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Arrhythmia & Electrophysiology Review Volume 7 • Issue 4 • Winter 2018

Volume 7 • Issue 4 • Winter 2018

www.AERjournal.com

Identifying Risk and Management of Acute Haemodynamic Decompensation During Catheter Ablation of Ventricular Tachycardia Daniele Muser, Simon A Castro, Jackson J Liang and Pasquale Santangeli

Arrhythmia Mechanisms Revealed by Ripple Mapping George Katritsis, Vishal Luther, Prapa Kanagaratnam and Nick WF Linton

Team Management of the Ventricular Tachycardia Patient Pok Tin Tang, Duc H Do, Anthony Li and Noel G Boyle

Catheter Ablation of Paroxysmal Atrial Fibrillation Originating from Non-pulmonary Vein Areas Satoshi Higa, Li-Wei Lo and Shih-Ann Chen

Proposed Circuits of AVNRT Based on the Role of the Inferior Nodal Extensions

Implantation of a Subcutaneous ICD Coil

Mapping of Non-pulmonary Vein Trigger

ISSN – 2050-3369

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S AV E T H E D AT E

Please join us at the 40th Annual Heart Rhythm Scientific Sessions in San Francisco, CA May 8 - 11, 2019. I M P O R TA N T D AT E S : Abstract Submission Site Closes Member Registration Opens Nonmember Registration Opens

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Volume 7 • Issue 4 • Winter 2018

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

Section Editor – Arrhythmia Mechanisms / Basic Science

Section Editor – Clinical Electrophysiology and Ablation

Section Editor – Implantable Devices

Andrew Grace

Hugh Calkins

Angelo Auricchio

University of Cambridge, UK

John Hopkins Medical Institution, Baltimore, USA

Fondazione Cardiocentro Ticino, Lugano, Switzerland

Charles Antzelevitch

Warren Jackman

Mark O’Neill

Lankenau Institute for Medical Research, Wynnewood, USA

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

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

Uppsala University, Uppsala, Sweden

Pierre Jaïs

IRCCS Policlinico San Donato, Milan, Italy

Johannes Brachmann

University of Bordeaux, CHU Bordeaux, France

Carina Blomström-Lundqvist

Carlo Pappone Sunny Po

Klinikum Coburg, II Med Klinik, Germany

Prapa Kanagaratnam

Josep Brugada,

Imperial College Healthcare NHS Trust, London, UK

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

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

Josef Kautzner

Antonio Raviele

Institute for Clinical and Experimental Medicine, Prague, Czech Republic

ALFA – Alliance to Fight Atrial Fibrillation, Venice-Mestre, Italy

Pedro Brugada

Karl-Heinz Kuck

Barts Heart Centre, St Bartholomew’s Hospital, London, UK

University of Brussels, UZ-Brussel-VUB, Belgium

Asklepios Klinik St Georg, Hamburg, Germany

Alfred Buxton

Pier Lambiase

Beth Israel Deaconess Medical Center, Boston, USA

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

David J Callans University of Pennsylvania, Philadelphia, USA

Samuel Lévy

A John Camm

Aix-Marseille University, France

St George’s University of London, UK

Cecilia Linde

Riccardo Cappato

Karolinska University, Stockholm, Sweden

Edward Rowland Frédéric Sacher Bordeaux University Hospital, Electrophysiology and Heart Modelling Institute (LIRYC), France

Richard Schilling Barts Health NHS Trust, London, UK

William Stevenson Vanderbilt School of Medicine, USA

Richard Sutton

IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy

Gregory YH Lip

Ken Ellenbogen

University of Birmingham, UK

National Heart and Lung Institute, Imperial College London, UK

Virginia Commonwealth University, Richmond, VA, USA

Francis Marchlinski

Panos Vardas

Sabine Ernst

University of Pennsylvania Health System, Philadelphia, USA

Heraklion University Hospital, Greece

Royal Brompton and Harefield NHS Foundation Trust, London, UK

John Miller

Marc A Vos

Indiana University School of Medicine, USA

University Medical Center Utrecht, The Netherlands

Hein Heidbuchel

Fred Morady

Hein Wellens

Antwerp University and University Hospital, Antwerp, Belgium

Cardiovascular Center, University of Michigan, USA

University of Maastricht, The Netherlands

Gerhard Hindricks

Sanjiv M Narayan

Katja Zeppenfeld

Stanford University Medical Center, USA

Leiden University Medical Center, The Netherlands

Andrea Natale

Douglas P Zipes

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

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

University of Leipzig, Germany

Carsten W Israel JW Goethe University, Germany

Junior Associate Editor Afzal Sohaib Imperial College London, UK Managing Editor Jonathan McKenna • Production Aashni Shah • Design Tatiana Losinska Sales & Marketing Executive William Cadden • Sales Director Rob Barclay Publishing & Editorial Director Leiah Norcott • Key Account Director David Bradbury Chief Executive Officer David Ramsey • Chief Operating Officer Liam O'Neill

Official journal of

Editorial Contact jonathan.mckenna@radcliffe-group.com Circulation & Commercial Contact david.ramsey@radcliffe-group.com •

Cover images www.stock.adobe.com | Cover design Tatiana Losinska

Cardiology

Lifelong Learning for Cardiovascular Professionals 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 © 2018 All rights reserved ISSN: 2050-3369 • eISSN: 2050–3377

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Established: October 2012

Aims and Scope •  Arrhythmia & Electrophysiology Review aims to assist time-pressured physicians to keep abreast of key advances and opinion in the arrhythmia and electrophysiology sphere. •  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. • The journal endeavours, through its timely teaching reviews, to support the continuous medical education of both specialist and general cardiologists, and disseminate knowledge of the field to the wider cardiovascular community.

Structure and Format • Arrhythmia & Electrophysiology Review is a quarterly journal comprising review articles and 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 Section Editors and Editorial Board. • Articles are fully referenced, providing a comprehensive review of existing knowledge and opinion. • Each edition of Arrhythmia & Electrophysiology Review is replicated in full online at www.AERjournal.com.

Frequency: Quarterly

Current Issue: Winter 2018

• Once the authors have amended a manuscript in accordance with the reviewers’ comments, the manuscript is returned to the reviewers to ensure the revised version meets their quality expectations. Once approved, the manuscript is sent to the Editor-in-Chief for final approval prior to publication.

Submissions and Instructions to Authors • Contributors are identified by the Editor-in-Chief with the support of the Section Editors and Managing Editor, and guidance from the Editorial Board. •  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. • Subsequently, the Managing Editor provides an ‘Instructions to Authors’ document and additional submission details. •  The journal is always keen to hear from leading authorities wishing to discuss potential submissions, and will give due consideration to any proposals. Please contact the Jonathan McKenna for further details at jonathan.mckenna@radcliffe-group.com. The ‘Instructions to Authors’ information is available for download at www.AERjournal.com.

Reprints All articles included in Arrhythmia & Electrophysiology Review are available as reprints (minimum order 1,000). Please contact Liam O’Neill at liam.oneill@radcliffe-group.com.

Distribution and Readership Editorial Expertise Arrhythmia & Electrophysiology Review is supported by various levels of expertise: • Overall direction from an Editor-in-Chief, supported by Section Editors and an 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 members of the journal’s Peer Review Board as well as other experts appointed for their experience and knowledge of a specific topic. • An experienced team of Editors and Technical Editors.

Arrhythmia & Electrophysiology Review is distributed quarterly through controlled circulation to general and specialist senior cardiovascular professionals in Europe. All manuscripts published in the journal are free-to-access online at www.AERjournal.com and www.radcliffecardiology.com.

Abstracting and Indexing Arrhythmia & Electrophysiology Review is abstracted, indexed and listed in PubMed, Embase, Scopus, Google Scholar and Summon by Serial Solutions. All articles are published in full on PubMed Central one month after publication.

Copyright and Permission Peer Review • On submission, all articles are assessed by the Editor-in-Chief or Managing Editor to determine their suitability for inclusion. •  The Managing Editor, following consultation with the Editor-in-Chief, Section Editors and/or a member of the Editorial Board, sends the manuscript to members of the Peer Review Board, 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 either 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.

Radcliffe Cardiology is the sole owner of all articles and other materials that appear in Arrhythmia & Electrophysiology Review unless otherwise stated. Permission to reproduce an article, either in full or in part, should be sought from the journal’s Managing Editor.

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

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Supporting life-long learning for arrhythmologists Arrhythmia & Electrophysiology Review, led by Editor-in-Chief Demosthenes Katritsis and underpinned by an editorial board of world-renowned physicians, comprises peer-reviewed articles that aim to provide timely update on the most pertinent issues in the field. Available in print and online, Arrhythmia & Electrophysiology Review’s articles are free-to-access, and aim to support continuous learning for physicians within the field.

Call for Submissions Arrhythmia & Electrophysiology Review publishes invited contributions from prominent experts, but also welcomes speculative submissions of a superior quality. For further information on submitting an article, or for free online access to the journal, please visit: www.AERjournal.com

Radcliffe Cardiology Arrhythmia & Electrophysiology Review is part of the Radcliffe Cardiology family. For further information, including free access to thousands of educational reviews from across the speciality, visit: www.radcliffecardiology.com

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Contents

Foreword

227

Everything Flows – Heraclitus Demosthenes Katritsis, Editor-in-Chief

BHRS Foreword

228

Arrhythmia & Electrophysiology Review is Now the Official Journal of the British Heart Rhythm Society Richard Schilling

Expert Opinion

230

Catheter Ablation of Atrioventricular Nodal Re-entrant Tachycardia: Facts and Fiction Demosthenes G Katritsis

Clinical Arrhythmias

232

Arrhythmias and Heart Rate: Mechanisms and Significance of a Relationship

238

Team Management of the Ventricular Tachycardia Patient

247

Heart Rate Variability: An Old Metric with New Meaning in the Era of Using mHealth technologies for Health and Exercise Training Guidance. Part Two: Prognosis and Training

Antonio Zaza, Carlotta Ronchi and Gabriella Malfatto Pok Tin Tang, Duc H Do, Anthony Li and Noel G Boyle

Nikhil Singh, Kegan James Moneghetti, Jeffrey Wilcox Christle, David Hadley, Victor Froelicher and Daniel Plews

Electrophysiology and Ablation

256

Percutaneous Treatment of Non-paroxysmal Atrial Fibrillation: A Paradigm Shift from Pulmonary Vein to Non-pulmonary Vein Trigger Ablation? Domenico G Della Rocca, Sanghamitra Mohanty, Chintan Trivedi, Luigi Di Biase and Andrea Natale

261

Arrhythmia Mechanisms Revealed by Ripple Mapping

265

Catheter Ablation for Atrial Fibrillation in Systolic Heart Failure Patients: Stone by Stone, a CASTLE

George Katritsis, Vishal Luther, Prapa Kanagaratnam and Nick WF Linton

Dimitrios Vrachatis, Spyridon Deftereos, Vasileios Kekeris, Styliani Tsoukala and Georgios Giannopoulos

273

Catheter Ablation of Paroxysmal Atrial Fibrillation Originating from Non-pulmonary Vein Areas Satoshi Higa, Li-Wei Lo and Shih-Ann Chen

282

Identifying Risk and Management of Acute Haemodynamic Decompensation During Catheter Ablation of Ventricular Tachycardia Daniele Muser, Simon A Castro, Jackson J Liang and Pasquale Santangeli

Drugs and Devices

288

Defibrillation Threshold Testing: Current Status

294

Haemodynamic Monitoring Devices in Heart Failure: Maximising Benefit with Digitally Enabled Patient Centric Care

Justin Hayase, Duc H Do and Noel G Boyle

Leah M Raj and Leslie A Saxon

226

Š RADCLIFFE CARDIOLOGY 2018


Foreword

Everything Flows – Heraclitus

I

n previous editorials, I have reflected upon our policy to continually improve the journal in every possible way. We live in a digital era and we have access to an overwhelming amount of information online and whoever fails to adapt is doomed

to become extinct. I am, therefore, delighted to introduce our collaboration with the British Heart Rhythm Society (BHRS), a learned establishment of the British medical tradition that has international aspirations under the inspired leadership of Richard Shilling. Arrhythmia & Electrophysiology Review is honoured to be the official home of BHRS,

and we are all confident that this shared journey will culminate in exciting educational and scientific achievements. BHRS members are most welcome to submit their work, express their views on the journal’s content and suggest ways we can improve and maintain our high scientific standards with an international orientation, which is the aim of this publication. n Demosthenes G Katritsis Editor-in-Chief, Arrhythmia & Electrophysiology Review Hygeia Hospital, Athens, Greece

DOI: https://doi.org/10.15420/aer.2018.7.4.FO1

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BHRS Foreword

Arrhythmia & Electrophysiology Review is Now the Official Journal of the British Heart Rhythm Society

A

rrhythmia & Electrophysiology Review (AER) has become one of the key

ways that clinicians interested in heart rhythm management stay up to date with the latest science in electrophysiology. The quality of the articles

has been crucial to the success of the journal and this is a result of the hard work of the contributors and the skill and dedication of the editorial team, led by

Dr Demosthenes Katritsis. In the previous issue, Hugh Calkins joined as Section Editor for Clinical Electrophysiology and Ablation and reflected on the progress made in the understanding and treatment of heart rhythm problems. I share his feeling of privilege that I have had the opportunity to be part of the race to discovery that electrophysiology has been over the last 30 years. Looking back on my procedure reports from the mid- to late-1990s, I am amazed at how ignorant and naïve we were and I wonder whether I will feel the same – when I come to my retirement at the end of the next decade – looking back on those that I write today. AER has documented much of this progress and the quality of the content is stunning. While it is difficult to choose, I would suggest that those who are new to the journal go back to read Ramanan Kumareswaran and Francis E Marchlinski’s Practical Guide to Ablation for Epicardial Ventricular Tachycardia: When to Get Access, How to Deal with Anticoagulation and How to Prevent Complications (July 2018), Josep Brugada and Roberto Keegan’s article on Asymptomatic Ventricular Pre-excitation: Between Sudden Cardiac Death and Catheter Ablation (March 2018) and Angelo Auricchio and colleagues’ editorial on Key Lessons from the ELECTRa Registry in the Modern Era of Transvenous Lead Extraction (August 2017).1–3 Authors can feel assured that their contributions are widely read and debated. A good indicator of this is the correspondence that many articles stimulate, an example being His Bundle Pacing: A New Frontier in the Treatment of Heart Failure by Nadine Ali et al. (June 2018), which was particularly popular among my colleagues.4 AER has been good at spotting trends and addressing clinical challenges. My personal predictions as to the areas likely to see the greatest growth or innovation over the next five years will be: His bundle pacing, simplification of AF ablation (including better mapping tools for persistent AF), better risk stratification of patients at risk of sudden death, the role of MRI and implantable defibrillators and the role of catheter ablation in ventricular ectopy as a supplementary therapy for patients with cardiomyopathy. David Callans gave a nice overview of this final subject in the December 2017 issue.5

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BHRS Foreword

AER has become the official journal of the British Heart Rhythm Society (BHRS). The BHRS is the first heart rhythm society established in the world; it is a reflection of our history at the BHRS that it was established as the British Pacing and Electrophysiology Group, because it pre-dated the innovation of ablation. While the UK is going through the painful process of disconnecting itself from Europe, we at the BHRS continue to be committed to partnership, scientific collaboration and friendship with our colleagues in Europe and worldwide, as we continue the exciting journey of discovery and improvement to make the lives of patients with heart rhythm problems better and longer. The BHRS’s work supporting AER in its mission to inform, educate and stimulate clinicians will be a key part of our desire to be open and outward looking. At the recent national Heart Rhythm Congress, issues of AER had to be replaced twice on our stand because they proved so popular. As scientists and clinicians, we will face many challenges over the next few years but I am optimistic that the future is bright for a community so keen to inform and educate themselves. Richard Schilling President, British Heart Rhythm Society, and Consultant Cardiologist, Barts Heart Centre, London, UK

1. 2. 3. 4. 5.

 umareswaran R, Marchlinski FE. Practical guide to ablation for epicardial ventricular tachycardia: when to get access, how to deal with anticoagulation and how to prevent K complications. Arrhythm Electrophysiol Rev 2018;7:159–64. https://doi.org/10.15420/aer.2018.10.2. Brugada J, Keegan R. Asymptomatic Ventricular Pre-excitation: Between Sudden Cardiac Death and Catheter Ablation. Arrhythm Electrophysiol Rev 2018;7:32–8. https://doi. org/10.15420/aer.2017.51.2; PMID: 29636970. Auricchio A,Regoli F, Conte G, Caputo ML. Key Lessons from the ELECTRa Registry in the Modern Era of Transvenous Lead Extraction. Arrhythm Electrophysiol Rev 2017;6:111-3. https://doi.org/10.15420/aer.2017.25.1; PMID: 29018517. Ali N, Keene D, Arnold A, et al. His Bundle Pacing: A New Frontier in the Treatment of Heart Failure. Arrhythm Electrophysiol Rev 2018;7:103–10. https://doi.org/10.15420/aer.2018.6.2; PMID: 29967682. Callans D. Premature Ventricular Contraction-induced Cardiomyopathy. Arrhythm Electrophysiol Rev 2017;6:153-5. https://doi.org/10.15420/aer.2017/6.4/EO1; PMID: 29326827.

DOI: https://doi.org/10.15420/aer.2018.7.4.FO2

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Expert Opinion

Catheter Ablation of Atrioventricular Nodal Re-entrant Tachycardia: Facts and Fiction Demosthenes G Katritsis Hygeia Hospital, Athens, Greece

Keywords Atrioventricular nodal re-entrant tachycardia, catheter ablation Disclosure: The author has no conflicts of interest to declare. Received: 19 October 2018 Accepted: 24 October 2018 Citation: Arrhythmia & Electrophysiology Review 2018;7(4):230–1. DOI: https://doi.org/10.15420/aer.2018.7.4.EO1 Correspondence: Demosthenes G Katritsis, Hygeia Hospital, Erithrou Stavrous 4, Athens 15123, Greece. E: dkatrits@dgkatritsis.gr

Although the exact circuit of atrioventricular nodal re-entrant tachycardia (AVNRT) still eludes us, AVNRT is the most common regular arrhythmia in humans, and therefore the most commonly encountered during ablation attempts for regular tachycardias.1–4 Catheter ablation for AVNRT is the current treatment of choice in symptomatic patients. It reduces arrhythmia-related hospitalisations and costs, and substantially improves quality of life.5–16 Catheter ablation approaches aimed at the fast pathway have been abandoned; slow pathway ablation, using a combined anatomical and mapping approach, is now the method of choice. This approach offers a success rate of 95 %, has a recurrence rate of approximately 1.3–4.0  %, and has been associated with a low risk of atrioventricular (AV) block that in most, but not all, studies is <1 %.9,10,15,17 How true are these assumptions, however, in the current era of catheter ablation? Recent reports have provided useful insights into

the technique and complications associated with catheter ablation,and several myths have been refuted, outlined below.5,18–20 We know now that the inferior nodal extensions represent the anatomical substrate of the slow pathway in all forms of AVNRT.4,21–23 The only legitimate question that still remains unanswered is the relative importance of the right and left extensions. Connexin staining and genotyping studies have identified the left inferior extension and the AV node itself as areas of low connexin 43 (Cx43) expression, and consequently slow conduction, thus suggesting that this is the main substrate of the slow pathway (Figure 1).24 The inferior nodal extensions at the inferior (posterior) part of the triangle of Koch and below the coronary sinus ostium, as depicted in the right anterior oblique projection, are the appropriate targets for

Figure 1: Proposed and Hypothetical Circuits of AVNRT Based on the Role of the Inferior Nodal Extensions and Connexin Genotyping Data A

B

A. Proposed circuits of AVNRT based on the role of the inferior nodal extensions. During typical AVNRT (slow–fast) right- or left-sided circuits may occur with antegrade conduction through the inferior inputs and retrograde conduction through the superior inputs or the anisotropic atrionodal transitional area. In atypical AVNRT, conduction occurs anterogradely through the left or right inferior inputs, and retrogradely through the other. Depending on the orientation of the circuit, we may record the so-called fast–slow, slow–slow, or indeterminate types. B. Hypothetical circuits of AVNRT based on connexin genotyping data. Areas in blue have a high expression of Cx43 and therefore display characteristics of fast conduction. These are the right inferior extension, and the lower nodal bundle. There is also a smooth transition in Cx43 at the interface of the transitional cells and the node. Areas in yellow, such as the compact node and the left inferior extension, have very low Cx43 expression and are capable of slow conduction. Therefore, the critical “isthmus” of the AVNRT circuit is likely to be the left inferior nodal extension, regardless of AVNRT type. AAT = atrionodal transition area; AVNRT = atrioventricular nodal re-entrant tachycardia; CS = coronary sinus; FO = foramen ovale; LI = left inferior; LNB = lower nodal bundle; RI = right inferior; S = superior inputs; TV = tricuspid valve; TC = transitional cells. Source: Katritsis and Efimoy, 2018.24 Reproduced with permission from Oxford University Press.

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Catheter Ablation of Atrioventricular Nodal Re-entrant Tachycardia successful ablation, either from the right or left septal side.18–20,25 Slow pathway ablation or modification as described is effective in both typical and atypical AVNRT.19 It is no longer necessary to create higher lesions or perform mapping during tachycardia. These techniques are obsolete and potentially dangerous, as they can damage the AV node.26,27 There is no “upper pathway” in the AVNRT circuit, and the concept of a “lower common pathway” is disputed and of no practical significance.28 Residual dual AV nodal conduction is not predictive of recurrence, and its abolition should not be sought at the expense of prolonged ablation.20 Non-inducibility of the arrhythmia, usually after ablationinduced junctional rhythm and despite isoproterenol challenge, is the most credible endpoint for success.5,18–20 This procedure can be accomplished in both typical and atypical AVNRT with no risk of AV block. We now have substantial evidence demonstrating that we can offer a radical cure for this arrhythmia without any subsequent need for permanent pacing.5,18–20 Acute success rates as a result of rendering the tachycardia noninducible can be achieved in all patients. Recurrence rates are 2 %

1.

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 atritsis DG, Josephson ME. Classification, electrophysiological K features and therapy of atrioventricular nodal reentrant tachycardia. Arrhythm Electrophysiol Rev 2016;5:130–5. https:// doi.org/10.15420/AER.2016.18.2; PMID: 27617092. Orejarena LA, Vidaillet H, DeStefano F, et al. Paroxysmal supraventricular tachycardia in the general population. J Am Coll Cardiol 1998;31:150–7. https://doi.org/10.1016/S07351097(97)00422-1; PMID: 9426034. Porter MJ, Morton JB, Denman R, et al. Influence of age and gender on the mechanism of supraventricular tachycardia. Heart Rhythm 2004;1:393–6. https://doi.org/10.1016/j. hrthm.2004.05.007; PMID: 15851189. Katritsis DG, Camm AJ. Atrioventricular nodal reentrant tachycardia. Circulation 2010;122:831–40. https://doi. org/10.1161/CIRCULATIONAHA.110.936591; PMID: 20733110. Katritsis DG, Zografos T, Katritsis GD, et al. Catheter ablation vs. antiarrhythmic drug therapy in patients with symptomatic atrioventricular nodal re-entrant tachycardia: a randomized, controlled trial. Europace 2017;19:602–6. https://doi. org/10.1093/europace/euw064; PMID: 28431060. Bathina M, Mickelsen S, Brooks C, et al. Radiofrequency catheter ablation versus medical therapy for initial treatment of supraventricular tachycardia and its impact on quality of life and healthcare costs. J Am Coll Cardiol 1998;82:589–93. https:// doi.org/10.1016/S0002-9149(98)00416-0; PMID: 9732885. Cheng CF, Sanders GD, Hlatky MA, et al. Cost-effectiveness of radiofrequency ablation for supraventricular tachycardia. Ann Intern Med 2000;133:864–76. https://doi.org/10.7326/00034819-133-11-200012050-00010; PMID: 11103056. Kalbfleisch SJ, Calkins H, Langberg JJ, et al. Comparison of the cost of radiofrequency catheter modification of the atrioventricular node and medical therapy for drugrefractory atrioventricular node reentrant tachycardia. J Am Coll Cardiol 1992;19:1583–7. https://doi.org/10.1016/07351097(92)90621-S; PMID: 1593054. Scheinman MM, Huang SUE. The 1998 NASPE Prospective Catheter Ablation Registry. Pacing Clin Electrophysiol 2000;23:1020–8. https://doi.org/10.1111/j.1540-8159.2000. tb00891.x; PMID: 10879389. Spector P, Reynolds MR, Calkins H, et al. Meta-analysis of ablation of atrial flutter and supraventricular tachycardia. J Am Coll Cardiol 2009;104:671–7. https://doi.org/10.1016/j. amjcard.2009.04.040; PMID: 19699343. Farkowski MM, Pytkowski M, Maciag A, et al. Gender-related differences in outcomes and resource utilization in patients undergoing radiofrequency ablation of supraventricular tachycardia. Europace 2014;16:1821–7. https://doi.org/10.1093/ europace/euu130; PMID: 24919538. Goldberg AS, Bathina MN, Mickelsen S, et al. Long-term outcomes on quality-of-life and health care costs in patients with supraventricular tachycardia (radiofrequency catheter ablation versus medical therapy). J Am Coll Cardiol 2002;89:1120–3. https://doi.org/10.1016/S00029149(02)02285-3; PMID: 11988206. Larson MS, McDonald K, Young C, et al Quality of life before and after radiofrequency catheter ablation in patients with drug refractory atrioventricular nodal reentrant tachycardia. J Am Coll Cardiol 1999;84:471–3. https://doi.org/10.1016/S00029149(99)00338-0; PMID: 10468092.

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in typical and 5 % in atypical AVNRT.18,19 Recurrence is usually seen within the 3 months following a successful procedure in symptomatic patients with frequent episodes of tachycardia.20,25,29,30 However, in those aged ≤18 years, recurrence may occur up to 5 years postablation.31 Success rates are lower (82  %) and the risk of heart block higher (14 %) in patients with complex congenital heart disease.32 Advanced age is not a contraindication for slow pathway ablation.33 The pre-existence of first-degree heart block carries a higher risk of late AV block and the avoidance of extensive slow pathway ablation is preferable in this setting.34 Cryoablation may carry a lower risk of AV block, but this mode of therapy is associated with a significantly higher recurrence rate.35–37 Its favourable safety profile and higher long-term success rate in younger people make it especially attractive in children.38 There is no procedure-related mortality in most published studies, although in the Latin American Catheter Ablation Registry there was one death (corresponding to 0.02 % mortality) following tamponade.39 I believe that there is no such risk associated with AVNRT ablation in experienced centres today. n

14. B  ubien RS, Knotts-Dolson SM, Plumb VJ, Kay GN. Effect of radiofrequency catheter ablation on health-related quality of life and activities of daily living in patients with recurrent arrhythmias. Circulation 1996;94:1585–91. https://doi. org/10.1161/01.CIR.94.7.1585; PMID: 8840848. 15. Bohnen M, Stevenson WG, Tedrow UB, et al. Incidence and predictors of major complications from contemporary catheter ablation to treat cardiac arrhythmias. Heart Rhythm 2011;8:1661–6. https://doi.org/10.1016/j.hrthm.2011.05.017; PMID: 21699857. 16. Enriquez A, Ellenbogen KA, Boles U, Baranchuk A. Atrioventricular nodal reentrant tachycardia in implantable cardioverter defibrillators: diagnosis and troubleshooting. J Cardiovasc Electrophysiol 2015;26:1282–8. https://doi. org/10.1111/jce.12772; PMID: 26249214. 17. Morady F. Catheter ablation of supraventricular arrhythmias: State of the art. Heart Rhythm 2004;15:124–39. https://doi. org/10.1016/j.hrthm.2004.10.020; PMID: 15028093. 18. Katritsis DG, John RM, Latchamsetty R, et al. Left septal slow pathway ablation for atrioventricular nodal reentrant tachycardia. Circ Arrhythm Electrophysiol 2018;11:e005907. https://doi.org/10.1161/CIRCEP.117.005907; PMID: 29540373. 19. Katritsis DG, Marine JE, Contreras FM, et al. Catheter ablation of atypical atrioventricular nodal reentrant tachycardia. Circulation 2016;134:1655–63. https://doi.org/10.1161/ CIRCULATIONAHA.116.024471; PMID: 27754882. 20. Katritsis DG, Zografos T, Siontis K, et al. End-points for successful slow pathway catheter ablation in typical and atypical atrioventricular nodal reentrant tachycardia: a contemporary, multicenter study. JACC Clin Electrophysiol. In press. 21. Katritsis DG, Becker A. The atrioventricular nodal reentrant tachycardia circuit: A proposal. Heart Rhythm. 2007;4:1354–60. https://doi.org/10.1016/j.hrthm.2007.05.026; PMID: 17905343. 22. Katritsis DG, Josephson ME. Classification of electrophysiological types of atrioventricular nodal re-entrant tachycardia: a reappraisal. Europace 2013;15:1231–40. https://doi.org/10.1093/europace/eut100; PMID: 23612728. 23. Katritsis DG, Marine JE, Latchamsetty R, et al. Coexistent types of atrioventricular nodal re-entrant tachycardia. Implications for the tachycardia circuit. Circ Arrhythm Electrophysiol 2015;8:1189–93. https://doi.org/10.1161/ CIRCEP.115.002971; PMID: 26155802. 24. Katritsis DG, Efimov IR. Cardiac connexin genotyping for identification of the circuit of atrioventricular nodal re-entrant tachycardia. Europace 2018. https://doi.org/10.1093/europace/ euy099; PMID: 29860485; epub ahead of press. 25. Kalbfleisch SJ, Strickberger SA, Williamson B, et al. Randomized comparison of anatomic and electrogram mapping approaches to ablation of the slow pathway of atrioventricular node reentrant tachycardia. J Am Coll Cardiol 1994;23:716–23. https://doi.org/10.1016/0735-1097(94)90759-5; PMID: 8113557. 26. Suzuki A, Yoshida A, Takei A, et al. Visualization of the antegrade fast and slow pathway inputs in patients with slow-fast atrioventricular nodal reentrant tachycardia. Pacing Clin Electrophysiol 2014;37:874-83. https://doi.org/10.1111/ pace.12363; PMID: 25041269. 27. Chen H, Shehata M, Ma W, et al. Atrioventricular block during slow pathway ablation: entirely preventable? Circ Arrhythm Electrophysiol 2015;8:739–44. https://doi.org/10.1161/

CIRCEP.114.002498; PMID: 26082530. 28. K  atritsis DG. Upper and lower common pathways in atrioventricular nodal reentrant tachycardia: refutation of a legend? Pacing Clin Electrophysiol 2007;30:1305–8. https://doi. org/10.1111/j.1540-8159.2007.00861.x; PMID: 17976089. 29. Jackman WM, Beckman KJ, McClelland JH, et al. Treatment of supraventricular tachycardia due to atrioventricular nodal reentry by radiofrequency catheter ablation of slowpathway conduction. N Engl J Med 1992;327:313–8. https://doi. org/10.1056/NEJM199207303270504; PMID: 1620170. 30. Khairy P, Van Hare GF, Balaji S, et al. PACES/HRS Expert consensus statement on the recognition and management of arrhythmias in adult congenital heart disease. Developed in partnership between the Pediatric and Congenital Electrophysiology Society (PACES) and the Heart Rhythm Society (HRS). Heart Rhythm 2014;11:e102–65. https://doi.org/10.1016/j.hrthm.2014.05.009; PMID: 24814377. 31. Backhoff D, Klehs S, Müller MJ, et al. Long-term follow-up after catheter ablation of atrioventricular nodal reentrant tachycardia in children. Circ Arrhythm Electrophysiol 2016;9. Pii: e004264. https://doi.org/10.1161/CIRCEP.116.004264; PMID: 27784739. 32. Papagiannis J, Beissel DJ, Krause U, et al. Atrioventricular nodal reentrant tachycardia in patients with congenital heart disease. Outcome after catheter ablation. Circ Arrhythm Electrophysiol 2017;10. pii: e004869. https://doi.org/10.1161/ CIRCEP.116.004869; PMID: 28687669. 33. Rostock T, Risius T, Ventura R, et al. Efficacy and safety of radiofrequency catheter ablation of atrioventricular nodal reentrant tachycardia in the elderly. J Cardiovasc Electrophysiol 2005;16:608–10. https://doi.org/10.1111/j.15408167.2005.40717.x; PMID: 15946358. 34. Li YG, Gronefeld G, Bender B, et al. Risk of development of delayed atrioventricular block after slow pathway modification in patients with atrioventricular nodal reentrant tachycardia and a pre-existing prolonged PR interval. Eur Heart J 2001;22:89–95. https://doi.org/10.1053/euhj.2000.2182; PMID: 11133214. 35. Deisenhofer I, Zrenner B, Yin Y-H, et al. Cryoablation Versus Radiofrequency Energy for the Ablation of Atrioventricular Nodal Reentrant Tachycardia (the CYRANO Study). Circulation 2010;122:2239–45. https://doi.org/10.1161/ CIRCULATIONAHA.110.970350; PMID: 21098435. 36. Hanninen M, Yeung-Lai-Wah N, Massel D, et al. Cryoablation versus RF ablation for AVNRT: a meta-analysis and systematic review. J Cardiovasc Electrophysiol 2013;24:1354–60. https://doi. org/10.1111/jce.12247; PMID: 24016223. 37. Matta M, Anselmino M, Scaglione M, et al. Cooling dynamics: a new predictor of long-term efficacy of atrioventricular nodal reentrant tachycardia cryoablation. J Interv Card Electrophysiol 2017;48:333–41. https://doi.org/10.1007/s10840-016-0208-4; PMID: 27943134. 38. Pieragnoli P, Paoletti Perini A, Checchi L, et al. Cryoablation of typical AVNRT: Younger age and administration of bonus ablation favor long-term success. Heart Rhythm 2015;12:2125–31. https://doi.org/10.1016/j.hrthm.2015.05.035; PMID: 26031373. 39. Keegan R, Aguinaga L, Fenelon G, et al. The first Latin American Catheter Ablation Registry. Europace 2015;17:794–800. https:// doi.org/10.1093/europace/euu322; PMID: 25616407.

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Clinical Review: Clinical Arrhythmias

Arrhythmias and Heart Rate: Mechanisms and Significance of a Relationship Antonio Zaza, 1,2 Carlotta Ronchi 1 and Gabriella Malfatto 3 1. Dipartimento di Biotecnologie e Bioscienze, Università degli Studi Milano-Bicocca, Milan, Italy; 2. CARIM, Maastricht University, Maastricht, the Netherlands; 3. Istituto Auxologico Italiano - IRCCS Ospedale San Luca, Milan, Italy

Abstract The occurrence of arrhythmia is often related to basic heart rate. Prognostic significance is associated with such a relationship; furthermore, heart rate modulation may result as an ancillary effect of therapy, or be considered as a therapeutic tool. This review discusses the cellular mechanisms underlying arrhythmia occurrence during tachycardia or bradycardia, considering rate changes per se or as a mirror of autonomic modulation. Besides the influence of steady-state heart rate, dynamic aspects of changes in rate and autonomic balance are considered. The discussion leads to the conclusion that the prognostic significance of arrhythmia relationship with heart rate, and the consequence of heart rate on arrhythmogenesis, may vary according to the substrate present in the specific case and should be considered accordingly.

Keywords Arrhythmia, heart rate, autonomic modulation, membrane current, calcium handling, cellular energetics, steady-state, dynamics Disclosure: The authors have no conflicts of interest to declare. Acknowledgement: This work was supported by an institutional Fund for Research (Fondo di Ateneo per la Ricerca) of Milano-Bicocca University to A Zaza. Received: 3 March 2018 Accepted: 17 May 2018 Citation: Arrhythmia & Electrophysiology Review 2018;7(4):232–7. DOI: https://doi.org/10.15420/aer.2018.12.3 Correspondence: Antonio Zaza, MD, FESC, Dipartimento di Biotecnologie e Bioscienze, Università degli Studi Milano-Bicocca Bldg. U3, Piazza della Scienza 2, 2016 Milan, Italy. E: antonio.zaza@unimib.it

The incidence of ventricular arrhythmias is often related, within an individual, to the rate of their underlying sinus rhythm (heart rate). The direction of this relationship is generally considered to entail some prognostic significance: whereas ectopic activity suppressed by tachycardia is assumed to be benign, an arrhythmia enhanced by tachycardia is regarded with more concern. Is this assumption valid in general terms? Does it have a mechanistic explanation? To what extent does it apply to arrhythmias occurring in different pathological conditions? The purpose of this short review is to discuss how arrhythmogenesis, by its diverse mechanisms, can be affected by heart rate.

Effect of Heart Rate on Myocardial Electrical Stability Heart rate, by itself, has important consequences for at least three factors relevant to electrical stability: • the pattern of membrane current expression during the action potential; • intracellular Ca2+ dynamics; and • cellular energetic competence. Furthermore, heart rate reflects autonomic balance, which has its own effects on these factors.

Membrane Currents Membrane current response to tachycardia is mostly relevant to repolarisation and is normally characterised by a net increment of outward (repolarising) current. The main players in this change are

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an increment in the slow depolarisation-activated K+ current (IKs), whose conductive state accumulates at short diastolic intervals, and a decrease in the high-threshold Ca2+ current (ICaL), which may incompletely recover from inactivation during tachycardia.1 Sympathetic activation, which normally coexists with tachycardia, amplifies rate-induced IKs enhancement, but, to keep up contractile function, it also increases ICaL.2–5 Therefore, both heart rate increment and direct adrenergic modulation of channels contribute to accelerate repolarisation during tachycardia; their concerted action is required for repolarisation stability. Faster repolarisation ensures that propagation velocity and safety (which depend on the availability of the Na+ current) are not compromised by excessive shortening of diastolic intervals. A further consequence of more frequent activation is increased Na+ entry into the cell, which leads to activation of the Na+/K+ pump. The latter carries outward current, which contributes to stabilise diastolic potential, thus preventing its spontaneous depolarisation; this accounts for overdrive suppression of automatic foci.6 Impulse propagation depends on excitation rate only if the diastolic interval is too short to allow for full recovery of the current which supports it (i.e. diastolic interval shorter than refractory period). In normal ventricular myocardium, recovery of the Na + current (INa) is complete within the end of the action potential; the latter shortens as rate increases, thus making refractoriness rate-adaptive. Therefore, as indicated by constancy of QRS duration over the whole range of physiological rates, propagation is largely independent of heart rate.1 INa recovery may be delayed beyond full repolarisation (post-repolarisation refractoriness) by Na+-channel blockers (Class IC in particular)7 and by loss of diastolic polarisation; furthermore, when a small gap of unexcitable tissue is included in the propagation path,

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Arrhythmias and Heart Rate refractoriness may become independent of action potential duration and even acquire an opposite rate-dependency.8 Rate-dependency of conduction (e.g. in bundle branch block) may appear in such conditions; however, it is not necessarily present under conditions of conduction impairment in ventricular myocardium. For instance, in severely fibrotic porcine hearts subjected to hypokalemia, ventricular conduction was depressed, but rate-dependency occurred only above 240 BPM.9 Because of its less polarised diastolic potential and specific INa-gating properties,10 atrial myocardium may be more prone than ventricular myocardium to develop post-repolarisation refractoriness and, thus, conduction rate-dependency;1 however, it is unclear whether this may occur within a physiological range of rates. Post-repolarisation refractoriness and conduction rate-dependency are instead typical of nodal tissue, in which propagation is supported by a Ca2+ current (ICaL) with slow recovery kinetics. However, sinus tachycardia is physiologically induced by sympathetic activation, which enhances ICaL; therefore, unless ICaL conductance is reduced (e.g. by drugs), even nodal conduction is largely rate-independent. To summarise, considering rate-dependent conduction slowing as a general factor in tachycardiainduced arrhythmias may, in our view, be incorrect. Bradycardia prolongs repolarisation, on the other hand. Longer repolarisation is intrinsically more labile to perturbations11,12 and, as such, prone to become spatially inhomogeneous and temporally variable.13 Moreover, repolarisation velocity is pivotal in preventing partial ICaL recovery and its immediate reactivation during the action potential plateau, which would result in major perturbation of the action potential profile (early-afterdepolarisations, EADs).14 Prolonged repolarisation, either primary or acquired, is notoriously associated with proarrhythmia. While EADs represent the most obvious arrhythmia-initiating event, even in the absence of EADs the tendency of prolonged repolarisation is to be more variable, both in space (repolarisation dispersion or heterogeneity) and time (repolarisation variability). This may lead to the steep voltage gradients, likely setting the stage for local conduction block, which characterise the sites of onset of life-threatening rhythms.15 Fortunately, bradycardia is normally associated with low adrenergic activity, which helps to maintain inward and outward current components in balance. Overall, changes of membrane current expression during the action potential are such as to confer electrical stability in the case of tachycardia, but much less during bradycardia. Nonetheless, heart rate changes are pivotal in cardiovascular adaptation to metabolic needs; therefore, we can assume that normal myocardium is rigged to face wide heart rate changes. This is conceivably achieved through concerted modulation of sinus node pacemaker rate and of the function of working myocytes.

Intracellular Ca 2+ Dynamics Heart rate has profound effects on intracellular Ca2+ dynamics, which contribute to adapt contractility to the changes in cycle duration. Tachycardia increases the Ca2+ influx/efflux ratio, thereby increasing cell Ca2+ content.16 Adrenergic stimulation contributes to this by enhancing Ca2+ influx (through ICaL) and by stimulating a Ca2+ pump (SERCA2a), which supports fast uptake of the ion by the sarcoplasmic reticulum (SR).16 Under normal conditions, cell Ca2+ content, especially in the SR, is tightly controlled by a complex of feedback mechanisms, which keep it near a set point.17 While the joint effects of tachycardia and adrenergic activation move the set point to increase the Ca2+ available to trigger contraction, the feedback system guarantees

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achievement of a new steady-state and prevents progressive Ca2+ overload.18 This set of mechanisms ensures SR stability, i.e. capability of the intracellular store to release Ca2+ only in response to the appropriate trigger (the action potential).19 Nonetheless, tachycardia and adrenergic stimulation are undoubtedly stress conditions for the Ca2+ handling system: if any of its components is abnormal, as occurs in common primary and acquired diseases, SR instability is more likely to ensue at high heart rate.20,21 Thus, the appearance of arrhythmias during sinus tachycardia per se, or as a reporter of sympathetic activation, may suggest mechanisms related to abnormality of the Ca2 -handling machinery. Intracellular Ca2+ dynamics are relevant to arrhythmogenesis because cytosolic Ca2+ ‘talks’ to membrane potential through Ca2+ sensitive mechanisms.19 For instance, due to its stoichiometry, the Na+/Ca2+ exchanger moves a positive charge in the inward direction whenever extruding a Ca2+ ion from the cell; a rise in cytosolic Ca2+ fuels the exchange, thus resulting in membrane depolarisation. Also, the speed of ICaL inactivation, which affects the amount of inward current during repolarisation, strongly depends on formation of a Ca2+/calmodulin complex at the inner mouth of the channel.22 Such a crosstalk translates variability of intracellular Ca2+ dynamics into variability of repolarisation,23,24 with consequences of relevance for arrhythmogenesis. SR instability has a pivotal role in multiple arrhythmogenic mechanisms, including DADs, EADs, repolarisation alternans, and repolarisation variability in general.19,21,23,24

Energetic Competence Heart rate is the major determinant of oxygen consumption by both chemical (mainly Na+ and Ca2+ pumping) and mechanical (sarcomere shortening) components of cardiac work. To cope with it, mitochondrial production of reduced substrates fuelling the electron transport chain (i.e. nicotinamide adenine dinucleotide) is tightly controlled by mitochondrial Ca2+, whose concentration increases during tachycardia as it grossly follows that of cytosol.25,26 Under these conditions, inadequate availability of O2 (the electron acceptor) paradoxically increases mitochondrial production of reactive oxygen species (ROS), likely because of an imbalance between their generation and scavenging, and reduces ATP generation. ROS-induced proarrhythmia is well known: SR instability induced by peroxidation of "ryanodine receptor" channels has a strong proarrhythmic potential, but dysfunction of other ion channels (e.g. enhancement of the late Na+ current) is also involved.27–33 Furthermore, a drop in the ATP/ADP ratio activates the sarcolemmal ATP-sensitive current (IKATP), which may dramatically shorten repolarisation and impair cell excitability locally,34,35 resulting in marked electrical heterogeneity. Therefore, in the context of ischaemic heart disease, the immediate proarrhythmic potential of tachycardia is obvious; indeed, tachycardia-induced arrhythmias may represent an ischaemia equivalent.

Is the Relation Between Arrhythmia and Heart Rate Relevant to Prognosis and Therapeutic Strategy? Arrhythmia Facilitation by Tachycardia In light of the arguments above, whereas tachycardia may afford greater electrical stability in the normal heart, it may well be an arrhythmia trigger when an abnormal substrate is present. The latter may be provided by extremely common conditions, such as ischaemic heart disease, or rarer but very serious ones, such as ryanodine receptor dysfunction of genetic origin (as in catecholamine-

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Clinical Review: Clinical Arrhythmias Figure 1: Steady-state Cycle Length-dependency of Adrenergically Induced Current in Guinea Pig Ventricular Myocytes A

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induced polymorphic ventricular tachycardias).36 This, together with the generally benign nature of overdrive-suppressible enhanced automaticity (parasystolic rhythms), might lead to the conclusion that ectopic beats manifesting selectively at low heart rates should not be associated with the substrate required for their degeneration into complex, life-threatening arrhythmias.

Arrhythmia Facilitation by Bradycardia A substantial body of evidence indicates that, contrary to the view above, pronounced bradycardia may also facilitate life-threatening arrhythmias, as predicted by its destabilising effect on repolarisation. Susceptibility to torsade de pointes (TdP) ventricular tachycardias, the type of arrhythmia more specifically linked to repolarisation instability, characterises experimental models of bradycardia37 and may be observed in patients with AV block resulting in low ventricular rates.38 The question is then whether low heart rate is by itself responsible for arrhythmogenesis. In dogs with chronic AV block (CAVB), an extensively characterised proarrhythmia model, bradycardia may trigger TdP only after inducing myocardial remodelling:39 a set of functional and structural myocardial modifications resulting from chronic adaptation to low heart rate. Repolarisation of remodelled myocardium is generally characterised by downregulation of outward currents and upregulation of inward ones, resulting in slightly prolonged action potential duration and reduced repolarisation reserve.40 This experimental observation is matched by clinical data showing that, among AV block patients, those developing TdP are characterised by longer QT intervals and specific features in repolarisation profile.38 Therefore, as in the

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A: The myocyte was clamped by action potential (AP) waveforms (upper) recorded and applied (AP clamp) at two cycle lengths. Isoproterenol-induced current (Iiso , lower), recorded by subtraction between isoproterenol and control currents, is aligned with the AP waveform (dotted line = 0 level). B: Average AP waveforms with net transmembrane current (Inet) (upper) and Iiso profiles (bottom); confidence intervals shown by dotted contours; on the x axis, time is expressed as percentage of action potential duration (APD90 ). Cycle length prolongation (equivalent to a rate change from 240 to 60 BPM) caused dramatic changes in Iiso profile. During the transition between phases 2 and 3 (red dotted line in Figure 1A), Iiso switched from outward to strongly inward at the longer cycle length. Modified from Rocchetti et al. 2006.41 Reproduced with permission from Wiley.

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Each animal was studied in control (C), after right (RSGx) or left (LSGx) stellectomy (in the sequence specified in the caption), and after removal of the remaining ganglion (BSGx) or beta-adrenergic blockade. A: Changes in action potential duration (APD) at infinite cycle length (APDmax ), extrapolated from steady-state APD–cycle length relationships; B: changes in the time constant (tau, in number of beats) of APD relaxation after sudden cycle length shortening (APD adaptation kinetics). RSGx (open symbols) and LSGx (filled symbols) had opposite effects on APDmax and tau; whereas BSGx (or beta-blockade) reversed the effects of RSGx, it amplified those of LSGx. This suggests that, while weakly affecting ventricular repolarisation on its own, RSGx reflexly increased activity through left-sided sympathetic nerves. Reproduced from Zaza et al. 1991.44 Reproduced with permission from Wolters-Kluwer. APD = action potential duration; BSGx = bilateral stellectomy; C = control; LSGx = left stellectomy; RSGx = right stellectomy.

case of tachycardia-induced arrhythmias, arrhythmia ensuing during bradycardia may indicate the presence of a substrate, represented in this case by reduced repolarisation reserve. Notably, such a substrate may result from myocardial remodelling of whatever aetiology, thus making pronounced bradycardia a concern in all conditions of myocardial hypertrophy/failure. A special condition, sensitising repolarisation to the destabilising effect of bradycardia, may be provided by a mismatch between sinoatrial and ventricular responses to sympathetic activation. Action-potential clamp (AP-clamp) experiments in guinea pig ventricular myocytes showed that the composite current activated by beta-adrenergic receptors (largely IKs + ICaL) switched from partly outward to entirely inward when the pacing rate was reduced.41 Notably, at slow rates the excess inward (depolarising) current impinged on the transition between action potential phases 2 and 3, i.e. when EADs commonly occur (Figure 1).

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Arrhythmias and Heart Rate Figure 3: Model Interpretation of Early-afterdepolarisation Induction by Sudden Adrenergic Challenge A

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A: Sudden exposure to isoproterenol (horizontal bar) leads to APD shortening if the kinetics of channel response to PKA-mediated phosphorylation are assumed equal (τIKs = τICaL) and to APD lengthening + EADs if the slower rate of IKs phosphorylation (Figure 3D) is considered (τIKs > τICaL). B: Comparison of APD time-course between the two conditions (grey: τIKs = τICaL; black: τIKs > τICaL); C: Maximal APD (APDmax, grey) and EADs numerosity (EAD, black) following sudden ISO challenge as a function of τIKs. D: Experimental results (dotted lines from Liu et al. 201248) and model reproduction (solid lines) of the response of IKs (green) and ICaL (black) to sudden isoproterenol challenge. The shaded area shows the time of EADs onset. Modified from Xie et al. 2013.49 Reproduced with permission from Elsevier. APD = action potential duration; EADs = early-afterdepolarisations; ICaL = high threshold Ca2+ current ; IKs = slow component of depolarization-activated K+ current; ISO= isoproterenol; PKA = protein kinase A.

Bradycardia-induced distortion of the current profile in these experiments was so remarkable to suggest that profound repolarisation abnormalities should be a necessary consequence of inadequate ventricular rate response to sympathetic activation, even when the currents are intrinsically normal. Evidence that this is fortunately not the case in vivo (in the CAVB dog and AV block patients mentioned above) may be partly explained by specificities in the guinea pig action potential,42 but also by failure of membrane current to feedback on membrane potential course under AP-clamp conditions. In other words, under physiological conditions, current distortions would produce changes in the AP profile that may minimise their effect. Nonetheless, the AP-clamp experiments do show that subnormal rate response to sympathetic activation may impose a very significant stress on repolarisation reserve. Before the role of genetic channel abnormalities was recognised, long QT syndrome was experimentally reproduced in normal hearts by an imbalance between the activities of left- and right-sided sympathetic nerves.43 Whereas the effects of left stellectomy (i.e. sympathyectomy) on static and dynamic aspects of ventricular repolarisation were similar to those of bilateral denervation, right stellectomy had opposite effects (Figure 2).44 Notably, whereas sinus rate is mostly under the influence of right-sided nerves, left-sided ones prevail in the control of ventricular electrophysiology.43 The concept of "inadequate rate response" introduces a quantitative argument in the discussion of the correlation between heart rate and arrhythmias. For instance, in long QT syndromes, cardiac arrest may be preceded by an increase in heart rate,45 as expected when arrhythmias are triggered by sympathetic activation. However, because of prolonged repolarisation and, in the case of IK deficits, also because of defective sinus automaticity, long QT syndrome patients are intrinsically bradycardic, with subnormal

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rate response to sympathetic activation,46 the latter being a likely contributor to the genesis of TdP. This has, of course, therapeutic implications in the potential benefits of positive chronotropy, by pacemakers or drugs, under conditions of repolarisation instability. In conclusion, from the mechanistic viewpoint, when considering the relation between heart rate and arrhythmias, the question should be ‘how appropriate is sinus rate to autonomic balance?’, rather than ‘is heart rate high (or low)?’.

The Importance of Dynamics We have thus far considered tachycardia and bradycardia as static conditions; nonetheless, emerging evidence indicates that the link between heart rate and arrhythmogenesis may also reside in the dynamics of transitions between different heart rates. This argument is well illustrated by examples, again in the field of repolarisation syndromes. Cardiac arrest in patients with prolonged repolarisation may occur upon sudden emotional stress (e.g. an alarm going off), rather than during sustained physical exercise; this is especially the case for IKr defects.47 This has been elegantly interpreted by showing that ICaL response to an adrenergic surge is considerably faster than IKs response, thus facilitating EADs (Figure 3).48,49 Thus, even if a suitable balance may be preserved during sustained exercise, a dangerous mismatch between depolarising and repolarising currents may occur during sudden sympathetic activation. While the case of prolonged repolarisation syndromes is the most obvious example, sudden transitions between states of vagal and sympathetic activity, and the resulting heart rate changes, may contribute to the high incidence of arrhythmic events during deep sleep stages, particularly when associated with ventilation abnormalities (a powerful trigger of autonomic reflexes).50

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Clinical Review: Clinical Arrhythmias In patients with genotype LQT1 of long QT syndrome, membrane current response to adrenergic activation is unbalanced due to primary IKs deficit, thus making these patients particularly susceptible to sympathetic activation, especially with sustained exercise.47 However, the search for concomitant factors affecting the arrhythmic risk has led to the unexpected observation of a higher baroreceptor sensitivity (BRS) in symptomatic versus asymptomatic mutation carriers (still associated with slightly higher heart rate).51 Since high BRS is held to reflect parasympathetic dominance (and found to be protective under other conditions), the finding is surprising, and leads to consider other mechanisms in the contribution of rate changes to cardiac arrest. It has been suggested that high BRS implies brisker autonomic and heart rate changes during haemodynamic perturbations.51 IKs is among the main factors underlying APD adaptation to sudden rate fluctuations: the stiffer repolarisation typical of LQT1 might decrease the tolerance to these fluctuations.52 Indeed, stiffer repolarisation is the sole mechanism we found to potentially account for the severe electrical instability in a calmodulin mutation (F142L) associated with QT prolongation.53 Further investigation is required to confirm this view; nonetheless, these findings highlight the possibility that arrhythmogenesis may also result from a mismatch between the dynamicity of repolarisation and that of heart rate.

Conclusion With the exception of parasystolic rhythm, in which appearance at slow rates is likely due to relief from overdrive suppression of an automatic focus, attribution of prognostic significance to arrhythmia relationship

1.

 oyett MR, Jewell BR. Analysis of the effects of changes in B rate and rhythm upon electrical activity in the heart. Prog Biophys Mol Biol 1980;36:1–52. https://doi.org/10.1016/00796107(81)90003-1; PMID: 7001542. 2. Severi S, Corsi C, Rocchetti M, Zaza A. Mechanisms of betaadrenergic modulation of I(Ks) in the guinea-pig ventricle: insights from experimental and model-based analysis. Biophys J 2009;96:3862–72. https://doi.org/10.1016/j.bpj.2009.02.017; PMID: 19413992. 3. Volders PG, Stengl M, van Opstal JM, et al. Probing the contribution of IKs to canine ventricular repolarization: key role for beta-adrenergic receptor stimulation. Circulation 2003;107:2753–60. https://doi.org/10.1161/01. CIR.0000068344.54010.B3; PMID: 12756150. 4. Rocchetti M, Besana A, Gurrola GB, et al. Rate-dependency of delayed rectifier currents during the guinea-pig ventricular action potential. J Physiol 2001;534:721–32. https://doi. org/10.1111/j.1469-7793.2001.00721.x; PMID: 11483703. 5. Reuter H. Calcium channel modulation by neurotransmitters, enzymes and drugs. Nature 1983;301:569–74. https://doi. org/10.1038/301569a0; PMID: 6131381. 6. Vassalle M. Electrogenic suppression of automaticity in sheep and dog Purkinje fibers. Circ Res 1970;27:361–77. https://doi.org/10.1161/01.RES.27.3.361; PMID: 5452735. 7. Kirchhof PF, Fabritz CL, Franz MR. Postrepolarization refractoriness versus conduction slowing caused by class I antiarrhythmic drugs: antiarrhythmic and proarrhythmic effects. Circulation 1998;97:2567–74. https://doi.org/10.1161/01. CIR.97.25.2567; PMID: 9657478. 8. Davidenko JM, Antzelevitch C. Electrophysiological mechanisms underlying rate-dependent changes of refractoriness in normal and segmentally depressed canine Purkinje fibers. The characteristics of post-repolarization refractoriness. Circ Res 1986;58:257–68. https://doi. org/10.1161/01.RES.58.2.257; PMID: 3948343. 9. Motloch LJ, Ishikawa K, Xie C, et al. Increased afterload following myocardial infarction promotes conductiondependent arrhythmias that are unmasked by hypokalemia. JACC Basic Transl Sci 2017;2:258–69. https://doi.org/10.1016/j. jacbts.2017.02.002; PMID: 28798965. 10. Burashnikov A, Di Diego JM, Zygmunt AC, et al. Atriumselective sodium channel block as a strategy for suppression of atrial fibrillation: differences in sodium channel inactivation between atria and ventricles and the role of ranolazine. Circulation 2007;116:1449–57. https://doi.org/10.1161/ CIRCULATIONAHA.107.704890; PMID: 17785620. 11. Zaza A. Control of the cardiac action potential: The role of repolarization dynamics. J Mol Cell Cardiol 2010;48: 106–11. https://doi.org/10.1016/j.yjmcc.2009.07.027; PMID: 19666029. 12. Barandi L, Virag L, Jost N, et al. Reverse rate-dependent changes are determined by baseline action potential duration

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with heart rate should carefully consider the substrate likely present in the individual patient. The same is also true for deciding whether heart rate increase or decrease may be a logical antiarrhythmic approach, or can be safely tolerated as a therapy side-effect. In many cases this may be straightforward (e.g. bradycardia-induced arrhythmias in a long QT syndrome patient, or tachycardia-induced arrhythmias clearly related to ischaemia); however, other cases may be more ambiguous. For instance, in heart failure, arrhythmia facilitation by tachycardia may suggest SR instability (or energetic incompetence); however, lowering heart rate in a likely remodelled context may conceivably carry some risk, particularly if adrenergic activation remains unopposed. n

Clinical Perspective • H eart rate may affect electrical stability per se, or reflect autonomic balance. • Depending on the substrate, arrhythmias can be facilitated by either tachycardia or bradycardia. •  Preferential occurrence of an arrhythmia during bradycardia may imply low risk only if the features typical of parasystole can be detected. • Inadequate heart rate response to sympathetic activation may contribute to electrical instability. • Sudden changes in heart rate and/or autonomic balance may contribute to electrical instability.

in mammalian and human ventricular preparations. Basic Res Cardiol 2010;105:315–23. https://doi.org/10.1007/s00395-0090082-7; PMID: 20127488. Winter J, Shattock MJ. Geometrical considerations in cardiac electrophysiology and arrhythmogenesis. Europace 2016;18:320–31. https://doi.org/10.1093/europace/euv307; PMID: 26585597. January CT, Riddle JM. Early afterdepolarizations: mechanism of induction and block. A role for L-type Ca2+ current. Circ Res 1989;64:977–90. https://doi.org/10.1161/01.RES.64.5.977; PMID: 2468430. Dunnink A, Stams TR, Bossu A, et al. Torsade de pointes arrhythmias arise at the site of maximal heterogeneity of repolarization in the chronic complete atrioventricular block dog. Europace 2017;19:858–65. https://doi.org/10.1093/ europace/euw087; PMID: 28525920. Endoh M. Force-frequency relationship in intact mammalian ventricular myocardium: physiological and pathophysiological relevance. Eur J Pharmacol 2004;500:73–86. https://doi. org/10.1016/j.ejphar.2004.07.013; PMID: 15464022. Dibb KM, Graham HK, Venetucci LA, et al. Analysis of cellular calcium fluxes in cardiac muscle to understand calcium homeostasis in the heart. Cell Calcium 2007;42:503–12. https:// doi.org/10.1016/j.ceca.2007.04.002; PMID: 17509680. Venetucci LA, Trafford AW, O’Neill SC, Eisner DA. The sarcoplasmic reticulum and arrhythmogenic calcium release. Cardiovasc Res 2008;77:285–92. https://doi.org/10.1093/cvr/ cvm009; PMID: 18006483. Zaza A, Rocchetti M. Calcium store stability as an antiarrhythmic endpoint. Curr Pharm Des 2015;21:1053–61. https://doi.org/10.2174/1381612820666141029100650; PMID: 25354186. Baartscheer A, Schumacher CA, Belterman CN, et al. SR calcium handling and calcium after-transients in a rabbit model of heart failure. Cardiovasc Res 2003;58:99–108. https:// doi.org/10.1016/S0008-6363(02)00854-4; PMID: 12667950. Wan X, Laurita KR, Pruvot EJ, Rosenbaum DS. Molecular correlates of repolarization alternans in cardiac myocytes. J Mol Cell Cardiol 2005;39:419–428. https://doi.org/10.1016/j. yjmcc.2005.06.004; PMID: 16026799. Zuhlke RD, Pitt GS, Deisseroth K, et al. Calmodulin supports both inactivation and facilitation of L-type calcium channels. Nature 1999;399:159–62. https://doi.org/10.1038/20200; PMID: 10335846. Nemec J. Nonalternans repolarization variability and arrhythmia – the calcium connection. J Electrocardiol 2016;49:877–82. https://doi.org/10.1016/j. jelectrocard.2016.08.003; PMID: 27600096. Johnson DM, Heijman J, Bode EF, et al. Diastolic spontaneous calcium release from the sarcoplasmic reticulum increases beat-to-beat variability of repolarization in canine ventricular myocytes after beta-adrenergic stimulation.

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Circ Res 2013;112:246–56. https://doi.org/10.1161/ CIRCRESAHA.112.275735; PMID: 23149594. Maack C, O’Rourke B. Excitation-contraction coupling and mitochondrial energetics. Basic Res Cardiol 2007;102:369–92. https://doi.org/10.1007/s00395-007-0666-z; PMID: 17657400. Dorn GW, Maack C. SR and mitochondria: calcium cross-talk between kissing cousins. J Mol Cell Cardiol 2013;55:42–9. https:// doi.org/10.1016/j.yjmcc.2012.07.015; PMID: 22902320. Murphy MP. How mitochondria produce reactive oxygen species. Biochem J 2009;417:1–13. https://doi.org/10.1042/ BJ20081386; PMID: 19061483. Nickel A, Kohlhaas M, Maack C. Mitochondrial reactive oxygen species production and elimination. J Mol Cell Cardiol 2014;73:26–33. https://doi.org/10.1016/j.yjmcc.2014.03.011; PMID: 24657720. Xie W, Santulli G, Reiken SR, et al. Mitochondrial oxidative stress promotes atrial fibrillation. Sci Rep 2015;5:11427. https://doi.org/10.1038/srep11427; PMID: 26169582. Niggli E, Ullrich ND, Gutierrez D, et al. Posttranslational modifications of cardiac ryanodine receptors: Ca(2+) signaling and EC-coupling. Biochim Biophys Acta 2013;1833:866–75. https://doi.org/10.1016/j.bbamcr.2012.08.016; PMID: 22960642. Santulli G, Xie W, Reiken SR, Marks AR. Mitochondrial calcium overload is a key determinant in heart failure. Proc Natl Acad Sci USA 2015;112:11389–94. https://doi.org/10.1073/ pnas.1513047112; PMID: 26217001. Ward CA, Giles WR. Ionic mechanism of the effects of hydrogen peroxide in rat ventricular myocytes. J Physiol 1997;500(Pt 3):631–42. https://doi.org/10.1113/jphysiol.1997. sp022048; PMID: 9161981. Zaza A, Belardinelli L, Shryock JC. Pathophysiology and pharmacology of the cardiac “late sodium current”. Pharmacol Ther 2008;119:326–39. https://doi.org/10.1016/j. pharmthera.2008.06.001; PMID: 18662720. Brown DA, O’Rourke B. Cardiac mitochondria and arrhythmias. Cardiovasc Res 2010;88:241–9. https://doi. org/10.1093/cvr/cvq231; PMID: 20621924. Gambardella J, Sorriento D, Ciccarelli M, et al. Functional role of mitochondria in arrhythmogenesis. Adv Exp Med Biol 2017;982:191–202. https://doi.org/10.1007/978-3-319-553306_10; PMID: 28551788. Priori SG, Chen SR. Inherited dysfunction of sarcoplasmic reticulum Ca2+ handling and arrhythmogenesis. Circ Res 2011;108:871–83. https://doi.org/10.1161/ CIRCRESAHA.110.226845; PMID: 21454795. Vos MA, de Groot S, Verduyn SC, et al. Enhanced susceptibility for acquired torsade de pointes arrhythmias in the dog with chronic, complete AV block is related to cardiac hypertrophy and electrical remodeling. Circulation 1998;98:1125–35. https://doi.org/10.1161/01.CIR.98.11.1125; PMID: 9736600.

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Arrhythmias and Heart Rate

38. C  ho MS, Nam GB, Kim YG, et al. Electrocardiographic predictors of bradycardia-induced torsades de pointes in patients with acquired atrioventricular block. Heart Rhythm 2015;12:498–505. https://doi.org/10.1016/j.hrthm.2014.11.018; PMID: 25460857. 39. Dunnink A, van Opstal JM, Oosterhoff P, et al. Ventricular remodelling is a prerequisite for the induction of dofetilide-induced torsade de pointes arrhythmias in the anaesthetized, complete atrio-ventricular-block dog. Europace 2012;14:431–6. https://doi.org/10.1093/europace/eur311; PMID: 21946817. 40. Michael G, Xiao L, Qi XY, et al. Remodelling of cardiac repolarization: how homeostatic responses can lead to arrhythmogenesis. Cardiovasc Res 2009;81:491–9. https://doi. org/10.1093/cvr/cvn266; PMID: 18826964. 41. Rocchetti M, Freli V, Perego V, et al. Rate-dependency of beta-adrenergic modulation of repolarizing currents in the guinea-pig ventricle. J Physiol 2006;574:183–93. https://doi. org/10.1113/jphysiol.2006.105015; PMID: 16484299. 42. Sala L, Hegyi B, Bartolucci C, et al. Action potential contour contributes to species differences in repolarization response to beta-adrenergic stimulation. Europace 2017. https://doi. org/10.1093/europace/eux236; PMID: 29045640. 43. Yanowitz R, Preston JB, Abildskov JA. Functional distribution of right and left stellate innervation to the ventricles: production

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jphysiol.2011.218164; PMID: 22183728. 49. X  ie Y, Grandi E, Puglisi JL, ey al. Beta-adrenergic stimulation activates early afterdepolarizations transiently via kinetic mismatch of PKA targets. J Mol Cell Cardiol 2013;58:153–61. https://doi.org/10.1016/j.yjmcc.2013.02.009; PMID: 23481579. 50. Zeidan-Shwiri T, Aronson D, Atalla K, et al. Circadian pattern of life-threatening ventricular arrhythmia in patients with sleep-disordered breathing and implantable cardioverterdefibrillators. Heart Rhythm 2011;8:657–62. https://doi. org/10.1016/j.hrthm.2010.12.030; PMID: 21185402. 51. Schwartz PJ, Vanoli E, Crotti L, et al. Neural control of heart rate is an arrhythmia risk modifier in long QT syndrome. J Am Coll Cardiol 2008;51:920–9. https://doi.org/10.1016/j. jacc.2007.09.069; PMID: 18308161. 52. Nemec J, Buncova M, Bulkova V, et al. Heart rate dependence of the QT interval duration: differences among congenital long QT syndrome subtypes. J Cardiovasc Electrophysiol 2004;15:550–6. https://doi.org/10.1046/j.1540-8167.2004.03096.x; PMID: 15149424. 53. Rocchetti M, Sala L, Dreizehnter L, et al. Elucidating arrhythmogenic mechanisms of long-QT syndrome CALM1-F142L mutation in patient-specific induced pluripotent stem cell-derived cardiomyocytes. Cardiovasc Res 2017;113:531–41. https://doi.org/10.1093/cvr/cvx006; PMID: 28158429.

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Clinical Review: Clinical Arrhythmias

Team Management of the Ventricular Tachycardia Patient Pok Tin Tang 1 , Duc H Do 2 , Anthony Li 3 and Noel G Boyle 2 1. Cardiology Department, John Radcliffe Hospital, Oxford, UK; 2. UCLA Cardiac Arrhythmia Center, UCLA Health System, David Geffen School of Medicine at UCLA, Los Angeles, California, USA; 3. Cardiology Department, St George’s University Hospital, London, UK

Abstract Ventricular tachycardia is a common arrhythmia in patients with structural heart disease and heart failure, and is now seen more frequently as these patients survive longer with modern therapies. In addition, these patients often have multiple comorbidities. While anti-arrhythmic drug therapy, implantable cardioverter-defibrillator implantation and ventricular tachycardia ablation are the mainstay of therapy, well managed by the cardiac electrophysiologist, there are many other facets in the care of these patients, such as heart failure management, treatment of comorbidities and anaesthetic interventions, where the expertise of other specialists is essential for optimal patient care. A coordinated team approach is therefore essential to achieve the best possible outcomes for these complex patients.

Keywords Ventricular tachycardia, ventricular arrhythmia, ventricular tachycardia ablation, radiofrequency catheter ablation, ICD, anti-arrhythmic drugs, structural heart disease, ventricular tachycardia storm, multidisciplinary team management Disclosure: The authors have no conflict of interest to declare. Acknowledgement: The authors acknowledge the efforts of Cynthia Romero in preparing this manuscript. Received: 7 July 2018 Accepted: 3 August 2018 Citation: Arrhythmia & Electrophysiology Review 2018;7(4):238–46. DOI: https://doi.org/10.15420/aer.2018.37.2 Correspondence: Noel G Boyle, David Geffen School of Medicine at UCLA, 100 UCLA Medical Plaza, Suite 660, Los Angeles, CA 90095-1679, USA. E: NBoyle@mednet.ucla.edu

Ventricular arrhythmias remain a major contributor to cardiac morbidity and mortality worldwide, despite ongoing research and implementation of novel therapeutic interventions. Modern management of patients with ventricular arrhythmias requires a multidisciplinary team approach, especially in complex presentations with a background of multiple medical comorbidities.1,2 Such teams may include cardiac electrophysiologists (EP), heart failure specialists, general cardiologists and cardiac surgeons, as well as nurses, psychologists and primary care physicians. In emergency presentations with sustained or recurrent ventricular tachycardia (VT) or multiple ICD shocks (‘VT storm’), additional involvement of emergency physicians, intensivists, cardiac anaesthetists and coronary care unit (CCU) staff may be required. Antiarrhythmic medications, ICD implantation and catheter ablation are the cornerstones of current VT management. Recently, catheter ablation has gained a prominent and earlier role in the management of patients with VT. Caring for patients undergoing catheter ablation of VT in dedicated units with integrated multidisciplinary care has been shown to lead to improved outcomes (Figure 1).3

presenting with sustained VT, then reviewing the special situation of VT storm or incessant VT.

Sustained Ventricular Tachycardia Patients with VT may present with palpitations, syncope or ICD shocks where a device is present; in addition, their clinical status and haemodynamic stability will vary. Patients may present to primary or emergency care, or in general cardiology outpatient clinics. Therefore, the recognition of VT through the presence of a wide complex tachycardia on ECG is important for frontline caregivers. Wide complex tachycardias are most often VT and should be treated as such unless proven otherwise. The differential includes supraventricular tachycardia (SVT) with aberrancy, with abnormal baseline QRS, drug effects or electrolyte imbalances, and ventricular pacing. Multiple algorithms for ECG diagnosis of VT have been proposed, which have been well described elsewhere.4 VT algorithms are complex, leading to difficulties in application. With this in mind, simplified algorithms requiring only singlelead measurements such as the Vereckei criteria5 and Pava criteria6 have been developed, although their overall accuracy may be reduced.

In this article, we review the team approach and process of managing VT patients. The patient’s journey often begins in the clinic or emergency room, proceeding to some or all of the following areas: coronary care unit, cardiac catheterisation and EP labs, cardiac operating room, recovery unit, rehab unit to discharge home.

Initial Management and Antiarrhythmic Therapy

At each step, multiple teams need to be involved and coordinated to optimise the patient’s care. In our centre, the primary cardiologist coordinates the patient’s care with close involvement of the cardiac EP team throughout the hospital stay. We will first consider the patient

In haemodynamically unstable sustained VT, the priority is stabilisation and electrical cardioversion. In haemodynamically stable VT, a history, an examination and a 12-lead ECG should be obtained, and treatment with antiarrhythmic medications initiated. If the VT morphology suggests

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It is most useful to approach the initial investigation and management of VT by its causes, broadly divided into those occurring in structurally normal hearts and those in the context of structural heart disease (SHD; Figure 2).

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The Ventricular Tachycardia Patient idiopathic outflow tract VT (left bundle pattern with inferior axis), IV beta-blockers may terminate the arrhythmia. Otherwise, IV amiodarone is considered the most effective first choice for pharmacological management.1,7 IV procainamide can be safely administered at a slow infusion rate, with efficacy for VT termination of 60–80 %, superior to amiodarone.8 Lidocaine has a lower efficacy of around 15–30  %, but is commonly used.7,9 It is important to closely monitor patients while administering antiarrhythmics for haemodynamically stable VT, as hypotension is a side-effect of both amiodarone and procainamide, which can lead to worsening of symptoms and haemodynamically unstable VT: in these cases, prompt sedation and cardioversion is required.

Figure 1: Schematic Showing the Progression of Patients through Multidisciplinary Management of Ventricular Tachycardia

UCLA Cardiac Arrhythmia Center Integrated team management of complex arrhythmias

CCU

Intensivists, heart failure specialists and anaesthesiologists

VT patient presentation: medical and ICD management

CCU nurses Cardiac electrophysiology

EP lab

Cardiac anaesthesiologists, EP lab nurses

Catheter ablation of VT

Cardiac electrophysiologist, EP lab technicians

Cardiac unit

Intensivists, heart failure specialists, CT surgeons

Post-ablation management

Cardiac nurses, Cardiac electrophysiology

Home care

Primary care and heart failure specialists

Discharge and follow-up care

Cardiac EPs, NPs, ICD clinic staff

Investigations and Imaging After acute termination, further investigation into the underlying cause is necessary. A thorough history and examination will help identify any risk factors and potential causes for SHD or primary arrhythmic syndromes. Review of the baseline 12-lead ECG may provide evidence of underlying myocardial disease or arrhythmia syndromes (WolffParkinson-White, long QT, Brugada). A 12-lead ECG of the clinical VT is of great value, as this can indicate aetiology and exit site of VT.10 In rare cases, invasive electrophysiological study may be required to confirm diagnosis.1 Coronary angiography should be undertaken in all patients with recurrent VT to define the coronary anatomy. In patients with ICDs, device interrogation should be undertaken as soon as the patient is stabilised. The device log can provide a full history of the number of VT episodes, therapies delivered and whether shocks are appropriate, inappropriate or even phantom in nature. Additional ECG investigations, such as signal-averaged ECG, can be useful in detection of late potentials and diagnosis of specific cardiomyopathies, such as arrhythmogenic right ventricular cardiomyopathy (ARVC). Imaging is also indicated to detect the presence of SHD. In patients with known SHD, it may be useful to perform repeat imaging to assess current function and progression of disease. Echocardiography is the first-line investigation and can also provide an acute estimate of the left ventricular ejection fraction (LVEF). Where there is diagnostic uncertainty, contrast-enhanced cardiac MRI (CMR) can give further clarity; in addition, a significant proportion of apparently normal hearts at echocardiography may subsequently display structural disease on CMR imaging.11 Detection of late gadolinium enhancement (LGE) has been shown to correlate with the risk of arrhythmia and sudden cardiac death, and areas of scarring identified on CMR imaging have been demonstrated to correlate with areas of scarring on electroanatomic mapping and histopathology.12,13 CMR imaging aids diagnosis, risk stratification and planning for ablation. It can reveal significant details of complex scars, which can help focus mapping and ablation efforts.14 However, CMR imaging has been an investigation that has previously been contraindicated in many patients with ventricular arrhythmias, SHD and heart failure, where the prevalence of implanted cardiac devices is high. Specific concerns have included device lead heating causing thermal myocardial injury, arrhythmias, lead failure, and device failure or malfunction.15 To overcome this, MRI-conditional devices and imaging protocols for extra-thoracic studies with non-conditional devices have been developed over recent years with demonstration of safety.16 This involves assessment of specific criteria (strong indication for imaging, no abandoned leads, device implant older than 6 weeks), use of a strict protocol with continuous monitoring during imaging,

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CCU = cardiac care unit; CT = cardiothoracic; EP = electrophysiology; NP = nurse practitioner; VT = ventricular tachycardia. Modified from Tung et al., 2013.87 Used with permission from American Heart Association/Wolters Kluwer.

and cooperation between radiologists, radiographers and a supervising appropriately trained (advanced cardiovascular life support [ACLS]) physician or specialist nurse practitioner.17 The effects of device artefact on image interpretability have also been a significant problem with MRI. In a single-centre observational study of a standardised CMR imaging protocol in 111 consecutive cardiac MRI studies in patients with ICDs, Do et al. found that use of a wideband protocol for LGE imaging led to a high proportion of interpretable studies unaffected by artefact (87 %).18 No adverse events (arrhythmias, generator/lead failures) were detected during imaging or up to 6 months’ follow-up. Nuclear imaging may be of value in selected cases. A study of patients with unexplained non-ischaemic cardiomyopathy and ventricular arrhythmias showed that nearly half had focal abnormal cardiac fluorine-18 fluoro-2-deoxyglucose (FDG) uptake when investigated with fasting PET/CT. Notably, over half of PET-positive patients who underwent CMR imaging had studies negative for LGE; in the rest, LGE and FDG uptake were well correlated. Areas of PET abnormality matched low-voltage scar regions on electroanatomic mapping, which further corresponded with histological analysis.19

Management of ICDs In patients with ventricular arrhythmias in the context of SHD (i.e. the secondary prevention population), ICD implantation is indicated in almost all cases. While the ICD is effective in preventing sudden cardiac death due to VT or ventricular fibrillation in patients with heart failure, it does not prevent occurrence of VT, and many patients with an ICD will present with one or multiple shocks.20–22 Recurrent ICD shocks have been shown to lead to increased morbidity and mortality, likely a reflection of the progression of underlying cardiac disease.23–25 In patients with recurrent ICD shocks, reprogramming of ICDs by the EP team can help to minimise shocks. The use of overdrive or anti-tachycardia pacing (ATP) to terminate haemodynamically stable

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Clinical Review: Clinical Arrhythmias Figure 2: The Aetiology of VT in the Structurally Normal Heart and in Structural Heart Disease Presentation with VT

Underlying structural heart disease

Structurally normal heart

Idiopathic VT

Outflow tract VT

Fascicular VT

Brugada syndrome

Primary arrhythmic syndromes

Papillary muscle VT

Long QT syndrome

Ischaemic cardiomyopathy

IDCM

Short QT syndrome

Non-ischaemic cardiomyopathy

ARVC

HCM

Cardiac sarcoidosis

Chagas disease

CPVT

ARVC= arrhythmogenic right ventricular cardiomyopathy; CPVT = catecholaminergic polymorphic ventricular tachycardia; ICDM = idiopathic dilated cardiomyopathy; HCM = hypertrophic cardiomyopathy; VT = ventricular tachycardia.

VTs before shocks has been shown to be effective, with similar rates of VT acceleration, VT duration, syncope and sudden death when compared to shock only.26 Reprogramming detection zones and detection intervals is a balancing act that involves allowing for selftermination of ventricular arrhythmias against not delaying therapy for symptomatic or haemodynamically unstable arrhythmias. In patients presenting with ventricular arrhythmias and recurrent device therapies, device interrogation should be performed, with adjustment of rate detection zones and intervals based on the cycle length of clinical VTs; this is in contrast with primary prevention devices, where higher rate cut-offs and longer detection intervals are usually feasible to prevent shocks.27 Finally, the role of inappropriate shocks in recurrent therapies should not be ignored. SVTs represent the most common cause of these, and the use of SVT discriminators can help reduce inappropriate shocks. Onset, stability and morphology criteria help discrimination between SVTs and VTs; this is particularly the case in patients with a history of VT in lower rate zones, where clinical VT characteristics can be accounted for in the discriminator algorithm.28

In a recent meta-analysis, the use of antiarrhythmic drugs led to a 34 % reduction in appropriate ICD therapies;29 the majority of these effects were observed in studies of amiodarone against control medical therapy. Beta-blockers and amiodarone are often used as combination therapy, with improved outcomes and suppression of VT recurrence. This has been shown to be superior to both beta-blockers alone, and sotalol alone.30 Mexiletine, a class IB antiarrhythmic, has been shown in small non-randomised studies to reduce VT recurrence when used as an adjunct to amiodarone in amiodarone-refractory VT,31 and is most commonly used in this setting. Sotalol has been shown to be safe and effective in reducing mortality and ICD shocks.32 However, given its inferiority in subsequent studies when compared against beta-blockers and amiodarone,30 it is primarily used as a second-line therapy. Finally, ranolazine is an inhibitor of the late inward sodium current initially used in the anti-anginal and anti-ischaemic setting, and subsequently found to be effective in VT suppression in the setting of recurrent ICD shocks refractory to other antiarrhythmic drugs.33 This is currently being investigated in a larger scale population in the Ranolazine Implantable CardioverterDefibrillator trial (RAID, NCT01215253).34

Medical Therapy In the structurally normal heart with normal heart function, idiopathic VTs such as outflow tract VT, papillary muscle VT and fascicular VT can be managed with an initial trial of beta-blockers or calcium channel blockers. Although efficacy can be limited, their side-effect profile is relatively favourable. These are used both acutely and for long-term suppression of arrhythmias. In patients with SHD and VT, antiarrhythmic drugs can be used in conjunction with ICD programming to minimise shocks. Beta-blockers have been shown to decrease mortality in patients with VT, heart failure and reduced EF, and are often used in the absence of contraindications. However, they are ineffective when used as monotherapy for prevention of VT recurrence.

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However, antiarrhythmic drug use has not been shown to improve survival. In particular, despite well-characterised benefits in VT suppression, amiodarone appears to be associated with increased allcause mortality.29 Amiodarone use is associated with a high incidence of side effects, primarily affecting the thyroid, lungs, liver and skin;35 patients on amiodarone need to be regularly monitored with blood tests. Significant discontinuation rates (18–38 %) for amiodarone have been noted in multiple trials.30,36–38

Catheter Ablation of Ventricular Tachycardia Catheter ablation of VT was first described in the 1980s,39 and has since gained an increasingly prominent role in the management of many types of VT.40 With the development of electroanatomic

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The Ventricular Tachycardia Patient mapping, advances in ablation technology and the development of epicardial approaches, ablation has become an effective intervention in an increasingly broad range of VT aetiologies, and is now deployed increasingly early in the management of recurrent VT. The impact of catheter ablation has been studied in a variety of causes of VT. In idiopathic VT (outflow tract, fascicular, papillary), ablation can be undertaken in patients intolerant of or refusing medical therapy, in cases where VT has led to reduction in LVEF, or where outflow tract PVCs are found to trigger malignant arrhythmias; procedural success rate is high, with low risk.41 In ischaemic cardiomyopathy, multiple small-scale trials (‘Substrate Mapping and Ablation in Sinus Rhythm to Halt Ventricular Tachycardia’, SMASH-VT; ‘Ventricular Tachycardia Ablation in Coronary Heart Disease’, VTACH) have demonstrated reductions in ICD therapies and greater freedom from VT for patients undergoing ablation and ICD implantation compared to ICD implantation alone.42,43 In the recent ‘Ventricular Tachycardia Ablation Versus Escalated Antiarrhythmic Drug Therapy in Ischemic Heart Disease’ (VANISH) trial, catheter ablation was also found to be superior to escalation of antiarrhythmic therapy in reducing the incidence of a composite primary endpoint of death, VT storm and appropriate ICD shocks.35 In non-ischaemic cardiomyopathies, outcomes are mixed. Studies in idiopathic dilated cardiomyopathy (IDCM) appear to show higher rates of VT recurrence when compared to ablation in ischaemic cardiomyopathy,44 for multiple underlying reasons. Mapping and ablation of IDCM is more challenging: the substrate is often less well defined and patchy, and in locations where ablation is less effective such as intramurally, septally or in the basal anterior LV wall.45 A study of patients with unexplained cardiomyopathy and ventricular arrhythmias who underwent PET/CT showed that a significant proportion had arrhythmogenic inflammatory cardiomyopathy, with diagnoses of cardiac sarcoidosis in 36 %.19 Immunosuppressive therapy was effective in controlling VT and preventing recurrence either as monotherapy or in conjunction with ablation, demonstrating a role for inflammation in the generation and maintenance of ventricular arrhythmias. In these cases, patients may benefit from joint management with other specialties, such as pulmonologists in sarcoidosis, as cardiomyopathy is rarely the sole manifestation of this disease. The use of combined endo-epicardial mapping and ablation in ARVC has achieved good outcomes,46,47 with significantly less VT recurrence than with endocardial mapping only.48–50 The application of epicardial ablation has recently been extended to Brugada syndrome, where targeting of the right ventricular outflow tract can eliminate the Brugada pattern and prevent recurrence of VT in a subset of cases.51,52 The trend towards earlier ablation appears to be supported by improved outcomes in the literature: in one retrospective study of ischaemic and non-ischaemic cardiomyopathy, ablation within 30 days of first documented VT was associated with significantly higher rates of acute procedural success (defined as noninducibility of VT at end of ablation), and freedom from VT recurrence, although cardiac mortality was not significantly different;53 this is a finding replicated by other studies in the field.42,43,54 Although none of the aforementioned studies have demonstrated a reduction in all-cause mortality with catheter ablation, analysis of patient outcomes from large multicentre registries has demonstrated that freedom from VT recurrence post-

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procedure is associated with lower all-cause mortality and progression to transplantation.55 Catheter ablation of VT is a complex procedure: management is best undertaken in dedicated units, with integrated multidisciplinary care.3 Some evidence suggests that increased procedural time may result in higher rates of in-hospital mortality.56 As a result, a structured approach to ablation is necessary. Pre-procedurally, this includes optimisation of patient comorbidities, particularly heart failure with specialist input, withholding anticoagulants and antiarrhythmic medications, and planning for approach of the arrhythmogenic substrate with imaging and preparation of equipment and personnel. Although pre-procedural protocols vary between centres, specific examples of the general approach are available in the literature.57 Intra-procedurally, familiarity with mapping techniques and manoeuvres, ability to appropriately assimilate information, and awareness of limitations and alternatives is essential to prevent the futility of inefficient or ineffectual procedure time.57 The development of modern electroanatomic mapping systems, in combination with preprocedural imaging, has enabled real-time visualisation of substrates during mapping.58 Post-procedurally, admission to CCU, with multidisciplinary input from CCU staff, EP teams, heart failure specialists, nursing staff and physiotherapists, helps detection of complications and optimisation of post-procedural recovery. Post-procedural testing can help identify patients who may need further interventions.57

Management of VT Storm and Incessant VT VT storm is defined as three or more separate episodes of sustained VT requiring intervention (such as ICD shock or ATP) within 24 hours. This is a medical emergency requiring prompt intervention with a multidisciplinary team approach to stabilise the patient, initiate therapies and optimise the patient for further interventions (Table 1 and Figure 3). On admission, patients with significant medical comorbidities, or with VT that is not haemodynamically tolerated, should be admitted to a coronary care or intensive care unit. Initial stabilisation and resuscitation is often carried out by the CCU team following ACLS protocols to stabilise the patient, with cardioversion if necessary. Reversible causes of electrical storm should be sought and corrected where applicable, such as acute ischaemia, electrolyte imbalances, drug-induced proarrhythmia and decompensated heart failure.

ICD Programming and Initiation of Antiarrhythmic Medications If the patient has an ICD in situ, device interrogation is required to determine the nature of shocks, and to reprogram the device to minimise shocks, through the use of ATP, extending VT detection duration and increasing rate detection thresholds where appropriate. Anti-arrhythmic medications are the first-line therapy in emergency departments and CCUs, as discussed earlier. Amiodarone is most commonly used, along with lidocaine, and in some cases procainamide. Maximising beta-blockade in this situation is important in breaking the cycle of sympathetic stimulation, which initiates VT, and, fuelled by ongoing stress responses from repeated shocks, often provokes further episodes of VT.

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Clinical Review: Clinical Arrhythmias Table 1: Phases and Teams in the Management of VT Storm 1. Initial Stabilisation ACLS protocols/cardioversion (ED/CCU team and nursing) ICD programming (cardiac EP team) Initiate antiarrhythmic drugs (CCU/EP team) Treat heart failure (CCU team) Imaging, where feasible (echocardiogram, TOE, CT, MRI, PET) Mechanical support for cardiogenic shock (interventional cardiology/surgery) Thoracic epidural anaesthesia if indicated (anaesthesia) Unique aetiologies, e.g. sarcoidosis (pulmonologists, immunologists) 2. Managing Patient During VT Ablation Prepping the patient (nursing and laboratory staff) NIPS study (EP team) Monitoring the patient (anaesthesia) IV antiarrhythmic drugs and pressor support (anaesthesia) EP study and RF ablation (EP team) Communication with CCU medical and nursing teams

VT storm.60,61 The largest study to date of patients presenting with VT storm or incessant VT found that TEA could be safely performed, with a response seen in over half of patients.62 In some patients where response was observed, it was possible to wean off antiarrhythmic medications, or extubate patients. Thus, TEA can be employed as a substitute for deep sedation, and can be an effective bridging therapy allowing for stabilisation before further definitive therapy, such as catheter ablation (Figure 3). The authors suggest that TEA should be considered in patients without other reversible factors for VT storm, no contraindications to thoracic epidural catheter placement (e.g. infection or continuous therapeutic anticoagulation required), and where VT is not controlled despite the use of two or more antiarrhythmic medications. Percutaneous stellate ganglion blockade is another autonomic modulatory intervention that can be performed at the bedside. Although descriptions of its efficacy have primarily taken the form of case reports, a recent meta-analysis showed beneficial effects in reduction of ventricular arrhythmia episodes and defibrillation, allowing patients in some cases to proceed to further definitive treatment such as ablation or transplantation.63

Immediate post procedure care (anaesthesia and nursing) Intermediate post procedure care (CCU team and nursing) Other procedures: cervical sympathectomy (cardiac surgery), renal denervation (EP) 3. Outpatient Management Team Primary physician Heart failure nurses and physicians ICD clinic â&#x20AC;&#x201C; device follow-up Arrhythmia/EP clinic Cardiac rehabilitation Social worker support/family support ACLS = advanced cardiovascular life support; CCU = cardiac care unit; ED = emergency department; EP = electrophysiology; NIPS = noninvasive programmed stimulation; RF = radiofrequency; TOE = transaesophogeal echocardiogram; VT = ventricular tachycardia.

Sedation Sedation in VT storm can be beneficial in reducing sympathetic tone, along with the pain associated with repeated shocks, and is used often. In particular, patients who are haemodynamically unstable with VT may require general anaesthesia with intubation, potentially with mechanical haemodynamic support. However, sedation can lead to further decompensation in the form of severe hypotension in patients who have limited haemodynamic reserve, and must be managed carefully; in addition, prolonged intubation is not ideal.

Thoracic Epidural Anaesthesia and Percutaneous Stellate Ganglion Blockade As the role of the sympathetic nervous system in the generation and maintenance of ventricular arrhythmias is increasingly recognised, therapies that modulate the sympathetic nervous system, such as cardiac sympathetic denervation and renal denervation have gained prominence in the management of refractory VT.59 However, these procedures cannot be feasibly performed in the acute phase, and are usually reserved for those patients with VT refractory to catheter ablation. Thoracic epidural anaesthesia (TEA), on the other hand, is an intervention that can be more easily instigated acutely: originally used for perioperative pain relief, it also provides sympathetic blockade at the level of T1â&#x20AC;&#x201C;T4, and has been shown to be effective in controlling

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Mechanical Haemodynamic Support Devices The use of mechanical haemodynamic support may be necessary to maintain end-organ perfusion in presentations with VT storm. It is essential to seek input from heart failure specialists and cardiac surgeons in assessing and planning to use haemodynamic support options. Available devices include intra-aortic balloon pumps (IABP), percutaneous left ventricular assist devices (pLVAD) such as the Impella and TandemHeart systems, and extracorporeal membrane oxygenation (ECMO). The IABP has historically been the most commonly used of these, although pLVAD and ECMO, which give additional support, are being increasingly employed in specialised centres in recent years. Haemodynamically unstable VT storm is not the only setting in which mechanical haemodynamic support is used in VT. It is also used in preparation for ablation in patients with poor LVEF at baseline, when VT induction will likely result in acute haemodynamic decompensation (AHD).64 The need for a large arterial cannula for maximal output in the TandemHeart system necessitates arterial cutdown and insertion by an interventionalist with experience in use of the device. ECMO presents an even greater challenge, requiring coordination from intensivists, perfusionists and cardiac/vascular surgeons to initiate and monitor its use.

Risk Stratification and Patient Management for Catheter Ablation of VT Catheter ablation in the setting of VT storm has been shown to suppress acute recurrence and stabilise the patient in the short term, even if the procedure is not completely successful;65 in longer term follow-up, procedural success is associated with reduced VT storm and improved survival, although risk of recurrence remains high.65,66 In the VANISH trial, catheter ablation led to reduced occurrence of VT storm compared with escalation in antiarrhythmic therapy.35 Combined endocardial and epicardial mapping and ablation can be used in this setting, in patients who satisfy criteria suggestive of epicardial substrate or circuit.67 As VT ablation carries high risk of post-procedural morbidity and mortality, pre-procedural risk assessment is important. This should

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The Ventricular Tachycardia Patient aim to guide selection of patients not appropriate for ablation, and to identify high-risk cases that may require more aggressive optimisation with involvement of intensivists and perfusionists for prophylactic haemodynamic support. The use of existing models can be useful to predict medium- to longterm survival in patients being considered for catheter ablation, which can then be weighed against the risk/benefit of proceeding. The Seattle Heart Failure Model, a commonly used and widely available tool for estimating mortality in patients with heart failure, has been shown to accurately identify those at high risk of mortality within 6 months of VT ablation when modified with the inclusion of risk modifiers for VT storm and ICD shocks. This not only acts as a useful tool to justify not undertaking ablation in some patients, but also aids discussions with patients and families regarding expectations for prognosis.68 A major risk of performing VT ablation is periprocedural acute haemodynamic decompensation (AHD), defined as persistent hypotension that requires mechanical support or procedure discontinuation. This is often secondary to the severity of the underlying cardiac disease, and aspects of ablation, such as induction of anaesthesia, repeated induction and termination of VT, and fluid overload from catheter irrigation. AHD is a particular concern for patients with heart failure and multiple comorbidities – common findings in patients undergoing ablation – although identification of those most at risk has not always been simple. A single-centre study characterised the incidence of and risk factors for AHD in 193 patients undergoing catheter ablation.69 This occurred in 11 % of cases, and eight clinical variables were significantly associated with increased risk: age over 60 years; use of general anaesthesia; ischaemic cardiomyopathy; more severe heart failure (New York Heart Association [NYHA] class III/IV); reduced LVEF; presentation with VT storm; diabetes; and chronic obstructive pulmonary disease. Based on the associated odds ratios, the authors developed the PAAINESD score, a 35-point scale divided into three risk categories (Figure 4 and Table 1). In the study, AHD occurred in 2  %, 6  % and 24  % of patients in each category, respectively. Additionally, patients with AHD in the study had significantly higher mortality at 6 months and 1 year, with a tendency towards higher 30-day mortality. This was supported by a subsequent large-scale multicentre retrospective application of the PAAINESD score to 2,061 patients undergoing VT ablation, using data from the International VT Ablation Center Collaboration Group (IVTCC). PAAINESD scores were significantly higher in cases of early mortality (within 31 days postablation), compared with survivors and deaths beyond 31 days.70 The developers of the PAAINESD score thus suggest that it could be used to predict AHD and early mortality in patients undergoing catheter ablation, which could be minimised not only with appropriate patient selection, but also through more aggressive pre-procedural optimisation and use of prophylactic haemodynamic support. In support of this, one nonrandomised study investigating the role of pre-emptive implantation of pLVAD (Impella, TandemHeart) before ablation compared with rescue pLVAD reported similar PAAINESD scores in the pre-emptive and rescue pLVAD groups, but a significantly higher 30-day mortality rate in the rescue pLVAD group (58  %), compared against both the pre-emptive pLVAD (4  %) and no-pLVAD (2  %) groups.71 Similarly, in a separate retrospective uncontrolled observational study, the use of ECMO as rescue haemodynamic support was associated with a high mortality rate (overall 76 %).72

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Figure 3: An Overview of Management for Patients Presenting with VT Storm VT storm

ACLS: cardioversion, AAD (amiodarone/lidocaine)

Identify/treat reversible causes

ICD reprogramming

Beta-blockers/AAD escalation

Intubation/ deep sedation

TEA as bridge

VT ablation as feasible

Sympathectomy/ renal denervation

OHT/VAD AAD = antiarrhythmic drugs; ACLS = advanced cardiac life support; OHT = orthotopic heart transplant; TEA = thoracic epidural anaesthesia; VAD = ventricular assist device; VT = ventricular tachycardia.

The PAAINESD score may also help to improve quantification of risk in patients who have risk factors for early mortality, but may actually represent lower risk candidates for ablation. Surveys of centres offering VT ablation and analyses of registries indicate that the rate of ablation is lower in groups such as the elderly and those with severe heart failure.73 Data suggest that ablation often occurs later in the management pathway, and thus likely later in the disease course for elderly patients, with a preference for escalation of antiarrhythmic medications.74 Rates of elective VT ablation in the elderly tend to be lower than in younger populations.75 Following on from this, ablation later in disease, in the emergency setting of VT storm or delaying ablation in presentations with VT storm may increase procedural risk and adversely affect outcomes.54 Such issues are highlighted by IVTCC group registry analyses that have investigated safety and efficacy outcomes, firstly in elderly patients (over 70 years) compared with younger patients,76 and secondly in severe heart failure patients (NYHA class IV compared with NYHA class II/III).77 In general, in-hospital and 1-year mortality were higher in elderly and NYHA IV patients, who overall represented a higher risk group, although acute procedural success and complication rates were not significantly different. Notably, in both studies, rates of successful ablation with long-term VT-free survival were not significantly different between groups. In addition, long-term VT-free survival translated to improved overall survival in elderly/severe heart failure patients compared with patients in the same group with VT

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Clinical Review: Clinical Arrhythmias

PAAINESD risk score Variable

Score

Pulmonary disease (chronic obstructive pulmonary disease)

5

Age >60 years

3

Anaesthesia (general)

4

Ischaemic cardiomyopathy

6

NYHA class III or IV

6

Ejection fraction <25 %

3

Storm (VT)

5

Diabetes

3

Source: Santangeli et al., 2017.88 Reproduced with permission from Elsevier.

recurrence. These results are consistent with smaller scale studies of elderly patients undergoing VT ablation, and subgroup analyses of SMASH-VT and VANISH.35,42,74

Figure 4: Relation between the PAAINESD Score and Incidence of Periprocedural Acute Haemodynamic Decompensation in a Single-Centre Cohort of Patients Undergoing VT Ablation

Incidence of acute haemodynamic decompensation (%)*

Table 2: The PAAINESD Score for Predicting Risk of Acute Haemodynamic Decompensation

30

Predictors of AHD – PAAINESD Score n=193 patients with scar-related VT

25 20 15 10 5 0

T1 (<10 points)

T2 (10–16 points)

T3 (≥17 points)

PAAINESD Score (Tertile)

These studies demonstrate that VT ablation can be performed safely in appropriately selected patients with high-risk features. It is important to note that freedom from VT recurrence resulted in significantly better overall survival than in patients where VT recurred. This highlights an area of risk stratification that might benefit from further study: the identification of patients who are most likely to respond to VT ablation, with low rates of VT recurrence, and who therefore have the most potential for survival benefit.

Further Procedures Although ablation procedures have a relatively high success rate, a significant number of VTs remain refractory to ablation. In such cases, further interventions may be considered. First of all, repeat ablation may be indicated. If the original ablation procedure involved only endocardial mapping and ablation, a repeat procedure with epicardial mapping and ablation may be able to prevent further VT. In some patients, efforts at ablation may have been hindered by difficulties in accessing the substrate, such as for VT originating from the interventricular septum. In such instances, interventions such as transcoronary ethanol ablation may be effective.78 Traditional epicardial access may be hindered by the presence of pericardial adhesions. Here, surgical epicardial access gained with the assistance of cardiothoracic surgeons may be a safe alternative.79

*Sustained hypotension (SBP <80–90 mmHg) despite increasing doses of vasopressors and requiring mechanical haemodynamic support or procedure discontinuation. AHD = acute haemodynamic decompensation; NYHA = New York Heart Association; SBP = systolic blood pressure; VT = ventricular tachycardia. Source: Santangeli et al., 2017.88 Reproduced with permission from Elsevier.

clear discussions with patients and relatives are held in advance to explain the rationale behind clinical decision-making and to determine the wishes of the patient while they are able to communicate them. Discussion regarding measures such as device deactivation should be approached in advance.81 It may be useful to discuss with palliative care teams before procedures, and for them to review and meet the patient and family, to smooth the process of transition to supportive care when this is appropriate.

Outpatient and Home Care It is difficult to predict the long-term outcomes of VT ablation in individual patients. Estimates of VT recurrence and mortality presented in the literature are based on a wide range of studies that have investigated outcomes of ablation in a variety of VT aetiologies with differences in prior therapy, number of procedures and ablation techniques used.82 In general, 1-year recurrence rates are approximately 30 % to 43  %; 2-year recurrence rates are around 50 %.35,43,44,55,83 Future studies may give more accurate estimates of outcomes in specific populations of patients with VT.82

Autonomic modulation procedures may be indicated in the setting of ongoing refractory VT. Surgical cardiac sympathetic denervation can significantly reduce the incidence of ICD shocks in refractory VT.80 Renal denervation has also been shown to prevent VT recurrence in small case series.59 VT ablation may be used as a bridging procedure to insertion of left ventricular assist devices or cardiac transplant, in which case the procedure and post-operative care should be undertaken with involvement from transplant teams and cardiac surgeons.

Recurrent admissions with heart failure are common in patients with SHD, although possibly reduced after ablation, and likely represent progression of disease status. 83 The 1-year mortality rate postablation is reported at about 15–20 %; again, this varies depending on aetiology and VT-free survival status, and is often reported as a composite with transplant-free survival.55,84 Much of this is driven by progressive heart failure and is not necessarily surprising given the knowledge that ICD shocks are associated with increased risk of mortality from heart failure.25

In some cases, the role of further interventions may be limited or ablation may have been undertaken as a palliative procedure, to minimise the burden of distressing ventricular arrhythmias. It is important that in cases where these situations are anticipated, that

Patients require ongoing care and regular review after discharge. Care in the community is primarily conducted by the patient’s primary care physician and general cardiologist, heart failure specialist nurses and cardiac device technicians, but further specialist input from

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The Ventricular Tachycardia Patient heart failure and electrophysiology teams may be required. The use of home monitoring systems in patients with implanted devices may be useful to monitor for VT recurrence. Patients may require re-do ablations, further interventions, or cardiac transplantation, as discussed above. Finally, psychological support for the patient is important: although life-saving, repetitive shocks can exacerbate anxiety and reduce quality of life, at least in the short term, as well as increasing subsequent risk of death.85,86 It is important to support the patient to build confidence, and to allow patients to maintain a good quality of life despite this.

Conclusion Management of patients with ventricular arrhythmias is complex. In outpatient or non-specialist settings prompt referral is important, and this is achieved by ensuring good links between community care givers and hospital teams. In-hospital management requires multispecialty input in a dedicated specialist setting. Co-ordination of care, in our hospital by the coronary care unit attending cardiologist and team, ensures that appropriate additional specialist input is sought, and investigations and interventions can be coordinated. Catheter ablation has assumed an increasingly prominent role in the treatment of VT. Although early referral of patients for catheter ablation is desirable, appropriate patient selection is required using existing risk-stratification schemes. Further studies will better quantify the timing and benefits of catheter ablation in specific subpopulations of patients with VT.

1.

 edersen CT, Kay GN, Kalman J, et al. EHRA/HRS/APHRS P expert consensus on ventricular arrhythmias. Europace 2014;16:1257–83. https://doi.org/10.1016/j.hrthm.2014.07.024; PMID: 25179489. 2. Fumagalli S, Chen J, Dobreanu D, et al. The role of the Arrhythmia Team, an integrated, multidisciplinary approach to treatment of patients with cardiac arrhythmias: results of the European Heart Association survey. Europace 2016;18:623–7. https://doi.org/10.1093/europace/euw090; PMID: 27174994. 3. Della Bella P, Baratto F, Tsiachris D, et al. Management of ventricular tachycardia in the setting of a dedicated unit for the treatment of complex ventricular arrhythmias. Circulation 2013;127:1359–68. https://doi.org/10.1161/ CIRCULATIONAHA.112.000872 PMID: 23439513. 4. Garner JB, Miller JM. Wide complex tachycardia – ventricular tachycardia or not ventricular tachycardia, that remains the question. Arrhythm Electrophysiol Rev 2013;2:23–9. https://doi. org/10.15420/aer.2013.2.1.23; PMID: 26835036. 5. Vereckei A, Duray G, Szénási G, et al. New algorithm using only lead aVR for differential diagnosis of wide QRS complex tachycardia. Heart Rhythm 2008;5:89–98. https://doi. org/10.1016/j.hrthm.2007.09.020; PMID: 18180024. 6. Pava LF, Perafán P, Badiel M, et al. R-wave peak time at DII: a new criterion for differentiating between wide complex QRS tachycardias. Heart Rhythm 2010;7:922–6. https://doi. org/10.1016/j.hrthm.2010.03.001; PMID: 20215043. 7. deSouza IS, Martindale JL, Sinert R. Antidysrhythmic drug therapy for the termination of stable, monomorphic ventricular tachycardia: a systematic review. Emerg Med J 2015;32:161–7. https://doi.org/10.1136/ emermed-2013-202973; PMID: 24042252. 8. Ortiz M, Martín A, Arribas F, et al. Randomised comparison of intravenous procainamide vs. intravenous amiodarone for the acute treatment of tolerated wide QRS tachycardia: the PROCAMIO study. Eur Heart J 2017;38:1329–35. https://doi. org/10.1093/eurheartj/ehw230; PMID: 27354046. 9. Komura S, Chinushi M, Furushima H, et al. Efficacy of procainamide and lidocaine in terminating sustained monomorphic ventricular tachycardia. Circ J 2010;74:864–9. https://doi.org/10.1253/circj.CJ-09-0932; PMID: 20339190. 10. Josephson ME, Callans DJ. Using the twelve-lead electrocardiogram to localize the site of origin of ventricular tachycardia. Heart Rhythm 2005;2:443-446. https://doi. org/10.1016/j.hrthm.2004.12.014; PMID: 15851350. 11. White JA, Fine NM, Gula L, et al. Utility of cardiovascular magnetic resonance in identifying substrate for malignant ventricular arrhythmias. Circ Cardiovasc Imaging 2012;5:12–20. https://doi.org/10.1161/CIRCIMAGING.111.966085; PMID:

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Finally, at the centre of care remains the patient, for whom recurrent arrhythmias and worsening heart failure often bring significant morbidity and mortality. It is important to discuss options, risks and prognosis to allow patients to make informed choices about their care. The combination of a patient-centred approach with modern treatment modalities and appropriate specialist care is vital to ensuring optimal outcomes in patients presenting with VT.

Clinical Perspective • M  odern management of patients with ventricular arrhythmias is complex, and requires a multidisciplinary team approach in experienced units to ensure optimal outcomes. •  Appropriate initial investigations and prompt referral to specialist care are key to optimal management of ventricular tachycardia, as well as establishing underlying aetiology, which has significant implications for management. •  Medical therapy may be effective in some cases, but may have significant side effects. ICD therapy prevents sudden cardiac death, but can lead to recurrent shocks, which results in increased morbidity and mortality, likely an indication progression of underlying disease. •  Radiofrequency catheter ablation has gained an increasingly prominent role in the management of ventricular arrhythmias, although further studies are required to define the risk and outcomes of procedures in individual patients. • We discuss and give an overview of the management of patients presenting with ventricular tachycardia storm, including the evolving role of neuromodulation.

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ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

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Clinical Review: Clinical Arrhythmias

Heart Rate Variability: An Old Metric with New Meaning in the Era of Using mHealth technologies for Health and Exercise Training Guidance. Part Two: Prognosis and Training Nikhil Singh, 1 Kegan James Moneghetti, 2,3 Jeffrey Wilcox Christle, 3 David Hadley, 4 Victor Froelicher 3 and Daniel Plews 5 1. Department of Medicine, Keck School of Medicine of University of Southern California, Los Angeles, CA, USA; 2. Department of Medicine, St Vincent’s Hospital, University of Melbourne, Australia; 3. Division of Cardiovascular Medicine, Department of Medicine, Stanford School of Medicine, Stanford, CA, USA; 4. Cardiac Insight Inc, Seattle, USA; 5. Sports Performance Research Institute New Zealand, Auckland University of Technology, Auckland, New Zealand

Abstract It has been demonstrated that heart rate variability (HRV) is predictive of all-cause and cardiovascular mortality using clinical ECG recordings. This is true for rest, exercise and ambulatory HRV clinical ECG device recordings in prospective cohorts. Recently, there has been a rapid increase in the use of mobile health technologies (mHealth) and commercial wearable fitness devices. Most of these devices use ECG or photo-based plethysmography and both are validated for providing accurate heart rate measurements. This offers the opportunity to make risk information from HRV more widely available. The physiology of HRV and the available technology by which it can be assessed has been summarised in Part 1 of this review. In Part 2 the association between HRV and risk stratification is addressed by reviewing the current evidence from data acquired by resting ECG, exercise ECG and medical ambulatory devices. This is followed by a discussion of the use of HRV to guide the training of athletes and as a part of fitness programmes.

Keywords Heart rate variability, exercise, athletic training, mobile health technologies, prognosis, athletic performance Disclosure: David Hadley and Victor Froelicher are partial owners and developers of ECG analysis software Cardiac Insight. There is no mention of their products in this review. Nikhil Singh, Kegan James Moneghetti, Jeffrey Christle and Daniel Plews have no conflicts of interest to declare. Received: 26 April 2018 Accepted: 7 August 2018 Citation: Arrhythmia & Electrophysiology Review 2018;7(4): 247–55. DOI: https://doi.org/10.15420/aer.2018.30.2 Correspondence: Daniel Plews, Sports Performance Research Institute, AUT University, AUT-Millennium, 17 Antares Place, Mairangi Bay, Auckland, New Zealand. E: daniel.plews@aut.ac.nz

Estimation of Prognosis Using HRV The association of heart rate variability (HRV) and prognosis, both for all-cause and cardiovascular (CV) mortality, has been studied using ECG at rest, with exercise and in the ambulatory setting. A metaanalysis by Hillebrand and colleagues found that, using both resting and ambulatory ECG monitoring, lower HRV is associated with a 32–45 % increased risk of first CV event in patients without known CV disease.1 Additionally, elevated HRV demonstrates a protective effect, with an increase in standard deviation of the normalised NN interval (SDNN) of 1  % resulting in an approximate 1  % reduction of fatal or non-fatal CV disease event.

Resting ECG for HRV Prognosis The Zutphen study assessed HRV obtained from resting ECGs in 878 men aged 50–65 years, referred to as the middle-aged cohort, who were followed up 15 years later.2 Participants from the original population and new patients formed a group of 885 patients, referred to as the elderly cohort. Using resting 15–30 seconds of 12-lead ECG data to calculate SDNN, the investigators found increased rates of coronary heart disease mortality (RR 2.1, 95 % CI [1.1–4.1]) and allcause mortality (RR 2.1, 95  % CI [1.4–3.0]) among patients with HRV <20 ms (compared with 21–39 ms) in the middle-aged cohort at 5-year follow-up. No significant change in mortality was noted in patients with the highest HRV (≥40 ms). No association with mortality was found in the elderly cohort.

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The Rotterdam study enrolled 5,272 patients aged 55 years (mean =  69  ±  9) and acquired 10-second rest 12-lead ECGs.3 SDNN values were put into quartiles with the 25th, 50th, and 75th percentiles corresponding to values of 9.6 ms, 15.2 ms, and 25.9 ms, respectively. The investigators found that patients in the lowest quartile had an 80 % increase (HR 1.80, 95  % CI [1.0–3.2]) for cardiac mortality compared with patients in the third quartile after adjustments for age and sex. Patients in the highest quartile had the most pronounced adjusted risk for cardiac mortality (HR 2.3, 1.3–4.0), suggesting that low or high SDNN can be associated with mortality in an older population. The Atherosclerosis Risk In Communities (ARIC) study used a casecohort method of analysing 900 patients without CAD and using 2-minute ECGs, SDNN, root mean square of the differences in successive R-R intervals (RMSSD), and percentage of R-R intervals that differ by 50 ms (pNN50).4 Demographic-adjusted survival analysis showed increased RR of all-cause death and incident coronary artery disease in the lowest tertile compared with intermediate and highest tertiles for all variables. RR of mortality for SDNN in the lowest tertile (<30 ms) was 2.10 compared with the intermediate group. Yoo and colleagues compared HRV with the Framingham Risk Score to determine if HRV values could serve as an acceptable substitute for a CHD risk assessment.5 The study involved 85 adults using resting ECG measurements in the seated position taken after 20 minutes of rest.

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Clinical Review: Clinical Arrhythmias Table 1: Nomenclature for Common Heart Rate Variability Measurements Abbreviation

Units

Description

SDNN

ms

Standard deviation of NN intervals

SDRR

ms

Standard deviation of RR intervals

pNN50

%

Percentage of successive RR intervals that differ by more than 50 ms

RMSSD

ms

Root mean square of successive RR interval differences

HF

ms2/Hz/nu

High-frequency power

LF

ms2/Hz/nu

Low-frequency power

Patients with Framingham risk >10 % were found to have significantly depressed SDNN, RMSSD, and in high-frequency (HF) values. These signals, however, appeared to be isolated to men and there was no statistically significant relationship between Framingham risk score and HRV among women in this small cohort. These findings extend to cohorts with established CV disease. Studying only patients with dilated cardiomyopathy, La Rovere and colleagues found reductions in HRV to be predictive of sudden death.6 A resting ECG of 8 minutes’ duration was obtained with spontaneous respiration, as well as a controlled breathing period. Patients with dilated cardiomyopathy were found to have reductions in low frequency (LF) power with spontaneous (30 ms2 versus 45 ms2, p=0.01) and controlled-breathing (28 ms2 versus 41 ms2, p=0.02). Reduced LF power during controlled breathing was found to be predictive of sudden death during a 3-year follow-up period (RR 2.8, 95 % CI [1.2–6.8]), independent of left ventricular dimensions. Resting HRV measurements have been used to link enhanced sympathetic autonomic nervous system (SANS) activity with myocardial destabilisation and arrhythmogenic potential. HRV, however, serves as an indirect measurement of SANS, given its action on baroreceptors and the sinoatrial node. Periodic repolarisation dynamics (PRD), which can be obtained by focusing on low-frequency patterns of resting 3D ECGs, may serve as a more direct measurement.7 Factors that lead to heterogeneous sympathetic activation, such as previous MI, diabetes, and inherited channelopathies, are all associated with greater PRD at rest. Previous studies have shown resting PRD to predict post-MI mortality independent of established risk factors such as left ventricular ejection fraction, the Global Registry of Acute Coronary Events (GRACE) score, increased QT-variability index, and reduced HRV.8 Current studies are ongoing to better understand the role of PRD in identifying patients for prophylactic ICD placement.

Ambulatory ECG for HRV Prognosis While the ECG is the established gold standard for cardiac monitoring, technological advances have allowed for commercial products to be developed to allow for out-of-hospital monitoring. Both ECG and photo-based plethysmography have been validated as accurate measures of HR, and commercial products using these methods of detection have allowed for accurate and prolonged detection of arrhythmias such as AF.9 With increasing evidence for HRV as a prognostic tool, there have been attempts to validate these homebased technologies for HRV as well.

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Studying patients from the original Framingham study, Tsuji et al found an increased risk of all-cause mortality in patients with depressed HRV.10 Using 2-hour ambulatory ECG monitoring, the investigators considered 736 patients from the original Framingham study. They found that, with adjustment for age, sex, and clinical risk factors, patients 1 SD below the mean for SD of NN intervals (SDNN), LF, very LF (VLF), HF and total power all had increased risks of all-cause mortality over 4 years. SDNN was the only time-domain factor with elevated risk after adjustment (HR 1.38, 95 % CI [1.13–1.70], p=0.019). Decreased values of LF were associated with highest adjusted risk (1.70, 95 % CI [1.37–2.09], p=0.001) of all HRV parameters. Additionally, a study combining patients from the original Framingham study and the Framingham Offspring Study (n=2,501, average age 53 years), demonstrated that with 2-hour ambulatory ECG monitoring, patients with lower SDNN had significantly higher rates of heart disease (12.40 versus 2.06).11 A long-term prospective study by Kikuya reported results from ambulatory BP data obtained from 1,542 subjects (mean 62 years, 40  % male) in Japan.12 BP and HR measurements were taken every 30  minutes using an ambulatory cuff-oscillometric device, as the patients went about their normal day and night routines. Patients were divided by SDNN into three groups (mean - SD, mean ± SD, mean + SD) for analysis. A significant inverse linear relationship was noted for daytime HRV and cardiovascular death (p=0.008) during the mean follow-up period of 8.5 years, even after adjustment for use of beta blockers. The lowest HRV tertile was found to have HR of 3.64 (p=0.02). Changes in night-time HRV did not show a similar risk of CV death. The Autonomic Tone and Reflexes After MI (ATRAMI) study considered the prognostic value of SDNN in 1,284 patients with recent MI.13 Patients with MI within the previous 28 days were enrolled in the study and followed with ambulatory Holter monitoring for SDNN analysis. Baroreflex sensitivity was also assessed by measuring rate-pressure response to. infusion of phenylephrine. Multivariate analysis showed that patients with SDNN <70 ms or baroreflex sensitivity <3 ms/mmHg showed increased risk of cardiac mortality. In patients with depression of both parameters, 2-year mortality was 17  % compared with 2  % in patients where the parameters had remained stable. Klieger et al. demonstrated similar post-MI results,with a RR of mortality of 5.3 in post-MI patients with SDNN <50ms compared with those that had >100  ms.14 The Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI-2) study analysed the usefulness of HRV in patients who had a recent MI that had been treated with fibrinolytic therapy.15 Of 567 patients, 7.8 % died of cardiovascular causes during 1,000 days of follow-up. HRV parameters exhibited elevated RR for SDNN (RR 3.0), RMSSD (RR 2.8) and NN50 (RR 3.5). While often used to predict mortality, a review by Reed et al looked at HRV as a predictor of ventricular tachyarrhythmias (VTA).16 Vybrial et al showed no consistent changes in HRV indices in 24 patients who wore Holter monitors and developed ventricular fibrillation.17 Huikuri et al, however, found significant reductions in HR and HRV indices (SDANN, HF, LF) in post-MI patients who developed ventricular tachycardia compared with those without arrhythmic events.18 These changes occurred in the 1-hour period preceding VTA, and the degree of reduction was more pronounced in patients with sustained arrhythmias. Shusterman et al demonstrated that the presence of a change in HRV alone,19 within a 2-hour period before arrhythmic events, could predict the development of VTAs.20

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HRV and mHealth Table 2: Mortality Risk Associated with Various Heart Rate Variability Measurements Using Resting ECG Study

Number of Patients

Monitoring Method

HRV Parameters

Conclusions

Zutphen study Dekker et al. 19972

878 (middle-aged cohort) 885 (elderly cohort)

Resting ECG, 15–30 sec

SDNN

SDNN <20 ms associated with increased risk of CHD (RR 2.1, 95 % CI [1.1–4.1]) and allcause mortality (RR 2.1, 95 % CI [1.4–3.0])

Rotterdam study De Bruyne et al. 19993

5,272

Resting ECG, 10 sec

SDNN

SDNN in lowest and highest quartiles had increased risk of cardiac mortality; HR 1.8 (95 % CI [1.0–2.3]) and 2.3 (95 % CI [1.3–4.0]) respectively

ARIC study Dekker et al. 20004

900

Resting ECG, 2 min

SDNN, rMSSD, SDSD, pNN50

Increased risk of all-cause mortality for patients in the lowest tertile of all parameters (RR 1.47–1.91)

Yoo et al. 20115

85

Resting ECG

SDNN, rMSSD, VLF, LF, HF, LF/HF, TP

SDNN (28ms versus 36ms, p=0.037), rMSSD (28ms versus 29ms, p=0.007), and lnHF (4.7ms2 versus 5.5ms2, p=0.008) are depressed in patients with FRS >10 %

La Rovere et al. 20036

444

Resting ECG, 8 min

SDNN, LF and HF

Increased risk of sudden death with reduced LFP (RR 2.8, 95 % CI [1.2–6.8], p=0.02)

FRS = Framingham risk score; HF = high frequency power; HRV = heart rate variability; LF = low frequency power; LF/HF = low frequency to high frequency power ratio; ln HF = natural log of the high-frequency measurement; pNN50 = percentage of RR intervals that differ by 50ms; rMSSD = root mean square of the differences in successive R-R intervals; SDNN = standard deviation of NN intervals; SDSD = standard deviation of absolute differences between successive intervals; TP = total power; VLF = very low frequency power.

Table 3: Mortality Risk Associated with Various Heart Rate Variability Measurements Using Ambulatory ECG Study Name

Number of

Monitoring Method

HRV parameters

Conclusions

Patients Tsuji et al. 199410 (Framingham)

736

2-hour ambulatory ECG

VLFP, LFP, HFP, LFP/HFP, TP, SDNN, rMSSD, pNN50+

lnLF <1 SD from mean had increased all-cause mortality (HR 1.70, 95 % CI [1.37–2.09])

Tsuji et al. 199611 (Framingham Offspring)

2,501

2-hour ambulatory ECG

VLFP, LFP, HFP, LFP/HFP, TP, SDNN, rMSSD, pNN50+

All HRV parameters except LFP/HFP associated with increased risk of cardiac events (p=0.016–0.0496); adjusted HR for lnSDNN <1 SD from mean 1.45 (95 % CI [1.13–1.85], p=0.003)

Kikuya et al. 200012

1,542

Ambulatory blood pressure monitor

SDNN

Patients in lowest tertile have increased risk of all-cause mortality (HR 3.70, p=0.003)

La Rovere et al. 199813 ATRAMI trial

1,284

24-hour Holter monitor

SDNN

SDNN <70 ms had increased risk of CV-related death (RR 5.3, 95 % CI [2.49–11.4], p<0.0001) compared to >105 ms

Klieger et al. 198714

808

24-hour Holter monitor

SDNN

SDNN <50ms had increased risk of all-cause mortality compared with >100 ms (34 % versus 9 %, p <0.0001, RR 5.3)

Zuanetti et al. 199615 GISSI-2 trial

567

24-hour Holter monitor

SDNN, rMSSD, NN50+

Risk of all-cause mortality elevated for NN50+ <200, SDNN <70 ms, or rMSSD <17.5 ms (RR 2.8–3.5)

Adamson et al. 200418

288

CRT-P

SDAAM

Elevated risk of all-cause mortality for SDAAM < 50 ms (HR 3.20, p=0.02)

Sherazi et al. 201519 MADIT-CRT trial

719

CRT-D

SDNN, SDANN, SDNNIX, rMSSD, VLF, LF, HF, LF/HF

SDNN <93ms associated with increased all-cause mortality (HR 2.10, 95 % CI [1.14–3.87], p=0.017)

Nolan et al. 199817 UK-Heart trial

433

24-hour Holter monitor

SDNN, rMSSD, sNN50

SDNN <93ms has all-cause mortality RR 1.62 (95 % CI [1.16–2.44])

CRT-D = cardiac resynchronisation therapy defibrillator; CRT-P = cardiac resynchronisation therapy pacemaker; HF = high frequency power; HRV = heart rate variability; LF = low frequency power; LF/HF = low frequency to high frequency power ratio; ln HF = natural log of the high-frequency measurement; pNN50 = percentage of RR intervals that differ by 50ms; rMSSD = root mean square of the differences in successive R-R intervals; SD = standard deviation; SDAAM = SD of 5 min median A-A intervals; SDANN = SD of 5 min R-R intervals; SDNN = standard deviation of NN intervals; SDNNIX = mean SD of all R-R intervals; TP = total power; VLF = very low frequency power.

Focusing on patients with an ejection fraction lower than 35 %, New York Heart Association (NYHA) functional class III or IV, and QRS duration >130 ms, Adamson and colleagues sought to assess the feasibility of implantable cardiac resynchronisation devices for prognostic purposes in an ambulatory setting.21 Using atrial intervals, HRV was defined as the standard deviation of median 5-minute a-a intervals over each 24-hour period (SDAAM). They found that the patients with the lowest SDAAM (<50 ms) had the highest all-cause mortality (HR 3.2, p=0.02) and CV-related death (HR 4.4, p=0.01) compared with higher SDAAM

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values over a 12-month follow-up period. Additionally, absolute SDAAM values were lower in the inpatients who were included in the study. The Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT) trial followed patients with ejection fraction lower than 30 %, QRS duration >130 ms, and nonischaemic heart failure with NYHA functional class I or II, randomising them to either cardiac resynchronisation therapy (CRT-D) or ICD alone.22 In a retrospective analysis of these patients, Sharazi et al found that

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Monitored during training period

4 weeks of overload training (100 % more than usual) + 2 week recovery

1 junior skier

9 M, well-trained endurance athletes

7 with overtraining Diagnosed as having overtraining syndrome syndrome, 8 controls; 8 endurance trained

Hedelin et al. 200034

Bosquet et al. 200335

Mourot et al. 200437

3 week, 2 week overload 1 week taper

62-day period prior Olympic Gold medal

11 M endurance athletes

3 M Olympic gold medallists FOR

Dupuy et al. 201340

Plews, et al. 201327

47 elite nordic skiers. Over 4-year period during fatigued and 27 M, 30 F non-fatigued state

34 F wrestlers

Schmitt el al. 201367

Tian et al. 201368

28 endurance trained 1 week light, 3-week overload, 1 week recovery Beginning of each training phase

TD

TD

TD

Lower HRV after heavy training supine rest/overtraining. Lower HRV after standing

Overtrained athletes trend of lowered HRV for four weeks of overload and raised HRV after recovery period; non-overtrained athletes had raised HRV for duration of the training period

Main Findings

Raised HRV during FOR

Lowered HRV during SWS, no change to HRV in 4-hour recording during FOR

Lowered HRV in overtrained group

Overtrained had a lower HRV orthostatic, HRV supine and relaxation

No change in HRV during sleep; overtrained had a lower HRV upon waking

Lowered HRV following overload period, raised HRV following recovery period

Lowered HRV when suffering from OT syndrome

No change in HRV, lower performance, higher fatigue, reduced Lctpeak

Raised HRV during OT; lowered HRV during recovery

Supine 5 min spontaneous breathing

Morning resting, 1 min sitting

Morning resting, 3 min standing

Morning resting Supine, standing

Supine HRV using Omega Wave standardised procedure

Resting, 8 min supine, 7 min standing

No change to HRV during FOR

Lowered HRV during overload (FOR)

Raised HRV during FOR

Raised HRV standing, No change to HRV supine during FOR

Large changes in HRV associated with both FOR and NFOR

Lowered HRV when fatigued

Morning resting Supine 8 min, standing Raised HRV during FOR supine and standing 7 min

Morning resting 5 min supine

Nocturnal HRV over 4 hours and during SWS

Morning resting, 5 min supine

Supine, orthostatic and relaxation

During sleep and 5 min supine rest upon waking

Supine (no specific details given)

Electrocardiographic 20 min supine, 10 min tilted 60°

5 h nocturnal period (spontaneous respiration)

Supine and head tilt (12 breaths/min respiration rate)

Supine and 70° vertical tilt (0.2 Hz No change in HRV respiration rate), duration not reported

25-min supine, 5 min standing

5-min supine (0.2 Hz respiration rate)

HRV Recording Method

F = female; FD = frequency domain; FOR = functionally overreached; HRV = heart rate variability; Lctpeak = peak blood lactate concentration following an incremental exercise test, M = male; NFOR = non functionally overreached; OT = overtraining; SWS = slow wave sleep; TD = time domain

Morning resting every day

Morning resting every day

Coates et al. 201838

5 weeks, 1 week baseline, 2-week overload, 2-week taper

1 week light, 2 week heavy, 10-day taper

10 F swimmers

Bellenger et al. 201742 12 M cyclists

TD, FD

FD

TD

TD

TD, FD

TD

TD, FD

TD, FD

TD, FD

TD, FD

FD

FD

FD

TD, FD

TD, FD

HRV Analysis Method

Morning resting every-day; values TD averaged over 1 week

Resting values weekly

Before training on various occasions

Every-day; values averaged over 1 week

Every day, values averaged over 1 week

Pre/post 2 week overload, post 1 week taper

Flatt et al. 201743

1 week light, 2 weeks heavy, 10-day taper

Bellenger et al. 201644 15 M runners/ triathletes

During 11 international competitions during 2007, 2010, 2011

21 M triathletes

Le Meur et al. 201341

3-week overload period to FOR

1 F NFOR 1 M control 77-day period; 23-hour training (± 3) per week

Plews et al. 201266

Morning resting every day; values averaged over 1-week

3-6 weeks after overtraining diagnosis

Hynynen et al. 200865 6 M, 6 F overtrained; Post-training period 6 M, 6 F controls

Hyynen et al. 200636

3-6 weeks after overtraining diagnosis

1 week before training, after 1 week of training and after four days of recovery after training

After a diagnosis of overtraining syndrome

Baseline, after 4 and 6 weeks

Pre, post and recovery

Before and after the 6-day training camp

6 M, 6 F overtrained, Post-training period 12 control

2-week overload training

6 days of overload training (50 % raised training load)

6 M, 3 F elite canoeists

Hedelin et al. 200063

Baumert et al. 200664 5 M, 5 F endurance athletes

6–9 weeks

9 F, well-trained

Uusitalo et al. 200062

Before and after 4 weeks and after 9 weeks

Individualised training programme, progressively Before and after 4 weeks, after increased training load for 6−9 weeks; 6−9 weeks of training, after 4−6 weeks of recovery training 4−6 weeks of recovery training

9 F, endurance trained athletes

Uusitalo et al. 199833

HRV Measurement Timing

Exercise

Number of Participants, Sex and Fitness Level

Study

Table 4: Summary of Studies Showing the Effects of Functional Overreaching, Non-Functional Overreaching and Overtraining on Vagal-Related HRV

Clinical Review: Clinical Arrhythmias

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HRV and mHealth patients in the lowest tertile of SDNN (≤93 ms) had higher rates of death or heart failure (24 % versus 17 %, p=0.004).22 Similar outcomes were shown using frequency domain measures such as VLF (28  % versus 14  %, p<0.001). The overall results agreed with the UK Heart Failure Evaluation and Assessment of Risk Trial (UK-Heart) trial, which showed increased risk of death in patients with heart failure and depressed SDNN values.20 In their sub-study analysis, the MADIT-CRT investigators concluded that ambulatory HRV analysis in heart failure patients may identify patients who would most benefit from CRT; low HRV showed no benefit with CRT-D versus ICD alone, while patients with preserved HRV treated with CRT-D had a lower risk of death. It appears that not only can HRV be used to assess the risk of death and hospitalisation in patients with heart failure, but it may also be used to determine candidates for CRT-D therapy.

Exercise HRV and Prognosis In the first study of exercise, HRV and prognosis, Dewey and colleagues performed time and frequency-domain HRV analysis on R-R interval data taken from 1,335 subjects (95 % male; mean age 58 years) during the first and last 2 minutes of treadmill testing and the first 2 minutes of recovery.23 Cox survival analysis was performed for the 53 cardiovascular and 133 all-cause deaths that accrued during the 5-year mean follow-up. After adjusting for potential confounders, greater root mean square successive difference in R-R interval during peak exercise and recovery, greater HF power and percentage of HF power, lower percentage of LF power, and lower ratio of LF to HF during recovery were significantly associated with increased risks for all-cause and CV death. Of all time-domain variables considered, the log of the root mean square successive difference during recovery was the strongest predictor of CV mortality (adjusted HR 5.0, 95 % CI [1.5–17.0]) for the top quintile compared with the lowest quintile). Log HF power during recovery was the strongest predictor of CV mortality in the frequency domain (adjusted HR 5.9, 95 % CI [1.3–25.8], for the top quintile compared with the lowest quintile). They concluded that exercise-induced HRV variables during and after clinical exercise testing strongly predict both CV and all-cause mortality independent of clinical factors and exercise responses in a clinical population. Despite the strong association found in the study by Dewey et al., other investigators, such as Nieminen et al., have argued that these findings may be predominantly driven by heart rate alone.23,24 As HRV is associated with HR physiologically (autonomic system) and mathematically (R-R interval), further consideration of this relationship is required to integrate these variables in risk stratification. Pradhapan and colleagues explored this by assessing the effect of HR correction on pre- and post-exercise HRV.25 They selected 1,288 patients from the Finnish Cardiovascular Study cohort. Inclusion criteria included completing a maximum effort exercise test and good quality HRV measurement for at least 2 minutes during rest, immediately before exercise and during post-exercise recovery. All participants were followed for cardiac and non-cardiac mortality for a mean time of 54 months. The investigators concluded that exercise-induced HRV parameters (RMSSD, VLF power, LF power, p<0.001 pre- and post-exercise) strongly predict cardiac morality with similar but weaker association found for non-cardiac mortality. Consistent with contemporary data presented by Sacha et al, they showed that when predicting both cardiac and non-cardiac morality, weakening HRV dependence on HR at rest improved prognostic capacity.26 Future studies are required to quantify the clinical significance of HRV recorded during exercise with a different HR and respiratory rate.

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Rest and Exercise HRV for Training The use of HRV as a tool to track and monitor the status of athletes has gained much interest over recent years.27 The desire to be the best often pushes the athlete to the fine line between the maximisation of effective training (achieved by duration, frequency and intensity) and ineffective training (e.g. maladaptation, non-functional overreaching and overtraining).28 Given the fact that adaptive responses to a training load or stimulus are individual,29–31 it is understandable that the ability to independently assess positive or negative training adaptation would be advantageous to athletes, sport scientists and coaches alike.

HRV and Training Maladaptation The hypothesis behind the early detection of non-functional overreaching (NFOR) or overtraining (OT) and fatigue is the possibility of assuring adequate recovery through specified rest between training. By allowing recovery based on the constantly changing dynamic of the athlete and the amount of further training needed, the recovery optimises future performance. The performance begins to decline if the recovery is not adequate, resulting in a continuum from functional overreaching (F-OR), NFOR, OT and, eventually, overtraining syndrome (OTS).32 In athletes, changes in the patterns of their autonomic nervous system (ANS) reflected by altered HRV may serve as useful objective parameters for managing their physical fatigue. Information regarding the extent to which the body recovers after training may provide useful data to avoid NFOR, OT and OTS. Many studies have examined HRV and overtraining have revealed ambivalent findings, with increases, decreases, and no change in HRV reported (Table 4).33–36 In one case study, a junior skier with reported OT had a substantially increased HRV and the values subsequently decreases once the athlete had undergone a recovery period.34 Conversely, Mourot et al.37 showed that overtraining was associated with decreased HRV. Seven athletes had endurance training and had been clinically diagnosed with OTS. However, given the continuum from F-OR to OTS, and the difficulty in deciphering between stages, these differences observed may be due to inconsistencies in the accurate diagnosis of the fatigue stage.38,39 This may be one of the reasons why more recent studies have focused on F-OR rather than NFOR and OT,which can be quantified by decreases and subsequent increases in performance (after a taper period).38,40–42 Accordingly, these data demonstrate the importance of understanding where each athlete sits on this continuum of fatigue (F-OR NFOR OT OTS). Such knowledge is critical for the accurate interpretation of HRV results to regulate athlete training. Plews et al. showed substantial reductions in HRV in an NFOR elite triathlete before a competitive race.27 It was suggested that the equivocal findings in HRV studies considering NFOR, OT or OTS, may also be due to problems with recording methodologies. As day-to-day HRV values are too variable, the authors demonstrated that when HRV were averaged over a 1-week period, they consistently showed substantially lower HRV values because of NFOR. Such findings have been subsequently supported by other research studies.41,44,45

HRV and Training Adaptation Endurance training elicits marked changes in cardiorespiratory function in both sedentary and active individuals, concomitant to changes in cardiac vagal activity, as evidenced by reduced resting and exercise HR.46 As such, the individualised nature of changes in HRV is fundamental to its use as a marker of training adaptation.47

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Clinical Review: Clinical Arrhythmias Table 5: Longitudinal and Cross-Sectional Studies Related to the Effects of Long-Term Exercise Training on VagalRelated HRV and Performance/Fitness Study

Number of Participants, Sex and Fitness Level

Exercise

HRV Measurement Timing

HRV Analysis Method

HRV Recording Method

Main Findings

Hedelin et al. 200063

8 M, 9 F elite junior cross-country skiers and canoeists

7 months of training during competitive season

Before and after 7-month training period

FD

5 min supine (spontaneous respiration), 1 min supine (0.2 Hz respiration rate), 5 min 70° vertical tilt

No change to HRV after training; higher pretraining HRV related to raised VO2 max

Yamamoto et al. 200169

7 M healthy students

40 min cycling training at 80 % VO2 peak four times a week (matched with raised fitness)

Pre-exercise, 10 min, 20 min post-exercise. Baseline, after 4, 7, 28 and 42 days of training

TD, FD

5 min seated (0.25 Hz respiration rate)

Raised HRV = raised VO2 max

Iellamo et al. 200250

7 M elite junior rowers

9 months of progressively raised training load (from detrained to maximal training state)

Baseline, after 3 and 6 months (75 % training load), after 9 months (100 % training load)

FD

10 min supine (spontaneous respiration)

Lowered HRV = higher rowing performance

Pichot et al. 200270

6 M sedentary middle-aged adults

2 months of intensive training plus 1 month of overload

Baseline, 2 × during weeks 3, 5, 7, and 8 (intensive), 1 × during week 9 (transition), 2 × during week 10–14 (overload), 1 × during week 21 (post detraining)

TD, FD

24 hour ‘Holter’ recording, 4-hour nocturnal period analysed (spontaneous respiration)

Raised HRV = raised VO2 max

Portier et al. 200151

8 M elite runners

3 weeks of moderate and 12 weeks of intensive training

End of each training phase

TD, FD

4 min 16 sec, tilt test

Higher HRV = no change to VO2 max

Carter et al. 200371

12 M, 12 F

12 weeks (2 x 4 weeks of training, 2 week taper)

Beginning and end of training programme

TD, FD

Resting 10 min supine

Higher HRV = higher 2-mile running performance

Garet et al. 200472

4 M, 3 F swimmers

3 weeks of intensive training, 2 week taper

Noctural HRV the night before competition and in the rest week, + 2 times per week in weeks 1–5

TD, FD

6 hours night sleep

Higher HRV = higher swimming performance

Mourot et al. 200448

8 M sedentary adults

Control subjects performed 3 × 45 min sessions per week for 6 weeks

Pre- and post- training intervention for control subjects

TD, NL

10 min supine, standing, steadystate exercise, seated (spontaneous respiration)

Higher HRV = higher VO2 max

Atlaoui et al. 200773

9 M, 4 F elite swimmers

4 weeks of overload, 3 weeks of taper

After 27 weeks of normal training (pre-overload), after overload, after taper

TD, FD

5 min supine on waking (spontaneous respiration)

No change to HRV after training; Raised HRV = raised swimming performance

Manzi et al. 200974

8 M recreational endurance athletes

6 months of individualised training culminating with a marathon

Pre-training (detrained state), after 8, 16, and 24 weeks of training

FD

10 min supine (spontaneous respiration recorded rate of 0.26−0.27 Hz)

Lowered HRV = raised marathon performance

Buchheit et al. 201075

14 M moderately trained runners

9-week training programme

Resting waking values measured daily, after exercise measured every 2 weeks

TD

5 min supine on waking, and 3 min standing after a 5 min submaximal exercise test (both spontaneous respiration)

Raised HRV = improved 10 km running performance and MAS (responders to training)

Buchhiet et al. 201176

15 M soccer players

11 days of training in heat

Recorded during warm-up on days 3, 4, 5, 9, 10 and 11

Last 3 min of resting 5 min post-exercise

Raised HRV = raised yo-yo intermittent recovery test

Buchhiet et al. 201152

55 M soccer players

Within 2 months of the start of the competitive season

Before incremental test

Resting 10 min

Lowered HRV = associated raised VO2 max

Buchheit et al. 201245

46 M age 15.1 ± 1.5 years

Three consecutive testings (October, January and May)

Post-submaximal run in the afternoon (3 pm)

TD

Resting 5 min after exercise

Raised HRV = raised estimate maximal cardiorespiratory function

Grant et al. 201377

145 healthy 18–22 years

Cross-sectional

Before VO2max testing

TD, FD, Poincare plot and HR

10 min recording in the morning before midday

HR accounted for 17 % of the variation in VO2max. HRV only added an additional 3.1 %

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HRV and mHealth Table 5. Continued Boullosa et al. 201378

8 M professional football players

8 weeks of training

Nocturnal HRV before testing

TD, FD

Average of four daily, continuous 3-hour sleep recordings

Raised HRV = no change in yo-yo intermittent recovery test

Buchheit et al. 201379

18 M Australian football players

2 weeks of training

Post-submaximal run in the afternoon

TD

Resting 3 min post-exercise

Higher HRV = higher yo-yo intermittent recovery test

Vesterinen et al. 201380

28 M recreational runners

28 weeks, 14 weeks basic, 14 weeks intensified training

Three consecutive nights before/after each training period

TD, FD

4 hours of nocturnal HRV over three consecutive nights

Raised HRV = raised . V O2max. + ½ marathon performance

Da Silva et al. 201481

6 M, runners

7 weeks of training

30 min before laboratory test

TD, FD

Resting sitting position, last 5 min of 10 min

Raised HRV = raised . V O2max. and 5K running performance

Wallace et al. 201482

7 trained runners

15 weeks endurance training

Morning resting values every day

TD, FD, Poincare plot

5 min supine, 5 min standing

No change to HRV (SD1) = raised 1,500 m running time

Flatt et al. 201683

12 F elite soccer

First 3 weeks of 5-week endurance programme

Morning resting values every day

TD

Resting 1 min (last 55 sec) supine

No change to HRV = raised yo-yo intermittent recovery test

F = female; FD = frequency domain; HR = heart rate; HRV = heart rate variability; M = male; MAS = maximal aerobic speed; NL = non-linear; SWEET = square-wave endurance exercise test; TD = time domain

The changes in HRV in response to endurance training programmes have been extensively studied (Table 5). In people who have been sedentary or who have trained recreationally, endurance training for 2, 6 and 9 weeks has been shown to induce parallel increases in aerobic fitness and HRV.45,48,49 For example, previously sedentary

substantial higher. Accordingly, in such cases, increases in HRV are indicative of coping with intensified training (i.e. F-OR), not increases in performance. Improved performance was only observed after the taper period when HRV had reduced back towards baseline levels.

men completed 9 weeks of intensive endurance training followed by 4 weeks of overload training and had large increases in maximal aerobic capacity (+20 %) and vagal-related HRV (+67  %).50 While this is the response typically seen in sedentary and recreationally trained people after a period of endurance training, the response in people who have an extensive training history can be decidedly different. In these athletes, the HRV response to training is inconsistent, with longitudinal studies showing no change in fitness (VO2 max uptake) despite increases in HRV, and cross-sectional studies showing lower HRV in association with superior fitness.52,52 In elite distance runners training for 18 weeks (6 weeks moderately intensive and 12 weeks intensive) culminating in a half marathon or marathon, there was no change in VO2 max, but a 45  % increase in HRV.45 Conversely, in 55 young male soccer players, lower HRV was associated with higher VO2 max and maximum aerobic speed.49

Taking these data into account, it has been suggested that there is a bell-shaped relationship between vagally related HRV and fitness/ performance.49 This, to some extent, may also be due to HRV saturation which is often seen in athletes with extensive training histories and low resting heart rates.54

Plews et al. used data from elite rowers at the Olympics.53 They showed a consistent HRV trend before peak performance, with substantial increases in HRV (above baseline) before a decline to baseline values as the competition approached (during a taper period).Such trends have since been validated in experimental studies by both Le Meur et al. and Bellenger et al. with athletes functionally adapting to training (F-OR).41,44 Le Meur et al. showed that triathletes who responded positively to 3 weeks of overload training had substantial increases in RMSSD (96 % chance of an HRV increase) followed by reductions to baseline after a 1-week taper. Those classified in the F-OR had large increases in running performance over an incremental running rest (effect size 1.17 ± 0.22). Similarly, Bellenger et al showed HRV increases in triatheletes (effect size  =  0.62 ± 0.26) after a 2-week heavy training period. These increases were reduced after a 10-day taper which coincided with improved 5 km running time trial performance (effect size -0.34 ± 0.08). Importantly, in both these studies, there were observed reductions in performance after the training overload period, when HRV was

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Using HRV to Guide Training Given the usability of HRV to track training adaptations, it could be used as a tool to guide daily training. Three studies have shown training guided by the daily recordings of HRV to be superior (at increasing fitness and exercise performance) to training based on conventional methods.55–57 Recently, Vesterinen et al. investigated the effectiveness of using HRV to prescribe training on a day-to-day basis.57 Forty recreational endurance runners were divided into the HRV-guided experimental training group (EXP) and traditional pre-defined training (TRAD). After a 4-week preparation training period, the TRAD group trained according to a predefined training programme including two-to-three moderate (MOD) and high-intensity training (HIT) sessions per week during an 8-week intensive training period. The timing of MOD and HIT sessions in EXP was based on HRV measured every morning. RMSSD was used to prescribe training because of its greater reliability than other HRV spectral indices.58 A 7-day rolling average of RMSSD was calculated because it has been proposed to be more sensitive to track changes in the training status compared with single-day values.53 The MOD/HIT session was programmed if HRV was within an individually determined smallest change. Otherwise, low-intensity training was performed. VO2 max and 3,000 m running performance were measured before and after both training periods. The number of MOD and HIT sessions was significantly lower (p=0.021, effect size 0.98) in the EXP group (13.2 ±  6.0 sessions) compared with TRAD (17.7 ± 2.5 sessions). No other differences in training were found

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Clinical Review: Clinical Arrhythmias between the groups. The 3,000 m run time improved in EXP (2.1 % T 2.0 %, p=0.004) but not in the TRAD group (1.1 % T 2.7 %, p=0.118) during the intensive training period. A small but clear between-group difference (effect size  =  0.42) was found in the change in running performance over 3,000 m. VO2 max improved in both groups (EXP: 3.7 %, ± 4.6 %, p=0.027;TRAD: 5.0 % ± 5.2 %, p=0.002).They concluded that there was potential in using resting HRV to prescribe endurance training by individualising the timing of vigorous training sessions.

meta-analysis was to interpret how vagally derived indices of HR could be used to inform training decisions. Focusing on HRV only here, they suggested that improved exercise performance was associated with increases in resting RMSSD (effect size =  0.58). However, there was also a small increase in resting RMSSD (effect size = 0.26) associated with decreases in performance. This supports the idea that, although HRV measures can be useful, they should still be used alongside other measures of training tolerance to aid decision-making.

Two studies by Kiviniemi et al. also showed superior responses to training when guided by daily HRV, similar to Vesterinen et al.55–57 Greater improvements in VO2 max and maximal attainable workload56 in groups of trained subjects who performed high-intensity training when morning resting HRV was high, and low-intensity training when these values were low. This was despite the HRV-guided training group performing HIT sessions less frequently than a traditional training group (average three compared with 4-hour HIT sessions per week). Hence, adaptation was improved when lower intensity training was completed when vagal modulation of HR was attenuated.

Conclusions

A study from 2018 split 17 well-trained cyclists into two groups.59 Group one followed a training plan guided by morning resting HRV (HRV-G, n=9), whereas group 2 followed a more traditional approach (TRAD, n=8). Following a similar design to Kiviniemi, on days when the 7-day rolling average of RMSSD fell outside the predetermined individual smallest range, the HRV-G training group would carry out low intensity training or rest rather than moderate-intensity training or HIT.55 The TRAD

The past decade has shown that HRV provides valuable prognostic information that can contribute to risk scores and cardiac variables such as echocardiographic measurements and exercise capacity. There is strong evidence to suggest that elevated HRV has a protective effect against CV disease. Conversely, exercise and HRV show the opposite relationship. Greater HRV during recovery from exercise is associated with an increased risk of all-cause and cardiovascular death. However, other investigators have argued that these findings may be predominantly driven by heart rate alone and further research is required in this area. Over more recent years, the area of HRV and athlete monitoring has been investigated. It is now generally accepted that substantial reductions in HRV are associated with negative adaptations to training and HRV increases are associated with positive adaptations, with an inverted U shape being the optimal trend in HRV in athletes before they reach peak performance. Furthermore, studies that have based daily training sessions on morning resting HRV values have had mostly positive outcomes.

group’s training regimens included scheduled low-intensity, moderateintensity, HIT and high-intensity interval training. There were no statistical differences in volume or intensity distribution in either group during the experimental period. Although there were no between-group differences, the HRV-G group substantially increased in peak power output (5.1 ± 4.5 %; p=0.024), upper threshold power (13.9 ± 8.8  %; p=0.004) and 40 km time trial performance (7.3 ± 4.5 %; p=0.005). The TRAD group did not improve significantly in any of these performance measures after their training period. This again supports the possible efficacy of HRV-G training being a suitable method to enhance training adaptations in athletes.

In the era of wearable monitoring devices and increased interest in personalised approaches to lifestyle modification, HRV may provide useful information to direct lifestyle change, guide exercise regimens and monitor for over-training. Given the advancement in wearable HRV recording devices, research is needed to understand the complex relationships between physiology and performance and day-to-day trends. Furthermore, future population studies are needed to assess the potential of HRV information acquired through wearable devices which use photo-based plethysmography and ECG technology and validate its value as a prognostic marker.

Methodological considerations are important when using HRV to monitor training in athletes. However, it is generally accepted that reductions in HRV are associated with negative performance outcomes, and increases associated with a positive response to higher training loads (Tables 4 and 5). However, such changes must be taken within the context of the training phase (i.e heavy training versus taper), and fitness status of the individual.60 Both supportive and opposing views have been highlighted in a recent HRV and exercise training meta-analysis by Bellenger et al.61 The aim of this

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Med Sci Sports Exerc 2000;32:1480–4. https://doi. org/10.1097/00005768-200008000-00017; PMID: 10949015. 64. Baumert M, Brechtel L, Lock J, et al. Heart rate variability, blood pressure variability, and baroreflex sensitivity in overtrained athletes. Clin J Sport Med 2006;16:412-7. https://doi. org/10.1097/01.jsm.0000244610.34594.07; PMID: 17016118. 65. Hynynen E, Uusitalo A, Konttinen N, et al. Cardiac autonomic responses to standing up and cognitive task in overtrained athletes. Int J Sports Med 2008;29:552–8. https://doi. org/10.1055/s-2007-989286; PMID: 18050058. 66. Plews DJ, Laursen PB, Kilding AE, Buchheit M. Heart rate variability in elite triathletes, is variation in variability the key to effective training? A case comparison. Eur J Appl Physiol. 2012;112:3729-41. https://doi.10.1007/s00421-012-2354-4; PMID: 22367011. 67. Schmitt L, Regnard J, Desmarets M, et al. Fatigue shifts and scatters heart rate variability in elite endurance athletes. PLoS One 2013;8:e71588. https://doi.org/10.1371/journal. pone.0071588; PMID: 23951198. 68. Tian Y, He ZH, Zhao JX, et al. Heart rate variability threshold values for early-warning nonfunctional overreaching in elite female wrestlers. J Strength Cond Res 2013;27:1511–9. https:// doi.org/10.1519/JSC.0b013e31826caef8; PMID: 23715265. 69. Yamamoto K, Miyachi M, Saitoh T, et al. Effects of endurance training on resting and post-exercise cardiac autonomic control. Med Sci Sports Exerc 2001;33:1496–502. https://doi. org/10.1097/00005768-200109000-00012; PMID: 11528338. 70. Pichot V, Busso T, Roche F, et al. Autonomic adaptations to intensive and overload training periods: a laboratory study. Med Sci Sports Exerc 2002;34:1660–6. https://doi. org/10.1097/00005768-200210000-00019; PMID: 12370569. 71. Carter JB, Banister EW, Blaber AP. The effect of age and gender on heart rate variability after endurance training. Med Sci Sports Exerc 2003;35:1333–40. https://doi.org/10.1249/01. MSS.0000079046.01763.8F; PMID: 12900687. 72. Garet M, Tournaire N, Roche F, et al. Individual Interdependence between nocturnal ANS activity and performance in swimmers. Med Sci Sports Exerc 2004;36:2112–8. https://doi.org/10. 1249/01.MSS.0000147588.28955.48; PMID: 15570148. 73. Atlaoui D, Pichot V, Lacoste L, et al. Heart rate variability, training variation and performance in elite swimmers. Int J Sports Med 2007;28:394–400. https://doi. org/10.1055/s-2006-924490; PMID: 17111320. 74. Manzi V, Castagna C, Padua E, et al. Dose-response relationship of autonomic nervous system responses to individualized training impulse in marathon runners. Am J Physiol Heart Circ Physiol 2009;296:H1733–40. https://doi. org/10.1152/ajpheart.00054.2009; PMID: 19329770. 75. Buchheit M, Chivot A, Parouty J, et al. Monitoring endurance running performance using cardiac parasympathetic function. Eur J Appl Physiol 2010;108:1153–67. https://doi.org/10.1007/ s00421-009-1317-x; PMID: 20033207. 76. Buchheit M, Voss SC, Nybo L, et al. Physiological and performance adaptations to an in-season soccer camp in the heat: associations with heart rate and heart rate variability. Scand J Med Sci Sports 2011;21:e477-85. https://doi.org/10.1111/ j.1600-0838.2011.01378.x; PMID: 22092960. 77. Grant CC, Murray C, Janse van Rensburg DC, et al. Comparison between heart rate and heart rate variability as indicators of cardiac health and fitness. Front Physiol 2013;20:337. https://doi. org/10.3389/fphys.2013.00337; PMID: 24312058. 78. Boullosa DA, Abreu L, Nakamura FY, et al. Cardiac autonomic adaptations in elite Spanish soccer players during preseason. Int J Sports Physiol Perform 2013;8:400–9. https://doi.org/10.1123/ ijspp.8.4.400; PMID: 23170746. 79. Buchheit M, Racinais S, Bilsborough JC, et al. Monitoring fitness, fatigue and running performance during a pre-season training camp in elite football players. Sci Med Sport 2013; 16:550–5. https://doi.org/10.1016/j.jsams.2012.12.003; PMID: 23332540. 80. Vesterinen V, Häkkinen K, Hynynen E, et al. Heart rate variability in prediction of individual adaptation to endurance training in recreational endurance runners. Scand J Med Sci Sports 2013;23:171–80. https://doi.org/10.1111/j.16000838.2011.01365.x; PMID: 21812828. 81. Da Silva DF, Verri SM, Nakamura FY, et al. Longitudinal changes in cardiac autonomic function and aerobic fitness indices in endurance runners: a case study with a high-level team. Eur J Sport Sci 2014;14:443–51. https://doi.org/10.1080/17 461391.2013.832802; PMID: 23998661. 82. Wallace L, Slattery KM, Coutts AJ. A comparison of methods for quantifying training load: relationships between modelled and actual training responses. Eur J Appl Physiol 2014;114:11–20. https://doi.org/10.1007/s00421-013-2745-1; PMID: 24104194. 83. Flatt A, Esco MR. 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Clinical Review: Electrophysiology and Ablation

Percutaneous Treatment of Non-paroxysmal Atrial Fibrillation: A Paradigm Shift from Pulmonary Vein to Non-pulmonary Vein Trigger Ablation? Domenico G Della Rocca, 1 Sanghamitra Mohanty, 1 Chintan Trivedi, 1 Luigi Di Biase 1,2,3 and Andrea Natale 1,4,5,6 1. Texas Cardiac Arrhythmia Institute, St David’s Medical Center, Austin, Texas, USA; 2. Arrhythmia Services, Department of Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, New York, USA; 3. Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy; 4. Interventional Electrophysiology, Scripps Clinic, La Jolla, CA, USA; 5. Department of Cardiology, MetroHealth Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA; 6. Division of Cardiology, Stanford University, Stanford, CA, USA

Abstract Pulmonary vein antrum isolation is the most effective rhythm control strategy in patients with paroxysmal AF. However, catheter ablation of non-paroxysmal AF has a lower success rate, even when persistent isolation of pulmonary veins (PVs) is achieved. As a result of arrhythmia-related electophysiological and structural changes in the atria, sites other than the PVs can harbour triggers. These non-PV triggers contribute to AF relapse. In this article, we summarise the rationale and current evidence supporting the arrhythmogenic role of non-PV triggers and our ablation approach to patients with non-paroxysmal AF.

Keywords Atrial fibrillation, catheter ablation, non-pulmonary vein trigger, outcomes Disclosure: Luigi Di Biase is a consultant for Biosense Webster, Boston Scientific, Stereotaxis and St Jude Medical; and has received speaker honoraria from Medtronic, Atricure, EPiEP and Biotronik. Andrea Natale has received speaker honoraria from Boston Scientific, Biosense Webster, St Jude Medical, Biotronik and Medtronic; and is a consultant for Biosense Webster, St Jude Medical and Janssen. All other authors have no conflicts of interest to declare. Received: 8 October 2018 Accepted: 2 November 2018 Citation: Arrhythmia & Electrophysiology Review 2018;7(4):256–60. DOI: https://doi.org/10.15420/aer.2018.56.2 Correspondence: Andrea Natale, Texas Cardiac Arrhythmia Institute, St David’s Medical Center, 3000 North I–35, Suite 720, Austin, TX 78705, USA. E: dr.natale@gmail.com

AF is the most common sustained arrhythmia, and carries an increased risk of cardiovascular and cerebrovascular complications. The latest estimates on the prevalence of AF portray an alarming scenario, with a steep increase in the number of people developing AF and prediction that the number affected will more than double in the next 40 years.1 Among the strategies to restore and maintain sinus rhythm, AF ablation has emerged as an effective approach, with mounting evidence also supporting a role for ablation in patients with comorbidities and other concomitant cardiovascular disorders.2–5 Since the pivotal study by Haïssaguerre, et al. demonstrating the role of ectopic beats from the pulmonary veins (PVs) in initiating paroxysms of AF,6 PV isolation and, subsequently, PV antrum isolation (PVAI) have become the standard strategy in patients undergoing AF ablation. Although catheter ablation is the most effective rhythm control strategy in patients with paroxysmal AF, and PVAI is the mainstay of the procedure, patients with non-paroxysmal AF show a significantly lower success rate with PVAI alone, compared to those with paroxysmal AF. Many ablation strategies have been proposed to achieve better outcomes in non-paroxysmal AF.7–10 Of these, adjuvant substrate modification (e.g. linear ablation and ablation of complex fractionated electrograms) has found a widespread use in clinical practice. However, in the randomised Substrate and Trigger Ablation for Reduction of Atrial Fibrillation II (STAR-AF II) trial,7 neither linear ablation nor ablation of complex fractionated electrograms in addition to PVAI was found to be superior to PVAI alone in patients with persistent AF.

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Similarly, contrasting results from small, non-randomised studies, based on inadequate mapping systems, are very far from corroborating the effectiveness of other substrate-based ablation strategies targeting localised, organised re-entrant activity (e.g. high frequency areas and rotors).8 From a pathophysiological standpoint, spontaneous firings from the PVs are frequently the only arrhythmogenic triggers involved in paroxysmal AF initiation. However, as arrhythmia persists, especially in patients with comorbidities and/or other cardiac and extra-cardiac diseases, the pathogenic role of PVs decreases and other atrial areas become involved in triggering AF. These non-PV triggers may arise from specific sites outside the PVs;the most frequent locations are the left atrial posterior wall (PW), left atrial appendage (LAA), crista terminalis, interatrial septum (IAS) and other thoracic veins, such as the coronary sinus (CS) and the superior vena cava (SVC).11–14 Even though no consensus has been reached on the ablation strategy to adopt in non-paroxysmal AF in order to improve longterm outcomes, several groups have reported higher arrhythmia-free survival rates in non-paroxysmal AF patients undergoing ablation of non-PV sites, either induced by a provoking pharmacological test and/ or empirically targeted.7–10,15–19

Non-pulmonary Vein Trigger Ablation in Non-paroxysmal AF Given the progressive nature of AF, electrical and structural changes affect the atria as a result of arrhythmia persistence. AF

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Percutaneous Treatment of Non-paroxysmal AF Figure 1: Standard Catheter Set-up

Our standard catheter set-up during the isoproterenol challenge test and normal activation pattern: the 20-pole catheter with electrodes spanning from the superior vena cava, right atrium/ crista terminalis (blue) to the coronary sinus (green); the ablation catheter in the right superior pulmonary vein recording the far-field inter-atrial septum (violet); and the 10-pole circular mapping catheter in the left superior pulmonary vein recording the far-field left atrial appendage activity (red).

promotes electrical and structural remodelling, which increases atrial vulnerability to sustain atrial tachyarrhythmias. Persistence of AF determines atrial structural and functional derangement, as a result of extracellular matrix remodelling, cell-to-cell coupling abnormalities, and disorganised distribution of gap junction proteins (e.g. connexin-40 and -43). Additionally, myocyte density shows regional heterogeneities, which contribute to the development of areas of slow conduction and abnormal electrical properties.

Achieving permanent PV isolation is challenging and may require multiple procedures. The incidence of PV reconnection is very variable in studies and PV re-isolation in combination with elimination of detected non-PV triggers should be the strategy of choice in patients with recurrences.15,23–25 Of note, Prabhu et al. demonstrated that PV

Structural and electrical remodelling, fibrosis, and areas of slow conduction represent a perfect substrate for perpetuation of atrial tachyarrhythmia, but do not explain AF initiation, since there cannot be AF without a trigger inducing it. This paradigm has been the foundation of every AF ablation procedure. PV isolation has been the standard approach ever since triggers initiating AF were described in the late 1990s.6 However, when the changes in the atrial substrate occur, PVs become less likely to trigger AF and it is not uncommon to observe PVs electrically silent due to atrial remodelling and fibrosis in patients with a long history of AF who are undergoing their first catheter ablation. At the same time, other extra-pulmonary atrial sites with preserved rapid conduction may retain the ability to harbour ectopic beats triggering AF, owing to abnormal automaticity, triggered activity, or micro-re-entry. This mechanism has also been observed in dogs undergoing rapid pacing to elicit arrhythmia-induced atrial structural and functional changes.20 After several days of pacing, atrial cells display increased action potential durations, and delayed afterdepolarisation‐induced triggered activity of atrial tissue is responsible for the development of atrial tachyarrhythmias.

Similarly, our group reported the procedural findings and ablation outcomes of 305 AF patients after two or more failed catheter ablations.25 Of the enrolled patients, 89 (29 %) had persistent AF and 134 (44  %) had LSPAF. Even though PV reconnection was a common finding (n=226; 74  %), non-PV triggers were documented in 285 patients (93  %) and targeted for ablation in 202 (66.2  %). In these patients, empirical isolation of the LAA and CS were performed in the occurrence of persistent PV isolation and absence of nonPV triggers elicited by the high dose isoproterenol challenge test. Specifically, 79 (39  %) of the latter had empirical isolation of LAA and CS, owing to the absence of PV reconnection and other non-PV triggers detected by the isoproterenol challenge test. After 4.2±1.3 years of follow-up, arrhythmia-free survival was 81  % and 8  % in patients with or without non-PV trigger ablation, respectively, non-PV trigger ablation being the strongest predictor of recurrences at multivariate analysis (HR 8.6; 95  % CI [5.7–13.1]; p<0.0001). Despite PV reconnection, only ablation of either detectable non-PV triggers or empirical ablation led to higher rates of arrhythmia-free survival (83 % in patients with detectable non-PV trigger ablation and 78 % for empirical ablation; p=0.44).

The viability of this concept has been confirmed by several clinical studies enrolling patients with persistent and long-standing persistent AF (LSPAF), in which ablation strategies targeting the atrial substrate (e.g. scar homogenisation, linear lesions and ablation of complex fractionated electrograms) did not show a significant benefit over PVAI alone.7,21,22 On the contrary, when ablation of extra-pulmonary triggers is performed in combination with PVAI, the outcomes significantly improve.13–17

To date, there is no standard definition for “significant” non-PV triggers or agreement on the protocol to adopt to induce them. As a result, their prevalence is widely variable in studies. Some investigators classify as significant only those non-PV triggers initiating reproducible sustained (>30s) atrial tachyarrhythmias, whereas others include those initiating runs of non-sustained (<30s) focal atrial tachycardia or leading to repetitive premature atrial contractions (PACs).15–17,19,22,26–28

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activity, specifically rapidity of PV firing and the presence of fibrillatory activity, does not predict catheter ablation outcomes in patients with persistent AF.24

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Clinical Review: Electrophysiology and Ablation Figure 2: Activation in the Distal Duo-decapolar Catheter for Ectopic Bets Originating from the Coronary Sinus

left atrial PW to the oesophagus, real-time temperature monitoring is performed by moving an oesophageal probe along the oesophagus in order to align the ablation electrode with the temperature probe. Power and contact force titration are also necessary, regardless of the location of the probe, as the real size and position of the oesophagus do not perfectly correspond to the probe’s position. Subsequently, a pharmacological challenge test with high dose isoproterenol (starting at 20 µg/min and up to 30 µg/min for 10–15 minutes) is performed in sinus rhythm. During the challenge test, catheters are positioned with the following set-up (Figure 1): • a  20-pole catheter with electrodes spanning from the SVC, right atrium and crista terminalis to the CS; •  an ablation catheter in the right superior PV recording the farfield IAS; and • a 10-pole circular mapping catheter in the left superior PV recording the far-field LAA activity. Localisation of non-PV triggers can be easily performed as follows:

A: Frequent premature atrial contractions (green; see colour legend in Figure 1) originating from the coronary sinus recorded in a 65-year-old woman with persistent AF and severe left atrial scar during the high-dose isoproterenol challenge test. B: A premature atrial contraction from the coronary sinus triggered AF.

A lower prevalence of non-PV triggers has been reported in studies utilising low doses and/or an incremental infusion of isoproterenol, especially when AF ablation is performed under deep sedation or general anaesthesia. In this specific case, the likelihood to induce non-PV triggers is lower. A higher dose of isoproterenol appears to be necessary and even non-sustained focal atrial tachycardias and repetitive PACs should be considered significant and eventually targeted for ablation. Patients with non-paroxysmal AF tend to display a high prevalence of non-PV triggers, as well as specific sub-populations of patients, specifically female, elderly, obese individuals, and those suffering from sleep related breathing disorders such as heart failure, hypertrophic cardiomyopathy and valvular heart disease. Among them, the likelihood of arrhythmia relapse due to non-PV triggers is higher; therefore, it appears reasonable to target those extra-pulmonary sites for ablation at the time of the first procedure.

Our Approach to Catheter Ablation of Non-paroxysmal AF In our laboratory, all procedures are conducted under general anaesthesia. All anti-arrhythmic drugs are discontinued for at least five half-lives before the procedure, in order to reduce the likelihood of non-inducibility. The standard ablation protocol includes empirical PV antra, left atrial PW, and SVC isolation. PW isolation includes the entire PW down to the CS and to the left side of the septum anterior to the right superior PV until electrical silence is achieved. Given the close proximity of the

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• e arliest activation in the proximal duo-decapolar catheter for ectopic beats originating from the right atrium; • earliest activation in the distal duo-decapolar catheter for ectopic bets originating from the CS (Figure 2); • earliest far-field activity recorded from the circular mapping catheter before the distal CS for beats originating from the LAA (Figure 3); and • earliest far-field activity recorded from the ablation catheter, usually preceding the early activation of both the CS and the proximal duodecapolar catheter for beats originating from the IAS. If needed, a detailed activation mapping is performed to better localise the site of origin of non-PV triggers. Our definition for significant nonPV triggers includes those initiating AF, atrial flutter, sustained and non-sustained atrial tachycardia, as well as frequent PACs ≥10/min. The ablation strategy of choice is complete isolation when targeting triggers from the SVC, the LAA, and the CS, and focal ablation for other atrial structures (e.g. IAS, crista terminalis). In our lab, SVC isolation is performed by targeting the septal segment of the SVC–right atrial junction, and continues posteriorly and inferiorly with ablation of sites of early activation until electrical isolation is achieved.28 This approach eliminates any risk of sinus node injury or SVC stenosis. Similarly, the chances of phrenic nerve injury are very limited and can be easily prevented by performing high-output pacing to localise the course of the nerve. In some patients with factors predisposing to the development of nonPV triggers (female gender, sleep apnoea, obesity) or an arrhythmia history suggesting a higher prevalence of triggers (e.g. late recurrence post-PVAI), isolation of the LAA and the CS can be performed empirically, if triggers from these structures are not elicited during the isoproterenol challenge test. Empirical isolation of LAA and CS is usually reserved for specific subpopulations of patients, specifically those with LSPAF whose PVs and PW have severe scarring at the time of the first procedure, and in all

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Percutaneous Treatment of Non-paroxysmal AF Figure 3: Far-field Activity Recorded from the Circular Mapping Catheter before the Distal Coronary Sinus for Beats Originating from the Left Atrial Appendage

A: PAC originating from the left atrial appendage (red; see colour legend in Figure 1) triggering atrial tachycardia. B: The earliest activation is recorded in the 10-pole circular mapping catheter placed in the left superior pulmonary vein and in proximity to the left atrial appendage (red star).

LSPAF patients at the time of redo-procedure in the eventuality that LAA and/or CS triggers are not disclosed by the isoproterenol challenge. As demonstrated in the Effect of Empirical Left Atrial Appendage Isolation on Long-term Procedure Outcome in Patients With Persistent or Longstanding Persistent Atrial Fibrillation Undergoing Catheter Ablation (BELIEF) randomised trial,empirical electrical isolation of the LAA at the time of the first procedure may significantly improve arrhythmia-free survival without increasing complications (unadjusted HR for recurrence with standard ablation without empirical LAA isolation: 1.92; 95 % CI [1.3–2.9]; p<0.001).17 In patients with persistent AF, we perform empirical CS isolation at the time of repeat procedure when PVs are persistently isolated and no other non-PV triggers are detected. In the same cohort of patients, empirical LAA isolation is performed on a case-by-case basis, owing to the need for long-term oral anticoagulation if isolation-induced mechanical dysfunction of the LAA is confirmed by transoesophageal echocardiogram. SVC is isolated in all patients, either empirically or because triggers from this structure are detected.

Conclusion Although PVAI is the mainstay of each AF ablation, mounting evidence has demonstrated a pivotal role of non-PV triggers in early and late atrial tachyarrhythmia relapse and progression.

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Patients with non-paroxysmal AF display a higher prevalence of triggers from sites other than the PVs and targeting these arrhythmogenic foci is of utmost importance to achieve better long-term outcomes. Their localisation can be easily achieved by means of multi-electrode catheters positioned in specific areas of the right and left atrium during the pharmacological challenge test. Moreover, empirical non-PV trigger ablation may further improve long-term freedom from atrial arrhythmias in selected cohorts of AF patients. n

Clinical Perspective • P  ulmonary vein antrum isolation is the standard approach in patients undergoing AF catheter ablation. •  Although highly effective in patients with paroxysmal AF, pulmonary vein antrum isolation alone has a low success rate in non-paroxysmal AF patients. Spontaneous firings from the pulmonary veins) are frequently the only arrhythmogenic triggers involved in paroxysmal AF initiation. •  However, patients with non-paroxysmal AF display a higher prevalence of triggers from sites other than the pulmonary veins. Detection and ablation of these foci is of utmost importance to achieve better long-term outcomes.

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CIRCEP.116.004239; PMID: 27784738. 20. S  tambler BS, Fenelon G, Shepard RK, et al. Characterisation of sustained atrial tachycardia in dogs with rapid ventricular pacing-induced heart failure. J Cardiovasc Electrophysiol 2003;14:499–507. https://doi.org/10.1046/j.15408167.2003.02519.x; PMID: 12776867. 21. Fink T, Schlüter M, Heeger CH, et al. Stand-alone pulmonary vein isolation versus pulmonary vein isolation with additional substrate modification as index ablation procedures in patients with persistent and long-standing persistent atrial fibrillation: the randomised Alster-Lost-AF Trial (ablation at St. Georg Hospital for long-standing persistent atrial fibrillation). Circ Arrhythm Electrophysiol 2017;10:pii:e005114. https://doi.org/10.1161/CIRCEP.117.005114; PMID: 28687670. 22. Mohanty S, Mohanty P, Di Biase L, et al. Long-term follow-up of patients with paroxysmal atrial fibrillation and severe left atrial scarring: comparison between pulmonary vein antrum isolation only or pulmonary vein isolation combined with either scar homogenisation or trigger ablation. Europace 2017;19:1790–7. https://doi.org/10.1093/europace/euw338; PMID: 28039211. 23. Lin D, Santangeli P, Zado ES, et al. Electrophysiologic findings and long-term outcomes in patients undergoing third or more catheter ablation procedures for atrial fibrillation. J Cardiovasc Electrophysiol 2015;26:371–7. https://doi.org/10.1111/

jce.12603; PMID: 25534677. 24. P  rabhu S, Kalla M, Peck KY, et al. Pulmonary vein activity does not predict the outcome of catheter ablation for persistent atrial fibrillation: A long-term multicentre prospective study. Heart Rhythm 2018;15:980–6. https://doi.org/10.1016/ j.hrthm.2018.02.029; PMID: 29501669. 25. Mohanty S, Trivedi C, Gianni C, et al. Procedural findings and ablation outcome in patients with atrial fibrillation referred after two or more failed catheter ablations. J Cardiovasc Electrophysiol 2017;28:1379–86. https://doi.org/10.1111/ jce.13329; PMID: 28841251. 26. Santangeli P, Zado ES, Hutchinson MD, et al. Prevalence and distribution of focal triggers in persistent and long-standing persistent atrial fibrillation. Heart Rhythm 2016;13:374–82. https://doi.org/10.1016/j.hrthm.2015.10.023; PMID: 26477712. 27. Hayashi K, An Y, Nagashima M, et al. Importance of nonpulmonary vein foci in catheter ablation for paroxysmal atrial fibrillation. Heart Rhythm 2015;12:1918–24. https://doi. org/10.1016/j.hrthm.2015.05.003; PMID: 25962801. 28. Gianni C, Sanchez JE, Mohanty S, et al. Isolation of the superior vena cava from the right atrial posterior wall: a novel ablation approach. Europace 2018;20:e124–32. https://doi.org/10.1093/europace/eux262; PMID: 29016788.

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Clinical Review: Electrophysiology and Ablation

Arrhythmia Mechanisms Revealed by Ripple Mapping George Katritsis, 1 Vishal Luther, 1 Prapa Kanagaratnam 1 and Nick WF Linton 2 1. Department of Cardiac Electrophysiology, Imperial College Healthcare, London,UK; 2. Department of Bioengineering, Imperial College London, UK

Abstract Ripple mapping is a novel method of 3D intracardiac electrogram visualisation that allows activation of the myocardium to be tracked visually without prior assignment of local activation times and without interpolation into unmapped regions. It assists in the identification of tachycardia mechanism and optimal ablation site, without the need for an experienced computer-operating assistant. This expert opinion presents evidence demonstrating the benefit of Ripple Mapping, compared with traditional electroanatomic mapping techniques, for the diagnosis and management of atrial and ventricular tachyarrhythmias during electrophysiological procedures.

Keywords Atrial tachycardia, catheter ablation, electroanatomic mapping, ripple mapping, ventricular tachycardia Disclosure: George Katritsis has no conflicts of interest to declare. Imperial Innovations holds intellectual property relating to Ripple Mapping on behalf of Prapa Kanagaratnam and Nick Linton, who have also received royalties from Biosense Webster, Inc. Vishal Luther, Prapa Kanagaratnam and Nick Linton have received consulting fees with respect to Ripple Mapping from Biosense Webster, Inc. Received: 27 July 2018 Accepted: 13 August 2018 Citation: Arrhythmia & Electrophysiology Review 2018;7(4):261–4. DOI: https://doi.org/10.15420/aer.2018.44.3 Correspondence: Nick Linton, Department of Cardiology, Hammersmith Hospital, Imperial College Healthcare NHS Trust, Du Cane Road, London W12 0HS, UK. E: n.linton@imperial.ac.uk

The introduction of cardiac electroanatomic mapping systems in the mid-1990s has permitted investigators to record intracardiac electrograms (EGMs) with accurate spatial localisation in 3D.1 These 3D mapping systems have enabled the display of the cardiac chambers as an anatomical shell upon which voltage, or activation, information can be displayed. Most commonly, colour is used to represent the variation of a single parameter that has been derived from the EGM at each sampled location. Typically, the local activation time (LAT) is interpolated across the shell to create an isochronal map.2 3D mapping is an established tool in the identification of arrhythmia mechanisms, as well as in the localisation of anatomical sites critical to arrhythmia maintenance as a guide to ablation.3 However, there is little objective evidence about the efficacy of these techniques. Current methods of mapping atrial tachycardia (AT) or ventricular tachycardia (VT), as well as their substrates, are not without limitation.4 First, data interpolation algorithms used by 3D mapping systems assume that data between two mapped points are uniform. However, in scar tissue where activation is not continuous, these estimates can lead to error.2 Second, identification of the mechanism relies on isochronal maps in which LAT is compared with the timing of a stable reference signal, such as the surface ECG for VT or an EGM from the coronary sinus in AT. The measurement of this timing is plotted according to a colour scale. Only a single activation time can be annotated for each EGM. Complex EGMs with low amplitude, long and fractionated potentials are often encountered in low-voltage myocardium and can be important indicators of deranged conduction over tissue critical to the maintenance of arrhythmias.5 Incorrect assignment of LAT of only a single EGM can give rise to misleading activation maps, even when high-density mapping is used.6 Third, a timing window of interest (WOI) must be created, to ensure that EGMs from the same beat are compared, by specifying a time interval both before and after the

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reference point. The operator must choose this WOI appropriately. Different WOIs influence the isochronal colour display and this can lead to difficulties interpreting the arrhythmia mechanism.7 Ripple mapping (RM) was introduced as a different method of 3D EGM visualisation to ameliorate the limitations faced by conventional 3D mapping techniques. EGMs are aligned according to a stable reference point and displayed in their entirety as dynamic bars that protrude perpendicularly from the chamber geometry. The length of each bar, at a particular time relative to the reference, is proportional to the magnitude of each EGM at that time.8 Following collection of multiple EGMs, the endocardial activation sequence can be appreciated by the movement of each bar relative to its neighbour, creating a ripple effect (Figure 1 and Figure 2).9,10 RM avoids the need to annotate EGM activation time and does not require setting of a WOI. Only acquired points are displayed on the ripple map so there is no data interpolation in the generation of the map. In the same way as a decapolar coronary sinus catheter will have an earliest and latest EGM, a ripple map will have bars that move early or late relative to the reference EGM, but in 3D. The operator can infer that the direction of activation will be from the earliest moving bars to the latest moving bars. This pattern of activation becomes more obvious as the number of bars increases; typically for atrial arrhythmias 1,000–2,000 points will produce an effective ripple map. If a LAT map is collected with 50 points, standard automated algorithms will ‘fill in’, with colour, the spaces between (interpolation). This is not real data; it assumes the activation is uniform and predictable between points. This may be acceptable in healthy myocardium but in scarred tissue it will create a false map. If the same data are played as a ripple map, the sparsity of points makes it difficult to determine the direction of wavefronts and, in effect, prevents the operator from interpreting an inadequate map. Conversely, ensuring local time annotation is correct with

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Clinical Review: Electrophysiology and Ablation Figure 1: Electrogram Representation During a Ripple Map

Figure 3: Activation Map, Bipolar Voltage Map and Ripple Map of a Post-AF Ablation Atrial Tachycardia

Five electrograms have been collected across the anterior wall of the left atrium during tachycardia and the location of each data point is projected on the anatomical shell. The Ripple Mapping algorithm aligns all of the electrograms from each point according to a stable fiducial reference signal. In this example, a coronary sinus signal (yellow electrogram) was chosen as reference. The system has aligned each of the five electrograms with the peak of the coronary sinus reference electrogram (highlighted here with a red dashed line). The Ripple Map for every electrogram collected is played through time (0–100 ms). Deflections (negative or positive) away from the isoelectric line from every mapped point are projected as a perpendicular white bar (white arrows). As time progresses, bars are seen to ascend up the anterior wall. When played quickly as a movie, this gives the impression of propagation as the bar movement progresses in relation to its neighbouring points.

Figure 2: Ripple Map of Counterclockwise Typical Right Atrial Flutter

CS = coronary sinus; IVC = inferior vena cava; SVC = superior vena cava.

2,000 points is challenging, but not necessary with a ripple map. RM preserves the entire voltage–time relationship of an EGM. Myocardial areas central to arrhythmia mechanisms, such as scar, often display EGMs with low amplitude, fractionated and double potentials. Such EGM information can be lost in traditional voltage or activation maps because only a single value – of timing or voltage – is assigned to an EGM in creating the map. A fractionated EGM can be tagged on an activation or bipolar voltage map as a region of interest because it represents slow conduction. In a ripple map, the bar at a fractionated EGM will appear to move continuously with low amplitude over the entire duration of the EGM. However, RM contextualises the fractionated EGM with respect to surrounding tissue. For example, if the point is at a slow conducting isthmus, a ripple map will show the bar starting to move when the late portion of the re-entrant circuit reaches the isthmus and it will continue to move until the breakout of the earliest part of the re-entrant circuit. Furthermore, if it is a long isthmus, such as with an ischaemic VT diastolic pathway, there will be early and late fractionated EGMs that will demonstrate the direction of activation if viewed as a ripple map. Simple fractionated EGM mapping by tagging cannot do this. Using RM to define the activation direction within the diastolic pathway of ischaemic VT can also differentiate between the central common pathway and blind alleys, which cannot be done with simple fractionation mapping.

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Left atrial tachycardia following prior AF ablation. Owing to the presence of two ‘early’ sites on the local activation time map, the propagation pattern was difficult to interpret. No Ripple bars were seen below 0.15 mV; tissue below this threshold was displayed in red and above this threshold in purple. The left atrium is seen in LAO with the mitral valve en face. (a–d) A Ripple wavefront rotated clockwise around the mitral annulus. A line of ablation between the mitral annulus and left lower pulmonary vein terminated atrial tachycardia. AP = Anteroposterior; LAA = Left atrial appendage; LAO = Left anterior oblique; LLPV = Left lower pulmonary vein; LUPV = Left upper pulmonary vein; Mod PA = Modified posteroanterior view; PA = Posteroanterior view; RLPV = Right lower pulmonary vein; RUPV = Right upper pulmonary vein.

In certain atrial arrhythmias scar may be present throughout the atrium. Complex and fractionated EGMs may therefore occur in many areas not critical to arrhythmia mechanism. Simple fractionation mapping cannot differentiate between areas that are critical to the circuit and those that are bystanders. However, all areas will cause problems for LAT assignment algorithms. As RM does not assign a LAT, it is less susceptible to such errors. Fractionation tagging can help to direct the operator to regions that need manual LAT validation, but in high-density mapping, with more than 1,000 points, this can be labour intensive during an already complex procedure. RM is unique because it is not obligatory for the anatomical shell to be coloured. This means that colour can be used to display other information, such as data from MRI. However, we have found that simultaneous display of the bipolar EGM voltage is helpful in interpretation of ripple map activation, particularly when understanding arrhythmia mechanisms and their relation to scarred substrates.11,12 RM has been incorporated into a commercially available electroanatomic mapping system, CARTO® 3 (Biosense Webster), so it can be used to guide ablation at the time of mapping. In the following sections we will review our experience of RM in elucidating the mechanisms of tachycardia within atrial and ventricular scar.

Ripple Mapping in Atrial Tachycardia ATs often occur in patients with prior AF ablation. As well as pre-existing tissue abnormalities, ablation creates scar tissue forming a substrate for re-entry.13 AT mapping aims to define this re-entrant circuit within areas of low voltage and slow conducting tissue. Conventional

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Arrhythmia Mechanisms Revealed by Ripple Mapping Figure 4: Ventricular Tachycardia Substrate Identified By Ripple Mapping During Pacing

A substrate map collected from the left ventricle, during pacing, in a patient with prior anteroseptal myocardial infarction. A channel of electrograms was seen to travel from the base to the apex through the scar (highlighted from red to purple along a standard rainbow spectrum). The corresponding electrograms show increasing local activation of the delayed electrogram through the channel.

mapping of these arrhythmias can be misled by misannotation of LAT or incorrect settings of the WOI. Early studies using RM demonstrated the potential for improved accuracy in determining the arrhythmia mechanism, compared with conventional mapping, by overcoming these limitations.9,10 We described active tissue thresholding, which helps to define the critical isthmus sites supporting re-entry as a target for ablation: by superimposing ripple activation on a bipolar voltage display, areas without any visible ripple activation can be inferred to be scar and colour-coded red on a voltage map.11 An example of this is illustrated in Figure 3 for mapping an organised AT in an atrium with previous extensive ablation for AF, where the local activation colour sequence is uninterpretable. There is no consensus on the voltage threshold that defines atrial scar, unlike in the ventricle where scar has been defined as a voltage below 0.5 mV.4 In a 20-patient study examining RM in post-ablation ATs, operators were able to map the conducting atrial circuit around scar – by defining scar as tissue without ripple propagation – to identify the optimal site for ablation in all cases.11 However, changes in bipolar voltage amplitude can occur with changes of atrial activation sequence owing to the anisotropic characteristics of cardiac tissue, or when variation of atrial activation sequence leads to wavefront collision.14 Further studies have demonstrated that scar distribution in the ablated atrium is generally fixed. This may offer a future means of substrateguided ablation for AT in the many symptomatic patients who are noninducible on the day of their procedure or as ‘primary prevention’ at the time of ablation for persistent AF.15 RM looks different from conventional activation mapping, but we have shown that experienced CARTO operators using the system for the first time achieved high diagnostic accuracy and ablation success.16

Ripple Mapping in Ventricular Tachycardia Scar-related VT is dependent on channels of surviving tissue within the scar that support re-entry. These channels are defined by areas of late activating EGMs (late potentials) and fractionation. Detailed mapping studies of EGMs collected during sinus rhythm

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Figure 5: Ripple Map of Scar-Related Ventricular Tachycardia

An activation map was collected in ventricular tachycardia using a PentaRay® (Biosense Webster, Inc) catheter from a patient with prior MI and an apical aneurysmal scar. (Left) A bipolar voltage map set to display scar at conventional thresholds (0.5–1.5 mV) outlines the extent of the apical aneurysm. (Right) An outline of the ventricular tachycardia circuit as illustrated by Ripple Mapping is seen. Having travelled through scar, breakout occurred (yellow star) within apparent core scar less than 0.5 mV (contained within blue outline) 60 ms ahead of the QRS onset. Tissue devoid of ripple wavefronts below 0.15 mV was seen and defined as scar (red). The channel exit did not reside in the ‘scar border zone’ as currently defined (0.5–1.5 mV).

within these supposed channels have recorded a gradient of early to late activation, supporting the notion that these channels are interconnected.17,18 EGMs within ventricular scar often have two or more components; the local signal from within scar and the larger far-field signal from the thicker surrounding tissue or the epicardial surface. Mapping of VT and its substrate relies on annotation of the diastolic potential in VT or the late potential in sinus rhythm. Conventional LAT maps only allow one annotation of activation time. This may result in error from misannotating the larger far-field signal as local activation, or errors caused by noise. There is also loss of information if there is more than one late potential. Analysis of VT substrate ripple maps demonstrated that activation can be visually followed through the scar to identify these channels (Figure 4).19 Within these channels, we considered activation identified by RM to be genuine – rather than noise – when three closely neighbouring RM bars appeared on the map with similar timing. The appearance of sequential RM activation of three or more bars obviates the need to annotate LAT and identify propagation manually. By identifying conducting channels within scar using RM, bipolar voltage map thresholds can be reassessed on a patient-specific basis. At least one such channel was identified in all 18 patients studied. Sites of entrainment with concealed fusion, excellent pace maps and termination also co-located to such channels identified by RM, highlighting the heterogenous nature of scar architecture serving as the substrate for VT.19 RM allows two distinct wavefronts to be seen on the cardiac surface, the far-field wavefront followed by the delayed local wavefront representing the potential channel within scar. Mapping with small tip, narrowly spaced multielectrode catheters can reduce the contribution of far-field signal. In doing so, wavefronts of ripple activation were appreciated even in tissue with activation as low as 0.15 mV, further challenging the universal bipolar voltage definition of ventricular scar as <0.5 mV.12 An example of this, when mapping in VT, is highlighted in Figure 5.

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Clinical Review: Electrophysiology and Ablation During sinus rhythm or ventricular pacing, clusters of ripple activation can be appreciated within scar. The direction of activation further characterised active scar into conducting channels. Convergent activation of scar towards its centre, via such channels, was clearly visible by RM. In a prospective study of 15 post-infarct patients, conducting channels within ventricular scar were identified in all patients and distinguished from far-field signal. Importantly, in patients where stable VT was mapped, the diastolic pathway co-located with channels mapped in sinus rhythm in all patients. Substrate ablation of these channels rendered 85 % of patients non-inducible for VT and 70 % free from VT at 6 months.12 There remain unanswered questions in VT RM. While the channel of slow conduction through the scar can be defined, the optimal strategy for ablation requires further study. Whether these channels within ventricular scar are anatomically fixed in location or

1.

2.

3.

4.

5.

6.

7.

 en-Haim SA, Osadchy D, Schuster I, et al. Nonfluoroscopic, in B vivo navigation and mapping technology. Nat Med 1996;2: 1393–5. https://doi.org/10.1038/nm1296-1393; PMID: 8946843. Del Carpio Munoz F, Buescher TL, Asirvatham SJ. Threedimensional mapping of cardiac arrhythmias: what do the colors really mean? Circ Arrhythm Electrophysiol 2010;3:e6–11. https://doi.org/10.1161/CIRCEP.110.960161; PMID: 21156773. Earley MJ, Showkathali R, Alzetani M, et al. Radiofrequency ablation of arrhythmias guided by non-fluoroscopic catheter location: a prospective randomized trial. Eur Heart J 2006;27:1223–9. https://doi.org/10.1093/eurheartj/ehi834; PMID: 16613932. Josephson ME, Anter E. Substrate mapping for ventricular tachycardia: assumptions and misconceptions. JACC Clin Electrophysiol 2015;1:341–52. https://doi.org/10.1016/ j.jacep.2015.09.001; PMID: 29759461. Cassidy DM, Vassallo JA, Miller JM, et al. Endocardial catheter mapping in patients in sinus rhythm: relationship to underlying heart disease and ventricular arrhythmias. Circulation 1986;73:645–52. https://doi.org/10.1161/01. CIR.73.4.645; PMID: 3948367. Luther V, Sikkel M, Bennett N, et al. Visualizing localized reentry with ultra-high density mapping in iatrogenic atrial tachycardia: beware pseudo-reentry. Circ Arrhythm Electrophysiol 2017;10:e004724. https://doi.org/10.1161/CIRCEP.116.004724; PMID: 28356307. Soejima K. How to troubleshoot the electroanatomic map. Heart Rhythm 2010;7:999–1003. https://doi.org/10.1016/ j.hrthm.2010.03.037; PMID: 20348025.

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8.

9.

10.

11.

12.

13.

functional – arising in regions of non-uniform anisotropy – is also not fully understood.

Future Direction RM is a tool that preserves information from the EGMs on a map. We have discussed its use in complex arrhythmia, but it can offer multiple further potential uses: mapping of gaps within wide area circumferential ablation or linear lesions, documenting conduction block across linear lesions, determining the relationship between the endocardial and epicardial ventricular substrate and mapping the conduction system in His–Purkinje-related VT (fascicular tachycardia and bundle branch re-entry). In the case of AT, RM allows precise identification of the AT substrate in the scarred atrium. This may allow for substrate-guided ablation strategies, in sinus rhythm, for the treatment of AT. Early experiences demonstrate that RM is a promising technique.16

L inton NW, Koa-Wing M, Francis DP, et al. Cardiac ripple mapping: a novel three-dimensional visualization method for use with electroanatomic mapping of cardiac arrhythmias. Heart Rhythm 2009;6:1754–62. https://doi.org/10.1016/ j.hrthm.2009.08.038; PMID: 19959125. Jamil-Copley S, Linton N, Koa-Wing M, et al. Application of ripple mapping with an electroanatomic mapping system for diagnosis of atrial tachycardias. J Cardiovasc Electrophysiol 2013;24:1361–9. https://doi.org/10.1111/jce.12259; PMID: 24118203. Koa-Wing M, Nakagawa H, Luther V, et al. A diagnostic algorithm to optimize data collection and interpretation of ripple maps in atrial tachycardias. Int J Cardiol 2015;199:391–400. https://doi.org/10.1016/j.ijcard.2015.07.017; PMID: 26247796. Luther V, Linton NW, Koa-Wing M, et al. A prospective study of ripple mapping in atrial tachycardias: a novel approach to interpreting activation in low-voltage areas. Circ Arrhythm Electrophysiol 2016;9:e003582. https://doi.org/10.1161/ CIRCEP.115.003582; PMID: 26757985. Luther V, Linton NW, Jamil-Copley S, et al. A prospective study of ripple mapping the post-infarct ventricular scar to guide substrate ablation for ventricular tachycardia. Circ Arrhythm Electrophysiol 2016;9:e004072. https://doi.org/10.1161/ CIRCEP.116.004072; PMID: 27307519. Chae S, Oral H, Good E, et al. Atrial tachycardia after circumferential pulmonary vein ablation of atrial fibrillation: mechanistic insights, results of catheter ablation, and risk factors for recurrence. J Am Coll Cardiol 2007;50:1781–7. https://doi.org/10.1016/j.jacc.2007.07.044; PMID: 17964043.

14. B  radfield JS, Huang W, Tung R, et al. Tissue voltage discordance during tachycardia versus sinus rhythm: implications for catheter ablation. Heart Rhythm 2013;10: 800–4. https://doi.org/10.1016/j.hrthm.2013.02.020; PMID: 23434619. 15. Luther V, Qureshi N, Lim PB, et al. Isthmus sites identified by ripple mapping are usually anatomically stable: A novel method to guide atrial substrate ablation? J Cardiovasc Electrophysiol 2018;29:404–11. https://doi.org/10.1111/ jce.13425; PMID: 29341322. 16. Luther V, Cortez-Dias N, Carpinteiro L, et al. Ripple mapping: Initial multicenter experience of an intuitive approach to overcoming the limitations of 3D activation mapping. J Cardiovasc Electrophysiol 2017;28:1285–94. https://doi. org/10.1111/jce.13308; PMID: 28776822. 17. Berruezo A, Fernandez-Armenta J, Andreu D, et al. Scar dechanneling: new method for scar-related left ventricular tachycardia substrate ablation. Circ Arrhythm Electrophysiol 2015;8:326–36. https://doi.org/10.1161/CIRCEP.114.002386; PMID: 25583983. 18. Tung R, Mathuria NS, Nagel R, et al. Impact of local ablation on interconnected channels within ventricular scar: mechanistic implications for substrate modification. Circ Arrhythm Electrophysiol 2013;6:1131–8. https://doi.org/ 10.1161/CIRCEP.113.000867; PMID: 24162832. 19. Jamil-Copley S, Vergara P, Carbucicchio C, et al. Application of ripple mapping to visualize slow conduction channels within the infarct-related left ventricular scar. Circ Arrhythm Electrophysiol 2015;8:76–86. https://doi.org/10.1161/ CIRCEP.114.001827; PMID: 25527678.

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Clinical Review: Electrophysiology and Ablation

Catheter Ablation for Atrial Fibrillation in Systolic Heart Failure Patients: Stone by Stone, a CASTLE Dimitrios Vrachatis, 1 Spyridon Deftereos, 2,3 Vasileios Kekeris, 1 Styliani Tsoukala 1 and Georgios Giannopoulos 1,2 1. Department of Cardiology, ‘G Gennimatas’ General Hospital of Athens, Greece; 2. Section of Cardiovascular Medicine, Yale University School of Medicine, CT, USA; 3. Second Department of Cardiology, Medical School, Attikon Hospital, National and Kapodistrian University of Athens, Greece.

Abstract Heart failure (HF) and AF frequently coexist and are involved in a vicious cycle of adverse pathophysiologic interactions. Applying treatment algorithms that have been validated in the general AF population to patients with AF and HF may be fraught with risks and lack effectiveness. While firm recommendations on using catheter ablation for AF do exist, the subset of patients also suffering from HF needs to be further evaluated. Observational data indicate that a significant number of ablation procedures are performed in patients with coexistent HF. Initial randomised data on outcomes are encouraging. Apart from sinus rhythm maintenance, benefits have been observed in terms of other significant endpoints, including left ventricular ejection fraction, quality of life, exercise capacity and hospital readmissions for HF. Limited existing data on survival are also promising. In the present article, observational and randomised studies along with current practice guidelines are summarised.

Keywords Pulmonary vein isolation, radiofrequency, cryoballoon, cryoablation, catheter ablation, systolic heart failure, atrial fibrillation Disclosure: The authors have no conflicts of interest to declare. Received: 11 July 2018 Accepted: 28 October 2018 Citation: Arrhythmia & Electrophysiology Review 2018;7(4):265–72. DOI: https://doi.org/10.15420/aer.2018.41.2 Correspondence: Georgios Giannopoulos, Department of Cardiology, Athens General Hospital ‘G Gennimatas’, 154 Mesogeion Ave, 115 27, Athens, Greece. E: ggian@med.uoa.gr

Heart failure (HF) and AF share common pathophysiologic pathways and often coexist.1 Indeed, HF has been identified as the strongest predictor of AF in a Framingham Heart study population-based cohort.2 Moreover, HF and AF are involved in a vicious pathophysiological interplay. HF promotes AF mainly through raised atrial filling pressures, abnormal calcium handling, neurohormonal activation and adrenergic stimulation.3 Conversely, AF promotes HF through rapid ventricular rates, heart rate and pulse volume irregularity, and loss of left atrial kick.3

published in English reporting CA for AF in the setting of HF were considered eligible, and no publication year restrictions were applied. Additionally, the ‘snowball’ procedure was followed, i.e. references in the initially selected articles were scrutinised for identification of any other related studies. Guidelines, expert consensus documents and position statements on AF were scrutinised.

Results Non-randomised Studies

Optimal management (rate and rhythm control) of such patients is a point of debate. This subgroup is usually older and suffering from a range of comorbidities that may complicate therapeutic decisions. Meanwhile, over the last two decades catheter ablation (CA) has emerged as a treatment option for AF and has been widely utilised in clinical practice, which has been reflected in recent clinical practice guidelines.1 Congestive HF patients were under-represented in available trials on CA in AF, despite the fact that HF patients constitute a significant subset of the AF population.4 However, a range of studies have recently reported encouraging results, although there is a lack of standardisation in research protocols and result reporting. In the present article we aim to critically summarise data on CA in patients suffering from both HF and AF.

Methods Data for this article were collected through literature searches in PubMed, and searching the clinicaltrials.gov database to identify of any ongoing studies. The search query used was: ‘ablation’ (AND) ‘fibrillation’ (AND) ‘failure’. Original articles and meta-analyses

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A total of 22 observational studies on CA in HF were identified, evaluating 1,601 patients and 3,763 controls.5–26 These studies provided significant data on the safety and efficacy of CA procedures in this special population, which can be considered as high risk. A marked heterogeneity in their design and choice of controls (in addition to their non-randomised design) does not allow for firm conclusions to be drawn. In most of the studies, patients with AF and HF undergoing CA were compared with patients undergoing CA for AF who did not have HF (rather than AF/HF patients treated medically). As a result, non-randomised studies have mostly addressed the issue of whether HF negatively affects CA feasibility and safety to an unacceptable extent. The main findings of these non-randomised studies are summarised in Table 1 and will not be discussed in detail. As an overall appraisal, CA was found to be feasible and safe in patients with AF and HF. Sinus rhythm maintenance rates were quite heterogeneous, reported at a range of 26–73 % after a single procedure and 33–96 % after multiple procedures, which was not too distant from rates reported in control

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Clinical Review: Electrophysiology and Ablation Table 1: Non-Randomised Observational Studies Evaluating Catheter Ablation for AF in Left Ventricular Systolic Dysfunction Author

Sample Size (Control)

Study Group

LVEF (%)

Age (years)

NICM (%)

NYHA

Control Group (AF Patients Undergoing CA with…)

Followup (months)

Outcomes Study Group QoL

NYHA

Exercise

Control Group

LVEF

SR (%); sp (mp)

SR (%); sp (mp)

Capacity

Chen et al. 20045

94 (283)

36

56

20

2.7 ± 0.5

Normal EF

14

NR

NR

NS

73 (96)

87 (94)

Hsu et al. 20046

58 (58)

35

56

55

2.3 ± 0.5

EF ≥45 %

12

50 (78)

53 (84)

Tondo et al. 200617

40 (65)

33

57

45

2.8 ± 0.1

EF ≥40 %

14

NR

NR (87)

NR (92)

Gentlesk et al. 200720

67 (299)

42

54

82

NR

EF ≥50 %

20

NR

NR

NR

63 (86)

NR (87)

Efremidis et al. 200821

13 (0)

36

54

62

2.0 ± 0.7

NA

9

NR

NR

NR

62 (NR)

NA

Nademanee et al. 200822

129 (0)

31

67

NR

NR

NA

27

NR

NR

NR

58 (79)

NA

Lutomsky et al. 200823

18 (52)

41

56

83

NR

EF ≥50 %

6

NR

NR

NR

50 (NR)

73 (NR)

De Potter et al. 201024

36 (36)

41

52

50

NR

EF ≥50 %

16

NR

NR

NR

50 (70)

56 (70)

Choi et al. 201025

15 (15)

37

56

67

1.7 ± 0.8

EF ≤45 %, no CA but OMT for rate control

16

NR

NR

46 (73)

NA

Cha et al. 201126

111 (157 isolated diastolic dysfunction; 100 normal)

35

35

87

NR

EF ≥50 %

13

NR

NR

NR (62)

Anselmino et al. 20137

196 (0)

40

60

40

2.3 ± 0.9

NA

46

NR

45 (62)

NA

Calvo et al. 20138

97 (561)

40

53

63†

NR

Normal EF

6

NR

NR

NR

70 (83)

NR

Kucukdurmaz et al. 20139

11 (24)

39

56

100

NR

EF ≥50 %

16

NR

NR

NR

51 (NA)*

51 (NA)†

Kosiuk et al. 201410

73 (0)

37

59

59

NR

NA

40

NR

NR

NR

37 (NR)

NA

Nedios et al. 201411

69 (69)

31

60

51

2.4 ± 0.5

Without HF

28

NR

NR

40 (65)

NR (81)

Bunch et al. 201512

87 (292/213)

27

66

41

NR

i. HF with no CA ii. HF without AF

60

NR

NR

NR

39 (NR)

NR

Lobo et al. 201513

31 (0)

45

60

61

2.2 ± 0.6

NA

20

NR

NR

51 (77)

NA

Rillig et al. 201514

80 (0)

35

62

65

2 (2–3)

NA

72

NR

NR

35 (57)

NA

Kato et al. 201615

18 (0)

26

55

44

2.3 ± 0.5

NA

21

NR

NR

11 (61)

NA

Ullah et al. 201616

171 (1,102)

34

58

67

2.3 ± 0.7

EF ≥45 % without HF

43

NR

NR

26 (65)

40 (82)

Black-Meier et al. 201718

97 (133)

35

67

NR

2.2 ± 0.7

HF with EF ≥50 %

12

NR

NR

NR (33)

NR (34)

Geng et al. 201719

90 (304)

42

65

92

2.7 ± 0.6

HF – no CA, but OMT for rate control

14

MACEs reduced in study group

NR (82)

NA

*In this study, 63 % of the patients suffered from tachymyocardiopathy. †Data for overall population (study and control group). ↑ = statistically significant improvement; CA = catheter ablation; HF = heart failure; HFrEF = heart failure with reduced ejection fraction; EF = ejection fraction; iDD = isolated diastolic dysfunction; LVEF = left ventricular ejection fraction; MACE = major adverse cardiac event; NA = not applicable; NICM = non‐ischaemic cardiomyopathy; NR = not reported; NS = nonsignificant; NYHA = New York Heart Association; OMT = optical medical treatment; QoL = quality of life; SR = sinus rhythm maintenance post single (sp) or multiple (mp) procedures.

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Catheter Ablation for AF in Systolic Heart Failure Table 2: Randomised Trials Evaluating Radiofrequency Catheter Ablation for AF in Left Ventricular Systolic Dysfunction Study

PABA CHF27

Control Group

Sample Primary Size Endpoint (Control)

AVNA + 41 (40) bi-ventricular pacing

Age (years)

AF, NICM LVEF paroximal/ (%) (%) persistent (%)

Follow-up (months)

Study Group Outcomes

SR (%); Change in Functional sp (mp) LVEF (%) Capacity

Composite of LVEF, 6MWD and MLWHF

60

41/59

27

27 (TTE)

6

68 (88)

+8*

Improved 6MWD*

Survival No deaths in either group

Curing Atrial Rate control Fibrillation in Heart Failure28

22 (19)

LVEF by CMR

62

0/100

50

36 6 (CMR), 15 (RNV)

40 (50)

NS† (CMR); NS† +8* (RNV) 6MWD

No deaths in either group

ARC-AF29

Rate control

26 (26)

VO2 max

64

0/100

62

22 (RNV)

12

72 (92)

NS† (but trend favouring CA)

Improved VO2 max;* NS 6MWD†

1 death in CA group at 11 months

CAMTAF30

Rate control

26 (24)

LVEF

55

0/100

76

32 (TTE)

6

38 (81)

+8*

Improved VO2 max*

1 death in medical group

AATAC31

Rhythm 102 (101) control (amiodarone)

AF recurrence 62

0/100

38

29 (TTE)

24

– (70)

+8*

Improved 6MWD*

CA improved survival

CAMERAMRI32

Rate control

33 (33)

LVEF

59

0/100

100

35

6

56 (‡)

+18*

NS 6MWD†

No deaths in either group

CASTLE-AF33

Rate or rhythm control

179 (184)

Composite of 64 any death or hospitalisation for HF worsening

30/70

60

33 (TTE)

60

– (50)

+8*

Improved CA: All-cause 6MWD at 12 and CV mortality months* improved; hospitalisations improved

Change (i.e. final minus baseline) significantly greater in study versus control group. Change (i.e. final minus baseline) comparable between study versus control group. ‡ Average AF burden at 6 months was 1.6 ± 5.0 %, with an AF burden >10 % in 2 patients. 6MWD = 6-minute walk test distance; AVNA = atrioventricular nodal ablation; CA = catheter ablation; CMR = cardiac magnetic resonance; CV = cardiovascular; HF = heart failure; LVEF = left ventricular ejection fraction; MLWHF = Minnesota Living with Heart Failure; NICM = non‐ischaemic cardiomyopathy; NR = not reported; NS = non-significant; RF = radiofrequency ablation utilisation (versus cryoballoon ablation); RNV = radionuclide ventriculography; SR = sinus rhythm maintenance post single (sp) or multiple (mp) procedures; TTE = transthoracic echocardiography. * †

groups of patients with AF without HF. Additionally, post-procedural left ventricular ejection fraction (LVEF) increase as well as functional status improvement – as assessed by New York Heart Association (NYHA) classification and/or self-perceived quality of life questionnaires – were consistently observed.

Randomised Studies Seven randomised trials evaluating CA in HF are available to date, almost half of which are single-centre studies.27–33 All of the studies recruited patients with systolic HF, i.e. with impaired LVEF, and employed radiofrequency ablation.In four of the studies only patients with persistent AF were evaluated,28–31 while in the rest, both paroxysmal and persistent – including long-standing persistent – AF patients were included.27,33 In four studies CA was compared with rate control,27–30 while in the rest the control arm involved a rhythm control strategy or best medical treatment according to current guidelines with an effort to maintain sinus rhythm (Table 2).31,33

Pulmonary Vein Isolation versus Rate Control Atrioventricular node ablation (AVNA) and subsequent (bi-)ventricular pacing may be perceived as an extreme form of rate control in AF management. CA is currently the cornerstone of rhythm control approaches. The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study and its sub-analyses implied that neither rate nor rhythm control may be considered to be a superior approach, as the beneficial effect of sinus rhythm maintenance in the

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rhythm control arm was essentially counteracted by anti-arrhythmic medication side-effects.34 Following this line of thought, the Pulmonary Vein Antrum Isolation versus AV Node Ablation with Bi-Ventricular Pacing for Treatment of Atrial Fibrillation in Patients with Congestive Heart Failure (PABA CHF) trial investigators evaluated CA versus AVNA plus bi-ventricular pacing with an implantable cardioverter/defibrillator in patients with AF and concomitant systolic HF.27 A total of 41 patients (60 years old; 95 % males) were treated with CA versus 40 patients (61 years old; 88  % males) treated with AVNA and bi-ventricular pacing in this randomised, multicentre, open-label study. The CA group consisted of patients with a mean LVEF of 28  %. At 6  months sinus rhythm maintenance was observed in 68  % of patients after a single ablation procedure (88  % after multiple procedures). LVEF was significantly improved in the CA group (from 27  % at baseline to 35  % at 6 months), while in the ratecontrol group LVEF was comparable between baseline and follow-up. Additionally, left atrial diameter, 6-minute walk distance (6MWD) and self-perceived quality of life changes also favoured CA over AVNA plus bi-ventricular pacing. Complications were comparable in the two groups. Of note, patients with non-paroxysmal AF benefited more in terms of LVEF than those with paroxysmal AF.27 A number of other small, inconclusive studies have been published. A randomised, single-centre study by MacDonald et  al. found that the LVEF change at 6 months (evaluated with MRI) was comparable in

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Clinical Review: Electrophysiology and Ablation the two groups.28 In the Assess Catheter Ablation Versus Rate Control in the Management of Persistent Atrial Fibrillation in Chronic Heart Failure (ARC-AF trial) LVEF improved significantly in both the CA and rate control groups, but the magnitude of change was comparable between groups.29 The Catheter Ablation Versus Medical Treatment of Atrial Fibrillation in Heart Failure (CAMTAF) trial reported an increase in LVEF in the CA group in contrast to the medical management group in which a decrease was observed, accompanied by improvements in peak oxygen consumption, brain natriuretic peptide levels, NYHA classification and self-perceived quality of life.30 Of note, the Catheter Ablation Versus MEdical Rate Control in Atrial Fibrillation and Systolic Dysfunction (CAMERA-MRI) trial, a randomised, multicentre study, evaluated CA versus rate control and reported a significantly greater improvement in LVEF (as assessed by MRI) in the CA group.32 This was accompanied by favourable outcomes in natriuretic peptides, but not in functional improvement (as assessed by 6MWD).

Pulmonary Vein Isolation Versus Anti-arrhythmic Drug Therapy In the Ablation Versus Amiodarone for Treatment of Persistent Atrial Fibrillation in Patients with Congestive Heart Failure and an Implanted Device (AATAC) trial, Di Biase et al. investigated the effects of CA (102 patients) versus rhythm control with amiodarone (101 patients) in patients with persistent AF, dual-chamber ICD or cardiac resynchronisation therapy defibrillator in the setting of systolic HF.31 At 24 months, CA patients were arrhythmia free at a rate of 70  % (versus 34  % of the amiodarone-treated patients). Unplanned hospitalisations occurred at a lower frequency in the CA group (3.8 patients needed to treat in order to avoid one unplanned hospitalisation), while improvements in exercise capacity (6MWD) and self-perceived quality of life were greater in the CA group. Finally, a significant 24-month survival benefit was observed in the CA group (8 % versus 18 %; p=0.004). The most recent and largest randomised study, Catheter Ablation for Atrial Fibrillation with Heart Failure (CASTLE-AF), was published in 2018 and had a primary endpoint of a composite of death from any cause or hospitalisation for worsening HF.33 In an open-label, randomised trial Marrouche et al. compared radiofrequency CA (179 patients) with best medical treatment (rate or rhythm control; 184 patients) in patients with paroxysmal (30 %) or persistent (70 %) AF and systolic HF. All patients had an ICD or cardiac resynchronisation therapy defibrillator device implanted.33 The primary study endpoint occurred less frequently in the CA group (29 % versus 45 %, respectively; p=0.006) at a median followup of 39 months. Aside from this primary analysis, lower total mortality was observed in the CA group (13 % versus 25 %; p=0.01), along with lower cardiovascular mortality (11  % versus 22  %; p=0.009). These benefits were accompanied by lower AF burden, LVEF improvement and 6MWD increase in the CA group.

with HF. A total of 1,838 patients (59 years old; LVEF: 40 %; 59  % non-ischemic cardiomyopathy; follow-up 23 months) undergoing CA were included but no controls (i.e. patients treated medically) were evaluated. A significant improvement (13  % absolute increase) in LVEF was observed. Sinus rhythm (SR) maintenance after multiple CA procedures was 60  %, with 32  % of the population requiring a redo procedure. Procedure-related complications were estimated at an overall rate of 4.2 %. While three of the available meta-analyses also report results in controls,only two of them compared patients treated with ablation versus patients treated medically.35,38,40 Both Al Halabi et  al. (four studies; 111 ablation treated versus 108 medically treated patients) and Zhu et  al. (three studies; 71 ablation treated versus 68 medically treated patients) concluded that ablation is superior to medical treatment in terms of LVEF and functional improvement in AF patients with depressed LVEF.38,40 Of note, these two meta-analyses included all available randomised studies at the time of their publication.

Guidelines: Consensus Documents The most recent recommendation is the 2017 expert consensus statement on catheter and surgical ablation of AF. The experts suggest that it is reasonable that AF ablation should be offered in selected HF patients under the same criteria as if HF was not present (Class IIb; level of evidence: B-R).4 The 2016 European Society of Cardiology (ESC) guidelines for the management of AF, developed in accordance with the recent HF guidelines, make recommendations according to HF classification in HF with impaired LVEF, with mid-range LVEF and with preserved LVEF.1,41 Lack of sufficient data is underscored in the two latter categories. As far as patients with impaired LVEF are concerned, the 2016 ESC/EACTS guidelines suggest that CA may be considered in order to restore LVEF and improve quality of life without appointing a specific recommendation class. Furthermore, CA should be considered for symptom amelioration and enhancement of cardiac function when tachycardiomyopathy is suspected (Class IIa; level of evidence: B). Finally, the 2016 ESC guidelines suggest that CA for AF may be considered in patients with persisting symptoms and signs of HF, despite optimal medical treatment and adequate (ventricular) rate control in order to restore sinus rhythm and improve functional status (Class IIb-B).41

Ongoing Studies

Six meta-analyses are available to the best of our knowledge; a summary of their findings is presented in Table 3.35–40 Absolute LVEF increase (in the range of +6 % to +13  %) and ‘acceptable’ sinus rhythm maintenance and procedure-related complication rates are consistent findings.

Several studies are ongoing or have recently been completed. The Rhythm Control – Catheter Ablation with or Without Anti-arrhythmic Drug Control of Maintaining Sinus Rhythm versus Rate Control with Medical Therapy and/or Atrioventricular Junction Ablation and Pacemaker Treatment for Atrial Fibrillation (RAFT-AF) study (NCT01420393) has completed recruitment (~400 patients) and is scheduled to be completed by mid-2020. Patients with any AF type and coexistent HF have been randomised to CA and medical rate control management, and will be followed for approximately 2 years. The primary endpoint of RAFT-AF is a composite of all-cause mortality and HF hospital admission.

The largest meta-analytic cohort (without a control group) to date has been reported by Anselmino et al.37 The investigators included published results from observational and randomised studies evaluating CA in HF patients plus raw data from CA studies not primarily designed to evaluate, but which included, patients

The Atrial Fibrillation Ablation Compared to Rate Control Strategy in Patients with Impaired Left Ventricular Function (AFARC-LVF) study (NCT02509754) was scheduled to be completed at the end of 2017, but due to procedural issues enrollment has not yet started (information provided by study investigators). In this study, 180

Meta-analyses

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Catheter Ablation for AF in Systolic Heart Failure Table 3: Meta-analyses of Studies Evaluating Radiofrequency Catheter Ablation for AF in the Setting of Systolic Heart Failure Study

Sample

Studies

Age

NICM

LVEF

Follow-

Size

Included

(years)

(%)

(%)

up, months

(Control)

Outcomes

Complications

Redo (%)

(%)

SR (%); sp

Change in

(mp)

LVEF (%)

Wilton et al. 201035

483 (1,368)

8

52–67

11–74

27–41

6–27

~11

4–31

45–73 (4–31)

+11*

Dagres et al. 201136

354 (NA)

9

49–62

(22–83)

35–43

6–12

~7

NR

(42–88)

+11

1,838 (NA)

26

59

59

40

23

4–5

32

40 (60)

+13

Al Halabi et al. 201538

111 (108)

4

57–63

51–74

26

6–12

7

~30

(50–88)

+9**

Ganesan et al. 201539

914 (NA)

19

42–74

14–88

14–50

6–28

6

NR

57 (82)

+13

Zhu et al. 2016

71 (68)

3

57–63

50–77

15–32

6–12

8–15

NA

(50–88)

+6**

Anselmino et al. 2014

40

37

*p

for comparison with control group not provided. **p significant for comparison with rate control strategy. HFrEF = heart failure with reduced ejection fraction; LVEF = left ventricular ejection fraction; NA = not applicable; NICM = non‐ischaemic cardiomyopathy; NR = not reported; SR = sinus rhythm maintenance post single (sp) or multiple (mp) procedures.

patients with persistent AF, LVEF ≤35 % and recent HF diagnosis were to be randomised to CA versus medical rate control treatment. The primary endpoint was a composite LVEF >35 % and a NYHA class <2 at 6 months.

of expected payback. Moreover, detection of the exact HF patient subsets that are expected to profit from such procedures is an as yet unattained goal.

Sinus Rhythm Maintenance The Catheter Ablation versus Medical Therapy in Congested Hearts with AF (CATCH-AF) study is expected to be completed in 2019. A total of 220 patients with systolic HF (LVEF 20–45 %) and symptomatic AF will be randomised to CA versus medical rate control and will be followed for 1 year. The primary endpoint is the time to the first of the following: hospitalisation for HF, recurrence of AF or direct current cardioversion. Finally, the Atrial Fibrillation Management in Congestive Heart Failure with Ablation (AMICA) study was completed in mid-2017 and results are expected soon. A total of 202 patients with symptomatic AF and HF, and an indication for device implantation (implantable cardiac defibrillator with cardiac resynchronisation capabilities if appropriate) were randomised to either CA or a medical rate control strategy. The primary endpoint was LVEF at 1 year.

Discussion Application of ablation procedures in HF patients with AF initially raised obvious concerns regarding safety and efficacy. Published data from observational and randomised studies indicated that ablation procedures in patients with AF and left ventricular systolic dysfunction were not accompanied by major safety issues. Moreover, data from the US Nationwide Readmissions Registry indicate that, in 2013, almost one in five CA procedures had been conducted in patients with AF and coexistent HF (~2,500 procedures).42 Undeniably, patients with HF may feature frailty characteristics and this should be taken into consideration in the context of a holistic patient assessment, but HF should not be considered as a contraindication. This was firmly depicted in the most recent guidelines,in which selected HF patients are expected to be treated with AF ablation for HF under the same indications as non-HF patients.4 CA success – in terms of sinus rhythm maintenance – is a major point of interest. However, rhythm control success in HF patients should only be conceived as one aspect of the potential benefits and cannot simply be defined as a total absence of AF. Improvements in LVEF, functional capacity and quality of life should also be included in the full spectrum

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Predictors of SR maintenance after CA have drawn attention from researchers. A series of factors have been identified, but there is an ongoing debate on independent predictors of success.43 Nonparoxysmal AF (especially long-standing persistent AF) and impaired LVEF have been identified as negative predictors for success of CA regarding SR maintenance.4 However, observed SR maintenance rates after CA in AF plus HF patients who mainly suffered from persistent AF paint a noticeably less dire picture. In the available observational studies, SR maintenance after multiple CA procedures was reported at rates of 33–96 % (follow-up: 6–72 months), while in randomised studies rates of 50–88  % have been reported (Tables 1 and 2). These results are largely comparable with the reported rates of SR maintenance after CA in the general AF population4.

Left Ventricular Ejection Function Improvement LVEF improvement after CA for AF in HF patients appears to be a consistent finding in both observational and randomised studies. All but one of the observational studies reported improved LVEF after CA procedures (Table 1). Four out of five available randomised studies that compared CA versus rate control (in patients with AF and concurrent HF) showed a beneficial effect of CA (over rate control) in LVEF; of note, the fifth study showed a statistical trend in line with the rest.27–30,32 In favour of CA was also the comparison with rhythm control (under amiodarone; AATAC trial) and the comparison with medical management including rate and/or rhythm control (CASTLEAF trial).31,33 Finally, both available meta-analyses that provide a direct comparison of post-procedural change in LVEF after CA versus a rate control strategy show a beneficial effect on LVEF.38,40 LVEF improvement may well be attributed to the disruption of AF-related mechanisms that provoke and/or worsen HF (tachycardia, loss of atrial systolic function, ventricular rate irregularity, activation of neurohormonal pathways, and so on).3 In addition, these recent results indicate that our thus far established notion of ablation success is challenged by the fact that reduction in AF burden may in fact be more relevant in terms of prognosis compared with a traditional approach of a binary success/

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Clinical Review: Electrophysiology and Ablation failure outcome. To put it simply, the detrimental effects of AF may well be alleviated through the reduction of AF burden, even in the cases of failure to achieve permanent sinus rhythm maintenance. One should also not overlook the potentially beneficial effects that may arise from withdrawal of anti-arrhythmic drugs after CA.37 LVEF improvement in patients with systolic HF could possibly lead to a reduction in the proportion of patients in whom device therapy (implantation of ICDs and/or cardiac resynchronisation devices) is indicated.44 Finally, it should be noted that patients suffering from impairment of systolic left ventricular function as a result of tachymyocardiopathy are a discrete patient subset, although it may be initially difficult to classify them correctly at the time of first diagnosis – especially when AF and impaired systolic function are diagnosed simultaneously. These patients are expected to benefit the most from CA procedures and are likely to restore normal or nearnormal LV function.3,44

of CA. Still, it should be noted that these results refer to a general population of AF patients, irrespective of systolic function. In these preliminary results there was a tendency for better outcomes in patients with HF, but the interaction with HF status was apparently nonsignificant. Therefore, the publication of final results as well as post-hoc analyses will be eagerly awaited.

Complications: Readmissions According to available data, CA in HF is a relatively safe procedure. Procedure-related complications are reported at rates of 3–15 % (Tables 1–3). While some of them may be life threatening (i.e. pericardial tamponade), peri-procedural death is extremely rare.

Another advantage of CA treatment in systolic HF patients is improvement in functional capacity and self-perceived quality of life. While there is a lack of standardisation regarding patient functional assessment in the available studies, such data are frequently reported (NYHA classification, maximal oxygen consumption at peak exercise, 6MWD, quality of life indices). Available data from randomised and observational studies (Tables 1 and 2) are concordant in terms of the improvement in functional/exercise capacity and self-perceived quality of life after CA. Indeed, randomised trials (Table 2) indicate an additive benefit of CA over rate control or medical management (rate and/or rhythm control).

An analysis of the US Nationwide Readmissions Registry for 2013 reported a series of interesting real-life findings.42 A total of 885,270 admissions for HF exacerbation were evaluated; 364,447 were patients with coexisting AF. As expected, AF in HF patients was found to be a factor precipitating increased 90-day readmissions due to HF exacerbation (41 % versus 38 %; p<0.0001). CA treatment in HF patients (at index admission) was found to have beneficial effects. Patients who were offered CA treatment were readmitted for HF exacerbation less frequently (28 % versus 42 %; p<0.0001). In case of readmission, patients treated with CA were observed to be hospitalised for fewer days. It is noteworthy that both complications at index admission (in which CA was conducted) and total complications (index admission and readmissions) were comparable in patients who underwent CA and suffered from HF and those who were HF free. It is relevant to note that these data are purely observational but nevertheless useful in demonstrating that CA offered to select HF patients is safe and potentially beneficial in a reallife population.

Survival: Major Adverse Cardiac Events

Limitations

Most available studies were not powered to assess the effect of CA on survival and major adverse cardiac events (MACEs). However, available data are promising. In a retrospective, multicentre study by Geng et al., CA (versus rate control) in systolic HF was found to reduce MACEs mid-term (14 ± 5 months) in the CA group (hazard ratio 0.51; 95  % CI [0.32–0.82]; p=0.005), although it did not affect overall survival.19 In the recent, randomised CASTLE-AF trial, the composite of any death or hospitalisation for HF worsening was reduced in the CA group (versus optimal medical management) in patients with systolic HF, while total and cardiovascular mortality were also reduced.33

Available studies have evaluated the effect of radiofrequency CA. Procedural variants of radiofrequency CA – i.e. isolated pulmonary vein isolation or in combination with posterior wall isolation and/or ablation of non-pulmonary vein triggers – may well be a source of heterogenicity.31,37 Moreover, there is a need for procedural simplification and standardisation in this frail population.44 Indeed, frailty as assessed with reliable indices would be of value but it is not reported in the available studies. Furthermore, radiofrequency CA procedures have been reported to be less reproducible and more centre experience and caseload dependent in comparison to cryoballoon CA.45 Participant age in available studies would be an additional issue. While HF should not be considered as a contraindication for CA, we must bear in mind that available data on CA in HF patients have been derived from populations aged 50–60 years. Extrapolation to older and more fragile patients should be done with caution. In addition, trial subjects do differ unavoidably in terms of demographic characteristics from reallife patients. Based on population studies, women should represent 36–49 % of patients with AF and 40–53  % of patients with HF.46 In the available randomised trials evaluating CA in patients with AF and HF, women were grossly under-represented (at 4–27  %). Underrepresentation of women in HF studies has recently been commented on in an interesting paper by Scott et al.46.

Functional Improvement

Finally, the preliminary findings of the Catheter ABlation Versus ANtiarrhythmic Drug Therapy for Atrial Fibrillation (CABANA; NCT00911508) trial were announced in early 2018, but the full results have not been published (the oral presentation slides are available at www.cabanatrial. org). CABANA, when published, will be the largest (approximately 1,000 patients in each arm) randomised, multicentre trial to date with a 5-year follow-up to compare CA approach versus state-of-the-art (i.e. rate or rhythm) medical treatment. Despite its size, randomisation and choice of a clinical endpoint, certain flaws have already been pinpointed, including a large crossover percentage between randomisation arms and a change in the primary endpoint after initiation of the study. The primary endpoint was the composite of all-cause mortality, disabling stroke, serious bleeding or cardiac arrest. On the primary intention-to-treat analysis the study results were neutral, whereas the as-treated results were in favour

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Medical treatment variations may also be a source of discrepancy. However, such variations are currently included in the standard of care and it is reasonable that studies regarding CA will unavoidably be compared to this standard, as a range of ethical issues would otherwise arise.

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Catheter Ablation for AF in Systolic Heart Failure Finally, evaluation of the ‘real’ LVEF is a largely overlooked issue. Evaluation of LVEF under the same rhythm state at baseline and at final evaluation (i.e. sinus rhythm versus sinus rhythm or AF versus AF) is not universally possible for obvious reasons, and therefore represents a potential source of inherent systematic error of such studies. In view of the aforementioned limitations, while initial data are encouraging, important issues remain to be cleared. Therapeutic decisions should be based upon an individualised assessment of expected benefits and procedural risks. Procedural strategy (with regards to the radiofrequency ablation approach) should also be individualised and specific algorithms have been suggested to facilitate patient management.44

Conclusions CA for AF in systolic HF patients is a feasible and relatively safe technique. Available data suggest that, apart from sinus rhythm maintenance, patients show improvement in left ventricular systolic function, self-perceived quality of life and functional capacity (favouring ablation over medical management strategies). Limited data regarding

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13.

14.

 irchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines K for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 2016;37:2893–962. https:// doi.org/10.1093/eurheartj/ehw210; PMID: 27567408. Benjamin EJ, Levy D, Vaziri SM, et al. Independent risk factors for atrial fibrillation in a population-based cohort. The Framingham Heart Study. JAMA 1994;271:840–4. https://doi. org/10.1001/jama.1994.03510350050036; PMID: 8114238. Prabhu S, Voskoboinik A, Kaye DM & Kistler PM. atrial fibrillation and heart failure – cause or effect? Heart Lung Circ 2017;26:967–74. https://doi.org/10.1016/j.hlc.2017.05.117; PMID: 28684095. Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation. Heart Rhythm 2017;14:e275–e444. https://doi.org/10.1016/ j.hrthm.2017.05.012; PMID: 28506916. Chen MS, Marrouche NF, Khaykin Y, et al. Pulmonary vein isolation for the treatment of atrial fibrillation in patients with impaired systolic function. J Am Coll Cardiol 2004;43:1004–9. https://doi.org/10.1016/j.jacc.2003.09.056; PMID: 15028358. Hsu, L-F, Jaïs P, Sanders P, et al. Catheter ablation for atrial fibrillation in congestive heart failure. N Engl J Med 2004;351:2373–83. https://doi.org/10.1056/NEJMoa041018; PMID: 15575053. Anselmino M, Grossi S, Scaglione M, et al. Long-term results of transcatheter atrial fibrillation ablation in patients with impaired left ventricular systolic function. J Cardiovasc Electrophysiol 2013;24:24–32. https://doi.org/10.1111/j.15408167.2012.02419.x; PMID: 23140485. Calvo N, Bisbal F, Guiu E, et al. Impact of atrial fibrillationinduced tachycardiomyopathy in patients undergoing pulmonary vein isolation. Int J Cardiol 2013;168:4093–7. https://doi.org/10.1016/j.ijcard.2013.07.017; PMID: 23890896. Kucukdurmaz Z, Kato R, Erdem A, et al. Catheter ablation for atrial fibrillation results in greater improvement in cardiac function in patients with low versus normal left ventricular ejection fraction. J Interv Card Electrophysiol 2013;37:179–87. https://doi.org/10.1007/s10840-013-9794-6; PMID: 23625275. Kosiuk J, Nedios S, Darma A, et al. Impact of single atrial fibrillation catheter ablation on implantable cardioverter defibrillator therapies in patients with ischaemic and nonischaemic cardiomyopathies. Europace 2014;16:1322–6. https:// doi.org/10.1093/europace/euu018; PMID: 24532559. Nedios S, Sommer P, Dagres N, et al. Long-term follow-up after atrial fibrillation ablation in patients with impaired left ventricular systolic function: the importance of rhythm and rate control. Heart Rhythm 2014;11:344–51. https://doi. org/10.1016/j.hrthm.2013.12.031; PMID: 24374320. Bunch TJ, May HT, Bair TL, et al. Five-year outcomes of catheter ablation in patients with atrial fibrillation and left ventricular systolic dysfunction. J Cardiovasc Electrophysiol 2015;26:363–70. https://doi.org/10.101111/jce.12602; PMID: 25534572. Lobo TJ, Pachon CT, Pachon JC, et al. Atrial fibrillation ablation in systolic dysfunction: clinical and echocardiographic outcomes. Arq Bras Cardiol 2014;104:45–52. https://doi. org/10.105935/abc.20140167; PMID: 25387404. Rillig A, Makimoto H, Wegner J, et al. Six-year clinical outcomes after catheter ablation of atrial fibrillation in patients with impaired left ventricular function. J Cardiovasc Electrophysiol 2015;26:1169–79. https://doi.org/10.101111/ jce.12765; PMID: 26217925.

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survival in this patient population are also encouraging, but which specific subgroups of HF patients – if any – are most likely to benefit from a catheter-based intervention strategy is a matter to be determined in the future.

Clinical Perspective • H  eart failure (HF) patients with AF should be treated with the same indications as non-HF patients; pulmonary vein isolation for AF in HF patients is not accompanied by any major safety issues. •  Sinus rhythm maintenance rates in HF patients undergoing pulmonary vein isolation are largely comparable to non-HF patients. •  Functional improvement (greater than conventional medical treatment) after pulmonary vein isolation in HF patients is a consistent finding in the available literature. •  The limited available data suggest benefit in terms of hard clinical endpoints, including survival, in this population.

15. K  ato K, Ejima K, Fukushima N, et al. Catheter ablation of atrial fibrillation in patients with severely impaired left ventricular systolic function. Heart Vessels 2016;31:584–92. https://doi. org/10.1007/s00380-015-0635-7; PMID: 25633056. 16. Ullah W, Ling LH, Prabhu S, et al. Catheter ablation of atrial fibrillation in patients with heart failure: impact of maintaining sinus rhythm on heart failure status and long-term rates of stroke and death. Europace 2016;18:679–86. https://doi. org/10.1093/europace/euv440; PMID: 26843584. 17. Tondo C, Mantica M, Russo G, et al. Pulmonary vein vestibule ablation for the control of atrial fibrillation in patients with impaired left ventricular function. Pacing Clin Electrophysiol 2006:29;962–70. https://doi.org/10.101111/j.15408159.2006.00471.x; PMID: 16981920. 18. Black-Maier E, Ren X, Steinberg BA, et al. Catheter ablation of atrial fibrillation in patients with heart failure and preserved ejection fraction. Heart Rhythm 2018;15:651–7. https://doi.org/10.1016/j.hrthm.2017.12.001; PMID: 29222043. 19. Geng J, Zhang Y, Wang Y, et al. Catheter ablation versus rate control in patients with atrial fibrillation and heart failure. Medicine (Baltimore) 2017;96:e9179. https://doi.org/10.1097/ MD.0000000000009179; PMID: 29245366. 20. Gentlesk PJ, Sauer WH, Gerstenfeld EP, et al. Reversal of left ventricular dysfunction following ablation of atrial fibrillation. J Cardiovasc Electrophysiol 2007;18:9–14. https://doi. org/10.101111/j.1540-8167.2006.00653.x; PMID: 17081210. 21. Efremidis M, Sideris A, Xydonas S, et al. Ablation of atrial fibrillation in patients with heart failure: reversal of atrial and ventricular remodelling. Hellenic J Cardiol 2008;49:19–25. PMID: 18350778. 22. Nademanee K, Schwab MC, Kosar EM, et al. Clinical outcomes of catheter substrate ablation for high-risk patients with atrial fibrillation. J Am Coll Cardiol 2008;51;843–9. https://doi. org/10.1016/j.jacc.2007.10.044; PMID: 18294570. 23. Lutomsky BA, Rostock T, Koops A, et al. Catheter ablation of paroxysmal atrial fibrillation improves cardiac function: a prospective study on the impact of atrial fibrillation ablation on left ventricular function assessed by magnetic resonance imaging. Europace 2008;10:593–9. https://doi.org/10.1093/ europace/eun076; PMID: 18385123. 24. De Potter T, Berruezo A, Mont L, et al. Left ventricular systolic dysfunction by itself does not influence outcome of atrial fibrillation ablation. Europace 2010;12:24–9. https://doi. org/10.1093/europace/eun076; PMID: 18385123. 25. Choi AD, Hematpour K, Kukin M, et al. Ablation vs medical therapy in the setting of symptomatic atrial fibrillation and left ventricular dysfunction. Congest Heart Fail 2010;16:10–4. https:// doi.org/10.101111/j.1751-7133.2009.00116.x; PMID: 20078622. 26. Cha Y-M., Wokhlu A, Asirvatham SJ, et al. Success of ablation for atrial fibrillation in isolated left ventricular diastolic dysfunction: a comparison to systolic dysfunction and normal ventricular function. Circ Arrhythm Electrophysiol 2011;4:724–32. https://doi.org/10.101161/CIRCEP.110.960690; PMID: 1747059. 27. Khan MN, Jaïs P, Cummings J, et al. Pulmonary-vein isolation for atrial fibrillation in patients with heart failure. N Engl J Med 2008;359:1778–85. https://doi.org/10.1056/NEJMoa0708234; PMID: 18946063. 28. MacDonald MR, Connelly DT, Hawkins NM, et al. Radiofrequency ablation for persistent atrial fibrillation in patients with advanced heart failure and severe left ventricular systolic dysfunction: a randomised controlled trial. Heart 2011;97:740–7. https://doi.org/10.1136/

hrt.2010.207340; PMID: 21051458. 29. J ones DG, Haldar SK, Hussain W, et al. A randomized trial to assess catheter ablation versus rate control in the management of persistent atrial fibrillation in heart failure. J Am Coll Cardiol 2013;61:1894–903. https://doi.org/10.1016/ j.jacc.2013.01.069; PMID: 23500267. 30. Hunter RJ, Berriman TJ, Diab I, et al. A randomized controlled trial of Catheter Ablation Versus Medical Treatment of Atrial Fibrillation in Heart Failure (the CAMTAF trial). Circ Arrhythmia Electrophysiol 2014;7:31–8. https://doi.org/10.101161/ CIRCEP.113.000806; PMID: 24382410. 31. Di Biase L, Mohanty P, Mohanty S, et al. Ablation versus amiodarone for treatment of persistent atrial fibrillation in patients with congestive heart failure and an implanted device: results from the AATAC multicenter randomized trial. Circulation 2016;133:1637–44. https://doi.org/10.101161/ CIRCULATIONAHA.115.019406; PMID: 27029350. 32. Prabhu S, Taylor AJ, Costello BT, et al. Catheter ablation versus medical rate control in atrial fibrillation and systolic dysfunction. J Am Coll Cardiol. 2017;70:1949–61. https://doi. org/10.1016/j.jacc.2017.08.041; PMID: 28855115. 33. Marrouche NF, Brachmann J, Andresen D, et al. Catheter ablation for atrial fibrillation with heart failure. N Engl J Med. 2018;378:417–27. https://doi.org/10.1056/NEJMoa1707855; PMID: 29385358. 34. Corley SD, Epstein AE, DiMarco JP, et al. Relationships between sinus rhythm, treatment, and survival in the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) study. Circulation 2004;109:1509–13. https://doi. org/10.101161/01.CIR.0000121736.16643.11; PMID: 15007003. 35. Wilton SB, Fundytus A, Ghali WA,et al. Meta-analysis of the effectiveness and safety of catheter ablation of atrial fibrillation in patients with versus without left ventricular systolic dysfunction. Am J Cardiol 2010;106:1284–91. https://doi. org/10.1016/j.amjcard.2010.06.053; PMID: 21029825. 36. Dagres N, Varounis C, Gaspar T, et al. Catheter ablation for atrial fibrillation in patients with left ventricular systolic dysfunction. A systematic review and meta-analysis. J Card Fail 2011;17:964–70. https://doi.org/10.1016/j.cardfail.2011.07.009; PMID: 22041335. 37. Anselmino M, Matta M, D’Ascenzo F, et al. Catheter ablation of atrial fibrillation in patients with left ventricular systolic dysfunction: a systematic review and metaanalysis. Circ Arrhythmia Electrophysiol 2014;7:1011–8. https://doi.org/10.101161/CIRCEP.114.001938; PMID: 25262686. 38. Al Halabi S, Qintar M, Hussein A, et al. Catheter ablation for atrial fibrillation in heart failure patients: a meta-analysis of randomized controlled trials. JACC Clin Electrophysiol 2015;1:200–9. https://doi.org/10.1016/j.jacep.2015.02.018; PMID: 26258174. 39. Ganesan AN, Nandal S, Lüker J, et al. Catheter ablation of atrial fibrillation in patients with concomitant left ventricular impairment: a systematic review of efficacy and effect on ejection fraction. Heart Lung Circ 2015;24:270–80. https://doi. org/10.1016/j.hlc.2014.09.012; PMID: 25456506. 40. Zhu M, Zhou X, Cai H, et al. Catheter ablation versus medical rate control for persistent atrial fibrillation in patients with heart failure: A PRISMA-compliant systematic review and meta-analysis of randomized controlled trials. Medicine (Baltimore) 2016;95:e4377. https://doi.org/10.1097/ MD.0000000000004377; PMID: 27472728. 41. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart

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atrial fibrillation termination and clinical success of catheter ablation of persistent atrial fibrillation. Am J Cardiol 2012;110:545–51. https://doi.org/10.1016/ j.amjcard.2012.04.028; PMID: 22591670. 44. Anselmino M, Matta M, Castagno D, et al. Catheter ablation of atrial fibrillation in chronic heart failure: state-of-the-art and future perspectives. Europace 2016;18:638– 47. https://doi.org/10.1093/europace/euv368; PMID: 26857188. 45. Providencia R, Defaye P, Lambiase PD, et al. Results from a multicentre comparison of cryoballoon vs. radiofrequency ablation for paroxysmal atrial fibrillation: is cryoablation more

reproducible? Europace 2017;19:48–57. https://doi.org/10.1093/ europace/euw080; PMID: 27267554. 46. Scott PE, Unger EF, Jenkins MR, et al. Participation of women in clinical trials supporting FDA approval of cardiovascular drugs. J Am Coll Cardiol 2018;71:1960–9. https://doi. org/10.1016/j.jacc.2018.02.070; PMID: 29724348. 47. Verma A, Kalman, JM, Callans DJ. Treatment of patients with atrial fibrillation and heart failure with reduced ejection fraction. Circulation 2017;135:1547–63. https:// doi.org/10.101161/CIRCULATIONAHA.116.026054; PMID: 28416525.

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Clinical Review: Electrophysiology and Ablation

Catheter Ablation of Paroxysmal Atrial Fibrillation Originating from Non-pulmonary Vein Areas Satoshi Higa, 1 Li-Wei Lo 2,3 and Shih-Ann Chen 2,3 1. Cardiac Electrophysiology and Pacing Laboratory, Division of Cardiovascular Medicine, Makiminato Central Hospital, Okinawa, Japan; 2. Heart Rhythm Center, Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; 3. Institute of Clinical Medicine, Department of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan

Abstract Pulmonary veins (PVs) are a major source of ectopic beats that initiate AF. PV isolation from the left atrium is an effective therapy for the majority of paroxysmal AF. However, investigators have reported that ectopy originating from non-PV areas can also initiate AF. Patients with recurrent AF after persistent PV isolation highlight the need to identify non-PV ectopy. Furthermore, adding non-PV ablation after multiple AF ablation procedures leads to lower AF recurrence and a higher AF cure rate. These findings suggest that non-PV ectopy is important in both the initiation and recurrence of AF. This article summarises current knowledge about the electrophysiological characteristics of nonPV AF, suitable mapping and ablation strategies, and the safety and efficacy of catheter ablation of AF initiated by ectopic foci originating from non-PV areas.

Keywords Atrial fibrillation, non-pulmonary vein, trigger, catheter ablation Disclosure: The authors have no conflicts of interest to declare. Received: 26 August 2018 Accepted: 16 November 2018 Citation: Arrhythmia & Electrophysiology Review 2018;7(4):273–81. DOI: https://doi.org/10.15420/aer.2018.50.3 Correspondence: Shih-Ann Chen, Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, 201 Sec 2, Shih-Pai Road, Taipei, Taiwan. E: epsachen@ms41.hinet.net

Catheter ablation of AF has become an established therapy and may have the potential to cure this most commonly encountered sustained arrhythmia. Previous studies have demonstrated that pulmonary veins (PVs) are a major source of the ectopic beats that initiate AF. PV isolation in patients with symptomatic paroxysmal AF refractory to antiarrhythmic drugs is effective; however, it is difficult to eliminate all instances of AF.1–3 If ectopic foci consistently come from a non-PV area and a pattern of spontaneous onset of AF is onset confirmed, the earliest ectopic site is defined as the non-PV trigger initiating AF.2,4–7 Ectopy originating from non-PV areas can initiate AF and can cause it to recur after PV isolation.4–31 NonPV ablation after multiple AF ablation procedures decreases the risk of recurrence and increases the cure rate.10,19–21,23,25,28,29 Although several ablation strategies have been developed, the outcomes of ablation are not improved unless substrate modification targets AF triggers.30 Taking all of these considerations into account, non-PV ectopy plays important role in both AF initiation and recurrence.2,4–7,20,29,30,32–34 Mapping studies of non-PV foci have revealed that triggers are often found in anatomically predictable regions, such as the left atrial wall, thoracic veins and crista terminalis, and can be sustained or non-sustained triggers of AF. These areas can be mapped by specific multielectrode catheters positioned in key regions and ablated after the AF is induced and localised, or they can be ablated empirically without the induction of ectopy.1–34 This review focuses on catheter ablation of AF initiated by non-PV triggers, summarising the electrophysiological characteristics, mapping and ablation strategies, their safety and efficacy.

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Electrophysiological Features of AF Originating from Non-pulmonary Vein Areas Incidence of Initiators Several important concepts have been proposed regarding the role of non-PV ectopy in initiating AF.2,4–7 AF is initiated by non-PV disturbance of the cardiac rhythm in up to 39 % of cases.3,8–10,32–38 The left atrium (LA) (25.3  %), superior vena cava (SVC) (22.2  %), coronary sinus (CS) (18.0  %), right atrium (RA) including the crista terminalis (17.4  %), interatrial septum (7.9  %), and ligament of Marshall (LOM) (3.9  %) are the areas in which non-PV triggers of de novo AF are most commonly found (Table 1), whereas the SVC, interatrial septum and LA are the most common non-PV trigger sites in recurrent AF (Table 2).6–30 Furthermore, there is a higher incidence of non-PV triggers initiating AF in females and in patients with an enlarged LA.39

Pathophysiology Histological analysis of the embryonic sinus venosus has identified areas capable of spontaneous depolarisation at the junctions between different embryonic tissues, such as the RA–SVC junction, crista terminalis and CS ostium.40–42 The SVC is a major origin of nonPV triggers of AF.5,8,32–34,43–47 Heterogeneity of the SVC sleeve and arrhythmogenicity of cardiomyocytes isolated from the SVC have been reported.41,42 An excitation from the SVC can conduct to the RA through the myocardial extensions of the SVC sleeve.48–50 Diseased human atria are hypopolarised in comparison to normal atria, which may account for the abnormal automaticity and/or activity originating from the LA wall.51–53 The crista terminalis, which is an area exhibiting abnormal automaticity, anisotropy and slow conduction, may serve

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AER_Higa_FINAL.indd 274

18 (14 %)

31 (21 %)

127

147

Suzuki et al. 200410

Yamada et al. 200711

43 (20 %)

266 (37 %)

165 (11 %)

720

1531

Santangeli et al. 201624

865

7,823 1,273 (16.3 %)

Takigawa et al. 201728

Total

NA

NA

NA

NA

NA

NA

51±13

NA

NA

NA

NA

NA

NA

51±12

62±8

NA

NA

NA

NA

NA

NA

61±13

(years)

age

Mean

95

NA

57

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

6 M/1 F

NA

NA

NA

NA

NA

NA

NA

85

NA

NA

NA

NA

53

147

612

178

NA

NA

NA

86 M/46 F 779

13 M/4 F

NA

NA

NA

NA

NA

NA

1597

76

15 (18 %)

34

99

195||

423

11 (21 %)

58 (39 %)

85 (14 %)

43 (24 %)

28

13

29

146 (19 %)

19 (20 %)

17

6 (11 %)

38

20

83

86

73 (20 %)

ectopy

Total Non-PV

Foci

C

Velocity

C

NavX

CARTO/NavX

C

C

C

NavX

CARTO/NavX

CARTO

C

C

NavX

Array

NavX

C

Basket

C

C, ICE, CARTO

C

C, basket, ICE

Modality

Number of Ectopic Mapping

43 M/25 F 358

Gender

17 (PLSVC2)*

31

19 (PLSVC2)*

10

5

27

53

5

6

2

12

5

4

3*

27

SVC

278 (17.4 %)

CT 16

7

14

70

62

8

2

23

195

1

13

3

5

22

2

2

1

2

1

3

4

1

CS

27

11

27

10

10

5

2

13

2

2

5

7

FO (4)

1

IAS

11

10¶

6

14

7

143

10

17

7

7

1

PV os (1)

23

8

PW (3)

1

9

2

PW (15), MA (7)

PW (30), PV os (39), others (5)

PW (28)

LA

3

16

1

10

1

20

1

4

1

6

LOM

42‡

20‡

SVT

12**

2**

2

16**

Others

355 (22.2 %) 288 (18.0 %) 126 (7.9 %) 404 (25.3 %) 63 (3.9 %) 62 (3.9 %) 37 (2.3 %)

14

2

21

42

26

23

CT 5, TA 1, RAF 4 1

CT 4, RAF 3

CT 4

8

9

CT 1

CT 15

CT 1

CT 2

CT 5

CT 4

CT 11, TA 4, ER 13

5

CT 10

RA

Origin of Ectopy (No of Foci)

*Includes persistent left superior vena cava. †33 paroxysmal and 52 non-paroxysmal AF patients in Lo et al.,13 526 and 134 in Chang et al.,15 150 and 105 in Narui et al.,26 and 26 and 6 in Allamsetty et al.27 ‡Atrioventricular nodal re-entrant tachycardia and atrioventricular re-entrant tachycardia triggered AF. §Five foci were speculated to have an epicardial origin. **16, 2 and 12 foci were unmappable non-PV foci, respectively. ||Numbers of non-PV ectopic foci were estimated based on the percentage of patients with non-PV ectopic foci. ¶Non-PV triggers were observed in 34 % of the total population (26 paroxysmal and 6 nonparoxysmal AF). A total of 45 % of non-PV triggers (16 % of the total population) were observed in the aortic encroachment area. Array = EnSite™ Array™ noncontact mapping system (Abbott); Basket = basket catheter; C = conventional mapping; CARTO = CARTO® system (Biosense Webster); CS = coronary sinus; CT = crista terminalis; ER = Eustachian ridge; F = female; FO = fossa ovalis; IAS = interatrial septum; ICE = intracardiac echocardiography; LA = left atrium; LOM = ligament of Marshall; M = male; MA = mitral annulus; NA = data not available; NavX = EnSite™ NavX™ system (Abbott); PLSVC = persistent left superior vena cava; PV = pulmonary vein; PVos = ostia of an ablated pulmonary vein including the zone between ipsilateral veins; PW = left atrial posterior wall; RA = right atrium; RAF = right atrial free wall; SVC = superior vena cava; SVT = supraventricular tachycardia; TA = tricuspid annulus; Velocity = EnSite™ Velocity™ cardiac mapping system (Abbott). Some data reproduced with permission from Higa et al., 2011.34

68 (8 %)

32†

Allamsettey et al. 201727

11 (34 %)

34 (13 %)

255

26

Narui et al. 2017

95 (16 %)

579

Hung et al. 201725

7 (18 %)

39

Hasebe et al. 2016

22

Zhao et al. 201623

Hayashi et al. 2015

216

446

Kuroi et al. 201518

Hayashi et al. 201621

26 (6 %)

76

Cheng et al. 201417

70 (13 %)

13 (17 %)

300

Zhang et al. 201416

59 (19 %)

132 (20 %)

29 (10 %)

660†

Chang et al. 201315

530

17 (26 %)

65

Yamaguchi et al. 201014

304

17 (20%)

85†

Lo et al. 201520

NA

45

Lo et al. 200913

Valles et al. 2008

19

68 (17 %)

401

Beldner et al. 20049

12

36 (23 %)

Shah et al. 2003

160

ectopy

Non-PV

68 (28 %)

8

Total

Number of patients

240

Lin et al. 20036

Publication

Table 1: De Novo AF Originating from Non-pulmonary Vein Areas

Clinical Review: Electrophysiology and Ablation

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Catheter Ablation of Paroxysmal AF Table 2: Recurrent AF Originating from Non-pulmonary Vein Areas Publication

Number of patients Total Non-PV ectopy

Mean

Gender

age

Number of Ectopic Foci Total Non-PV ectopy

(years)

Mapping Modality

Origin of Ectopy (Percentage of Foci) RA

SVC CS

IAS

LA

LOM SVT Others

Takigawa et al. 200529

207

95 (46 %)*

63±11

69 male/ 26 female

NA

92

C

34

16

12

38†

Lo et al. 201520

94

11 (12 %)*

NA

NA

102

12 (12 %)

NavX

8

25

8

42

17

Lo et al. 2015

20

52

15 (29 %)

NA

NA

75

24 (32 %)

NavX

17

25

4

42

13

Mahonty et al. 201730

84

74 (88 %)§

NA

NA

NA

NA

CARTO

9||

64

22

69

*Incidence of non-PV foci during a second session of catheter ablation of paroxysmal AF. †In this study,35 foci (38 %) were unmappable non-PV foci. ‡Incidence of non-PV foci during the third to fifth catheter ablation of paroxysmal AF. §Incidence of non-PV foci during a second session of catheter ablation of paroxysmal AF with severe left atrial scarring. The non-PV triggers were mostly (90.5 %) located in areas outside the scar region. ||9 % of non-PV foci were located on the crista terminalis/superior vena cava. C = conventional mapping; CARTO = CARTO® system (Biosense Webster); CS = coronary sinus; IAS = interatrial septum; LA = left atrium; LOM = ligament of Marshall; NA = data not available; NavX = EnSite™ NavX™ system (Abbott); RA = right atrium; SVC = superior vena cava; SVT = supraventricular tachycardia. Some data reproduced with permission from Higa et al., 2011.34

as an arrhythmogenic substrate for AF initiation and perpetuation.54,55 Catecholamine-sensitive ectopy arising from the crista terminalis exhibits high-frequency depolarisations with fibrillatory conduction.6 The LOM is an embryological remnant of the left SVC and contains arrhythmogenic myocardial fibres with sympathetic innervation. Several reports have demonstrated the existence of catecholaminesensitive tissue within the LOM that has abnormal automaticity, and which could be a potential source of AF initiation.6,56–58

approach. If the initiator is likely to be in the RA, a duodecapolar catheter can be placed from the crista terminalis to the distal SVC for the simultaneous mapping of the right PVs, crista terminalis and SVC. Endocardial activation timing from the high RA, His bundle and distal/proximal portion of the CS can be used to predict non-PV ectopy (Figure 1).2,4–7,32–34 It is 100 % accurate in discriminating ectopy from the SVC or upper portion of the crista terminalis from PV ectopy.32–34,62 The interatrial septum should be the suspected initiator in cases with a monophasic positive narrow P wave in lead V1 or a relatively

The musculature within the CS also has arrhythmogenic activity, with spontaneous depolarisations induced by catecholamine loading.59,60 Abnormal dilatation due to an unroofed CS can be an

short activation time (≤15 ms) preceding P wave onset during ectopy. Simultaneous mapping of the right- and left-sided interatrial septum should be performed to avoid any misdiagnosis.32–34,63,64

arrhythmogenic focus of AF initiation.61 A recent study found that 45 % of non-PV triggers of AF were in the area of aortic encroachment, which equates to 16  % of the total population with AF. There is also an arrhythmogenic substrate exhibiting low voltage and fractionated electrograms with a prolonged duration in the anterior part of the LA at the site of aortic encroachment.27

Diagnosis Provoking Ectopy To successfully provoke ectopy with AF initiation, antiarrhythmic drugs should be discontinued for a period of at least five half-lives before the patient undergoes electrophysiological study. Spontaneous initiation of ectopic beats preceding AF should be observed at baseline or after isoproterenol loading.32–34 In the case of deep sedation or general anaesthesia, it is necessary to give the patient a high dose of isoproterenol to induce ectopy with AF initiation. Adenosine or adenosine triphosphate can also be used, especially in young patients with vagal AF and with a family history of AF.18 If ectopy does not occur, short-burst atrial pacing can be delivered with intermittent pauses or, failing that, atrial burst pacing to induce sustained AF. Careful monitoring for spontaneous reinitiation of AF is required after internal or external cardioversion. The induction of spontaneous AF initiation should be attempted at least twice to confirm the location of ectopy, the initiation pattern of spontaneous AF, and the earliest activation site (the AF initiator).2,4–7,32–34

Mapping Localisation of AF triggers is important for the catheter ablation of AF. If it is suspected that the trigger is based in the LA, a decapolar catheter should be inserted into the CS via the internal jugular vein and a circular mapping catheter placed in the LA using a transseptal

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AF Initiators with Right Atrial Origin Careful observation of P wave morphology is useful for predicting the approximate location of AF ectopy.32–34,65 A negative P wave or the presence of a negative component in V1 is predictive of an RA origin of AF initiation. Ectopy originating from the SVC or upper portion of the crista terminalis exhibits upright P waves in the inferior leads; ectopy from the CS ostium produces negative P wave polarity in the inferior leads; and ectopy from the middle portion of the crista terminalis results in biphasic P waves. Negative P waves with a long duration in V1 may be associated with RA free-wall ectopy, including the tricuspid annulus. If RA AF ectopy is suspected, the use of a duo-decapolar catheter is useful for mapping along the crista terminalis to the SVC.2,4–7,32–34 Bipolar signals from the proximal portion of the SVC usually exhibit a blunted atrial signal followed by a discrete sharp SVC signal during sinus rhythm.32–34 The activation sequence of these double potentials is reversed during SVC ectopy. Bipolar signals from the distal part of the SVC usually exhibit double potentials: the first component represents a SVC near-field sharp potential; and the second component, a right superior PV far-field blunted signal. During SVC ectopy, the activation sequence of these double potentials remains unchanged. The activation sequence is reversed during right PV ectopy. Intracardiac recordings along the crista terminalis also exhibit double potentials during sinus rhythm, with a high-to-low activation sequence.32–34 During crista terminalis ectopy, the atrial activation sequence of the double potentials is reversed. Noncontact mapping using an EnSite™ Array™ (Abbott) can accurately localise the ectopic foci with discrete depolarisations and clarify crista terminalis gap conduction-related small radius re-entry.32–34,66

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Clinical Review: Electrophysiology and Ablation Figure 1: Stepwise Algorithm for the Localisation of Non-pulmonary Vein AF Initiators

Ectopy initiating AF

Yes

No Mean AF cycle length during 1 min recording at RA free wall < proximal or distal CS

Δ (high right atrium – His) interval >0 ms

Yes

No

Yes

No

Reentrant right atrium AF

Reentrant left atrium AF

(CSp – CSd) interval >0 ms

SVC/crista terminalis mapping

Yes

No

Earliest site shows SVC potential inside or at SVC ostium

Earliest site shows PV potential inside or at RPV ostium

Earliest site shows PV potential inside or at LPV ostium

No

No

Yes

Yes

Earliest site shows LA potential followed by PV potential

Non-SVC

SVC

Non-PV near RPV

RPV, LPV

No Earliest site shows LA potential followed by PV potential

Earliest site shows LOM potential

Non-PV near LPV

LOM

∆ (high right atrium − His) represents the time interval from the high right atrial electrogram onset to the onset of the His atrial electrogram during sinus beats minus the same interval measured during ectopic atrial activity. CSp − CSd represents the difference in the atrial activation time between the proximal (p) and distal (d) CS atrial electrograms during an ectopic atrial beat. Source: Higa et al., 2006.32 Reproduced with permission from Elsevier. CS = coronary sinus; LOM = ligament of Marshall; LPV = left pulmonary vein; PV = pulmonary vein; RPV = right pulmonary vein; SVC = superior vena cava.

AF Initiators with Left Atrial Origin The time interval between the atrial activation of the decapolar catheter in the proximal CS and that in the distal CS is useful for predicting ectopic foci located near the right (>0 ms) or left PV antrum (<0 ms) (Figure 1).32–34,62 During sinus rhythm, the fusion potentials of a blunt signal and a rapid, deflecting sharp signal can be observed in the areas between the LA posterior wall and the PV antrum. The fusion potential consists of atrial and PV signals and can be found at the earliest activation site during LA posterior or PV antral ectopy. An alternating pattern of atrial and PV potentials can also be seen during ectopy.6,32–34 The Marshall ligament has multiple electrical connections to the musculature of the CS, LA posterior free wall and left PV; therefore, it is essential to differentiate a Marshall potential from a left PV or LA posterior free wall potential. A differential pacing method and/or direct recording of the LOM potential by a microelectrode catheter cannulated into the vein of Marshall can distinguish a PV potential from a Marshall potential (Tables 3 and 4).7,32–34,56,67,68 According to expert consensus statements, complex fractionated atrial electrogram (CFAE)-targeted ablation after PV isolation is feasible for substrate modification.69 Interestingly, our laboratory reported a close anatomical relationship between the distribution of CFAEs and non-PV AF initiators. All of the nonPV AF initiators were associated with continuous CFAE sites.70,71

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Recently, the efficacy of a novel self-reference mapping technique using a PentaRay® catheter (Biosense Webster) to localise non-PV triggers originating from the LA has been reported.72

Limitations of Mapping AF ablation can be a challenging and sometimes cumbersome task in cases of unmappable infrequent beats originating from uncommon areas. Activation mapping using fixed multipolar catheters and point-by-point mapping are not efficient for the identification of target ectopies in such cases. Single-beat analysis by noncontact mapping using the Array™ system (Figure 2) or non-invasive bodysurface mapping using the CardioInsight™ Mapping Vest system (Medtronic) can be useful tools in these situations.73

Ablation The earliest bipolar electrogram site with unipolar QS pattern recorded from the origin is the ablation target for non-PV ectopy. 2,4–7,32–34 Ablation of an ectopic focus and/or electrical isolation of an arrhythmogenic thoracic vein can be achieved with the application radiofrequency energy for around 30 seconds with a non-irrigated tip at 50–55 °C or with an irrigated tip at <25–30 W.2,4–6,32–34 A contact force catheter can be used to create durable transmural lesions. This method has a lower arrhythmia recurrence and a lower incidence of atrial tachyarrhythmias resulting from incomplete ablation due to proarrhythmic lesion gaps. However, caution should be taken to avoid the application of excessive

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Catheter Ablation of Paroxysmal AF energy and/or contact pressure at the posterior LA wall close to the oesophagus.

Figure 2: Mapping of Non-pulmonary Vein Triggers

Balloon-based cryoablation of the PV antral area, LA posterior wall and persistent left SVC can also be used to isolate arrhythmogenic myocardium. Complications can be minimised by using a cryocatheter at −30 °C to ice map the area near the atrioventricular node following the cryofreezing (−80 °C) of a para-Hisian or CS ostium trigger. Ice mapping can also be used during ablation near the sinus node when targeting SVC or the upper portion of the crista terminalis. Repeated AF induction protocols should be performed after ablation to assess the non-inducibility of the ablated ectopy.2 4–7,32–34

Vena Cava Triggers Electrical disconnection between the arrhythmogenic SVC and RA at the level of the RA–SVC junction is the preferred approach for minimising AF recurrence and SVC stenosis in patients with SVC triggers.32–34 The aim is to establish bidirectional (entrance and exit) conduction block between the RA and SVC. 5,32–34,47 Circular and basket catheters, and 3D mapping systems including the CARTO® (Biosense Webster), EnSite™ NavX™ Velocity (Abbott), EnSite™ Array™ noncontact mapping system, and Rhythmia HDx™ mapping system with IntellaMap Orion™ catheter (Boston Scientific) can guide SVC isolation.6,32–34,44–46,74–77 Persistent left SVC is also a well-recognised trigger site for AF.19,21,78–85 The connecting musculature means that multiple electrical signals are conducted to the posterolateral LA and middle portion of the CS from the left SVC trigger site. Complete left SVC isolation may be challenging, as it is close to the oesophagus and left phrenic nerve. There have been rare reports of inferior vena cava triggers.86,87 In these cases, the IVC triggers were successfully eliminated with a focal/isolation strategy.

(A) An isochronal map during an ectopy-initiated AF. During the ectopy, a focal activation originates from the left atrial middle posterior wall with unidirectional conduction block on the left side of the posterior wall, and the activation wavefront preferentially conducts toward the right pulmonary veins and spreads out to the rest of the left atrium (yellow arrows) followed by AF. (B) The unipolar virtual signals demonstrate “QS” morphology at the origin (virtual 6, from the second beat) and “rS” morphology (virtual 8, from the second beat) at the breakout site. Source: Higa et al., 2008.73 Reproduced with permission from Dr Jonathan S Steinberg. LAA = left atrial appendage; LIPV = left inferior pulmonary vein; LSPV = left superior pulmonary vein; RSPV = right superior pulmonary vein.

impedance rise occurs during CS ablation, and the application of radiofrequency energy should be stopped immediately to prevent any steam pops.

Marshall Ligament Triggers Interatrial Septal Triggers Focal ablation of the earliest activation site preceding the onset of AF should be performed until a complete elimination of the ectopy is achieved in patients with interatrial septal triggers. Near-simultaneous atrial activation of the multielectrode catheters located in the high RA, His bundle region and CS ostium can be observed in such cases. Simultaneous mapping of the right and left atrial septum is crucial to successfully locate and ablate this trigger.

For patients with Marshall ligament triggers, the earliest site with a LOM potential preceding the onset of AF is targeted using an endocardial and/or epicardial approach.32–34,92 The isolation of both the LOM and left PVs from the LA can be monitored with simultaneous mapping of the LOM and left PV ostia, maximising the chance of a successful procedure.32–34,56,67,93 Ethanol infusion into an arrhythmogenic vein of Marshall through angioplasty guidewire and balloon catheter in addition to PV isolation has recently been reported to have beneficial outcomes.94,95

Crista Terminalis Triggers Focal ablation of the earliest activation site in the crista terminalis during ectopy preceding AF onset should be performed until complete elimination of the ectopy initiating AF or >50 % reduction in the amplitude of the initial local electrogram at the ablation site.6,32–34 A region with transverse gap conduction in the crista terminalis can be an arrhythmogenic source of re-entry and also ectopy initiating AF. Linear ablation of the transverse gap should address both of these problems.32–34,66 Intracardiac echocardiography can provide real-time monitoring of the anatomical relationship between the crista terminalis and the catheter position during the procedure.

Coronary Sinus Triggers For patients with a CS trigger, electrical isolation of the arrhythmogenic CS musculature from the atrium by endocardial and/or epicardial ablation under the guidance of a 3D mapping system is preferable.32–34,71 The aim is to eliminate (entrance block) and/or dissociate (exit block) the CS potential.88–91 Care must be taken if an inappropriate

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Left Atrial Triggers For ectopy from the LA posterior wall, focal ablation of the earliest activation site should be performed (Figure 2). If unsuccessful, a boxshaped linear ablation needs to be added around the ectopy.6,32–34 Box isolation of the LA posterior wall in combination with PV isolation may be a therapeutic option in cases refractory to extensive focal ablation. The endpoint is complete elimination of the ectopy initiating AF, >50 % reduction in the electrogram amplitude of the ectopic focus, or isolation of the posterior LA wall.32–34,73 The left atrial appendage (LAA) has been reported to be a trigger of AF.96 Due to its large structure, triggers may arise from the LAA ostium, body or tip. Simultaneous mapping of the left superior PV and LAA can differentiate between a near-field sharp and a far-field blunt signals and identify true LAA triggers. Focal ablation can be applied to avoid LAA isolation. LAA isolation is only indicated when the patient can tolerate long-standing anticoagulation or a LAA occlusion device is indicated.

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Clinical Review: Electrophysiology and Ablation Table 3: Diagnostic Criteria for Non-pulmonary Vein Ectopy Initiating AF Location

Criteria

AF initiators from the right atrium

• D  ifference in the time interval between the atrial activation at the high right atrium and His bundle area during sinus rhythm and ectopy of <0 msec

Inferior vena cava, superior vena cava

• P  ositive (superior vena cava) and negative (inferior vena cava) P waves in the inferior leads and positive or biphasic P waves in V1 (superior vena cava) • Earliest ectopic activity in the vena cava during simultaneous mapping of the vena cava and right pulmonary vein (PV) • Reversal of the double-potential sequence during ectopy (vena cava potentials with a rapid deflection-far-field atrial potential sequence; distal-to-proximal venous activation sequence)

Crista terminalis (CT)

• Polarity of the P waves in the inferior leads: upper portion of the CT, positive; middle portion, biphasic; lower portion, negative • Earliest ectopic activity along the CT during simultaneous mapping of the CT, vena cava and right PV

Coronary sinus ostium

• Negative P waves in the inferior leads • Earliest ectopic activity in the coronary sinus ostium

AF initiators from left atrium

• D  ifference in time interval between the atrial activation at the high right atrium and His bundle area during sinus rhythm and ectopy of >0 msec

Left atrial free wall or left atrial appendage

• Atrial potentials with a rapid deflection-PV potential found after the earliest atrial activation

Ligament of Marshall (LOM)

• Earliest activation site along the vein of Marshall, posterolateral portion of the mitral annulus or left PV ostium • Reversal of the triple-potential sequence; the LOM potential is earlier than the left atrium or left PV potentials (LOM–left atrium–PV potentials sequence)

CT = crista terminalis; LOM = ligament of Marshall; PV = pulmonary vein. Source: Higa et al., 2006.33 Reproduced with permission from Elsevier.

Table 4: Targets for Ablation of AF Originating from Non-pulmonary Vein Areas AF Initiators

Target Sites

Mapping Tools

Inferior vena cava, superior vena cava

Breakthrough sites around right atrium–vena cava junction for an isolation

Circular catheter, Array, Grid, PentaRay or Rhythmia

Crista terminalis

Earliest crista terminalis activation site for a focal ablation

Unipolar recording with a multipolar catheter, Array, Grid, PentaRay or Rhythmia

Coronary sinus

Connection sites between the coronary sinus and atrial musculature for an isolation

Array, PentaRay or Rhythmia

Left atrial free wall, septum, appendage, mitral annulus

Earliest activation site for a focal ablation

Unipolar recording with a multipolar catheter, Array, Grid, PentaRay or Rhythmia

Ligament of Marshall (LOM)

Earliest LOM potential for a focal ablation

Multipolar recording of triple potentials during ectopy and direct mapping of LOM potentials by microelectrode catheter, Array, Grid, PentaRay or Rhythmia

Connection sites between the left atrium and LOM for an isolation

Multipolar recording of triple potentials during ectopy and direct mapping of LOM potentials by a microelectrode catheter, Array, Grid, PentaRay or Rhythmia

Right Side

Left Side

Array = EnSite™ Array™ Noncontact Mapping System (Abbott); Grid = Advisor™ HD Grid Mapping Catheter (Abbott); LOM = ligament of Marshall; PentaRay = PentaRay® Catheter (Biosense Webster); Rhythmia = Rhythmia Mapping System and InntellaMap Orion™ Mapping Catheter (Boston Scientific). Source: Higa et al., 2006.33 Reproduced with permission from Elsevier.

Efficacy and Safety of Catheter Ablation

Managing Complications

Ablation Outcomes

Overall complication rates are now relatively low as a result of vast improvements in our understanding of the nature and ablation of non-PV ectopy AF triggers. Injury to the sinus node, atrioventricular node, and phrenic nerve, thoracic vein stenosis, peri-oesophageal damage, gastric hypomotility, and pyloric spasms can all be caused by a non-PV trigger ablation.116–124

A relatively high success rate has been demonstrated following the ablation of RA triggers of AF. 6 There is a comparatively higher recurrence rate following the ablation of LA triggers. The average success, recurrence and complication rates are 99.3 %, 18.5  %, and 1.9  %, respectively, for AF originating from the vena cava.8,43–45,74,78–87,97–111 These rates are 78.0  %, 16.7  %, and 2.4  %, respectively, for AF originating from the Marshall ligament.6,56,67,68,94,112,113 A higher incidence of recurrent AF and non-PV AF sources has been reported in patients with metabolic syndrome and obstructive sleep apnoea. 114 Patients who have a greater extent of left atrial delayed enhancement on MRI have a higher recurrence rate after PV isolation, suggesting the existence of AF triggers in non-PV areas.115

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Complications can be minimised by using a titrated and minimum power setting, short duration of radiofrequency energy, and by monitoring for any sinus rate accelerations, PR or RR interval prolongations and for oesophageal temperature rises. An upstream pacing technique to monitor the phrenic nerve and/or compound muscle action potential can minimise phrenic nerve injury. To reduce the risk of atrio-oesophageal fistula formation, which carries a 60–75 % chance of mortality,

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Catheter Ablation of Paroxysmal AF surgeons should avoid extensive high-power ablation on the LA posterior and CS walls.119,121,122,125 The use of several luminal oesophageal temperature monitoring systems – SensiTherm™ (Abbott) and CIRCA S-Cath™ (CIRCA Scientific) – and protection systems, including oesophageal warming/cooling devices and deviators to avoid thermal injury, has recently been reported.126–130 Massive air emboli and newly developed thrombi that occur during the ablation procedure can be aspirated.131

Conclusion Evidence suggests that inducing the non-PV ectopic trigger responsible for initiating AF both before and after PV isolation is an indispensable step in both initial and repeat ablation/isolation procedures. Advances in mapping and alternative energy modalities with 3D navigation are likely to play an important role in the ablation of non-PV ectopy. Together, these advances and the systematic identification of the

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trigger foci and their successful elimination will improve overall AF ablation outcomes.

Clinical Perspective • The mechanisms of paroxysmal AF originating from nonpulmonary vein areas are automaticity, triggered activity, and microreentry. • The diagnosis is made on the basis of a spontaneous onset of the ectopic beats initiating AF during baseline or after provocative manoeuvres. • The earliest activation sites are the targets for focal ablation. • The myocardial sleeve surrounding the ostium of the vena cava is the target for isolation. • Success rates are >99 % for the vena cava and 78  % for the ligament of Marshall.

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126. Carroll BJ, Contreras-Valdes FM, Heist EK, et al. Multi-sensor esophageal temperature probe used during radiofrequency ablation for atrial fibrillation is associated with increased intraluminal temperature detection and increased risk of esophageal injury compared to single-sensor probe. J Cardiovasc Electrophysiol 2013;24:958–64. https://doi. org/10.1111/jce.12180; PMID: 23746064. 127. Koranne K, Basu-Ray I, Parikh V, et al. Esophageal temperature monitoring during radiofrequency ablation of atrial fibrillation: a meta-analysis. J Atr Fibrillation 2016;9:1452. https://doi. org/10.4022/jafib.1452; PMID: 29250252. 128. Tsuchiya T, Ashikaga K, Nakagawa S, et al. Atrial fibrillation ablation with esophageal cooling with a cooled waterirrigated intraesophageal balloon: a pilot study. J Cardiovasc Electrophysiol 2007;18:145–50. https://doi.org/10.1111/j.15408167.2006.00693.x; PMID: 17239114. 129. Arruda MS, Armaganijan L, di Biase L, et al. Feasibility and safety of using an esophageal protective system to eliminate esophageal thermal injury: implications on atrial-esophageal fistula following AF ablation. J Cardiovasc Electrophysiol 2009;20:1272–8. https://doi.org/10.1111/j.15408167.2009.01536.x; PMID: 19572955. 130. Parikh V, Swarup V, Hantla J, et al. Feasibility, safety, and efficacy of a novel preshaped nitinol esophageal deviator to successfully deflect the esophagus and ablate left atrium without esophageal temperature rise during atrial fibrillation ablation: The DEFLECT GUT study. Heart Rhythm 2018;15:1321–7. https://doi.org/10.1016/j.hrthm.2018.04.017; PMID: 29678784. 131. Kuwahara T, Takahashi A, Takahashi Y, et al. Clinical characteristics of massive air embolism complicating left atrial ablation of atrial fibrillation: lessons from five cases. Europace 2012;14:204–8. https://doi.org/10.1093/europace/ eur314; PMID: 21937478.

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Clinical Review: Electrophysiology and Ablation

Identifying Risk and Management of Acute Haemodynamic Decompensation During Catheter Ablation of Ventricular Tachycardia Daniele Muser, Simon A Castro, Jackson J Liang and Pasquale Santangeli Cardiac Electrophysiology, Cardiovascular Division, Hospital of the University of Pennsylvania, USA

Abstract Radiofrequency catheter ablation (CA) has an established role in the management of patients with structural heart disease presenting with recurrent ventricular tachycardia (VT). Due to the complex underlying substrate, high burden of comorbidities and concomitant heart failure (HF) status, these patients may be at higher risk of periprocedural complications. The prolonged low-output state related to VT induction and mapping, as well as the fluid overload due to irrigated CA and the use of general anaesthesia, may decompensate the HF status, leading to multiple-organ failure and increase in early post-procedural mortality. Proper identification of patients at high risk of periprocedural acute haemodynamic decompensation (AHD) has important implications in terms of procedural planning (i.e. prophylactic use of mechanical assistance devices) and pre-procedural management in order to optimise the HF status. In the present manuscript we focus on the clinical predictors of AHD and the strategies to improve pre-procedural risk stratification, as well as the evidence supporting the use of haemodynamic support during CA procedures.

Keywords Haemodynamic decompensation, ventricular tachycardia, catheter ablation, mechanical haemodynamic support Disclosure: The authors have no conflicts of interest to declare. Received: 29 May 2018 Accepted: 19 July 2018 Citation: Arrhythmia & Electrophysiology Review 2018;7(4):282–7. DOI: https://doi.org/10.15420/aer.2018.36.3 Correspondence: Pasquale Santangeli, Hospital of the University of Pennsylvania, 9 Founders Pavilion – Cardiology, 3400 Spruce St, Philadelphia, PA 19104, USA. E: pasquale.santangeli@uphs.upenn.edu

The role of catheter ablation (CA) in the management of ventricular tachycardia (VT) is becoming increasingly relevant, having repeatedly shown its superiority to medical therapy in reducing the arrhythmic burden, thus improving prognosis and quality of life in patients with structural heart disease presenting with VT.1–4 In such patients, recurrent VT and heart failure (HF) status are connected by a bidirectional link. Structural and functional changes related to advanced HF, such as progressive myocardial fibrosis, adrenergic hyperactivity, mechanical and electrical remodelling, and metabolic dysregulation, all contribute to the genesis and maintenance of VT, which may occur in up to 30 % of these patients.5 Moreover, indicators of advanced HF, such as very low ejection fraction and advanced New York Heart Association (NYHA) functional class, have been associated with an increased rate of periprocedural complications, VT recurrence and mortality in patients undergoing CA of VT.6–9 Ventricular arrhythmias (VAs) may worsen HF status, increasing mortality and hospitalisations.5,7 In this setting, pre-procedural risk stratification to identify high-risk patients can allow for preprocedural planning and optimisation of overall clinical status before the procedure, improving patient safety and post-procedural outcomes. We summarise the strategies currently available to predict the risk of AHD and the evidence supporting the use of HF optimisation tools during CA of VT.

Incidence and Predictors of Acute Haemodynamic Decompensation Acute haemodynamic decompensation during CA of VT has been defined by our group as sustained hypotension (i.e. systolic blood

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pressure <90 mmHg), despite increasing doses of vasopressors, that required emergent placement of a mechanical haemodynamic support (MHS; i.e. an intra-aortic balloon pump or left ventricular assist devices) and/or procedure discontinuation. We reported an AHD prevalence of 11 % in a series of 193 consecutive patients with drug-refractory scarrelated VT referred to our institution for CA. The occurrence of AHD during the procedure was associated with an almost sixfold increased risk of death after the procedure. Overall, 16  % of the patients died during a mean follow-up of 21 ± 7 months: 50  % in the AHD group versus 11 % in the group without AHD (p<0.001). Upfront identification of these patients is pivotal, given the strong impact on mortality. Using logistic regression analysis, we identified eight predictors associated with AHD: age >60 years (OR 3.24; 95  % CI 1.07–9.82; p=0.037); diabetes (OR 2.81; 95 % CI 1.15–6.90; p=0.024); ischaemic cardiomyopathy (OR 6.26; 95 % CI 1.81–21.62; p=0.004); left ventricular ejection fraction (LVEF) <25 % (OR 3.00; 95 % CI 1.27–7.07; p=0.012); chronic obstructive pulmonary disease (OR 5.46; 95  % CI 2.24–13.33; p<0.001); presentation with VT storm (OR 5.12; 95  % CI 1.84–14.22; p=0.002); NYHA functional class III/IV (OR 6.11; 95  % CI 2.53–14.75; p<0.001); and use of general anaesthesia (OR 3.56; 95 % CI 1.50–8.44; p=0.004).6 With the exception of general anaesthesia, all of these variables are non-modifiable markers of HF severity. On the basis of this analysis, the PAINESD risk score was developed by rounding the OR value to the next integer including the following variables: chronic obstructive pulmonary disease (5 points); age >60 years (3 points); ischaemic cardiomyopathy (6 points); NYHA functional

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Risk Stratification and Management of AHD class III or IV (6 points); LVEF <25 % (3 points); presentation with VT storm (5 points); and diabetes (3 points), with the maximum score being 31 points (Figure 1). The risk of periprocedural AHD increased across tertiles of risk score and was 1 % for first tertile (≤8 points), 6 % for second tertile (9–14 points) and 24 % for third tertile (≥15 points) (Figure 1). The use of this score may allow identification of patients at either very low (1 % for score ≤8 points) or high (24 % for score ≥15) risk of periprocedural AHD and might provide a simple tool to select patients who might benefit from prophylactic placement of MHS devices.

Figure 1: PAINESD Risk Score Intermediate risk 9–14 Low risk ≤8

PAINESD

Our findings were subsequently confirmed in an independent cohort of 93 patients with structural heart disease undergoing VT ablation. Patients who required emergent prophylactic percutaneous left ventricular assistance device (pLVAD) insertion due to AHD during the procedure had significantly higher PAINESD scores compared with a control group of patients who did not undergo pLVAD insertion (mean PAINESD score of 17.8 ± 3.8 in the rescue pLVAD group versus 13.4 ± 5.4 in the non-pLVAD group; p=0.01). Patients in the rescue pLVAD group also showed a significantly higher 30-day mortality compared with the non-pLVAD group (58.3 % versus 3.5 %; p=0.001).10 Similar findings have been recently reported in a large retrospective series of 2,061 patients with structural heart disease undergoing VT ablation included in the International VT Ablation Center Collaborative Group, which incorporates procedural and outcome data of 12 international sites that specialise in VT management. Patients who died within 30 days of the procedure had significantly higher PAINESD scores (16 ± 7) compared with those who died later (14 ± 6; p=0.006) or those who survived throughout the all-study follow-up (9 ± 6; p<0.001), as well as a higher requirement for periprocedural MHS (25 % versus 5 %; p<0.001) and higher rates of acute procedural failure (Figure 2).7

High risk ≥15

P

A

I

E

S

D

(pulmonary disease)

(age)

(ischaemic (NYHA) cardiomyopathy)

(ejection fraction)

(VT storm)

(diabetes)

5

3

6

3

5

3

N

6

AHD

Mortality 50 %

24 %

6%

11 %

1% ≤8

9–14

≥15

AHD

NO-AHD

PAINESD risk score (upper panel) to stratify the risk of acute haemodynamic decompensation (AHD; bottom left panel) in patients undergoing catheter ablation of ventricular tachycardia and its impact on subsequent mortality (bottom right panel). Modified from Santangeli et al.6 AHD = acute haemodynamic compensation; NO-AHD = no AHD; NYHA = New York Heart Association; VT = ventricular tachycardia.

Figure 2: Summary of the Principal Studies Validating the PAINESD Scoring System % 70

PAINESD

AHD

30-day mortality

VT recurrence

Mathuria et al. 2017 58.3

60

Pre-procedural Heart Failure Status Optimisation and Intra-procedural Haemodynamic Monitoring In patients presenting with recurrent VT in the setting of structural heart disease, there are several factors that may precipitate the overall haemodynamic performance. Some of these are modifiable and related to the procedure, such as the use of general anaesthesia or inotropes/vasopressors.11 Others are related to the acute clinical presentation, such as hypotension due to refractory VT/VF or cardiac stunning due to repeated ICD shocks. Accurate pre-procedural risk stratification is essential to minimise the risk of peri-procedural complications. Every effort should be made to optimise the haemodynamic status before the procedure, especially in patients presenting with severely depressed ejection fraction. When signs of volume overload (peripheral oedema, elevated jugular venous pressure) are present, decongestion should be pursued with the use of intravenous loop-diuretic therapy or continuous slow-flow ultrafiltration (in cases of diuretic resistance). In patients with low-output HF or frank cardiogenic shock, inotropic or vasodilator therapy may be required for stabilisation and to allow recovery of end-organ function.12 Unfortunately, complete optimisation of HF status is not always possible due to the high burden and incessant nature of VAs. In these cases, the use of MHS can lead to an overall improvement of heart mechanics, ventricular wall stress, myocardial oxygen consumption and end-organ perfusion. Invasive haemodynamic monitoring with pulmonary arterial catheters and arterial lines can allow for objective monitoring and tailoring of therapy to achieve haemodynamic goals.

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Muser et al. 2018 50 40

23

13

18

20

0

40

30

30

10

44

41

40

7

Prophylactic pLVAD

26

16.5

4 Non-pLVAD

17.8 13.4

12

Prophylactic pLVAD

3.5 Non-pLVAD

Rescue pLVAD

A summary of the principal studies validating the PAINESD scoring system for risk stratification of patients with structural heart disease undergoing catheter ablation of ventricular tachycardia. The bars show the correlation between PAINESD score, prevalence of periprocedural acute haemodynamic decompensation (AHD), cumulative mortality and ventricular tachycardia recurrence rate.10,20 AHD = acute haemodynamic compensation; pLVAD = percutaneous left ventricular assistance device; VT = ventricular tachycardia.

These concepts may be extended to intraprocedural monitoring and, in addition to cerebral oximetry (to evaluate cerebral desaturation during the procedure), may allow detection of early signs of AHD such as sustained hypotension, increases in pulmonary capillary wedge pressure, oliguria and increasing serum lactate.13,14

Haemodynamic Mechanical Support In high-risk patients and especially in those in whom an adequate pre-procedural HF optimisation is not possible due to the

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No control group

Patients used as own controls

IABP: 115

No control group

10

16

20

68

44

64

230

21

109

Miller et al., 201114

Lü et al., 201327

Miller et al., 201313

Aryana et al., 201417

Reddy et al., 201416

Baratto et al., 201625

Aryana et al., 201728

Enriquez et al., 201719

Kusa et al., 201718

75

Pre-emptive pLVAD: 75

Muser et al., 201820

pLVAD group: 65 ± 12 Control group: 64 ± 14

Pre-emptive pLVAD group: 65.8 ± 14 control group: 64.8 ± 9 rescue pLVAD: 68.8 ± 8

pLVAD group: 64 ± 11 Control group: 61 ± 15

60 ± 11

NA

63 ± 15

pLVAD group: 66 ± 12 Control group: 69 ± 10

66 ± 12

59 ± 12

63 ± 11

66 ± 15

55 (mean)

61 ± 6

Age, years

pLVAD group: 27 ± 10 Control group: 27 ± 12

Pre-emptive pLVAD group: 26 ± 9 control group: 28 ± 5 rescue pLVAD: 24 ± 14

pLVAD group: 26 ± 10 Control group: 39 ± 16

21 ± 13

NA

27 ± 9

pLVAD group: 29 ± 15 Control group: 25 ± 10

32 ± 10

30 ± 7

20 ± 9

31 ± 16

NA

NA

LVEF

pLVAD group: 81 Control group: 62

Pre-emptive pLVAD group: 61 control group: 66 rescue pLVAD: 50

pLVAD group: 80 Control group: 93

83

NA

69

pLVAD group: 89 Control group: 86

pLVAD group: 71 Control group: 71

50

ECMO: 60 Impella: 60 LVAD: 50

pLVAD group: 75 Control group: 67

100

68

Success, %

Acute Procedural

Impella 2.5/Impella CP

Impella/TandemHeart

80 with Impella 2.5 and 29 with Impella CP

ECMO (rescue insertion due to AHD)

pLVAD not otherwise specified

ECMO

Impella: 25 TandemHeart: 19

Impella 2.5/Impella CP

Impella 2.5

ECMO: 5 patients Impella: 5 patients LVAD: 6 patients

Impella

Impella

CPS

Support

Haemodynamic

Type of

pLVAD group: 33 Control group: 66

Pre-emptive pLVAD group: 4 Control group: 3.5 Rescue pLVAD: 58.3

pLVAD group: 32 Control group: 21

30

Redo VT ablation: pLVAD group: 10.2 Control group: 14.0

33

pLVAD group: 42 Control group: 50

pLVAD group: 26 Control group: 41

20

50

pLVAD group: 30 control group: 31

0

50

VT Recurrence, %

ECMO: extra-corporeal membrane oxygenation; IABP: intra-aortic balloon pump; LVEF: left ventricular ejection fraction; pLVAD: percutaneous left ventricular assistance device; VT ventricular tachycardia.

57

Rescue pLVAD:12 Pre-emptive pLVAD: 24

Mathuria et al., 201710

85

No control group

IABP: 22

34

IABP: 6 No MHS: 7

No control group

3

Abuissa et al., 201026

No control group

Group, n

Group, n

19

Control

Treatment

Carbucicchio et al., 200923

Study

pLVAD group: 40 Control group: 41

Pre-emptive pLVAD group: 26 Control group: 44 Rescue pLVAD: 40

pLVAD group: 12 Control group: 6

76

pLVAD group: 6.5 Control group: 19.1

12

pLVAD group: 36 Control group: 36

pLVAD group: 0 Control group: 6

10

6

NA

0

21

Transplant, %

Mortality/

Table 1: Principal Studies Investigating the Role of Haemodynamic Support in Patients Undergoing Catheter Ablation Ventricular Tachycardia

12 months

3 months

Median: 215 days

Median: 10 days

12 months

Median: 21 months

12 ± 5 month

19 ± 12 months

1 months

3 months

3 months

Mean: 7 months

Mean: 42 months

Follow-up

Clinical Review: Electrophysiology and Ablation

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Risk Stratification and Management of AHD Table 2: Characteristics of the Principal Mechanical Haemodynamic Support Devices Used for Catheter Ablation of Ventricular Tachycardia Device

Type of Support

Insertion

Contraindications

Potential Complications

Intra-aortic balloon pump

Counter-pulsation based on ECG or pressure triggers Improves coronary artery perfusion and cardiac afterload with limited effect on CO

Percutaneous insertion in the thoracic descending aorta through arterial femoral access

Moderate-to-severe AR Aortic plaques Severe PAD

Arterial thromboembolism including stroke Vascular injury at the insertion site Bleeding

TandemHeart

Centrifugal continuous-flow pump improving CO up to 3.5–5.0 l/min

Percutaneous insertion through femoral venous access + transseptal puncture (inflow) and through femoral arterial access (outflow)

Severe PAD Ventricular sepal defects Moderate-to-severe RV dysfunction

Arterial thromboembolism including stroke Vascular injury at the insertion site Cardiac tamponade Residual atrial septal defect Bleeding

Impella (2.5/CP/5.0)

Axial continuous-flow pump delivering blood from LV to aorta up to 5 l/min

Percutaneous through femoral arterial access or surgical through femoral or axillary artery cutdown

Moderate-to-severe AR Severe PAD Mechanical aortic valve Severe aortic stenosis LV thrombus Ventricular sepal defect Moderate-to-severe RV dysfunction

Arterial thromboembolism including stroke Vascular injury at the insertion site Aortic valve injury during device placement

ECMO (veno-arterial)

Centrifugal continuous-flow pump with extracorporeal oxygenator providing CO >4.5 l/min

Percutaneous or surgical insertion through femoral arterial and venous access

Severe PAD Uncontrolled coagulopathy

Arterial thromboembolism including stroke Vascular injury at the insertion site Bleeding

AR = aortic regurgitation; CO = cardiac output; ECMO = extra-corporeal membrane oxygenation; LV = left ventricular; PAD = peripheral artery disease; RV = right ventricular.

characteristics of the clinical VT, prophylactic placement of MHS devices should be considered to prevent periprocedural AHD and potentially reduce mortality. The main beneficial effects of MHS include maintenance of and adequate cardiac index and end-organ perfusion while promoting diuresis; reduction of intracardiac filling pressures, preventing significant increases in pulmonary pressures; reduction of left ventricular volume and wall stress; improvement of myocardial mechanics by reducing myocardial oxygen consumption; improvement of coronary perfusion; and support of systemic circulation and reduction of cardiac stunning due to multiple VT inductions for mapping and during ablation. However, the potential benefits of MHS must be weighed against the potential risks, such as arterial thromboembolism, bleeding and vascular complications at the insertion site. Unfortunately, most of the available evidence supporting the use of haemodynamic support comes from retrospective registers or small observational studies with a substantial lack of specifically designed large randomised controlled trials (Table 1). Studies comparing the use of various types of MHS (i.e. Impella® [Abiomed Inc.], TandemHeart [CardiacAssist Inc.]) to the use of intra-aortic balloon pump (IABP) or no MHS at all have repeatedly demonstrated improvement in acute procedural outcomes by permitting mapping and ablation during sustained VT, improving the likelihood of achieving short-term VT termination.15 However, studies have not convincingly demonstrated a benefit on long-term VT-free survival.13,14,16–18 Even if the main goal of VT ablation is always elimination of VT, improving procedural safety and short-term post-procedural mortality are also important endpoints. Data regarding the impact of MHS on mortality are conflicting. In a recent study by Kusa et al. including 194 patients undergoing VT ablation (109 with the use

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of pLVAD and 85 without), no differences in the primary endpoint of recurrent VT, heart transplantation or all-cause death were seen between the two groups after a median follow-up of 215 days (primary endpoint: 36 % in the pLVAD group versus 26  % in the non-pLVAD group; p=0.14). 18 A substantial lack of benefit related to the use of pLVAD was confirmed even after propensity score-matching analysis accounting for differences between the two groups, either in terms of acute procedural outcomes (VT inducibility at the end of the procedure: 14  % and 10  % in the p-LVAD and non-pLVAD groups; p=0.43) or long-term outcomes (death rate 5  % versus 8  %, p=0.50; heart transplantation rate 5  % versus 0  %, p=0.25; VT recurrence 26 % versus 21 %, p=0.29 in the pLVAD and non-pLVAD groups, respectively).Of note, in this series the decision for pLVAD insertion as well as its timing was made at the operator’s discretion considering haemodynamic instability during VT, frequency of VT episodes and severity of HF status. Therefore, both patients in whom the pLVAD was placed prophylactically and those in whom it was utilised as a ‘bailout’ therapy were included in the analysis, potentially affecting the outcomes.18 Mathuria et al. reported a higher 30-day mortality among high-risk patients undergoing rescue pLVAD placement after experiencing AHD during the CA procedure compared with high-risk patients in whom pLVAD was placed upfront (58.3 % versus 4 %; p=0.003). Interestingly, no significant difference in 30-day mortality was observed between high-risk patients in the prophylactic pLVAD group and low-risk patients in whom the procedure was safely terminated without the need for MHS (4  % versus 3.5  %; p=0.94) (Figure 2).10 These data suggest that the prophylactic (rather than rescue or bailout) use of MHS devices in high-risk patients undergoing VT ablation can result in the prevention of AHD and improved outcomes.

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Clinical Review: Electrophysiology and Ablation For example, our group has reported very poor outcomes in a series of 21 patients undergoing rescue cardiopulmonary support (CPS) with extra-corporeal membrane oxygenation (ECMO) for periprocedural AHD after CA of electrical storm. After a median follow-up of 10 days, 16 patients died while seven patients survived beyond 6 months post ablation, five remained free of VAs and three ultimately received a destination therapy (heart transplantation in two and LVAD in one). Among the patients who died, the cause of death was most commonly refractory HF (11 patients).19 We have recently confirmed these findings in a retrospective observational study comparing a group of 75 high-risk patients undergoing CA of scar-related VT in whom a prophylactic pLVAD (Impella) was implanted into a propensity score-matched control population of 75 patients who did not undergo prophylactic pLVAD placement. 20 The PAINESD risk score was used for propensity matching. We reported the occurrence of AHD in 7 % of patients in the prophylactic pLVAD group and in 23  % of them in the control population (p<0.01). The 12-month cumulative incidence of VT was 40  % in the prophylactic pLVAD group versus 41  % in the control group (p=0.97), while the 12-month incidence of death/transplant was 33  % versus 66  %, respectively (p<0.01). At multivariable analysis, the use of prophylactic pLVAD was associated with a 3.5-fold reduction in the risk of death or transplant.20 Interestingly, by stratifying the patients according to their PAINESD score, patients at high risk (PAINESD ≥15) showed a substantial mortality benefit, with a 2.3-fold lower mortality risk among patients treated with pLVAD (HR 0.43; 95 % CI [0.21-0.87]; p=0.02). Meanwhile, in the low-risk patients (PAINESD ≤8; HR 0.63; 95  % CI 0.24–1.66; p=0.35) there was no statistically significant benefit of pLVAD, suggesting that the observed mortality benefit seen in the overall study group was largely driven by high-risk patients (Figure 2).20 An analysis of patients from the Medicare Inpatient Standard Analytic File database found that those who underwent VT ablation with pLVAD were less likely than those treated with IABP to develop periprocedural AHD (9.1  % versus 23.5  %; p<0.001) and acute renal failure (11.7  % versus 21.7  %; p=0.01), and had lower rates of death (6.5  % versus 19.1 %; p=0.001), 30-day all‐cause hospital readmissions (27.0 % versus 38.7 %; p=0.04) and HF‐related (21.4 % versus 33.3 %; p=0.03) hospital readmissions. This was despite the fact that those in the pLVAD group had higher incidences of HF than those in the IABP group (84.3  % versus 73.0 %; p=0.01). No significant difference was observed in terms of redo‐VT ablation rates at 1 year (10.2 % versus 14.0 %; p=0.34).17 The are several types of MHS currently available. The choice of a specific device is strictly dependent on patient characteristics like overall HF status and the presence of significant valvular disorders, such as moderate-to-severe aortic regurgitation and right ventricular dysfunction. IABP, TandemHeart left atrial-to-femoral artery bypass, Impella and ECMO have been described in CA of VT, and it is the largest published experience so far with the Impella and TandemHeart systems (Table 2). IABP is frequently used in case of cardiogenic shock, especially in patients with severe coronary artery disease. The balloon is positioned in the descending aorta: it unloads during systole, decreasing cardiac afterload and inflates during diastole, augmenting diastolic pressure and therefore coronary artery perfusion with an overall improvement of the cardiac performance but without

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significantly impacting cardiac output (CO). Balloon counter-pulsation is triggered by pressure curve or ECG, limiting its performance in cases of fast/irregular rhythm. The Impella MHS system is a continuous-flow axial pump placed through the aortic valve to pump blood directly from the left ventricle to the ascending aorta and able to provide a CO up to 5.0 l/min depending on the specific device used (Impella 2.5/CP/5.0). Use of Impella requires systemic anticoagulation with intravenous heparin to achieve an activated clotting time (ACT) >250 seconds to prevent stop of the system caused by thrombus formation. In cases of epicardial mapping/ablation, pericardial access should be obtained before Impella placement and absence of pericardial bleeding must be confirmed before starting anticoagulation. In cases in which pericardial access was not planned upfront, the device can be removed or withdrawn into the descending aorta, maintaining irrigation and a low performance level to avoid thrombus formation in order to reverse anticoagulation and safely gain pericardial access.21 The TandemHeart support system consists of a left atrial-to-femoral artery bypass able to provide up to 5 l/min of output by the use of an external centrifugal pump. Access to the left atrium is obtained by transseptal puncture; a bolus of heparin is given before transseptal puncture, followed by infusion to maintain an ACT >300 seconds.22 Some patients with advanced HF have significant biventricular dysfunction and LVAD support may be inadequate. In these cases, devices providing biventricular support such as ECMO should be considered. Initial experiences with cardiopulmonary bypass used CPS, which consists of a centrifugal pump, an oxygen cylinder and a small heating system carried by a mobile cart and connected to the patient through an arterial and venous line. Percutaneous arterial cannulas typically measure 17–21 Fr, while venous cannulas range from 20–24 Fr. Adequate venous return is achieved by placement of the venous cannula inside the right atrium; the cannula is then connected to the inlet of the centrifugal pump, which pumps the blood through the oxygenator, heat exchanger and back to the patient. The use of CPS has shown promising results: in a series of 19 patients undergoing VT ablation, only one patient needed an emergency heart transplant and eventually died during the index hospitalisation while three more patients died during a median follow-up of 42 months.23 However, CPS has several limitations: the combination of relatively small cannulas with pump-driven venous return allows flows between 3 and 4 l/min. Moreover, the use of small-bore cannulas that may result in significant pressure gradients and eventually haemolysis, as well as the use of polypropylene oxygenators with porous fibres leading to plasma leakage and the use of non-thrombo-resistant surfaces makes CPS unsuitable for long-term applications.24 Most of these limitations were subsequently overcome by the use of ECMO that is designed for longterm (up to several weeks) circulatory support with flow >5 l/min. In particular, ECMO uses large-bore cannulas and specifically designed oxygenators either of true membrane type (continuous silicone surface precluding plasma leakage) or with relatively thrombo-resistant surfaces (heparin coated), allowing for less anticoagulation.24 In a recent study involving 64 high-risk patients undergoing CA of unstable VTs, pre-emptive ECMO was implanted in 59 patients,

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Risk Stratification and Management of AHD whereas rescue ECMO was used due to AHD in the remaining five patients. The use of ECMO allowed for the completion of the procedure in 92 % of the patients, achieving the endpoint of VT non-inducibility in 69 %, with an 88 % overall survival rate at 21-months follow-up. Only one patient did not survive to hospital discharge, one patient received LVAD, and three patients underwent heart transplantation.25

Conclusion Periprocedural AHD is a serious complication that may occur in patients with structural heart disease undergoing CA of scar-related VT and is associated with an increased risk of mortality. The PAINESD risk score has demonstrated an ability to identify patients at risk of AHD and can be used as a clinical risk-stratification tool in patients undergoing CA of VT. In high-risk patients, prophylactic implantation of a MHS device should be considered to reduce the risk of AHD and post-procedural adverse outcomes.

1.

L iang JJ, Muser D, Santangeli P. Ventricular tachycardia ablation clinical trials. Card Electrophysiol Clin 2017;9:153–65. https://doi.org/10.1016/j.ccep.2016.10.012; PMID: 28167083. 2. Santangeli P, Muser D, Maeda S, et al. Comparative effectiveness of antiarrhythmic drugs and catheter ablation for the prevention of recurrent ventricular tachycardia in patients with implantable cardioverter-defibrillators: a systematic review and meta-analysis of randomized controlled trials. Heart Rhythm 2016;13:1552–9. https://doi.org/10.1016/j.hrthm.2016.03.004; PMID: 26961297. 3. Liang JJ, Santangeli P, Callans DJ. Long-term outcomes of ventricular tachycardia ablation in different types of structural heart disease. Arrhythm Electrophysiol Rev. 2015;4:177–83. https://doi.org/10.15420/aer.2015.4.3.177; PMID: 26835122. 4. Sapp JL, Wells GA, Parkash R, et al. Ventricular tachycardia ablation versus escalation of antiarrhythmic drugs. N Engl J Med 2016;375:111–21. https://doi.org/10.1056/NEJMoa1513614; PMID: 27149033. 5. Saxon LA, Bristow MR, Boehmer J et al. Predictors of sudden cardiac death and appropriate shock in the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) trial. Circulation 2006;114:2766–72. https://doi.org/10.1161/CIRCULATIONAHA.106.642892; PMID: 17159063. 6. Santangeli P, Muser D, Zado ES, et al. Acute hemodynamic decompensation during catheter ablation of scar-related ventricular tachycardia: incidence, predictors, and impact on mortality. Circ Arrhythm Electrophysiol 2015;8:68–75. https://doi.org/10.1161/CIRCEP.114.002155; PMID: 25491601. 7. Santangeli P, Frankel DS, Tung R, et al. Early mortality after catheter ablation of ventricular tachycardia in patients with structural heart disease. J Am Coll Cardiol 2017;69:2105–15. https://doi.org/10.1016/j.jacc.2017.02.044; PMID: 28449770. 8. Muser D, Mendelson T, Fahed J, et al. Impact of timing of recurrence following catheter ablation of scar-related ventricular tachycardia on subsequent mortality. Pacing Clin Electrophysiol PACE 2017;40:1010–16. https://doi.org/10.1111/ pace.13149; PMID: 28744864. 9. Muser D, Santangeli P, Castro SA, et al. Long-term outcome after catheter ablation of ventricular tachycardia in patients with nonischemic dilated cardiomyopathy. Circ Arrhythm Electrophysiol 2016;9:e004328. https://doi.org/10.1016/​ j.jacep.2017.11.021; PMID: 30089558. 10. Mathuria N, Wu G, Rojas-Delgado F, et al. Outcomes of pre-

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Clinical Perspective Acute haemodynamic decompensation (AHD) is a severe complication that may occur in up to 10 % of patients undergoing catheter ablation of scar-related ventricular tachycardia (VT) and is associated with increased post-procedural mortality. Clinical factors correlated with AHD include advanced age, ischaemic cardiomyopathy, severe heart failure status and presentation with VT storm, as well as comorbidities such as diabetes and chronic obstructive pulmonary disease. Those variables are included in the PAINESD risk score, which has been demonstrated as an accurate and reproducible tool to identify patients at high risk of AHD. Pre-procedural identification of such patients is pivotal in order to optimise heart failure status and to select the best candidates who may benefit from prophylactic implantation of mechanical haemodynamic support.

emptive and rescue use of percutaneous left ventricular assist device in patients with structural heart disease undergoing catheter ablation of ventricular tachycardia. J Interv Card Electrophysiol Int J Arrhythm Pacing 2017;48:27–34. https://doi.org/10.1007/s10840-016-0168-8; PMID: 27497847. Sadek MM, Schaller RD, Supple GE, et al. Ventricular tachycardia ablation – the right approach for the right patient. Arrhythm Electrophysiol Rev 2014;3:161–7. https://doi.org/10.15420/aer.2014.3.3.161; PMID: 26835085. Santangeli P, Rame JE, Birati EY, Marchlinski FE. Management of ventricular arrhythmias in patients with advanced heart failure. J Am Coll Cardiol 2017;69:1842–60. https://doi. org/10.1016/j.jacc.2017.01.047; PMID: 28385314. Miller MA, Dukkipati SR, Chinitz JS, et al. Percutaneous hemodynamic support with Impella 2.5 during scarrelated ventricular tachycardia ablation (PERMIT 1). Circ Arrhythm Electrophysiol 2013;6:151–9. https://doi.org/10.1161/ CIRCEP.112.975888; PMID: 23255277. Miller MA, Dukkipati SR, Mittnacht AJ, et al. Activation and entrainment mapping of hemodynamically unstable ventricular tachycardia using a percutaneous left ventricular assist device. J Am Coll Cardiol 2011;58:1363–71. https://doi. org/10.1016/j.jacc.2011.06.022; PMID: 21920266. Koutalas E, Rolf S, Dinov B, et al. Contemporary mapping techniques of complex cardiac arrhythmias – identifying and modifying the arrhythmogenic substrate. Arrhythm Electrophysiol Rev. 2015;4:19–27. https://doi.org/10.15420/aer.2015.4.1.19; PMID: 26835095. Reddy YM, Chinitz L, Mansour M, et al. Percutaneous left ventricular assist devices in ventricular tachycardia ablation: multicenter experience. Circ Arrhythm Electrophysiol 2014;7: 244–50. https://doi.org/10.1161/CIRCEP.113.000548; PMID: 24532564. Aryana A, Gearoid O’Neill P, Gregory D, et al. Procedural and clinical outcomes after catheter ablation of unstable ventricular tachycardia supported by a percutaneous left ventricular assist device. Heart Rhythm 2014;11:1122–30. https://doi.org/10.1016/j.hrthm.2014.04.018; PMID: 24732372. Kusa S, Miller MA, Whang W, et al. Outcomes of ventricular tachycardia ablation using percutaneous left ventricular assist devices. Circ Arrhythm Electrophysiol 2017;10:pii:e004717. https://doi.org/10.1161/CIRCEP.116.004717; PMID: 28576780. Enriquez A, Liang J, Gentile J, et al. Outcomes of rescue cardiopulmonary support for periprocedural acute hemodynamic decompensation in patients undergoing

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catheter ablation of electrical storm. Heart Rhythm 2018; 15:75–80. https://doi.org/10.1016/j.hrthm.2017.09.005; PMID: 28917560. Muser D, Liang JJ, Castro SA, et al. Outcomes with prophylactic use of percutaneous left ventricular assist devices in high-risk patients undergoing catheter ablation of scar-related VT: a propensity-matched analysis. Heart Rhythm 2018. https://doi.org/10.1016/j.hrthm.2018.04.028; PMID: 29753944; epub ahead of press. Njeim M, Bogun F. Selecting the appropriate ablation strategy: the role of endocardial and/or epicardial access. Arrhythm Electrophysiol Rev 2015;4:184–8. https://doi.org/10.15420/ aer.2015.4.3.184; PMID: 26835123. Naidu SS. Novel percutaneous cardiac assist devices: the science of and indications for hemodynamic support. Circulation 2011;123:533–43. https://doi.org/10.1161/ CIRCULATIONAHA.110.945055; PMID: 21300961. Carbucicchio C, Bella PD, Fassini G, et al. Percutaneous cardiopulmonary support for catheter ablation of unstable ventricular arrhythmias in high-risk patients. Herz 2009;34:545– 52. https://doi.org/10.1007/s00059-009-3289-3; PMID: 20091254. von Segesser LK. Cardiopulmonary support and extracorporeal membrane oxygenation for cardiac assist. Ann Thorac Surg 1999;68:672–7. https://doi.org/10.1016/S00034975(99)00543-3; PMID: 10475469. Baratto F, Pappalardo F, Oloriz T, et al. Extracorporeal membrane oxygenation for hemodynamic support of ventricular tachycardia ablation. Circ Arrhythm Electrophysiol 2016;9:pii:e004492. https://doi.org/10.1161/ CIRCEP.116.004492; PMID: 27932426. Abuissa H, Roshan J, Lim B, Asirvatham SJ. Use of the Impella microaxial blood pump for ablation of hemodynamically unstable ventricular tachycardia. J Cardiovasc Electrophysiol 2010;21:458–61. https://doi.org/10.1111/j.15408167.2009.01673.x; PMID: 20039989. Lü F, Eckman PM, Liao KK, et al. Catheter ablation of hemodynamically unstable ventricular tachycardia with mechanical circulatory support. Int J Cardiol 2013;168:3859–65. https://doi.org/10.1016/j.ijcard.2013.06.035; PMID: 23863501. Aryana A, d’Avila A, Cool CL, et al. Outcomes of catheter ablation of ventricular tachycardia with mechanical hemodynamic support: an analysis of the Medicare database. J Cardiovasc Electrophysiol 2017;28:1295–302; http://doi.wiley. com/10.1111/jce.13312; PMID: 28800178.

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Clinical Review: Drugs and Devices

Defibrillation Threshold Testing: Current Status Justin Hayase, Duc H Do and Noel G Boyle UCLA Cardiac Arrhythmia Center, UCLA Health System, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

Abstract When the transvenous ICD initially came into use for primary and secondary prevention of sudden cardiac death, defibrillation threshold (DFT) testing was universally performed. However, DFT testing is no longer routinely recommended for transvenous ICD implantation except in certain situations. Risk scores can help guide the decision to perform DFT testing. The subcutaneous ICD represents an area of uncertainty, with limited data available regarding the role of DFT testing in these devices. Current guidelines give a class I recommendation for performing DFT testing at the time of implant. Further studies are needed before this recommendation can be safely dismissed.

Keywords Defibrillation threshold, transvenous defibrillator, subcutaneous defibrillator Disclosure: The authors have no conflicts of interest to declare. Received: 17 September 2018 Accepted: 15 November 2018 Citation: Arrhythmia & Electrophysiology Review 2018;7(4):288–93. DOI: https://doi.org/10.15420/aer.2018.54.2 Correspondence: Noel G Boyle, UCLA Cardiac Arrhythmia Center, UCLA Health System, David Geffen School of Medicine at UCLA, 100 UCLA Medical Plaza, Suite 660, Los Angeles, CA 90095-7392, USA. E: nboyle@mednet.ucla.edu

The ICD is an important therapy for both primary and secondary prevention of sudden cardiac death in selected patients. The role for defibrillation threshold (DFT) testing either intraoperatively or postoperatively has changed significantly over the past few decades, and it is no longer routinely recommended in patients undergoing left-sided transvenous ICD implantation.1–7 The definition of the DFT is a probabilistic value and is historically defined as the minimum energy required at which two shocks can successfully terminate VF, which dates back to the era of surgically implanted devices with epicardial patches.8 Such testing was routine for all ICDs in the past due to uncertainty surrounding the device and a desire to predict probability of success in treating ventricular arrhythmias. Generally, devices are programmed with a safety margin of at least 10 J, although some trial data indicates that a 5 J margin could provide equal efficacy.9 A number of different methods can be used for determining DFT, and no particular protocol has been shown to be superior compared with others (Figure 1). Additionally, some operators have employed the use of upper limit of vulnerability, which correlates well with the DFT and has been used in place of direct DFT testing with good reliability.10,11 While routine DFT testing in left-sided transvenous implants is no longer recommended, it is currently a class I recommendation to perform DFT testing for subcutaneous ICDs (S-ICD) although evidence to support this is limited.7 This review will address the considerations for DFT testing with transvenous ICDs including risks and contraindications, examine the impact of DFT testing on patient outcomes and explore some of the data for DFT testing in S-ICDs. We will also discuss our current approach to DFT testing during device implantation.

Managing Inadequate Safety Margins and Risks of Defibrillation Threshold Testing The ‘yield’ of DFT testing reveals an inadequate safety margin, leading to system revision. Observational data of DFT testing in the modern

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era has demonstrated a diminishing yield to ≤3 % as devices and techniques have improved.6 High output active generators with biphasic waveform and programmable waveform tilt have significantly reduced the incidence of inadequate safety margins.12–15 Although uncommon, when inadequate safety margins are encountered, various techniques can be employed to achieve a lower DFT. The single coil lead has become more commonly used, owing to data suggesting similar efficacy with fewer long-term lead complications compared with dual coil leads.16 However, dual coil systems may achieve a lower DFT and can be considered in the case of an inadequate safety margin.17 In the Inhibition of Unnecessary RV Pacing With AV Search Hysteresis in ICDs (INTRINSIC RV) study, 59 of 1,530 patients tested required system revision due to an inadequate safety margin.18 These revisions included reversing polarity, repositioning the RV lead, adding a subcutaneous array, or repeating testing at a later date after medical optimisation. In a study by Vischer et al., nine of 436 patients (2 %) tested required system revision by modifying the superior vena cava coil to either on or off, repositioning the lead and/or generator, adding a subcutaneous array, or adding a coronary sinus coil.19 Another study by Guenther et al. revealed 11 of 783 patients (1.4  %) tested required revision to achieve adequate DFT.3 These changes included reversing polarity, lead revision or adding a subcutaneous array. Another strategy, reported by Cesario et al., involves the implantation of an azygous vein coil.20 Specialised equipment for certain modifications is not standard, but can be acquired from device manufacturers (Figure 2). Although the risk of DFT testing is low, these risks must be carefully weighed against its potential benefits. Large registry data suggest the risk of major complications including stroke, pulmonary embolism, cardiogenic shock, or hypotension requiring resuscitation is an

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Defibrillation Threshold Testing Figure 1: Methods to Determine Defibrillation Threshold at Time of ICD Implant

Step-down method

Safety margin method

Induce VF

20 J Successful

Induce VF

Unsuccessful

Reinduce VF 15 J

10 J Successful 5J

Successful

Unsuccessful

Reinduce VF Unsuccessful

Reinduce VF Unsuccessful

Successful

Unsuccessful

20 J

Reinduce VF Unsuccessful

20 J Successful

Deliver rescue shock

Successful

Deliver rescue shock and modify system

Deliver rescue shock and modify system Rescue shock and additional testing

DFT ≤20 J

DFT determined

Step-up method

Binary method

Induce VF

Successful

5J Unsuccessful

Successful

35 J

25 J Unsuccessful Induce VF

Unsuccessful Deliver rescue shock and modify system

Successful

30 J

Reinduce VF

Unsuccessful

Successful

Reinduce VF Successful 20 J

DFT determined

Unsuccessful

Reinduce VF 15 J

Unsuccessful

DFT determined

Reinduce VF 10 J

Unsuccessful

Deliver rescue shock and modify system

Successful Reinduce VF

15 J

20 J

10 J

Successful

Reinduce VF

Unsuccessful Reinduce VF

5J

No method has demonstrated superiority compared with another. The step-up method and the safety margin method involve the fewest VF inductions. The safety margin method does not determine the exact DFT but can be used to determine an adequate safety margin. DFT = defibrillation threshold.

estimated 0.17–0.4 % and the risk of mortality is 0.016–0.07 %.21,22 The benefits of DFT testing include the ability to identify inadequate sensing of VF or an insufficient safety margin, which can prompt system revision to appropriately treat sudden cardiac death (Table 1). Kolb et al. performed a risk–benefit analysis, using figures of a reduction in mortality of 7–8  % using ICDs and an assumed yield for DFT testing of 2.5  % (likely to be an overestimate, considering that the study was published in 2009 and there have been improvements to newer devices).23 They found that the mortality prevention rate with DFT testing is less than 0.2  %, corresponding to one potential death being averted for every 500 tests.23 This suggests that methods of risk stratifying for those most likely to benefit from DFT testing are needed.

Selecting Patients for Defibrillation Threshold Testing Observational and registry data have identified certain risk factors as predictive of a higher DFT or an inadequate safety margin. Traditional

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risk factors include patients with non-ischaemic cardiomyopathy, younger age, lower ejection fraction, longer QRS interval, or undergoing generator replacement.24,25 Data suggest that antiarrhythmic medications can affect the DFT and chronic use of amiodarone tends to increase the DFT.26,27 Further effects of antiarrhythmic medication effects on DFT are shown in Table 2.28 The question of DFT testing in patients undergoing generator replacement is complex. In a review by Phan et al., the authors concluded that DFT testing should be performed for any generator change involving a hazard alert lead, but that routine DFT testing in this situation requires further study.4 Testing allows for the potential detection of ‘silent’ lead malfunction, but the incidence of this is likely to be low. Current guidelines have a class IIa recommendation for DFT testing when there is a generator change.7 Risk scores have been developed to help clinicians estimate the likelihood of an elevated DFT or inadequate safety margin for new implantation. An analysis of the National Cardiovascular Data Registry

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Clinical Review: Drugs and Devices Figure 2: Posteroanterior and Lateral Chest X-ray Images of a Patient Who Required Implantation of a Subcutaneous ICD Coil

are its simplicity and ease of use. Additionally, current guidelines assign a class IIa recommendation for DFT testing in patients undergoing right-sided transvenous ICD implantation or ICD pulse generator changes, though high-quality data are lacking.7 Another important element of DFT testing is the ability to appropriately detect ventricular arrhythmias. With improvements in transvenous device sensing capabilities and algorithms including the use of bandpass filters and automatic gain control, the need to detect ventricular arrhythmias has diminished.1 Current guidelines suggest that an R wave amplitude of ≥5 mV can reliably predict a device’s ability to sense VF.7 Recent data suggest, however, that an even smaller R wave amplitude in sinus rhythm of ≥3 mV is sufficient to reliably sense VF.31 Nonetheless, DFT testing should be considered in patients with abnormal pacing, sensing, or impedance values at the time of implant according to current guidelines.7

The patient was a 40-year-old man with a history of non-ischaemic cardiomyopathy who had previously undergone biventricular ICD implantation. He presented with VF and five failed shocks, with successful conversion only after the sixth defibrillation. DFT testing was performed and a 25 J shock in opposite polarity from the previously failed shocks was unsuccessful, requiring external defibrillation. A 58 cm 6996 SQ Medtronic lead was then placed in the left posterior axillary subcutaneous tissue and tunnelled to the device pocket. Repeat defibrillation testing was successful at 20 J.

Table 1: Advantages and Disadvantages of Defibrillation Threshold Testing Advantages

Disadvantages

Very low risk, with conservative estimate of 0.04 % major adverse event rate

Major adverse events can occur including: • Pulmonary embolism • Stroke • Hypotension requiring intervention • Cardiogenic shock

Patient and provider reassurance in specific clinical scenarios: • Right-sided transvenous implant • Secondary prevention • Generator change with hazard alert lead • Concern regarding pacing, sensing or impedance values

Low yield (<3 % with inadequate safety margin)

Determination of appropriate sensing capabilities

Increased cost and procedural time

Table 2: Effects of Antiarrhythmic Medications on Defibrillation Threshold 28 Increase

No change

Decrease

Amiodarone (chronic)

Beta blocker

Amiodarone (acute)

Atropine

Disopyramide

Sotalol

Diltiazem

Procainamide

Nifekalant

Verapamil

Propafenone

Flecainide

(NCDR) of 132,477 patients who had DFT testing at the time of ICD implantation from 2010 to 2012 yielded a risk score that was able to identify patients at greater risk of an inadequate defibrillation safety margin, using a combination of eight patient-specific variables.29 The EF-SAGA risk score was developed in a retrospective analysis of 1,642 consecutive patients who underwent ICD implantation with DFT testing at the time of implant (Table 3).30 The advantages of EF-SAGA

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Current guidelines also provide class III recommendations for DFT testing. Absolute contraindications to DFT testing include presence of intracardiac thrombus, AF without anticoagulation, severe aortic stenosis, acute coronary syndrome, or haemodynamic instability requiring inotropic support. Relative contraindications include severe un-revascularised coronary artery disease, recent coronary artery stent placement, recent stroke or transient ischaemic attack, and haemodynamic instability that does not require inotropic support.1,7 It should be noted that multiple observational studies have failed to show the clinical benefit of DFT testing.32–4 There are many hypotheses for this. First, the benefit of the ICD is small and accrues over time, which may make the benefit of DFT testing statistically difficult to demonstrate. Second, DFT testing occurs under controlled conditions under sedation and with medical optimisation, which is very different than what happens clinically where ventricular arrhythmias may be triggered by decompensated heart failure, electrolyte imbalance or MI. Additionally, the majority of arrhythmias are ventricular tachycardia (VT) rather than VF. For these reasons, DFT tested under laboratory conditions may be very different from what is encountered after device implantation.

Trial Data on Defibrillation Threshold Testing in Transvenous Devices We now have randomised data which confirms the lack of clinical benefit of routine DFT testing. The yield of DFT testing has declined over the years as devices and techniques have improved and this has raised doubts over the necessity of routine DFT testing and whether it affects patient outcomes. Two large clinical trials, the NO Regular Defibrillation Testing In Cardioverter Defibrillator Implantation (NORDIC ICD) trial and the Shockless IMPLant Evaluation (SIMPLE) trials, both published in 2015, have addressed this question.35,36 The NORDIC ICD trial was a randomised, multi-centre, non-inferiority study of 1,077 patients undergoing ICD implantation in Europe.35 Subjects were randomised to DFT testing with system revision if necessary versus no DFT testing. They were followed for 1 year with a primary endpoint of first shock efficacy. All subjects had their devices programmed to deliver 40 J regardless of DFT testing results. There was no difference in the primary endpoint of first shock efficacy for all true VT/VF episodes between the two groups. The group that underwent DFT testing had significantly more intraoperative hypotension. The trial excluded patients receiving right-sided implants or subcutaneous ICDs.

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Defibrillation Threshold Testing The SIMPLE trial was another randomised international, multi-centre, non-inferiority study of 2,500 patients that compared DFT testing with corresponding system modification versus no DFT testing at the time of implant.36 All subjects had their devices programmed to deliver a first shock energy of 31 J regardless of DFT testing results, and participants were followed up for an average of 1 year. The two groups had similar results related to the primary outcome of a composite of failed appropriate shock or arrhythmic death. There was no difference in overall safety outcomes between the two groups, but there were significantly more patients who received non-elective intubation in the DFT testing arm. Similar to the NORDIC trial, subcutaneous devices and right-sided implants were excluded. These trial data demonstrated the safety of standard device programming without DFT testing at the time of transvenous device implantation, which helped lead to the current guideline recommendations. However, data are still lacking regarding DFT testing after the initial implant. Whether to test DFT when there is a generator change or if there is a change in antiarrhythmic therapy, for example, are not addressed in the guidelines, but limited data suggest that such routine testing has a low yield.4,7,19,37 Of course, guideline recommendations are not a substitute for clinical judgement, so a patient presenting with multiple failed ICD shocks certainly warrants DFT testing and appropriate system modification (Figure 2).

Defibrillation Threshold Testing in Subcutaneous ICDs The S-ICD has become an important treatment option for prevention of sudden cardiac death. As an entirely extravascular system, its benefits include lower risk of systemic infections, less thrombogenicity and lower levels of lead malfunction.38 Currently, the maximum output of the device is 80 J and implant testing typically is performed at 65 J, with a successful defibrillation indicating a safety margin of 15 J. Current guidelines give a class I recommendation for DFT testing during implantation of S-ICDs, and this recommendation is primarily based on a paucity of data to support the safety of foregoing DFT testing.7 Although this is the guideline recommendation, a recent analysis of NCDR data demonstrated that DFT testing at the time of S-ICD implantation is performed in 71 % of cases and is mainly performed according to preference at each setting.39 Some observational data and propensity comparisons of S-ICD outcomes versus those of transvenous ICDs have emerged in recent years. In the Evaluation oF FactORs ImpacTing CLinical Outcome and Cost EffectiveneSS of the S-ICD (EFFORTLESS S-ICD) registry, 861 patients underwent DFT testing at the time of implant, representing 93.8  % of the study population and only 0.5  % had an inadequate safety margin.40 DFT testing prompted lead repositioning in an additional 1.7  % of patients, an overall yield similar to that for transvenous devices.  In a small observational study of 178 patients by Peddareddy et al., there was no significant difference in first shock efficacy among patients who had DFT testing at the time of S-ICD implant compared with those who did not.41 Randomised trials are needed to confirm this observational data and the safety of DFT testing at the time of S-ICD implant. An important distinction with the S-ICD compared with transvenous systems is that the S-ICD has a fixed lower-sensing floor of 0.08 mV and a low high-pass filter of 3 Hz, which can present issues regarding the appropriate detection and treatment of ventricular arrhythmias.

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Table 3: Risk Scores for Predicting Inadequate Safety Margin Risk score based on National Cardiovascular Data Registry data Patient Variable Heart failure class: • NYHA Class III • NYHA Class IV

Risk Points 1 point 3 points

EF-SAGA Risk Score Patient Variable

Risk Points

Ejection fraction <20 %

1 point

Secondary prevention indication

1 point

Secondary prevention indication

1 point

Age <70

1 point

Age <60 years

1 point

Male

1 point

Male

1 point

Renal dialysis

3 points

Amiodarone use

1 point

Race: • Black • Hispanic • Other

4 points 2 points 1 point

ICD type: • Single chamber • Biventricular device

2 points 1 point

No ischaemic heart disease

2 points

Predictors of inadequate safety margin based on National Cardiovascular Data Registry data for 132,477 patients who were selected for DFT testing at the time of ICD implantation. Risk of an inadequate safety margin in patients ranged from 4.9 % in those with a score of 0 points to 24.5 % in those with a score of ≥12 points.29 EF-SAGA risk score variables for predicting inadequate safety margin derived from 1,642 consecutive patients undergoing ICD implantation and DFT testing. Approximate risk of inadequate safety margin ranged from 0 % with a score of 0 points to 8.9 % with a score of 4–5 points.30 The significant differences in risk provided by these two scores are due to the differing study populations from which they were derived.

In a French study of 137 consecutive patients undergoing S-ICD implantation, 4 % had failure of the device to recognise and treat VF due to noise oversensing at the time of implant, which was resolved by changing the sensing vector.42 An emerging risk factor for inadequate safety margins in S-ICD implantation is obesity or being overweight. An analysis of the S-ICD Investigational Device Exemption study found higher BMI to be associated with a higher rate of first shock failure during device implantation.43 This also correlated with higher lead impedance measurements, presumably due to increased adipose tissue. A case report of high DFT testing and lead impedance with S-ICD lead position in the fat layer demonstrated an improved safety margin and lower impedance by repositioning the lead to just above the sternum.44 In a computer model, the optimal lead position involved placing the coil and generator directly against the fascia where there is no intervening fat.45 However, whether this optimal positioning can routinely achieve acceptable safety margins requires further research, particularly in light of a report demonstrating the inability to obtain an acceptable DFT in an obese patient despite repositioning.46 The recently developed ‘PRAETORIAN Score’ uses the posteroanterior and lateral chest X-ray to evaluate three elements of S-ICD positioning: sub-coil fat, generator position and sub-generator fat. The total score then assigns either low, intermediate, or high risk for an inadequate safety margin on DFT testing.47 These data showed a 99.6  % negative predictive value for a low-risk score in the validation cohort. The prospective evaluation of this scoring system is the subject of the PRospective, rAndomizEd Comparison of subcuTaneOus and tRansvenous ImplANtable Cardioverter Defibrillator Therapy (PRAETORIAN-DFT) trial which is currently enrolling participants.

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Clinical Review: Drugs and Devices The decision to perform DFT testing must be balanced against the fact that patients selected for an S-ICD are generally less likely to receive therapies from their devices. According to a propensity-score matched analysis of the EFFORTLESS and SIMPLE trial data, S-ICD patients received appropriate shocks 9.9 % of the time versus 13.8 % in matched transvenous ICD patients over a 3-year follow-up time.48 This is similar to another propensity-matched study, which found that appropriate ICD therapy was significantly higher in transvenous device patients.49 Theories as to why this discrepancy exists include that the S-ICD has a longer charging time, thus allowing more ventricular arrhythmias to self-terminate, and patients in these cohorts were selected for a S-ICD if they were thought to not have benefited from antitachycardia pacing therapy. These differences between the use of S-ICD and transvenous ICD therapy will affect the risk/benefit ratio when considering whether or not to perform DFT testing.

Our Approach In general, our decision to perform DFT testing at the time of implant is guided by the risk scores discussed above, as well as current guideline recommendations. In general, we perform DFT testing in patients receiving ICDs for secondary prevention or right-sided implants where we feel the benefit of DFT testing outweighs the risk. Otherwise, for standard left-sided device implantations with acceptable sensing (R wave amplitude ≥5 mV), pacing and impedance values we do not perform DFT testing. We also do not routinely perform DFT testing at the time of generator change unless there is a hazard alert lead or other pacing, sensing, or impedance values which might indicate lead failure. For S-ICD implantation, we perform DFT testing in all patients in the absence of contraindications. When DFT testing is indicated, we coordinate with the anaesthesia service for monitored anaesthesia care or general anaesthesia. For testing, we set the maximum programmable device sensitivity and induce VF with either rapid ventricular pacing at rates up to 50 Hz

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 werdlow CD, Russo AM, Degroot PJ. The dilemma of ICD S implant testing. Pacing Clin Electrophysiol 2007;30:675–700. https://doi.org/10.1111/j.1540-8159.2007.00730.x; PMID:17461879. Viskin S, Rosso R. The top 10 reasons to avoid defibrillation threshold testing during ICD implantation. Heart Rhythm 2008;5:391–3. https://doi.org/10.1016/j.hrthm.2008.01.006; PMID: 18313596. Guenther M, Rauwolf T, Bruggemann B, et al. Pre-hospital discharge testing after implantable cardioverter defibrillator implantation: a measure of safety or out of date? A retrospective analysis of 975 patients. Europace 2012;14: 217–23. https://doi.org/10.1093/europace/eur306; PMID: 21969525. Phan K, Kabunga P, Kilborn MJ, Sy RW. Defibrillator threshold testing at generator replacement: is it time to abandon the practice? Pacing Clin Electrophysiol 2015;38:777– 81. https://doi.org/10.1111/pace.12630; PMID: 25790073. Healey JS, Brambatti M. Is defibrillation testing necessary for implantable transvenous defibrillators? Defibrillation testing should not be routinely performed at the time of implantable cardioverter defibrillator implantation. Circ Arrhythm Electrophysiol 2014;7:347–51. https://doi.org/10.1161/ CIRCEP.113.000373; PMID: 24736424. Russo AM, Chung MK. Is defibrillation testing necessary for implantable transvenous defibrillators? Defibrillation testing is necessary at the time of implantable cardioverter defibrillator implantation. Circ Arrhythm Electrophysiol 2014;7:337-46. https:// doi.org/10.1161/CIRCEP.113.000371; PMID: 24736423. Wilkoff BL, Fauchier L, Stiles MK, et al. 2015 HRS/EHRA/ APHRS/SOLAECE expert consensus statement on optimal implantable cardioverter-defibrillator programming and testing. Heart Rhythm 2016;13:e50-86. https://doi.org/10.1016/j. hrthm.2015.11.018; PMID: 26607062. Marchlinski FE, Flores B, Miller JM, et al. Relation of the intraoperative defibrillation threshold to successful postoperative defibrillation with an automatic implantable cardioverter defibrillator. Am J Cardiol 1988;62:393–8. https:// doi.org/10.1016/0002-9149(88)90965-4. PMID: 3414516. Gold MR, Higgins S, Klein R, et al. Efficacy and temporal stability of reduced safety margins for ventricular

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or with low-energy shock delivery during the vulnerable period of ventricular repolarisation, according to the operator’s discretion. The method of DFT determination is operator dependent (Figure 1), as no particular method has been shown to be better than any other. After a first successful defibrillation, a second induction is performed to confirm the DFT or safety margin.

Conclusion Routine DFT testing is no longer recommended at the time of implantation of left-sided transvenous ICDs, a recommendation supported by findings from randomised trials. It is not unreasonable to consider DFT testing in selected patients, depending on the risk of an inadequate safety margin based on established risk scores such as the EF-SAGA or the NCDR-derived scores. While observational data suggest that DFT testing at the time of S-ICD implant may not be necessary in all patients, there is no randomised data to support this practice. Until such data become available, DFT testing should be performed at the time of S-ICD implant according to guideline recommendations.

Clinical Perspective • D efibrillation threshold (DFT) testing is not routinely recommended during implantation of left-sided transvenous ICD, which is supported by randomised trial data. •  The presence of patient-specific risk factors may prompt DFT testing according to operator discretion at the time of implantation in certain clinical situations. •  Current guidelines recommend DFT testing should be done at the time of subcutaneous ICD (S-ICD) implantation in the absence of contraindications. Limited data are available for DFT testing in S-ICD implantation and more robust studies are needed to demonstrate the safety of omitting the test.

defibrillation: primary results from the Low Energy Safety Study (LESS). Circulation 2002;105:2043–8. https://doi. org/10.1161/01.CIR.0000015508.59749.F5; PMID: 11980683. Hwang C, Swerdlow CD, Kass RM, et al. Upper limit of vulnerability reliably predicts the defibrillation threshold in humans. Circulation 1994;90:2308–14. https://doi. org/10.1161/01.CIR.90.5.2308; PMID: 7955188. Swerdlow CD, Shehata M, Chen PS. Using the upper limit of vulnerability to assess defibrillation efficacy at implantation of ICDs. Pacing Clin Electrophysiol 2007;30:258–70. https://doi. org/10.1111/j.1540-8159.2007.00659.x; PMID: 17338725. Gold MR, Foster AH, Shorofsky SR. Effects of an active pectoral-pulse generator shell on defibrillation efficacy with a transvenous lead system. Am J Cardiol 1996;78:540–3. https:// doi.org/10.1016/S0002-9149(96)00361-X; PMID: 8806339. Neuzner J, Pitschner HF, Huth C, Schlepper M. Effect of biphasic waveform pulse on endocardial defibrillation efficacy in humans. Pacing Clin Electrophysiol 1994;17:207–12. https://doi. org/10.1111/j.1540-8159.1994.tb01373.x; PMID: 7513406. Shorofsky SR, Foster AH, Gold MR. Effect of waveform tilt on defibrillation thresholds in humans. J Cardiovasc Electrophysiol 1997;8:496–501. https://doi.org/10.1111/j.1540-8167.1997. tb00817.x; PMID: 9160225. Poole JE, Bardy GH, Kudenchuk PJ, et al. Prospective randomized comparison of biphasic waveform tilt using a unipolar defibrillation system. Pacing Clin Electrophysiol 1995;18:1369–73. https://doi.org/10.1111/j.1540-8159.1995. tb02598.x; PMID: 7567589. Aoukar PS, Poole JE, Johnson GW, et al. No benefit of a dual coil over a single coil ICD lead: evidence from the Sudden Cardiac Death in Heart Failure Trial. Heart Rhythm 2013;10:970–6. https://doi.org/10.1016/j.hrthm.2013.03.046; PMID: 23562699. Kumar P, Baker M, Gehi AK. Comparison of single-coil and dual-coil implantable defibrillators: a meta-analysis. JACC Clin Electrophysiol 2017;3:12–9. https://doi.org/10.1016/j. jacep.2016.06.007; PMID: 29759689. Day JD, Olshansky B, Moore S, et al. High defibrillation energy requirements are encountered rarely with modern dual-chamber implantable cardioverter-defibrillator systems. Europace 2008;10:347–50. https://doi.org/10.1093/europace/

eun027; PMID: 18308755. 19. V  ischer AS, Sticherling C, Kuhne MS, et al. Role of defibrillation threshold testing in the contemporary defibrillator patient population. J Cardiovasc Electrophysiol 2013;24:437–41. https://doi.org/10.1111/jce.12042; PMID: 23210803. 20. Cesario D, Bhargava M, Valderrabano M, et al. Azygos vein lead implantation: a novel adjunctive technique for implantable cardioverter defibrillator placement. J Cardiovasc Electrophysiol 2004;15:780-3. https://doi.org/10.1046/j.15408167.2004.03649.x; PMID: 15250862. 21. Birnie D, Tung S, Simpson C, et al. Complications associated with defibrillation threshold testing: the Canadian experience. Heart Rhythm 2008;5:387–90. https://doi.org/10.1016/j. hrthm.2007.11.018; PMID: 18243813. 22. Brignole M, Raciti G, Bongiorni MG, et al. Defibrillation testing at the time of implantation of cardioverter defibrillator in the clinical practice: a nation-wide survey. Europace 2007;9:540–3. https://doi.org/10.1093/europace/eum083; PMID: 17507358. 23. Kolb C, Tzeis S, Zrenner B. Defibrillation threshold testing: tradition or necessity? Pacing Clin Electrophysiol 2009;32:570–2; discussion 572. https://doi.org/10.1111/j.15408159.2009.02328.x; PMID: 19422576. 24. Lin EF, Dalal D, Cheng A, et al. Predictors of high defibrillation threshold in the modern era. Pacing Clin Electrophysiol 2013;36:231–7. https://doi.org/10.1111/pace.12039; PMID: 23121046. 25. Russo AM, Sauer W, Gerstenfeld EP, et al. Defibrillation threshold testing: is it really necessary at the time of implantable cardioverter-defibrillator insertion? Heart Rhythm 2005;2:456–61. https://doi.org/10.1016/ j.hrthm.2005.01.015; PMID: 15840466. 26. Jung W, Manz M, Pizzulli L, et al. Effects of chronic amiodarone therapy on defibrillation threshold. Am J Cardiol 1992;70:1023–7. https://doi.org/10.1016/0002-9149(92)903542; PMID: 1414899. 27. Kuhlkamp V, Mewis C, Suchalla R, et al. Effect of amiodarone and sotalol on the defibrillation threshold in comparison to patients without antiarrhythmic drug treatment. Int J Cardiol 1999;69:271–9. https://doi.org/10.1016/S0167-5273(99)000558; PMID: 10402110.

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Defibrillation Threshold Testing 28. Ishikawa T. Effects of anti-arrhythmic drugs for pacing threshold and defibrilllation threshold. J Arrhythm 2011;27:239– 41. https://doi.org/10.1016/S1880-4276(11)80052-9. 29. Hsu JC, Marcus GM, Al-Khatib SM, et al. Predictors of an inadequate defibrillation safety margin at ICD implantation: insights from the National Cardiovascular Data Registry. J Am Coll Cardiol 2014;64:256–64; https://doi.org/10.1016/ j.jacc.2014.01.085; PMID: 25034061. 30. Shih MJ, Kakodkar SA, Kaid Y, et al. Reassessing risk factors for high defibrillation threshold: the ef-saga risk score and implications for device testing. Pacing Clin Electrophysiol 2016;39:483–9. https://doi.org/10.1111/pace.12838; PMID: 26931098. 31. Ruetz LL, Koehler JL, Brown ML, et al. Sinus rhythm R-wave amplitude as a predictor of ventricular fibrillation undersensing in patients with implantable cardioverterdefibrillator. Heart Rhythm 2015;12:2411–8. https://doi. org/10.1016/j.hrthm.2015.08.012; PMID: 26272520. 32. Blatt JA, Poole JE, Johnson GW, et al. No benefit from defibrillation threshold testing in the SCD-HeFT (Sudden Cardiac Death in Heart Failure Trial). J Am Coll Cardiol 2008;52:551–6. https://doi.org/10.1016/j.jacc.2008.04.051; PMID: 18687249. 33. Michowitz Y, Lellouche N, Contractor T, et al. Defibrillation threshold testing fails to show clinical benefit during long-term follow-up of patients undergoing cardiac resynchronization therapy defibrillator implantation. Europace 2011;13:683–8. https://doi.org/10.1093/europace/euq519; PMID: 21252192. 34. Bianchi S, Ricci RP, Biscione F, et al. Primary prevention implantation of cardioverter defibrillator without defibrillation threshold testing: 2-year follow-up. Pacing Clin Electrophysiol 2009;32:573–8. https://doi.org/10.1111/j.15408159.2009.02329.x; PMID: 19422577. 35. Bänsch D, Bonnemeier H, Brandt J, et al. Intra-operative

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defibrillation testing and clinical shock efficacy in patients with implantable cardioverter-defibrillators: the NORDIC ICD randomized clinical trial. Eur Heart J 2015;36:2500–7. https://doi.org/10.1093/eurheartj/ehv292; PMID: 26112885. Healey JS, Hohnloser SH, Glikson M, et al. Cardioverter defibrillator implantation without induction of ventricular fibrillation: a single-blind, non-inferiority, randomised controlled trial (SIMPLE). Lancet 2015;385:785–91. https://doi. org/10.1016/S0140-6736(14)61903-6; PMID: 25715991. Brunn J, Bocker D, Weber M, et al. Is there a need for routine testing of ICD defibrillation capacity? Results from more than 1000 studies. Eur Heart J 2000;21:162–9. https://doi. org/10.1053/euhj.1999.1716; PMID: 10637090. McLeod CJ, Boersma L, Okamura H, Friedman PA. The subcutaneous implantable cardioverter defibrillator: stateof-the-art review. Eur Heart J 2017;38:247–57. https://doi. org/10.1093/eurheartj/ehv507; PMID: 28182222. Friedman DJ, Parzynski CS, Heist EK, et al. Ventricular fibrillation conversion testing after implantation of a subcutaneous implantable cardioverter defibrillator: report from the national cardiovascular data registry. Circulation 2018;137:2463–77. https://doi.org/10.1161/ CIRCULATIONAHA.117.032167; PMID: 29463509. Boersma L, Barr C, Knops R, et al. Implant and midterm outcomes of the subcutaneous implantable cardioverterdefibrillator registry: The EFFORTLESS Study. J Am Coll Cardiol 2017;70:830-841. https://doi.org/10.1016/ j.jacc.2017.06.040; PMID: 28797351. Peddareddy L, Merchant FM, Leon AR, et al. Effect of defibrillation threshold testing on effectiveness of the subcutaneous implantable cardioverter defibrillator. Pacing Clin Electrophysiol 2018; https://doi.org/10.1111/pace.13416; PMID: 29893508. [Epub ahead of print]. le Polain de Waroux JB, Ploux S, Mondoly P, et al. Defibrillation testing is mandatory in patients with subcutaneous implantable

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cardioverter-defibrillator to confirm appropriate ventricular fibrillation detection. Heart Rhythm 2018;15:642–50. https://doi. org/10.1016/j.hrthm.2018.02.013; PMID: 29709229. Frankel DS, Burke MC, Callans DJ, et al. Impact of body mass index on safety and efficacy of the subcutaneous implantable cardioverter-defibrillator. JACC Clin Electrophysiol 2018;4:652–9. https://doi.org/10.1016/j.jacep.2017.11.019; PMID: 29798794. Hirao T, Nitta J, Sato A, et al. High defibrillation threshold with a subcutaneous implantable cardiac defibrillator due to the lead having been positioned in the fat layer. J Arrhythm 2018;34:198–200. https://doi.org/10.1002/joa3.12033; PMID: 29657596. Heist EK, Belalcazar A, Stahl W, et al. Determinants of subcutaneous implantable cardioverter-defibrillator efficacy: a computer modeling study. JACC Clin Electrophysiol 2017;3: 405-414. https://doi.org/10.1016/j.jacep.2016.10.016; PMID: 29759454. Levine JD, Ellins C, Winn N, et al. Failed maximal defibrillation threshold testing in the subcutaneous implantable cardioverter defibrillator. Cardiology 2017;136:29–32. https:// doi.org/10.1159/000447484; PMID: 27548370. Quast ABE, Baalman SWE, Brouwer TF, et al. A novel tool to evaluate the implant position and predict defibrillation success of the subcutaneous implantable defibrillator: the PRAETORIAN score. Heart Rhythm 2018;18:31012–9. https://doi. org/10.1016/j.hrthm.2018.09.029; PMID: 30292861. Brouwer TF, Knops RE, Kutyifa V, et al. Propensity score matched comparison of subcutaneous and transvenous implantable cardioverter-defibrillator therapy in the SIMPLE and EFFORTLESS studies. Europace 2018;20:f240-f248. https:// doi.org/10.1093/europace/euy083; PMID: 29771327. Brouwer TF, Yilmaz D, Lindeboom R, et al. Long-term clinical outcomes of subcutaneous versus transvenous implantable defibrillator therapy. J Am Coll Cardiol 2016;68:2047–55. https:// doi.org/10.1016/j.jacc.2016.08.044; PMID: 27810043.

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Clinical Review: Drugs and Devices

Haemodynamic Monitoring Devices in Heart Failure: Maximising Benefit with Digitally Enabled Patient Centric Care Leah M Raj and Leslie A Saxon University of Southern California, USC Center for Body Computing, Keck School of Medicine, Los Angeles, CA, USA

Abstract ICDs and resynchronisation devices are routinely implanted in patients with heart failure for primary prevention of sudden cardiac death or to treat the condition. The addition of device features and algorithms that directly or indirectly monitor cardiac haemodynamics to assess heart failure status can provide additional benefit by treating heart failure more continuously. Established and emerging devices and sensors aimed at treating or measuring cardiac haemodynamics represent the next era of heart failure disease management. Digitally enabled models of heart failure care, based on frequent haemodynamic measurements, will increasingly involve patients in their own disease management. Software tools and services tailored to provide patients with personalised information to guide diet, activity, medications and haemodynamic management offer an unprecedented opportunity to improve patient outcomes. This will enable physicians to care for larger populations because management will be exception based, automated and no longer depend on one-to-one patient and physician interactions.

Keywords Haemodynamic monitoring, implantable cardiac devices, digital health, software, heart failure disease management, implantable devices Disclosure: The authors have no conflict of interest to declare. Acknowledgement: The authors acknowledge the efforts of Cynthia Romero in preparing this manuscript. Received: 30 April 2018 Accepted: 24 August 2018 Citation: Arrhythmia & Electrophysiology Review 2018;7(4):294–8. DOI: https://doi.org/10.15420/aer.2018.32.3 Correspondence: Leslie A Saxon, USC Center for Body Computing, 12015 Waterfront Dr, Los Angeles, CA 90094, USA. E: saxon@usc.edu

This study reviews how haemodynamic monitoring devices that provide indirect or direct measures of heart failure status relate to cardiac rhythm management devices for the management of patients with the condition. The role of patient-facing software and services that provide information from these devices to patients can create a new model of heart failure disease management. In this care paradigm, patients are provided with daily data that can be used to aid in selfmanagement and provide exception-based data to physicians and care teams, allowing them to care for more patients more efficiently.1

Cardiac Rhythm Management Devices in Heart Failure Cardiac rhythm management devices, consisting of ICDs and resynchronisation devices, are routinely implanted in patients with heart failure for primary prevention of sudden cardiac death, as well as for the treatment of heart failure. In the US, roughly 100,000 ICDs are implanted each year.1 Based on current guidelines, ICD therapy is indicated in patients with left ventricular ejection fraction (LVEF) ≤35 % who are at least 40 days post MI and have functional class II or III heart failure.2 Similarly, cardiac resynchronisation therapy is indicated for patients with LVEF ≤35  % in sinus rhythm with a QRS duration >0.12 milliseconds and functional class III–IV heart failure on optimised medical therapy.2

The prevalence of heart failure is increasing and it is a long-term condition characterised by disease progression that is associated with a 30 % 5-year mortality rate.4 Gaining a deeper understanding of how to support patients with heart failure by developing a more holistic and continuous care model that considers every aspect of disease management and involves the patient and gives them tools to self-manage this complex, chronic condition is needed. Current consumer and FDA-regulated hardware, software and services that are already used by billions of consumers can be harnessed to serve this model. However, additional solutions need to be developed that empower and provide continuous support and education for patients with heart failure, as well as their personal care network, and facilitate communication between caregivers and provider teams.5

What Defines Haemodynamic Monitoring in Heart Failure? Heart failure progression and haemodynamic decompensation, most commonly manifesting as increased intracardiac pressure due to volume overload, are predictive of adverse events and mortality. Active ambulatory surveillance of intracardiac pressures, using indirect correlative or direct measurements, can guide early treatment intervention and reduce costs, hospitalisation and mortality.6–17

Heart Failure: A Long-term, Costly Condition Heart failure treatment costs are estimated to be more than $30 billion each year in the US.3 These costs pay for healthcare services such as ambulatory visits, admissions, procedures and pharmacologic therapy.3

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One of the first indirect assessments of haemodynamic status that can be measured from a cardiac rhythm monitoring device uses impedance measurements as a surrogate for intrathoracic impedance.

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Haemodynamic Monitoring Devices in Heart Failure Measured by the implanted device between the right ventricle lead and the pulse generator, impedance reductions correlate with increases in thoracic fluid volume. The utility of this measurement as an early indicator of heart failure decompensation is based on data showing that impedance reductions can be detected up to two weeks before a patient develops symptoms of heart failure decompensation.9 In a trial that compared device measured impedance changes to daily weight gain (the Fluid Accumulation Status Trial), intrathoracic impedance was reported to be a more sensitive and an earlier indicator for detecting heart failure events.10 However, there are significant limitations associated with using impedance changes to guide clinical decision making. Patients have no access to the measurements and it is incumbent upon the remote monitoring clinic to follow and evaluate the clinical significance of an impedance change. There is also a significant false positive rate of 1.5 detections per patient-year of follow-up.9 Causes of false-positive readings include lung disease or infection, pocket haematoma and body type (habitus).11 The recently completed Multisensor Chronic Evaluation in Ambulatory Heart Failure Patients (Multi-SENSE) trial evaluated and validated multiple device-based measurements of heart failure status in patients with cardiac resynchronisation therapy devices. The study prospectively evaluated a combination of intrathoracic impedance, heart and respiratory rate, heart sounds and activity. A proprietary composite algorithm based on these variables predicted heart failure events up to 34 days before patient presentation with 70 % sensitivity and 87.5 % specificity.12 While more accurate than thoracic impedance alone for predicting heart failure events, this algorithm lacks patient engagement or a defined care pathway for evaluating patients whose measurements indicate their heart failure is worsening. Furthermore, this is not a device that an implanting electrophysiologist or implantable device follow-up clinic is set up to manage. At most centres, the device follow-up care team reviewing ICD remote data is not the team monitoring patients’ heart failure status and titrating medications or recommending intervention. Nevertheless, trends in patient symptoms or activity can be collected using consumer devices, such as fitness trackers or smartphones with embedded activity sensors, and these can be used in the management of heart failure. This is because they measure functional status continuously and provide personalised data profiles of individual heart failure patients over time.5 Direct measurements of remotely collected intracardiac pressures present a clear and clinically actionable targets for intervention. There is an FDA-approved pulmonary artery pressure sensor that is indicated and labelled for this purpose. This device measures pulmonary artery pressure from a battery-free electromechanical sensor, which is implanted using a minimally invasive over-thewire technique in the distal pulmonary artery.13–15 Daily ambulatory pressures remotely collected from the sensor are used to direct heart failure medical therapy. The CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Heart Failure Patients (CHAMPION) trial assessed the rate of heart failure-related hospitalisations at 6  months in ambulatory class III heart failure patients who had been hospitalised within the previous 12 months. Patients were randomly assigned to pressure-directed heart failure therapy versus standard

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Table 1: Diagnostic Haemodynamic Pressure Sensors for Heart Failure Device

Location

Clinical Trial

Patient

Chronicle

Right ventricle

COMPASS-HF

CardioMEMs

Pulmonary artery CHAMPION

No

HeartPOD

Atrial septum

Homeostasis, LAPTOP-HF

No, yes

V-LAP

Atrial septum

Pre-clinical

No

Cardiac Rhythm Management Defibrillator

Right ventricle, coronary sinus

Multi-SENSE FAST

No

Access No

heart failure management. Those randomised to pressure-directed therapy experienced a 28 % reduction in hospitalisations related to heart failure.14 Post-FDA approval registries have also established long-term reductions in heart failure events and costs associated with the condition. These data show that patients with heart failure benefit outside a clinical trial and that this benefit extends over longer follow-up intervals that were studied in the clinical trial.15,16 Like those enrolled in trials of indirect measurements of heart failure status, in the CHAMPION study, patients were not given their pressure readings (Table 1). Instead, the information was provided to the care team on a secure website; it was reviewed at least weekly and guided recommended adjustments in medical management were provided to the patients. An earlier device, which measures right ventricular pressure with a right ventricular pressure-sensing lead, demonstrated that right ventricular pressure correlates with pulmonary artery diastolic pressure and that pressure excursions preceded heart failure clinical events. However, when studied in a clinical trial – the COMPASS-HF trial – the trial did not meet its pre-specified endpoints. This was attributed to a lack of aggressive management to reduce elevated pulmonary pressures as well as unexpectedly better outcomes than anticipated in patients not randomised to the sensor.17 Another haemodynamic pressure sensor, extensively studied in the Homeostasis and LAPTOP–HF trials, directly measures left atrial pressure using a trans-septal sensor. In these studies, patients were provided with a handheld device that recorded sensor readings and allowed them access to pressure tracings that were collected twice daily and wirelessly communicated to their heart failure care team. Patients were remotely prescribed pharmacological therapies via the handheld device, based on a preset algorithm that directed therapy based upon pressure ranges. The LAPTOP-HF trial was a prospective, multicentre, randomised study that enrolled patients with class III heart failure who had been admitted to hospital for heart failure within the past year. It defined safety as freedom from major adverse cardiovascular and neurological events within 12 months, and efficacy as a reduction in heart failure hospitalisations and all-cause mortality. Unfortunately, the data safety and monitoring board halted the trial against the recommendations of the study investigator leadership team after more than 500 of the planned 730 patients were enrolled because of a temporal clustering of transseptal related procedural complications. Patients continued to be followed after the trial was halted for the study endpoints of hospitalisation and mortality. Retrospective analysis of the outcome data revealed that the safety

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Clinical Review: Drugs and Devices Table 2: Therapeutic Haemodynamic Devices for Heart Failure Device

Location

Trial

Patient Access

V-Wave

Left atrium

VW-SP-1

No

IASD

Atrial septum

Reduce LAP-HF

No

Table 3: Haemodynamic Monitoring and Therapy Devices for End-stage Heart Failure Device

Location

Clinical Trial

Patient Access

Titan

Left atrium

Left Atrial Pressure Monitoring With an Implantable Wireless Pressure Sensor After Implantation of a LVAD

No

Left ventricular assist device

Left ventricle

NA

Yes

boundaries of the trial had not been crossed and that the patients who were managed with medical therapy, directed by left atrial pressure measures, had a 41 % reduction in heart failure hospitalisation at 12 months’ follow-up.17 These results support the concept that patients can be provided with their own haemodynamic data that allows them to work effectively in partnership with their treatment team in their own heart failure care. Despite these results, the sponsor did not seek FDA approval, as statistical power to detect a treatment difference was not achieved because the trial had been terminated prematurely. Another left atrial pressure sensor is in early preclinical testing. The V-LAP device is a left atrial leafless and wireless sensor that is implanted in the septum. Similar to the sensor used in the LAPTOP–HF trial, the V-LAP sensor records an atrial ECG and provides left atrial waveform morphology, potentially allowing other comorbidities such as valvular regurgitation and arrhythmias to be detected.18,19

Devices that Improve Haemodynamics A new generation of atrial shunt devices that aim to reduce left atrial pressure but do not incorporate implantable haemodynamic sensors is under investigation. Two devices are being studied in pivotal clinical trials and both work by creating atrial septal communications to allow for left to right atrial flow to reduce left atrial pressure.20–22 Both have shown safety in feasibility studies and have had a positive impact on cardiac haemodynamics in phase I and II trials (Table 2).20–22

End Stage Heart Failure and Haemodynamic Devices Of the 6 million people diagnosed with heart failure, roughly 250,000 have progressed to advanced disease (stage D), which is characterised by frequent admissions, inotrope use or mechanical circulatory support. 6 In these cases, because of the advanced stage of the disease, neither cardiac rhythm monitoring device therapies, such as resynchronisation, nor diagnostic sensors are efficacious. These patients have mortality rates of over 50 % in 6 months.22–25 Because too few donor hearts are available (2,000 donors per 100,000 potential candidates), ineligibility for transplant or clinical instability, many patients are treated with durable or permanent left ventricular assist devices (LVADs).26,27 In

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these patients, right and left heart failure is an acute and chronic complication of assist device therapy and heart failure is a frequent cause of hospital admission after device implant.27–29 Implantable pulmonary artery sensors are not well studied in this population but may have utility both to predict early eligibility for assist device before decompensation or instability and to prevent heart failure events after implant. A subgroup analysis from the CHAMPION trial showed that patients with a pulmonary artery pressure sensor who went on to require LVADs had more medication changes and were referred for and underwent transplantation earlier than those without a sensor.28 A recently published case study reported the use of a wireless pressure sensor for monitoring left atrial pressure during LVAD support (Table 3). The sensor is designed to guide pump speed, help manage intravascular volume and tailor the use of medications such as intravenous inotropes. Integrating haemodynamic pressure sensors into LVAD technology is an attractive strategy.29

Patient-Facing Data and Tools for All Heart Failure Management of heart failure across the disease spectrum includes pharmacological therapy, device implantation, patient education and clinic visits. It is clear that adherence to treatment plans slow down disease progression.6 However, compliance to treatment regimens and patient understanding and ability to manage their condition, especially before decompensation events, is suboptimal.30 For many patients with heart failure, drug regimens can include up to six medications, some scheduled up to three-times per day. Patients must also adhere to salt-restricted diets and observe fluid restrictions. While several studies have attempted to provide patients with a continuing model of disease management support outside hospital, little improvement has been made in reducing event rates with nurse phone calls or intermittent home visits.30,31 Cardiac rhythm devices and haemodynamic monitoring data provide crucial information to the treating physician. This continuous ambulatory data guides dynamic changes to medical therapy and improves all-cause outcomes. Given the daily fluctuations in heart failure haemodynamics, providing patients with objective data collected from these sensors can engage them in their own care and encourage them to work more closely with their care team and take a more active role in their disease management.2,5 However, most wireless monitoring allows only physician access and patients are kept blinded to their own pressure tracings or rhythm monitoring. This denial of data is completely out of sync with today’s culture of on-demand access to media, entertainment and financial data. For example, more than one billion people around the world have access to internet-connected phones and most use their smartphone as the primary method for internet search.32,33 Supporting this further, over 50 % of patients seek remote medical care.34 Apart from smartphone technology, wearable sensing devices that are designed to track metrics such as activity, calories spent and heart rate are overwhelmingly popular.35 Reports show that up to 25 % of Americans use a wearable sensor.34 These data suggest that patients want to feel empowered and directly involved in their health by implementing digital technology tools, which are easily available.

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Haemodynamic Monitoring Devices in Heart Failure With increasing patient interest and today’s connected medical technology, digital disease management has the potential to change the face of heart failure diagnosis and treatment. Continuous tracking of cardiac haemodynamics, medication adherence, activity and diet are perfectly suited to a digital model of care specific to the patient’s condition where diuretics can be increased, goal-directed medical therapy can be continuously optimised and lifestyle adjustments can be recommended.5,34 Software solutions can also provide a platform for asynchronous communication between patients, caregivers and providers. This allows for seamless data sharing, caregiver efficiency and a continuous model of patient-supported care.34,35 This is crucial in long-term conditions, such as heart failure where gaps in care and communication can lead to progression of the disease and adverse outcomes. The first smartphone-compatible implantable cardiac rhythm monitor has recently been approved by the FDA.36 This software app allows patients to interrogate their device and transmit data securely to their treating physician. Engaging the patient further by letting them view their continuous ECG and providing activity and other information that the smartphone can collect is a natural extension of this product’s capability that should be explored.

Conclusion While disease progression is inevitable for most patients with heart failure, outcomes can be improved with continuous monitoring and dynamic therapy adjustments. Recent digital technology such as pressure sensors and cardiac rhythm management devices have been proven to predict heart failure events and reduce hospitalisations.37–39 Most of these devices transmit data only to treatment teams and patients are left unaware of their own personal health information.

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 ond HG, Proclemer A. The 11th world survey of cardiac M pacing and implantable cardioverter-defibrillators: calendar year 2009 – a World Society of Arrhythmia’s project. Pacing Clin Electrophysiol 2011;34:1013–27. https://doi.org/10.1111/j.15408159.2011.03150.x; PMID: 21707667. Epstein AE, Dimarco JP, Ellenbogen KA, et al. ACC/AHA/HRS 2008 Guidelines for device-based therapy of cardiac rhythm abnormalities. Heart Rhythm 2008;5:e1–62. https://doi.org/ 10.1016/j.hrthm.2008.04.014; PMID: 18534360. Heidenreich PA, Trogdon JG, Khavjou OA, et al. Forecasting the future of cardiovascular disease in the United States: a policy statement from the American Heart Association. Circulation 2011;123:933–44. https://doi.org/10.1161/ CIR.0b013e31820a55f5; PMID: 21262990. Levy D, Kenchaiah S, Larson MG, et al. Long-term trends in the incidence of and survival with heart failure. N Engl J Med 2002;347:1397–402. https://doi.org/10.1056/NEJMoa020265; PMID: 12409541. Shinbane JS, Saxon LA. Digital monitoring and care: virtual medicine. Trends Cardiovasc Med 2016;26:722–30. https://doi. org/10.1016/j.tcm.2016.05.007; PMID: 27373351. 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. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;62:e147–239. https://doi.org/10.1016/ j.jacc.2013.05.019; PMID: 23747642. Desai AS, Bhimaraj A, Bharmi R, et al. Ambulatory hemodynamic monitoring reduces heart failure hospitalizations in “real-world” clinical practice. J Am Coll Cardiol 2017;69:2357–65. https://doi.org/10.1016/j.jacc.2017.03.009; PMID: 28330751. Yu CM, Wang L, Chau E, et al. Intrathoracic impedance monitoring in patients with heart failure: correlation with fluid status and feasibility of early warning preceding hospitalization. Circulation 2005;112(6):841–8. https://doi. org/10.1161/CIRCULATIONAHA.104.492207; PMID: 16061743.

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Patients are increasingly becoming more involved in tracking their own health using digital hardware and software, including downloading healthcare apps on their smartphones or investing in wearable sensors. Consumer and chronic care populations are already using wearable devices and devices such as mobile ECGs to monitor activity and health status.40 These new digital care models of heart failure management need to be prospectively studied and clinical workflows need to evolve to properly manage patients more continuously and efficiently. Protection of devices and data flow are paramount to patient trust in these solutions and regulations regarding cybersecurity.41 Nonetheless, providing patient-facing data and decision support for people with heart failure using digital healthcare and software tools should be a priority for research and validation.

Clinical Perspective • H  aemodynamic monitoring represents the next era in heart failure care. • Digital health software and services can help the patient and physician manage heart failure more continuously using more personalised data. •  Digital tools, including those that use data from implantable devices, will support disease management for patients with heart failure. • These tools are patient facing and should be studied. • New clinical workflows, including digital patient services and exception-based management require study and development.

10. A  braham WT, Compton S, Haas G, et al. Intrathoracic impedance vs daily weight monitoring for predicting worsening heart failure events: results of the Fluid Accumulation Status Trial (FAST). Congest Heart Fail 2011;17:51– 5. https://doi.org/10.1111/j.1751-7133. 2011.00220.x; PMID: 21449992. 11. Tang WH, Tong W. Measuring impedance in congestive heart failure: Current options and clinical applications. Am Heart J 2009;157:402–11. https://doi.org/10.1016/j. ahj.2008.10.016; PMID: 19249408. 12. Boehmer JP, Hariharan R, Devecchi FG, et al. A multisensor algorithm predicts heart failure events in patients with implanted devices: results from the MultiSENSE Study. JACC Heart Fail 2017;5:216–25. https://doi.org/10.1016/ j.jchf.2016.12.011; PMID: 28254128. 13. Verdejo HE, Castro PF, Concepcion R, et al. Comparison of a radiofrequency-based wireless pressure sensor to swan-ganz catheter and echocardiography for ambulatory assessment of pulmonary artery pressure in heart failure. J Am Coll Cardiol 2007;50:2375–82. https://doi.org/10.1016/ j.jacc.2007.06.061; PMID: 18154961. 14. Abraham, WT, Adamson PB, Bourge RC, et al. Wireless pulmonary artery haemondynamic monitoring in chronic heart failure: a randomized controlled trail. Lancet 2011; 377:658–66. https://doi.org/10.1016/S0140-6736(11) 60101-3; PMID: 21315441. 15. Raval NY, Shavelle D, Bourge RC, et al. Significant reductions in heart failure hospitalizations with the pulmonary artery pressure guided HF system: preliminary observations from the CardioMEMS Post Approval Study. J Card Fail 2017;23:S27. https://doi.org/10.1016/j.cardfail.2017.07.068. 16. Abraham WT, Adamson PB, Costanzo MR, et al. Hemodynamic monitoring in advanced heart failure: results from the LAPTOP-HF trial. J Card Fail 2016;22:940. https://doi. org/10.1016/j.cardfail.2016.09.012. 17. Abraham WT, Perl L. Implantable Hemodynamic monitoring for heart failure patients. J Am Coll Cardiol 2017;70:389–98. https://doi.org/10.1016/j.jacc.2017.05.052; PMID: 28705321. 18. Del Trigo M, Bergeron S, Bernier M, et al. Unidirectional left-toright interatrial shunting for treatment of patients with heart failure with reduced ejection fraction: a safety and proof-ofprinciple cohort study. Lancet 2016;387:1290–7. https://doi. org/10.1016/S0140-6736(16)00585-7; PMID: 27025435. 19. Sondergaard L, Reddy V, Kaye D, et al. Transcatheter treatment of heart failure with preserved or mildly reduced

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ejection fraction using a novel interatrial implant to lower left atrial pressure. Eur J Heart Fail 2014;16:796–801. https://doi. org/10.1002/ejhf.111; PMID: 24961390. Hasenfuss G, Hayward C, Burkhoff D, et al. A transcatheter intracardiac shunt device for heart failure with preserved ejection fraction (REDUCE LAP-HF): a multicentre, open-label, single-arm, phase 1 trial. Lancet 2016;387:1298–304. https://doi. org/10.1016/S0140-6736(16)00704-2; PMID: 27025436. Feldman T, Mauri L, Kahwash R, et al. Transcatheter interatrial shunt device for the treatment of heart failure with preserved ejection fraction (REDUCE LAP-HF I [Reduce Elevated Left Atrial Pressure in Patients With Heart Failure]): a phase 2, randomized, sham-controlled trial. Circulation 2018;137:364–75. https://doi.org/10.1161/CIRCULATIONAHA.117.032094; PMID: 29142012. Amat-Santos IJ, Bergeron S, Bernier M, et al. Left atrial decompression through unidirectional left-to-right interatrial shunt for the treatment of left heart failure: first-inman experience with the V-Wave device. EuroIntervention 2015;10:1127–31. https://doi.org/10.4244/EIJY14M05_07; PMID: 24832489. Hershberger RE, Nauman D, Walker TL, et al. Care processes and clinical outcomes of continuous outpatient support with inotropes (COSI) in patients with refractory endstage heart failure. J Card Fail 2003;9:180–7. https://doi.org/10.1054/ jcaf.2003.24; PMID: 12815567. Rogers JG, Butler J, Lansman SL, et al. Chronic mechanical circulatory support for inotrope-dependent heart failure patients who are not transplant candidates: results of the INTrEPID Trial. J Am Coll Cardiol 2007;50:741–7. https://doi. org/10.1016/j.jacc.2007.03.063; PMID: 17707178. Mancini D, Lietz K. Selection of cardiac transplantation candidates in 2010. Circulation 2010;122:173–83. https://doi.org/10.1161/CIRCULATIONAHA.109.858076; PMID: 20625142. Miller LW, Guglin M. Patient selection for ventricular assist devices: a moving target. J Am Coll Cardiol 2013;61:1209–21. https://doi.org/10.1016/j.jacc.2012.08.1029; PMID: 23290542. Kirklin JK, Naftel DC, Pagani FD, et al. Seventh INTERMACS annual report: 15,000 patients and counting. J Heart Lung Transplant 2015;34:1495–504. https://doi.org/10.1016/ j.healun.2015.10.003; PMID: 26520247. Feldman D, Naka Y, Cabuay B, et al. 241 A wireless hemodynamic pressure sensor before and after ventricular assist device placement: a sub-study of the CHAMPION trial.

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33. M  eeker M. Internet Trends 2017. Presented at Code Conference, 31 May 2017. Available at: www.kleinerperkins. com/perspectives/internet-trends-report-2017 (accessed 4 October 2018). 34. Saxon LA. Mobile health application solutions. Circ Arrhythm Electrophysiol 2016;9:e002477. https://doi.org/10.1161/ IRCEP.115.002477; PMID: 26810595. 35. Peden CJ, Saxon LA. Digital technology to engage patients: ensuring access for all. NEJM Catalyst 9 September 2017. Available at: https://catalyst.nejm.org/digital-healthtechnology-access (accessed 4 October 2018). 36. Food and Drug Administration. Confirm Rx™ Insertable Cardiac Monitor (ICM) System, Model DM3500. Letter to St Jude Medical, 29 September 2017. Available at: www.accessdata.fda.gov/ cdrh_docs/pdf16/K163407.pdf (accessed 4 October 2018). 37. Adamson PB, Abraham WT, Stevenson LW, et al. Pulmonary artery pressure-guided heart failure management reduces 30–day readmissions. Circ Heart Fail 2016;9:e002600. https://doi.org/10.1161/CIRCHEARTFAILURE.115.002600; PMID: 27220593.

38. J ermyn R, Alam A, Kvasic J, et al. Hemodynamic-guided heart-failure management using a wireless implantable sensor: infrastructure, methods, and results in a community heart failure disease-management program. Clin Cardiol 2017;40:170-6. https://doi.org/10.1002/clc.22643; PMID: 27878990. 39. Yu CM, Wang L, Chau E, et al. Intrathoracic impedance monitoring in patients with heart failure: correlation with fluid status and feasibility of early warning preceding hospitalization. Circulation 2005;112:841–8. https://doi. org/10.1161/CIRCULATIONAHA.104.492207; PMID: 16061743. 40. AliveCor. AliveCor data yield reaches 25mm ECGs largest data set of any consumer ECG device. Press release, 5 April 2018. Available at: www.alivecor.com/press/press_release/alivecordata-yield-reaches-25mm-ecgs (accessed 4 October 2018). 41. Saxon LA, Varma N, Epstein LM, et al. Factors influencing the decision to proceed to firmware upgrades to implanted pacemakers for cybersecurity risk mitigation. Circulation 2018;138:1274–6. https://doi.org/10.1161/ CIRCULATIONAHA.118.034781; PMID: 29748188.

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CSI FOCUS D-HF

DEVICE THERAPIES FOR HEART FAILURE DECEMBER 14 –15, 2018 FRANKFURT, GERMANY Join us at this unique meeting! Sessions include novel therapies for heart failure, ranging from telemedicine and neuromodulation to device-based volume management, valves and LV reconstruction. DEVICE DEVELOPMENT WORKSHOP Friday, 14 December 15:10 - 19:00 Real-world experience and practical advice with VCs, engineers and start-up entrepreneurs www.csi-congress.org/dhf/ddw COURSE DIRECTORS Horst Sievert, MD, Frankfurt, Germany Navin Kapur, MD, Boston, USA Stefan Anker, MD, Berlin, Germany William T. Abraham, MD, Columbus, USA

Register now at:

www.csi-congress.org/dhf 10% off registration fees with ‘DHFAER’

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The British Heart Rhythm Society is proud to partner AER in its effort to inform, educate and support clinicians with an interest in heart rhythm management.

We would encourage readers to become members. Membership is only £60 a year (£40 for nurse or trainee members). By joining the BHRS you are both supporting and being a member of the British heart rhythm community. You also have the following benefits:

Access to BHRS members areas on the website. This contains:

• Educational material like our monthly ECG and electrograms cases • Business cases, job descriptions and standard operating procedures – why do the work yourself when another member has already done it for you? • Slide presentations

Representation at the top level of UK and European health care.

The BHRS has advises the UK government on health care issues, training and policy related to heart rhythm care. We have a seat on the European Heart Rhythm Association national society working groups and the British Cardiovascular Society • Cardiac physiologist influence and representation at the Academy of Healthcare Science (AHCS), National School of Healthcare Science (NSHCS) and Improving Quality in Physiological Services (IQIPS) professional boards • Gaining and maintaining BHRS certification in Devices, Electrophysiology and Nursing/Clinical certification • Discounted rates for Heart Rhythm Congress (Membership fee is taken off the registration fee to attend) • A chance to influence BHRS by voting in council elections, and standing for office (council minutes are published openly on our website) • Access and support from a multidisciplinary council with the ability to raise concerns and voice opinion regardless of profession. We also regularly offer advice to our members who have professional concerns or challenges

To become a member go to our website http://www.bhrs.com/how-to-join

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