidelines for the management of HF, ivabradine can be useful to reduce hospitalisation for HF in patients with symptomatic stable chronic HF with reduced ejection fraction (LVEF ≤35%) who are receiving guideline-based treatment, including beta-blockers at a maximum tolerated dose, and who are having sinus rhythm with heart rate of ≥70 BPM at rest.6

Ivabradine in Induction of AF Current Approved Clinical Indications According to the European Society of Cardiology guidelines for heart failure, ivabradine should be considered in order to reduce the risk of hospitalisation due to HF or cardiovascular death in symptomatic patients with left ventricular ejection fraction (LVEF) ≤35%, a sinus rhythm and resting heart rate of ≥70 BPM despite treatment with beta-blockers, angiotensin-converting enzyme inhibitor or angiotensin receptor blocker and mineralocorticoid receptor antagonist.5 Ivabradine should be considered for the same indication in patients who are not able to tolerate beta-blockers or have contraindications. In these patients, angiotensin-converting enzyme inhibitor (or angiotensin receptor blocker) and mineralocorticoid receptor antagonist should also be given. While for the treatment of stable angina with symptomatic HF with reduced ejection fraction, ivabradine should be considered as an antianginal agent in patients with sinus rhythm and heart rate of ≥70 BPM as per recommended management in combination with betablockers or when beta-blockers are not tolerated.

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The If current, which is affected by ivabradine, was found to be present in the pulmonary vein myocardial sleeves, the wellrecognised triggers for AF.7 This may explain the risk of AF in patients receiving this drug. However, AF is commonly associated with HF and ischaemic heart disease, the current two clinical indications for the use of ivabradine, hence AF in this patient population may be an association rather than a drug-induced effect.8,9 The increased incidence of AF in patients receiving ivabradine for heart rate control in the setting of acute coronary syndromes or HF was a major concern in several previous trials. Early clinical studies of ivabradine, such as the International Trial on the Treatment of Angina With Ivabradine versus Atenolol (INITIATIVE) study and the Morbidity-mortality Evaluation of the If Inhibitor Ivabradine in Patients with Coronary Disease and Left Ventricular Dysfunction (BEAUTIFUL) trial focused on its effect on heart rate to control chest pain as an antianginal agent.10,11 The later Systolic

Ivabradine and AF Figure 1: Mechanism of Action of Ivabradine CENTRAL ILLUSTRATION: Mechanism of Action of Ivabradine

B Na+

HCN

Extracellular SVC

Na+

AO PA Intracellular

Ivabradine K+

SA node RA

K+

Action potential

Lowered heart rate

IVC Ivabradine-mediated slowing of diastolic depolarisation (If inhibition) Ao =Koruth, aorta; IVC = inferior = pulmonary artery; RA = right atria; RV = right ventricle; SA node = sinoatrial node; SVC = superior vena cava; K+ = potassium ions. J.S. et vena al. Jcava; AmPA Coll Cardiol. 2017;70(14):1777-84. Source: Koruth et al. 2017.1 Reproduced with permission from Elsevier.

Heart Failure Treatment with the If inhibitor ivabradine (SHIFT) trial, which included HF patients, showed a greater reduction in adverse events in patients with HF who received ivabradine. Considering the mechanism of action of ivabradine, the expected side-effect would be sinus bradycardia and not AF.12 However, the Study Assessing the Morbidity-Mortality Benefits of the If Inhibitor Ivabradine in Patients With Coronary Artery Disease (SIGNIFY), which is the largest randomised controlled trial involving coronary artery disease patients without HF, showed that frequency of AF and bradycardia were significantly higher in the ivabradine arm when compared with placebo.13 The SIGNIFY subgroup analyses, which were published later, showed that neither AF nor bradycardia were related to adverse events.14 A meta-analysis of 11 studies investigating the risk of AF with ivabradine treatment has shown that ivabradine treatment is associated with a 15% increase in the relative risk (RR) of AF. Furthermore, 208 patient years of treatment with ivabradine is required to cause one new case of AF. Some of the data on AF in this meta-analysis were obtained via personal communication.15 Another meta-analysis of the risk of AF with ivabradine treatment, which included eight randomised controlled trials (n=36,501), showed that the incidence of AF was 5.34% (n=1,126) in the ivabradine group and 4.56% (n=885) in the placebo group. There was a significantly higher incidence of AF (24% RRI) in the ivabradine group when compared with placebo (RR 1.24; 95% CI [1.08â&#x20AC;&#x201C;1.42] p=0.003).16

Ivabradine in Maintenance of Sinus Rhythm Data from several studies showed that ivabradine may have a role in the maintenance of sinus rhythm. A small study (65 patients) published in 2015 demonstrated that ivabradine added to amiodarone

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was more efficient than amiodarone alone in the maintenance of sinus rhythm in patients with left ventricular diastolic dysfunction and persistent AF who underwent sinus rhythm restoration, with similar rates of adverse events in both groups.17 The efficacy and safety of ivabradine in the maintenance of sinus rhythm in patients undergoing cardiac surgery were also addressed in a study by Iliuta et al. involving 527 patients undergoing elective valve replacement, coronary artery bypass grafting (CABG) or both.18 Patients had to have left ventricular systolic dysfunction, conduction abnormalities (defined as first degree atrioventricular [AV] block, left bundle branch block, bifascicular or trifascicular block) or both to be included in the study. Perioperatively, patients received metoprolol 100 mg per day, ivabradine 5 mg twice daily, or a combination of metoprolol 50 mg once daily and ivabradine 5 mg twice daily, and were followed for 30 days after the operation. The results revealed a lower incidence of postoperative AF in the combination therapy group (8.94%) than either metroprolol alone (9.66%) or ivabradine alone (19.77%; p<0.001). The combination therapy group also had a lower incidence of third-degree AV block and worsening heart failure (6.15% and 4.47%, respectively) than the metoprolol-only group (12.5% and 7.95%, respectively), while the incidence of such events was lowest in the ivabradine-only group (2.91% and 2.33, respectively).18 In 2016, a study by Abdel-salam et al. showed similar results. They randomised 740 patients undergoing elective CABG with or without valve replacement to perioperative administration of bisoprolol alone, ivabradine alone or a combination of both. Patients with an LVEF of <45% or prior history of AF or atrial flutter were excluded. The results demonstrated a reduced incidence of postoperative AF in the combination therapy group (4.2%) compared with the ivabradine-only group (15.1%) and the bisoprolol-only group (12.2%). The results were statistically significant (p<0.001).19

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Electrophysiology and Ablation The electrophysiological basis of using ivabradine for sinus rhythm maintenance may be explained by the changes that occur in the distribution of the channels that maintain the If current, termed the hyperpolarisation-activated cyclic nucleotide-gated (HCN) cation channels. Lai et al. found a significantly higher level of If gene expression in the free walls and appendages of both atria in patients with AF undergoing CABG compared with those without AF.20 HCN messenger RNA was also found to be significantly more abundant in the right atrial appendage samples of aged patients (34 patients) with AF compared with aged patients in sinus rhythm.21 On the other hand, another study showed a reduced level of HCN messenger RNA in the right atrial appendage of patients with chronic AF undergoing heart surgery compared with those in sinus rhythm. However, HCN protein expression showed no significant difference between the two groups, while the If current was higher in the AF group.22 These findings suggest that the If current plays a role in the complex pathophysiological procedure that initiates and maintains AF. If current inhibition by ivabradine may thus have a role in the prevention of AF.

Ivabradine in Rate Control The heart rate-lowering effect of ivabradine was recently demonstrated in animal models with AF. Meanwhile, Moubarak et al. reported adequate control of heart rate (by 24-hour ECG monitoring) in a patient with permanent AF and an ejection fraction of 35% who was receiving ivabradine for heart failure and no concomitant ratelowering drugs.23 This effect was confirmed by repeating the 24-hour ECG monitoring 1 week after stopping ivabradine therapy, showing a significant rise in the mean heart rate (80.1 BPM on ivabradine versus 87.6 BPM without ivabradine). Another case report showed a decrease in both the mean heart rate (84 BPM versus 102 BPM) and maximum heart rate during exercise (153 BPM versus 169 BPM) in a patient with an LVEF of 35% and permanent AF upon the initiation of ivabradine therapy.24 These were shortly followed by an open-labell trial that involved adding ivabradine therapy to six symptomatic patients with persistent or permanent AF who were already receiving maximum-tolerated doses of beta-blockers and had a resting heart rate of >110 BPM. This study demonstrated a significant reduction in both the mean resting heart rate (86.3 BPM at 3 months versus 109.5 BPM at baseline) and the maximal heart rate (143 BPM at 3 months versus 178 BPM at baseline) after the initiation of ivabradine therapy.25 Such findings clearly justified the conduction of a randomised controlled double-blind trial. In 2017, Wongcharoen et al. randomised 31 patients with non-paroxysmal AF who were already on standard rate-lowering therapy (beta-blockers, calcium channel blockers and digoxin) to ivabradine add-on therapy (n=21) versus placebo (n=11). There was a significant reduction in the 24-hour mean heart rate in the ivabradine group (86.0 ± 10.9 BPM at baseline to 79.2 ± 9.6 BPM after ivabradine, p<0.001). Ivabradine also showed a statistically significant reduction in the mean heart rate compared with placebo (6.9 ± 6.3 BPM with ivabradine versus 1.4 ± 6.0 BPM with placebo, p=0.024).26 The newly discovered use of ivabradine as rate-control therapy was extended to involve another subgroup of patients. In 2017, Fontenla et al. published a case study in which a patient with a prosthetic mitral valve, permanent AF, left bundle branch block and severe LV systolic dysfunction had previously received a cardiac resynchronisation therapy defibrillation (CRT-D) device follow-up showed a 74% of biventricular pacing due to rapid conduction of AF over the AV node. The patient was already on a maximum tolerated dose of beta-blockers

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and had a history of digitalis toxicity. The administration of 5 mg of ivabradine twice daily raised the percentage of biventricular pacing to 95%, providing a good alternative to AV-nodal ablation.27 Based upon these findings, a randomised controlled multicentre clinical trial: the IvaBRAdine blocK of Funny Current for Heart Rate Control in permanEnt Atrial Fibrillation (BRAKE-AF Study; NCT03718273), is currently being conducted to evaluate the rate-lowering effect of ivabradine on patients with permanent AF. In this study, patients with symptomatic permanent AF who are receiving maximum-tolerated doses of beta-blockers or calcium channel blockers and showing evidence of poorly controlled heart rate, are being randomised to therapy with either ivabradine or digoxin. The primary endpoints of this study are heart rate reduction and adverse events. The results of the confrontation between the 23-year-old drug ivabradine and the 200-year-old drug digoxin would certainly be interesting and would hopefully shed light on the efficacy and safety of ivabradine therapy in the large and overgrowing cohort of patients with AF. Given the evidence that we have, off-label use of ivabradine as an add-on therapy for rate control might be reasonable in selected patients after explaining the risks and benefits. The mechanism by which ivabradine achieves heart rate control is not completely understood. However, since HCN channels are not exclusive to the sinoatrial node and are also expressed in the AV node and the conduction system, albeit at a lower density, the effect of ivabradine on the HCN channels in the AV node is possibly the mechanism by which it lowers the heart rate during AF.28

Ivabradine for Other Indications Postural orthostatic tachycardia syndrome (POTS) is a form of orthostatic intolerance that usually occurs in younger adults and children. Patients frequently report palpitations, presyncope, and fatigue. The hallmark of this disorder is an exaggerated heart rate increase in response to postural change without arterial hypotension. Although optimal therapy of POTS is not established. It is currently recommended to avoid precipitating factors, encourage physical activity and volume repletion. Other options include fludrocortisone, beta-blockers and midodrine.29 Unfortunately, even after implementing all conventional therapy, fewer than 60% of patients report improvement of their symptoms.30 Given that the primary problem is an accelerated heart rate, several authors investigated ivabradine’s role in POTS. In a retrospective case series that included 22 patients, 60% of patients treated with ivabradine reported symptomatic improvement.31 In another prospective study that included eight patients diagnosed with POTS, ivabradine slowed the heart rate of POTS patients at rest by 4 ± 1 BPM and during a 5-minute head-up tilt, heart rate decreased from 118 ± 4 BPM to 101 ± 5 BPM (p<0.01).32 Given that there is limited data on ivabradine’s efficacy in POTS, a randomised controlled trial to access its efficacy is needed to further evaluate its role in this syndrome. Ivabradine has also been found to be effective in controlling the heart rate, termination of tachycardia as well as maintenance of sinus rhythm in patients with incessant atrial tachycardia.33–35 Recently, a small study conducted on 28 patients with incessant focal atrial tachycardia showed that ivabradine successfully achieved complete termination of the tachycardia (17 patients) or adequate reduction in the heart rate without a change in rhythm (one patient). Tachycardias originating from the atrial appendages were more likely to respond to ivabradine.36

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Ivabradine and AF Conclusion Ivabradine is a unique medication which has an approved indication for heart rate reduction in heart failure with reduced ejection fraction and angina in selected patients. Previously, ivabradine’s heart rate reduction was thought to be exclusively due to inhibition of If channels in the sinoatrial node. However, emerging data has shown channels that maintain the If current in the free wall of both atria. These findings support the idea that the If current plays a role in the

Koruth JS, Lala A, Pinney S, et al. The clinical use of ivabradine. J Am Coll Cardiol 2017;70:1777–84. https://doi.org/10.1016/j. jacc.2017.08.038; PMID: 28958335. 2. DiFrancesco D. Funny channels in the control of cardiac rhythm and mode of action of selective blockers. Pharmacol Res 2006;53:399–406. https://doi.org/10.1016/j.phrs.2006.03.006; PMID: 16638640. 3. Dyer AR, Persky V, Stamler J, et al. Heart rate as a prognostic factor for coronary heart disease and mortality: findings in three Chicago epidemiologic studies. Am J Epidemiol 1980;112:736–49. https://doi.org/10.1093/oxfordjournals.aje. a113046; PMID: 7457467. 4. Kannel WB, Kannel C, Paffenbarger RS, Cupples LA. Heart rate and cardiovascular mortality: the Framingham study. Am Heart J 1987;113:1489–94. https://doi.org/10.1016/00028703(87)90666-1; PMID: 3591616. 5. Ponikowski P, Voors A, Anker S, et al. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2016;37:2129–200. https://doi.org/10.1093/eurheartj/ehw128; PMID: 27206819. 6. Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/ HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. J Am Coll Cardiol 2017;70:776–803. https://doi. org/10.1016/j.jacc.2017.04.025; PMID: 28461007. 7. Hoppe UC, Beuckelmann DJ. Characterization of the hyperpolarization-activated inward current (If) in isolated human atrial myocytes. Cardiovasc Res 1998;38:788–801. https://doi.org/10.1016/s0008-6363(98)00047-9; PMID: 9747448. 8. European Heart Rhythm Association, European Association for Cardio-Thoracic Surgery, Camm AJ, et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J 2010;31:2369–429. https://doi. org/10.1093/eurheartj/ehq278; PMID: 20802247. 9. Suenari K, Cheng CC, Chen YC, et al. Effects of ivabradine on the pulmonary vein electrical activity and modulation of pacemaker currents and calcium homeostasis. J Cardiovasc Electrophysiol 2012;23:200–6. https://doi.org/10.1111/j.15408167.2011.02173.x; PMID: 21914029. 10. Tardif J-C, Ford I, Tendera M, et al. Efficacy of ivabradine, a new selective If inhibitor, compared with atenolol in patients with chronic stable angina. Eur Heart J 2005;26:2529–36. https://doi.org/10.1093/eurheartj/ehi586; PMID: 16214830. 11. Fox K, Ford I, Steg PG, et al. Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind,

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complex pathophysiological procedure that initiates and maintains AF. So far, there is evidence that ivabradine triggers AF and can contribute to the maintenance of sinus rhythm in people with AF. In addition, since those channels are expressed in the AV node and the conduction system as well, some studies have shown that ivabradine may have a role in rate control of AF as an add-on therapy. Given the diversity of the data, further randomised prospective studies are needed before recommending an expanded role for ivabradine.

placebo-controlled trial. Lancet 2008;372:807–16. https://doi. org/10.1016/S0140-6736(08)61170-8; PMID: 18757088. Swedberg K, Komajda M, Böhm M, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet 2010;376:875–85. https://doi. org/10.1016/S0140-6736(10)61198-1; PMID: 20801500. Fox K, Ford I, Steg PG, et al. Ivabradine in stable coronary artery disease without clinical heart failure. New Engl J Med 2014;371:1091–9. https://doi.org/10.1056/NEJMoa1406430; PMID: 25176136. Fox K, Ford I, Steg PG, et al. Bradycardia and atrial fibrillation in patients with stable coronary artery disease treated with ivabradine: an analysis from the SIGNIFY study. Eur Heart J 2015;36:3291–6. https://doi.org/10.1093/eurheartj/ehv451; PMID: 26385957. Martin RI, Pogoryelova O, Koref MS, et al. Atrial fibrillation associated with ivabradine treatment: meta-analysis of randomised controlled trials. Heart 2014;100:1506–10. https:// doi.org/10.1136/heartjnl-2014-305482; PMID: 24951486. Tanboğa ı̇H, Topçu S, Aksakal E, et al. The risk of atrial fibrillation with ivabradine treatment: a meta‐analysis with trial sequential analysis of more than 40000 patients. Clin Cardiol 2016;39:615–20. https://doi.org/10.1002/clc.22578; PMID: 27511965. Adamyan K, Tunyan L, Chilingaryan A. Comparative efficacy of amiodarone with ivabradine combination of amiodarone with bisoprolol combination in the prevention of atrial fibrillation recurrence in patients with left ventricular diastolic dysfunction. Rational Pharmacotherapy in Cardiology 2015;11:483–8. https://doi.org/10.20996/1819-6446-2015-11-5-483-488. Iliuta L, Rac-Albu M. Ivabradine versus beta-blockers in patients with conduction abnormalities or left ventricular dysfunction undergoing cardiac surgery. Cardiol Ther 2014;3:13–26. https://doi.org/10.1007/s40119-013-0024-1; PMID: 25135587. Abdel‐salam Z, Nammas W. Atrial fibrillation after coronary artery bypass surgery: can ivabradine reduce its occurrence? J Cardiovasc Electrophysiol 2016;27:670–6. https://doi. org/10.1111/jce.12974; PMID: 27006322. Lai LP, Su MJ, Lin JL, et al. Measurement of funny current (If) channel mRNA in human atrial tissue: correlation with left atrial filling pressure and atrial fibrillation. J Cardiovasc Electrophysiol 1999;10:947–53. https://doi.org/10.1111/ j.1540-8167.1999.tb01265.x; PMID: 10413374. Bryant SM, Kong CH, Watson J, et al. Altered distribution of ICa impairs Ca release at the t-tubules of ventricular myocytes from failing hearts. J Mol Cell Cardiol 2015;86:23–31. https://doi.org/10.1016/j.yjmcc.2015.06.012; PMID: 26103619. Stillitano F, Lonardo G, Giunti G, et al. Chronic atrial fibrillation alters the functional properties of If in the human atrium. J Cardiovasc Electrophysiol 2013;24:1391–400. https://doi. org/10.1111/jce.12212; PMID: 23869794. Moubarak G, Logeart D, Cazeau S, Solal AC. Might ivabradine be

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Corrigendum

Corrigendum to: Preventive Ventricular Tachycardia Ablation in Patients with Ischaemic Cardiomyopathy: Meta-analysis of Randomised Trials Roland R Tilz, 1 Charlotte Eitel, 1 Evgeny Lyan, 1 Kivanc Yalin, 1,2 Spyridon Liosis, 1 Julia Vogler, 1 Ben Brueggemann, 1 Ingo Eitel, 1 Christian Heeger, 1 Ahmed AlTurki 3 and Riccardo Proietti 4 1. University Heart Centre Lübeck, Lübeck, Germany; 2. Usak University, Faculty of Medicine, Department of Cardiology, Usak, Turkey; 3. Division of Cardiology, McGill University Health Centre, Montreal, Canada; 4. Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Padua, Italy

Citation: Arrhythmia & Electrophysiology Review 2019;8(4):304. DOI: https://doi.org/10.154210/aer.2019.8.4.CG1 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.

In the article by Tilz et al. entitled “Preventive Ventricular Tachycardia Ablation in Patients With Ischaemic Cardiomyopathy: Meta-analysis of Randomised Trials” (Arrhythmia & Electrophysiology Review 2019;8(3):173–9. https://doi.org/10.15420/aer.2019.31.3), the following correction should be made: The authors acknowledge that Prof Tilz and Dr Eitel contributed equally as first authors to this work. Dr Eitel fulfils the criteria of first authorship as she had critical input in conception, analysis, interpretation, intellectual contribution and writing of the article. The authors apologise for this error.

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