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Arrhythmia & Electrophysiology Review Volume 7 • Issue 3 • Summer 2018

Volume 7 • Issue 3 • Summer 2018

www.AERjournal.com

Practical Guide to Ablation for Epicardial Ventricular Tachycardia: When to Get Access, How to Deal with Anticoagulation and How to Prevent Complications Ramanan Kumareswaran and Francis E Marchlinski

Arrhythmogenic Inflammatory Cardiomyopathy: A Review Brenton S Bauer, Anthony Li and Jason S Bradfield

Long-QT Syndrome and Competitive Sports Frédéric Schnell, Nathalie Behar and François Carré

Transvenous Lead Extractions: Current Approaches and Future Trends Adryan A Perez, Frank W Woo, Darren C Tsang and Roger G Carrillo

A

Complex Fractioned Atrial Electrogram and Dominant Frequency Maps During AF

B

C

Classification Schema of AiC

Laserballoon ablation device’

ISSN – 2050-3369

Radcliffe Cardiology

Lifelong Learning for Cardiovascular Professionals

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Further Insight, Further Efficiency in mapping all your complex arrhythmias *In a single center study, after the first ablation set **Compared to the focal ablation catheter §Ischemic ventricular tachycardia in a single center study 1. Luther. V. et al. A Prospective Study of Ripple Mapping in Atrial Tachycardias. CIRCEP. 2016 2. Body Surface Morphology Matching Pre-Clinical Evidence Report. Test report: REP9819. June 2017 3. Imanli, H. et al, A Novel CARTO® Segmentation Software for Contrast enhanced Computed Tomography guided radiofrequency ablation in patients with atrial fibrillation. HRS poster. 2016 4. Jaïs, P. et al. Impact of New Technologies and Approaches for Post–Myocardial Infarction Ventricular Tachycardia Ablation During Long-Term Follow-Up. Circep. 2016 These products can only be used by healthcare professionals in EMEA. Important information: Prior to use, refer to the instructions for use supplied with this device for indications, contra-indications, side effects, warnings and precautions. The medical device herein mentioned is a class IIA and a regulated health product which bears the CE-Mark CE0344 (DEKRA). Manufacturer: Biosense Webster (Israel) Ltd. 4 Hatnufa Street Yokneam 2066717, ISRAEL EU Authorised Representative: Biosense Webster A Division of Johnson & Johnson Medical NV/SA Leonardo da Vincilaan 15, 1831 Diegem, BELGIUM © Johnson & Johnson Medical NV/SA 2018 | 078508-170813

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Volume 7 • Issue 3 • Summer 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

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

Richard Schilling Barts Health NHS Trust, London, UK

St George’s University of London, UK

Cecilia Linde

Riccardo Cappato

Karolinska University, Stockholm, Sweden

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

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 Catherine Hyland • 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 •

Editorial Contact Catherine Hyland catherine.hyland@radcliffe-group.com Circulation & Commercial Contact David Ramsey 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 that 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

© RADCLIFFE CARDIOLOGY 2018

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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: Summer 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 Catherine Hyland for further details at catherine.hyland@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

Cardiology

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11/08/2018 11:14


Lugano

Meeting of the 24th Scientific International Society of

Cardiovascular Pharmacotherapy (ISCP) Palazzo dei Congressi, Lugano, Switzerland

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The Polypill: A simple, inexpensive approach to reduce mortality and morbidity worldwide

A changing paradigm in management of dyslipidaemia

Atrial fibrillation Chronic heart failure: a paradigm shift

The emerging role of PCSK9 inhibitors after Odyssee

Acute heart failure

Anti-inflammatory treatment

How low to go with glucose, cholesterol and blood pressure in primary prevention of CVD

Medical vs invasive treatment strategies in stable CAD

Diabetes and cardiovascular disease

Emerging indications for new oral anticoagulation in CAD For information about the scientific programme, abstract submission, registration, accommodation and travelling to Lugano, visit

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Contents

Foreword

153

Preprints and STM publishing: A New Challenge to the Editors of Scientific and Medical Journals Demosthenes Katritsis, Editor-in-Chief

Guest Editorial

156

Progress Continues in Our Quest to Cure All Types of Cardiac Arrhythmias with Catheter Ablation Hugh Calkins

Expert Opinions

157

Do We Need an Implantable Cardioverter-defibrillator for Primary Prevention in Cardiac Resynchronisation Therapy Patients? Demosthenes G Katritsis and Angelo Auricchio

Clinical Reviews: Electrophysiology and Ablation

159

Practical Guide to Ablation for Epicardial Ventricular Tachycardia: When to Get Access, How to Deal with Anticoagulation and How to Prevent Complications Ramanan Kumareswaran and Francis E Marchlinski

165

Source Determination in Atrial Fibrillation

169

The Impact of Advances in Atrial Fibrillation Ablation Devices on the Incidence and Prevention of Complications

Rakesh Latchamsetty and Fred Morady

Fehmi Keçe, Katja Zeppenfeld and Serge A Trines

Clinical Reviews: Clinical Arrhythmias

181

Arrhythmogenic Inflammatory Cardiomyopathy: A Review

187

Long-QT Syndrome and Competitive Sports

193

Heart Rate Variability: An Old Metric with New Meaning in the Era of using mHealth Technologies for Health and Exercise Training Guidance. Part One: Physiology and Methods

Brenton S Bauer, Anthony Li and Jason S Bradfield Frédéric Schnell, Nathalie Behar and François Carré

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

Clinical Reviews: Drugs and Devices

199

Mechanisms Underlying the Actions of Antidepressant and Antipsychotic Drugs That Cause Sudden Cardiac Arrest Serge Sicouri and Charles Antzelevitch

210

Transvenous Lead Extractions: Current Approaches and Future Trends Adryan A Perez, Frank W Woo, Darren C Tsang and Roger G Carrillo

Letters

218

Letter to the Editor: His Bundle Pacing: A New Frontier in the Treatment of Heart Failure

218

Authors’ Reply: His Bundle Pacing: A New Frontier in the Treatment of Heart Failure

150

AER_7.3 CONT.indd 150

Theodoros Zografos Ahran Arnold, Nadine Ali, Daniel Keene, Mathew Shun-Shin, Zachary Whinnett and SM Afzal Sohaib

© RADCLIFFE CARDIOLOGY 2018

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Foreword

Preprints and STM publishing: A New Challenge to the Editors of Scientific and Medical Journals

A

PubMed search conducted on the 5th of July, 2018, reveals 111 articles for the word ‘preprint’. How exactly does one define a preprint? Preprints are online postings of scientific reports in a publicly accessible online venue, hosted by

not for profit preprint servers or repositories such as BioRxiv.org or arXiv.org, allowing authors to self-archive papers pre-peer review and before official publication in a journal. Preprint content has not undergone prior independent scientific evaluation. Preprint servers offer a relatively new service within the context of opportunities offered by our interconnected, digitised publishing environment. Through facilitating the rapid dissemination of innovative STM research, preprint servers and repositories allow

researchers and physicians to bring medical research to the light of day and to a wide audience, given that preprint content can be shared without being subject to any publication delays. Preprints have gained popularity with eminent investigators and scientists, and in a recent publication the editors of Circulation announced their willingness to allow preprints to be cited in works during an initial submission to the journal. I have expressed my concerns in a letter to the editors of Circulation,1 who have kindly responded offering their arguments in favour of preprints.2 I believe that reproduction of the two articles creates the environment for furthering a very much needed discussion on the potential merits and dangers of this new and burgeoning trend within STM publishing. n Demosthenes G Katritsis Editor-in-Chief, Arrhythmia and Electrophysiology Review Hygeia Hospital, Athens, Greece

1. 2. 3.

Katritsis DG. Preprints and cardiovascular science: prescient or premature? Circulation. 2018;137:1641–1642. DOI: 10.1161/CIRCULATIONAHA.117.032128 Nallamothu BK, Hill JA. Response by Nallamothu and Hill to Letter by Katritsis in response to ‘Preprints and cardiovascular science: prescient or premature?’ Circulation. 2018;137:1643–1644. DOI: 10.1161/CIRCULATIONAHA.118.032880 April 10, 2018 Nallamothu BK, Hill JA. Preprints and cardiovascular science: prescient or premature? Circulation. 2017;136:1177–1179. doi:10.1161/CIRCULATIONAHA.117.031238

https://doi.org/10.15420/aer.2018.7.3.FO

© RADCLIFFE CARDIOLOGY 2018

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Foreword

Letter to the Editor by Katritsis Regarding Article, “Preprints and Cardiovascular Science: Prescient or Premature?”

Citation: 2018;137:1641–1642. DOI: 10.1161/CIRCULATIONAHA.117.032128x April 10, 2018 1641

To the Editor: I read with great interest indeed the recent editorial by Nallamothu and Hill1 on the issue of preprints. With all due respect to our esteemed colleagues, I beg to differ. Preprints are online postings of scientific reports in a public venue (see BioRxiv.org or arXiv. org) before their official publication in a journal and without prior independent scientific evaluation. The Royal Society, one of the oldest learned societies on the planet, was founded in London in 1660, after >2000 years of periods of “barbarism and religion,” as Edward Gibbon has famously put it, since Plato’s Academia and Aristotle’s Lyceum. Henry Oldenburg was the first secretary of the Royal Society and the founding editor of the Philosophical Transactions of the Royal Society. As a theologian and natural philosopher, he did not feel qualified to judge all submitted papers, and thus he relied on the judgment of experts in relevant fields. This was the introduction of the peer review system that has endured the test of time for centuries during which publication was subjected to the time constraints of printed material. Of course, we now live in a revolutionary era regarding information dissemination, and our digital world calls for adaptation.2 However, this new unlimited freedom is haunted by the ghost of its inherent lack of verification and accountability. We are all familiar with the discussions on the potential role of Facebook in the recent US presidential elections.3 Regardless of whether it is true, the debate emphasizes the impact of the current digital environment of unrestricted dissemination of news, accurate or inaccurate, true or fake, in the public sphere. The same could be argued for important medical issues such as vaccines, among numerous others. The issue here is not whether manuscripts posted on preprint servers are considered prior publications, bypassing the Ingelfinger rule that prohibits simultaneous submission to >1 journal. The real issue is that the authors state, “We also will allow preprints to be cited in works (like abstracts) during an initial submission, with authors expected to update the reference once a preprint is accepted for publication at a journal.” What happens if the journal subsequently rejects the paper in the context of flawed methodology or bias that precludes reliable conclusions? There is increasing concern that a substantial amount of current published research findings may be false.4 Do we have to add to this uncertainty that undermines our faith in rationalism in medicine by unequivocally accepting such a new concept? As an editor of a cardiology journal, I find it difficult identify any single article, however high its quality and important its content, as publishable without corrections and revision. Peer reviewing is far from perfect, but at least it creates a barrier against subjective and willful publication. Preprinting may be seen as the unleashing of unlimited, unexamined, and random information on the internet. In a democracy, we cannot and should not prevent this from occurring in the general public. Perhaps we should try to constrain it in science. Demosthenes G Katritsis, Department of Cardiology, Hygeia Hospital, Athens, Greece.

1. 2. 3. 4.

Nallamothu BK, Hill JA. Preprints and cardiovascular science: prescient or premature? Circulation. 2017;136:1177–1179. doi:10.1161/CIRCULATIONAHA.117.031238. Katritsis D. Clinical electrophysiology: a glimpse into the future. Arrhythm Electrophysiol Rev. 2017;6:40. doi: 10.15420/aer.2017:6:2:ED1. Halpern S. How he used Facebook to win. June 8, 2017. http://www.nybooks.com/articles/2017/06/08/how-trump-used-facebook-to-win/. Accessed June 15, 2017. Ioannidis JP. Why most published research findings are false. PLoS Med. 2005;2:e124. doi: 10.1371/journal.pmed.0020124.

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Foreword

Response to Letter to the Editor Response by Nallamothu and Hill to Letter Regarding Article, “Preprints and Cardiovascular Science: Prescient or Premature?”

Citation: 2018;137:1641–1642. DOI: 10.1161/CIRCULATIONAHA.118.032880 April 10, 2018 1643

In Response: We thank Dr Katritsis for his letter on our article on preprints recently published in Circulation and Circulation: Cardiovascular Quality and Outcomes.1,2 We agree with many of his points. Like him, we recognize that we now live in a revolutionary era and the new digital world calls for adaptation beyond old models that have been in place for centuries. Where we tend to disagree, however, is with the potential implications of preprints in this environment. Dr Katritsis is concerned that preprints will add to confusion by not allowing for proper vetting of science before its official dissemination. He seems particularly worried about the use of citations of preprints while also mentioning that papers evolve over time and improve through peer review. These are both fair points. Regarding the question of allowing authors to cite preprints, we are hopeful that readers are sophisticated enough to understand the difference between a preprint citation and a peer reviewed publication. As we mentioned in our article, we see preprints in this regard as analogous to abstracts presented at scientific meetings or unpublished communications — which are occasionally referenced in articles — and we believe readers will also. And, while we wholeheartedly concur (as editors ourselves) that the peer review and editorial process bring enormous value to a paper, we do not see that preprints will diminish this process. It is unlikely in our mind that preprints (at least in the near-term) will lead authors to subvert or bypass journals. Will preprints unleash unlimited, unexamined, and random information in the internet? The concerns raised by Dr Katritsis are real, and we hope at Circulation and Circulation: Cardiovascular Quality and Outcomes to be careful in our experiment with this new approach. But we would point out that many of the examples he has expressed actually occurred despite peer review (eg, vaccines). This serves as a cautious reminder that peer review cannot serve alone as a fortification against inaccurate or fake science. Indeed, it could be that preprints — which are openly available to be examined and reviewed without pay firewalls or restrictions — could aid in the dissemination of science by allowing for a more critical view of reports that are simply taken at face value currently because of their peer-reviewed status. Brahmajee K. Nallamothu, MD, MPH Joseph A. Hill, MD Michigan Integrated Center for Health Analytics and Medical Prediction (MiCHAMP), Department of Internal Medicine, University of Michigan, and the Center for Clinical Management and Research, Ann Arbor VA Medical Center, MI (B.K.N.). Departments of Internal Medicine and Molecular Biology, Divisionof Cardiology, University of Texas Southwestern Medical Center, Dallas, TX (J.A.H.)

1. 2.

Nallamothu BK, Hill JA. Preprints and cardiovascular science: prescient or premature? Circulation. 2017;136:1177–1179. doi: 10.1161/CIRCULATIONAHA.117.031238. Nallamothu BK, Hill JA. Preprints and cardiovascular science: prescient or premature? Circ Cardiovasc Qual Outcomes. 2017;10:e000033. doi: 10.1161/HCQ.0000000000000033.

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Guest Editorial

Progress Continues in Our Quest to Cure All Types of Cardiac Arrhythmias with Catheter Ablation Hugh Calkins John Hopkins Medical Institution, Baltimore, USA

Citation: Arrhythmia & Electrophysiology Review 2018;7(3):156. DOI: https://doi.org/10.15420/aer.2018.7.3.GE1 Correspondence: Hugh Calkins, Professor of Medicine, Director of Electrophysiology, Johns Hopkins Medical Institutions, Baltimore, MD. E: hcalkins@jhmi.edu

I

am pleased to be appointed as AERâ&#x20AC;&#x2122;s section editor for Clinical Electrophysiology and Ablation.

I look forward to working with authors from throughout the world to put together insightful articles that help clinical electrophysiologists globally to keep up with our rapidly advancing field. From my perspective, the only thing that remains constant in our field is continued progress and change. Together, we are working to continuously improve the techniques and outcomes of catheter ablation. After graduating from my cardiology and electrophysiology fellowship at Johns Hopkins, I was fortunate to get a faculty position at the University of Michigan working with Dr Fred Morady. At that point in time radiofrequency (RF) energy had not been identified as an energy source for catheter ablation; direct current (DC) shock ablation, performed under general anaesthesia, was the standard approach for catheter ablation. Moreover, the only arrhythmias that were targets for ablation were ventricular tachycardia, posteroseptal accessory pathways and the atrioventricular (AV) node. The shift to RF energy occurred in 1989 during my first year on faculty at the University of Michigan. It was quickly determined that accessory pathways in all locations could be targeted for ablation, as well as ventricular tachycardia (VT) and the AV node. The next arrhythmia to emerge as a target was AV node re-entry. At first, a fast pathway approach was used. Several years later it was recognised that the posterior approach was associated with improved outcomes. Catheter ablation of atrial flutter was not being performed in 1989 as the re-entry circuit was not fully understood. It was in the early

156

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1990s that the re-entry circuit for typical atrial flutter was determined and, as a result, ablation of this arrhythmia became possible. By the mid 1990s the electrophysiology community was starting to focus on catheter ablation of atrial fibrillation. It was initially believed that ablation in the left atrium was too high risk. But pioneering electrophysiologists helped us move past this barrier. And of course the big breakthrough was identification of the pulmonary veins as the most common site of triggering of atrial fibrillation and also recognition of the importance of an ablation strategy guided by electroanatomic mapping. These seminal discoveries have paved the way for catheter ablation of atrial fibrillation to emerge as a safe and effective ablation procedure. While great progress has been made, much work lies ahead. While for many types of cardiac arrhythmias catheter ablation is a highly efficacious and safe ablation procedure, with little room for further improvement (atrial flutter, accessory pathways, the AV node, premature ventricular contractions (PVCs)), the outcomes of catheter ablation for more complex arrhythmias are modest. High on the list of unmet challenges are catheter ablation of atrial fibrillation and, in particular, persistent atrial fibrillation, catheter ablation of VT in structural heart disease, and catheter ablation of ventricular fibrillation. I remain optimistic that over the next decade we will dramatically improve the outcomes of ablation for these more complex arrhythmias. As progress is made, you can count on AER to provide insightful articles that will keep us all up to date and moving ahead in the rapidly progressing field of Clinical Electrophysiology and Ablation. n

Š RADCLIFFE CARDIOLOGY 2018

11/08/2018 11:21


Expert Opinion

Do We Need an Implantable Cardioverter-defibrillator for Primary Prevention in Cardiac Resynchronisation Therapy Patients? Demosthenes G Katritsis 1 and Angelo Auricchio 2 1. Hygeia Hospital, Athens, Greece; 2. Fondazione Cardiocentro Ticino, Lugano, Switzerland

Keywords Cardiac resynchronisation therapy, sudden cardiac death, non-ischaemic cardiomyopathy, implantable cardioverter-defibrillator Disclosure: The authors have no conflicts of interest to declare. Received: 26 June 2018 Accepted: 26 June 2018 Citation: Arrhythmia & Electrophysiology Review 2018;7(3):157–8. DOI: https://doi.org/10.15420/aer.2018.7.3.EO1 Correspondence: Demosthenes G Katritsis, Hygeia Hospital, Erithrou Stavrous 4, Athens 15123, Greece. E: dkatrits@dgkatritsis.gr

Despite the fact that more than 20 years have passed since the clinical introduction of cardiac resynchronisation therapy (CRT), one of the key questions – do we need an ICD for primary prevention of sudden cardiac death (SCD) in CRT patients? – is still unanswered.

retrospective cohort study using National Cardiovascular Registry data linked with Medicare claims, patients who were eligible for CRT-D according to established criteria and who received CRT-D had significantly lower risks for death and readmission than those who received an ICD therapy alone.6

Prospective Randomised Controlled Trials Multiple prospective randomised controlled trials have been conducted to establish the use of CRT in different categories of heart failure patients; these studies have consistently demonstrated the superiority of CRT compared with best medical therapy in improving ventricular function, the patient’s functional capacity, and prognosis. The greatest majority of prospective randomised controlled studies used a CRT device combined with an ICD (CRT-D). Indeed, past prospective randomised controlled trials of primary prevention in patients with heart failure indicated that ICD reduced mortality in post-MI patients with left ventricular ejection fraction (LVEF) <30 % (Multicentre Automatic Defibrillator Implantation Trial II; MADIT II), 1 and ischaemic or non-ischaemic cardiomyopathy in patients with LVEF <35  % (Sudden Cardiac Death in Heart Failure Trial; SCD-HeFT). 2 In patients with LVEF <35  %, advanced heart failure (New York Heart Association; NYHA class III or IV) due to ischaemic or non-ischaemic cardiomyopathies and a QRS interval >120 ms, the presence of ICD capabilities reduced mortality (Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure trial; COMPANION).3 Of note, the addition of CRT to patients who already require an ICD also reduces mortality. In the Resynchronisation–Defibrillation for Ambulatory Heart Failure Trial (RAFT) in patients with NYHA II or III heart failure, LEVF ≤30 %, and a QRS ≥120 ms or paced QRS ≥200 ms, the addition of CRT to an ICD improved survival, albeit at a cost of increased implantation-related complications (RAFT).4 In the MADIT with Cardiac Synchronisation Therapy (MADIT-CRT), in patients with ischaemic (NYHA I or II) or non-ischaemic (NYHA II) cardiomyopathy, LVEF ≤30  %, and QRS≥ 130 ms with left bundle branch block morphology, CRT offered a 11  % reduction in mortality compared with an ICD alone.5 In a real-world

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Clinical Daily Practice All that, however, contrasts with clinical daily practice in which approximately one-third of patients receive a CRT without an ICD function (CRT-P). The clinical justification to offer a sizable group of patients a CRT-P device is given by the lack of a perceived realistic, additional survival benefit, as provided by an ICD, in addition to what may be achieved by CRT-P alone. Clinical factors possibly associated with higher mortality due to heart failure rather than SCD (the latter can be effectively reduced only by an ICD) are advanced age, cardiovascular comorbidities, some neurological diseases associated with severe cognitive and/or physical impairment, psychiatric disorders, and life expectancy <1 year due to neoplasia. Another key factor that may justify the use of CRT-P instead of CRT-D could be represented by the aetiology, as occurs with nonischaemic cardiomyopathy (NICM). Both the Cardiomyopathy Trial (CAT)7 and Amiodarone Versus Implantable Cardioverter-Defibrillator Trial (AMIOVIRT)8 used single- and dual-chamber ICDs, but neither trial showed any survival benefit of ICDs in patients with NICM. Importantly, these studies involved small numbers of patients. In the Defibrillators in Non-Ischaemic Cardiomyopathy Treatment Evaluation (DEFINITE) study, in which 458 patients with NICM were randomised to medical therapy or an ICD, ICD therapy did not reduce total mortality, despite a significant reduction in SCD.9 In the recent Defibrillator Implantation in Patients With Non-ischaemic Systolic Heart Failure (DANISH) study, neither ICD nor CRT-D reduced total mortality in patients with NICM.10 Notably, only patients aged younger than 68 years had a significant reduction of SCD and overall mortality by CRT-D compared with CRT-P/best medical therapy. These studies cast doubt on the relative benefit of CRT-D versus CRT-P in patients with NICM, despite the promising results in favour of ICD in the non-ischaemic setting by a recent meta-analysis.11

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Expert Opinion New Developments Some recent data by Leyva et al., who evaluated mid-wall cardiac fibrosis by cardiac magnetic resonance, showed that CRT-D was markedly superior to CRT-P in terms of total mortality, cardiovascular mortality, and all composite endpoints in those patients with mid-wall fibrosis, whereas no benefit from CRT-D over CRT-P was observed in those patients without mid-wall fibrosis with respect to any of the endpoints.12 These findings indirectly substantiate the results of a metaanalysis by Disertori et al. indicating that late gadolinium enhancement by cardiac magnetic resonance is a powerful predictor of ventricular arrhythmic risk in patients with ventricular dysfunction, irrespective of aetiology.13 The prognostic power of late gadolinium enhancement is particularly strong in patients with severely depressed ejection fraction, which suggests its potential to improve patient selection for ICD implantation. However, to be put into practice, late gadolinium enhancement protocols need to be standardised with respect to execution modalities and the setting of diagnostic thresholds. New developments may also provide additional data and new insights. The value of electrophysiology testing in assessing the need for an ICD, at

1.

2.

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5.

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7.

 oss AJ, Zareba W, Klein H, et al. Prophylactic implantation M of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med 2002;346:877–83. https://doi.org/10.1056/NEJMoa013474; PMID: 11907286. Bardy GH, Lee KL, Poole JE, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 2005;352:225–37. https://doi.org/10.1056/ NEJMoa043399; PMID: 15659722. Bristow MR, Saxon LA, Boehmer J, et al. Cardiacresynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 2004;350:2140-50. https://doi.org/10.1056/NEJMoa032423; PMID: 15152059. Tang AS, Wells GA, Talajic M, et al. Cardiac-resynchronization therapy for mild-to-moderate heart failure. N Engl J Med 2010;363:2385–95. https://doi.org/10.1056/NEJMoa1009540; PMID: 21073365. Goldenberg I, Kutyifa V, Klein HU, et al. Survival with cardiacresynchronization therapy in mild heart failure. N Engl J Med 2014;370:1694–701. https://doi.org/10.1056/NEJMoa1401426; PMID: 24678999. Masoudi FA, Mi X, Curtis LH, et al. Comparative effectiveness of cardiac resynchronization therapy with an implantable cardioverter-defibrillator versus defibrillator therapy alone: a cohort study. Ann Intern Med 2014;160:603-11. https://doi. org/10.7326/M13-1879; PMID: 24798523. Bansch D, Antz M, Boczor S, et al. Primary prevention of sudden cardiac death in idiopathic dilated cardiomyopathy: the Cardiomyopathy Trial (CAT). Circulation 2002;105:1453–8. https://doi.org/10.1161/01.CIR.0000012350.99718.AD; PMID: 11914254.

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least in the ischaemic setting, continues to be debated.14 Such a possibility could further facilitate the selection of appropriate CRT-D candidates. Recent studies using His bundle pacing could further revolutionise the field of CRT. In some cases, a significant improvement of functional capacity and ventricular function has been observed.15–17 Whether and in which patients His bundle pacing may represent a suitable alternative to CRT remains to be determined. Similarly, whether improvement of the efficacy of CRT will be adequate to refute the need for an ICD in certain patients remains to be seen.

Conclusion Currently, and in the absence of hard data to guide clinical practice in this respect, we have to rely on the recommendations by the 2013 (and 2017) update of the American College of Cardiology/American Heart Association and 2016 European Society of Cardiology guidelines on heart failure, and recommend an ICD, with or without CRT, in patients with non-ischaemic or ischaemic (at least 40 days post-MI) heart failure, LVEF ≤35 %, and NYHA II/III.18,19 n

 trickberger SA, Hummel JD, Bartlett TG, et al. Amiodarone S versus implantable cardioverter-defibrillator: randomized trial in patients with nonischemic dilated cardiomyopathy and asymptomatic nonsustained ventricular tachycardia – AMIOVIRT. J Am Coll Cardiol 2003;41:1707–12. https://doi. org/10.1016/S0735-1097(03)00297-3; PMID: 12767651. Kadish A, Dyer A, Daubert JP, et al. Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy. N Engl J Med 2004;350:2151–8. https://doi. org/10.1056/NEJMoa033088; PMID: 15152060. Kober L, Thune JJ, Nielson JC, et al. Defibrillator implantation in patients with nonischemic systolic heart failure. N Engl J Med 2016;375:1221–30. https://doi.org/10.1056/NEJMoa1608029; PMID: 27571011. Golwala H, Bajaj NS, Arora G, Arora P. Implantable cardioverter-defibrillator for nonischemic cardiomyopathy: an updated meta-analysis. Circulation 2017;135:201–3.https://doi. org/10.1161/CIRCULATIONAHA.116.026056; PMID: 27993908. Leyva F, Zegard A, Acquaye E, et al. Outcomes of cardiac resynchronization therapy with or without defibrillation in patients with nonischemic cardiomyopathy. J Am Coll Cardiol 2017;70:1216–27. https://doi.org/10.1016/j.jacc.2017.07.712; PMID: 28859784. Disertori M, Rigoni M, Pace N, et al. Myocardial fibrosis assessment by LGE Is a powerful predictor of ventricular tachyarrhythmias in ischemic and nonischemic LV dysfunction: a meta-analysis. JACC Cardiovasc Imaging 2016;9:1046–55. https://doi.org/10.1016/j.jcmg.2016.01.033; PMID: 27450871. Katritsis DG, Zografos T, Hindricks G. Electrophysiology testing for risk stratification of patients with ischaemic cardiomyopathy:

15.

16.

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a call for action. Europace 2017. https://doi.org/10.1093/ europace/eux305; PMID: 29236981; epub ahead of press. Hindricks G. Permanent His bundle pacing is associated with reduction in mortality and morbidity compared to right ventricular pacing: results from the Geisinger His Bundle Pacing Registry. Presented at ACC.2018, 10–12 March 2018. Katritsis DG. Choice of ventricular pacing site: the end of nonphysiological, apical ventricular pacing? Arrhythm Electrophysiol Rev 2017;6:159–60. https://doi.org/10.15420/aer.2017.6.4:EO3; PMID: 29326829. Vijayaraman P, Dandamudi G, Zanon F, et al. Permanent His bundle pacing: recommendations from a multicenter His bundle pacing collaborative working group for standardization of definitions, implant measurements, and follow-up. Heart Rhythm. 2018;15:460–8. https://doi.org/10.1016/j. hrthm.2017.10.039; PMID 29107697. 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. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016;37:2129–200. https://doi.org/10.1093/eurheartj/ehw128; PMID: 27206819.

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Clinical Reviews: Electrophysiology and Ablation

Practical Guide to Ablation for Epicardial Ventricular Tachycardia: When to Get Access, How to Deal with Anticoagulation and How to Prevent Complications Ramanan Kumareswaran and Francis E Marchlinski Cardiac Electrophysiology Section, Cardiovascular Division, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA

Abstract Epicardial ablation is needed to eliminate ventricular tachycardia (VT) in some patients with nonischaemic cardiomyopathy. The 12-lead electrocardiogram of VT, pre-procedural imaging and endocardial unipolar voltage maps can predict a high likelihood of epicardial substrate and VT. A septal VT substrate may preclude the need for epicardial access and mapping and can be identified with imaging, pacing and voltage mapping. Pericardial access is usually obtained prior to systemic anticoagulation or after reversal of systemic anticoagulation. A unique set of complications can be encountered with epicardial access, mapping and ablation, which include haemopericardium, phrenic nerve injury, damage to major coronary arteries and pericarditis. Anticipating, preventing and, if necessary, managing these complications are paramount for patient safety. Best practices are reviewed.

Keywords Ventricular tachycardia, voltage mapping, epicardial ablation, electrocardiogram, complications of ventricular tachycardia ablation Disclosure: The authors have no conflicts of interest to declare. Acknowledgement: Support for this effort comes from the Katherine J Miller Research Fund, the Mark Marchlinski EP Research and Education Fund and the Pennsylvania Steel Company EP Research Fund. Submitted: 1 March 2018 Accepted: 10 July 2018 Citation: Arrhythmia & Electrophysiology Review 2018;7(3):159–64. DOI: https://doi.org/10.15420/aer.2018.10.2 Correspondence: Francis Marchlinski, Cardiac Electrophysiology Department, Division of Medicine, University of Pennsylvania Health System, 3400 Spruce Street, 9 Founders Philadelphia, PA 19104-4283, USA. E: Francis.Marchlinski@uphs.upenn.edu

Ventricular tachycardia (VT) is one of the most challenging medical conditions faced by cardiac patients and physicians treating them. Antiarrhythmic medications have limited effectiveness and are frequently poorly tolerated.1–4 Catheter ablation is increasingly used to treat patients successfully.1,5–7 Most VTs can be ablated endocardially but some require epicardial mapping and ablation. Electrophysiologists performing VT ablation need to know when to consider an epicardial approach, how to deal with anticoagulation during the procedure and ‘best’ techniques to minimise risk of procedural complications.

When to Suspect Epicardial Substrate Patients with VT in the setting of ischaemic cardiomyopathy (ICMPY) generally have endocardial substrate that can be eliminated with endocardial radiofrequency lesions. Less commonly a critical component of the circuit is located epicardially in this setting and epicardial access is required. In contrast patients with non-ischaemic left or biventricular cardiomyopathy (NICM), who characteristically have perivalvular substrate, frequently have anatomic changes that either extend to the epicardium or are primarily epicardial in location, and require direct epicardial ablation.7–9 Other disease states with a high propensity for requiring epicardial ablation include patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), cardiac sarcoidosis, Chagas disease and patients with a history of myocarditis.6,7,10–12 Patients with hypertrophic cardiomyopathy are unique in that apical scarring and epicardial substrate can be identified.13 Recently, there is evidence that epicardial right ventricular outflow tract may harbour substrate in patients with Type I Brugada

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syndrome and targeting this region may be beneficial to control VT/VF.14 The presence of any of these aforementioned disease states should raise the suspicion that epicardial m apping and ablation will be required. Pre-procedural planning is essential for any VT ablation. Cardiac imaging is performed most often prior to ablation procedures. Echocardiogram is useful in diagnosing the structural abnormality including regions of abnormal wall motion abnormality. Intracardiac echocardiogram (ICE) is useful during the procedure and can identify the region of abnormal substrate during the procedure (Figure 1). Cardiac MRI (CMR) is the best imaging modality currently available to localise the region of scar defined by late gadolinium enhancement (Figures 2 and 3). Electrophysiologists need to anticipate epicardial ablation when significant scar burden is localised to sub-epicardial or epicardial region. Twelve lead ECG recordings during VT hold vital clues to origin/exit of the VTs. The value of the 12-lead ECG for identifying epicardial origin is more limited in the setting of coronary disease in which the infarct produces activation delay with Q waves. The 12-lead ECG is most effectively applied in patients with idiopathic VT or VT in the setting of NICM to identify a probable epicardial origin. Wave fronts exiting the epicardium take longer to engage His-Purkinje fibres and therefore produce very slurred onset of QRS than wave fronts exiting from the endocardial VT circuits (Figure 4). When VTs exit from an endocardial region there is endocardial to epicardial activation which often forms a small R wave in the leads with the field of view facing the site of exit

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Clinical Reviews: Electrophysiology and Ablation Figure 1: Images from a Patient with Non-ischaemic Cardiomyopathy and Ventricular Tachycardia (VT) Exiting from Epicardium

Figure 3: Patient with Ventricular Tachycardia and an Abnormal Cardiac MRI

Cardiac MRI Abnormal Epi LGE Abnormal Epi Bipolar Voltage

Normal Endo Bipolar Voltage

Normal bipolar endocardial voltage

Abnormal bipolar epicardial voltage

Abnormal Endo Unipolar Voltage

ICE with abnormal brightness in Epi in the region of WMA

Mid Diastolic Potentials during VT become Abnormal Late Potentials with PVC and Sinus Rhythm

Epicardial Ablation with ablator pointing towards the myocardium

Intracardiac echocardiogram (ICE) image showed region of abnormal midmyocardial to epicardial echogenicity in the region of wall motion abnormality (WMA). Exit site of the VT was mapped and successfully ablated in that region.

VT was not inducible from either right ventricular or left ventricular endocardium. VT was easily and repeatedly induced and successfully ablated from right ventricular epicardium. Abnormal EGMs (voltage) were recorded from the right ventricular epicardium (*). Epicardial late potentials became mid diastolic potentials during VT.

Figure 2: Patient with Ventricular Tachycardia and an Abnormal Cardiac MRI

Figure 4: Patient with Non-ischaemic Cardiomyopathy with VT Exiting from Basal to Mid Inferior Wall

Endocardial voltage map

Cardiac MRI

EPICARDIAL VT IN A PATIENT WITH NON-ISCHAEMIC CARDIOMYOPATHY Exit site identified in the Epicardium -> 75 ms pre-QRS, confirmed with Entrainment

QS in Inf leads

Epicardial voltage map

Epicardial scar TMD QRSd

VT morphology meets the criteria for epicardial exit with initial slurring of QRS. QS pattern is seen in inferior leads. Maximum deflection index (MDI) ≥0.55. Normal bipolar endocardial voltage is seen but epicardial bipolar voltage was abnormal. Region of mid-myocardial to epicardial late gadolinium enhancement (LGE) corresponded with region of abnormal potentials/voltage.

(Figure 5). An epicardial origin in patients with VT in the setting of NICM can produce a Q wave.15 Most of the criteria used to identify epicardial VTs is either interval or morphologic criteria. Slurring in the initial portion of QRS is identified with pseudo delta wave ≥34 ms, intrinsicoid deflection ≥85 ms and shortest RS complex in precordial leads ≥121 ms (Figure 4).16 Maximum deflection index (MDI) is calculated by dividing the shortest QRS onset to earliest maximum precordial deflection by total QRS duration. MDI values ≥0.55 also suggest epicardial idiopathic VT.15 A Q wave in lead I suggests that the VT is from superior left lateral LV epicardium while Q waves in II, aVF, III suggest that the VT may be from inferior epicardium (Figure 5).15 QS complexes in V2 can be seen with anterior epicardial exit originating from the LV summit region right under the region of the V2 lead.17 We routinely start the case mapping endocardially given the fact that many of the VTs originate from the endocardium or the circuit shares

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endo and epicardial components and the recognised challenges and possible complications faced with epicardial access and ablation. Endocardial voltage maps carry pertinent information about mid/ epicardial substrate. Unipolar electrograms have a larger field of view compared to bipolar electrograms. This difference can be utilised to identify epicardial and midmyocardial substrate (Figures 1, 6 and 7). Normal unipolar voltage criteria were defined for left ventricle and right ventricular free wall, which are greater than 8.3 mV and 5.5 mV, respectively.18,19 Epicardial or midmyocardial scar is suspected when an area of unipolar abnormality is seen overlying normal bipolar voltage. A lower cut-off should be used when trying to identify deeper layers of scar through abnormal myocardium.11 Knowing when not to attempt epicardial ablation is as important as knowing when to attempt it in patients with non-ischaemic cardiomyopathy. When the endocardial voltage map suggests septal involvement and VT morphologies are consistent with either exiting

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Ablation for Epicardial Ventricular Tachycardia from the septum or adjacent to the septum either superiorly and/or inferiorly, then an epicardial approach for ablating those intraseptal arrhythmias will not be successful. Trans-septal activation time measures the time taken to activate the opposite side of the septum from the site of pacing. Trans-septal activation time of more than 40 ms was specific for intramural conduction delay and the presence of intramural substrate.20 Occasionally complete compartmentalisation of right and left ventricular septum can occur and activation from right to left basal septum has to travel from RV base to normal apical region down the RV septum and then return up the left side of the septum from apex to base resulting in delayed activation over 90 ms in duration.20 Left ventricular summit location is another challenging anatomic location with limited success rate with epicardial ablation. Ablation from the coronary venous anatomy may be limited by proximity to the coronary artery at the earliest site of activation in the distal great cardiac vein (GCV) or the anterior interventricular vein (AIV). Importantly, epicardial ablation targeting idiopathic VTs from the LV summit will frequently be limited by large proximal coronary arteries and a thick layer of fat and frequently ablation from adjacent endocardial aortic root or endocardium is preferred.21 Ablation from left ventricular endocardium or leftward aspect of right ventricular outflow tract will be ineffective if at a distance of more than 13 mm to the earliest site of activation in the coronary venous anatomy. VT from the more apical and lateral aspect of LV summit can be targeted epicardially. Successful sites met two out of three VT morphology criteria: 1) Q wave amplitude ratio in aVL/aVR >1.85; 2) R/S ratio >2 in V1; 3) no initial Q wave in V1.22

How to Deal with Anticoagulation During Epicardial Procedure Guidelines recommend that pericardial access be obtained prior to systemic anticoagulation or after reversal of systemic anticoagulation.23 There are observational data for safely performing pericardial access in heparinised patients at high volume centres with experienced operators.24,25 However, the authors caution against such an approach until further studies with larger patient populations are available. Anticoagulation can be administered to allow further endocardial mapping and ablation if pericardial entry is achieved without bleeding or with modest bleeding that stops. Continued monitoring for pericardial bleeding is warranted after anticoagulation. Our target ACT for right-sided endocardial ablation is around 250–300 s and left-sided endocardial ablation is 300–350 s with a target of 350s needed if long sheaths are used in the arterial system.

How to Obtain Percutaneous Epicardial Access Subxyphoid percutaneous epicardial access for VT ablation was first popularised by Sousa and colleagues.26 Their technique is the most widely used to obtain percutaneous epicardial access with minor variations by individual electrophysiologists. We perform subxyphoid pericardial puncture with a 17G-Tuohy needle with few modifications to the original description. The patient is generally placed under general anaesthesia for comfort and safety but can be done under sedation as long as the patient is comfortable without major movements. The starting place for entrance into the skin is approximately 1 cm below the subxyphoid process for an anterior approach and right under the rib margin adjacent to the xyphoid for a posterior approach. Local anaesthesia is administered in this region. Next, a decision needs to be made whether to enter the pericardium with an anterior approach or a posterior approach. Entering the pericardium away from ablation

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Figure 5: ECG clues for Epicardial versus Endocardial Exit Epicardial exit from Superior LV

Endocardial exit from Superior LV Lead I rS pattern

Lead I QS pattern

Epicardial exit from Inferior LV

Endocardial exit from Inferior LV

Inferior Leads QS pattern

Inferior leads rS pattern

QS pattern in I suggests VT exiting from superior left ventricular epicardium. QS pattern in inferior leads suggests VT exiting from inferior epicardium.

Figure 6: Patient with Non-ischaemic Cardiomyopathy with Larger Region of Unipolar Abnormality than Bipolar Abnormality

VT – QS in Lead I

Best Pacemap

Larger region of unipolar abnormality than bipolar abnormality 3 Fr Decapolar in AIV

QS pattern is seen in lead I, suggesting superior left ventricular epicardial exit site. Best pace map was found while pacing from the 3F decapolar catheter in anterior interventricular vein (AIV).

target sites is favourable for catheter manipulation and stability. The anterior approach involves a shallow angle to the skin and the posterior approach involves a deeper angle. Steep left lateral fluoroscopic views for an anterior approach and a left anterior oblique (LAO) and right anterior oblique (RAO) fluoroscopic views for a posterior approach help target the region of entry safely. RAO view locates the needle in the bas to apical axis (Figure 8A). LAO view marks the direction of the needle in anterior to posterior axis (Figure 8B). It is generally safer to enter away from the base where major epicardial coronary arteries are found. Distal left anterior descending artery is found at the apex and therefore targeting just posterior to the middle of the base to apical axis may be the safest approach. The Tuohy needle can be placed on the patient with the tip pointing towards the left shoulder and a brief fluoroscopic imaging in RAO projection will assess the angle of entry in the base to apical axis. Lifting the needle up and performing LAO fluoroscopy can assess

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Clinical Reviews: Electrophysiology and Ablation Figure 7: Patient with Non-ischaemic Cardiomyopathy with VT Exiting from Basal to Mid Inferior Wall (see Figure 4) 33 ms Pre-QRS in Anterior Interventricular Vein

RAO

3 Fr Decapolar in AIV

6 Fr Decapolar in AL branch

Ablator endocardially opposite AIV–> not early

LAO Pre QRS EGM was seen in the decapolar catheter in anterior interventricular vein (AIV). Ablator placed endocardially opposite the epicardial site did not show any early activation.

Figure 8: Patient with History of Previous Epicardial Ablation and Significant Adhesions Underwent an Epicardial Ablation Procedure B LAO

C

A RAO

LAO

A: RAO projection as the guidewire is advanced over a Tuohy needle. Notice the significant coiling of guidewire due to adhesions. Pericardial silhouette is identified by yellow interrupted line. Base/apex axis is identified by bidirectional solid yellow arrow. Entrance of the needle into the pericardial space is in the middle of the base/apex axis. White arrow identifies the direction of the guidewire through the needle. B: LAO projection in the same patient. Directions needed to take anterior and posterior approaches are shown with yellow solid arrows. Posterior approach is taken for this patient. White arrow identifies the direction of the guidewire out of the needle. C: LAO projection with guidewire advanced furthermore and starting to cross multiple chambers that do not share any valves.

the approximate angulation needed in anterior to posterior axis. Once the preliminary ‘best’ direction needed is assessed, the needle can then be advanced through the skin to the outer silhouette of the heart for few millimetres followed by removal of the stylet from the needle. At this point, a long guidewire is advanced through the needle. Small changes in the needle direction can be made as needed but we would recommend removing the needle all the way out of the body before major changes in the angle to prevent lacerating abdominal structures. The needle is advanced in small increments during expiration held 2/3 inspiratory effort when the patient is under general anaesthesia and the guidewire advanced out of the needle

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as soon as the needle penetrates the silhouette. When the needle reaches the heart border, ventricular pulsations will be transmitted from the needle tip. Premature ventricular contractions may also be seen. At this point a small contrast injection via the needle is optional and can identify tenting of the pericardium. Advancing the needle slightly with immediate advancing of the guidewire will safely obtain pericardial access. Often a ‘pop’ sensation is felt as the needle crosses the parietal pericardium similar to that noted when performing transseptal puncture. Slight withdrawal of the needle once the guidewire is clearly within the pericardial space as one feels the ‘pop’ may reduce the risk of ventricular wall laceration. Most of the long guidewire should be advanced all around the pericardium. Fluoroscopy is used to identify the guidewire crossing multiple chambers that don’t share valves to rule out entrance in to the cardiac chambers. This is usually easiest to appreciate in the LAO projection as the wire will outline the silhouette of the heart border. Intracardiac echocardiography can be used to identify the guidewire in the pericardial space and to confirm that it is not in the cardiac chambers. At this point, a long sheath can be advanced over the guidewire. Deflectable sheaths can be useful during mapping and ablation in the pericardial space. The mapping and ablation catheters are advanced to the pericardium though the sheath to perform mapping and ablation. Epicardial voltage maps need to be interpreted with caution. Dense epicardial fat decreases the voltage but the myocardium below it could be completely normal. These regions of dense fat are often found at the base of the heart and along major branches of the epicardial coronary arteries. Late potentials and abnormally fractionated electrograms are not normal and often represent a region of abnormal conduction and scar. The direction of the ablator is important when assessing voltage and or ablation. The mapping or ablation catheter needs to point towards the visceral pericardium and away from the parietal pericardium during mapping and ablation. Epicardial fat can also impede lesion delivery to the myocardium of interest. The ablation catheter energy delivery electrode can heat up quickly and reach a temperature cut off and limit power delivery due to lack of blood flow in the pericardium. Therefore, cooling the ablator tip with irrigation is recommended to deliver adequate power. The irrigation rate may not need to be as high as required in the endocardium and care must be maintained to adequately drain accumulating fluid to prevent cardiac compression.

How to Prevent and Manage Common Complications Bleeding Haemopericardium is a common adverse event seen with pericardial access, ranging from 5 % up to 30  % reported in literature.27,28 Pericardial bleeding can be categorised into early bleeding, bleeding during mapping and bleeding at the end of the procedure. Right ventricular puncture/laceration, coronary vessel puncture/ laceration, and/or adhesion disruption are common reasons for early haemopericardium. Bleb rupture, multiple punctures especially in the setting of anticoagulation and steam pops with RF ablation can cause bleeding during mapping and ablation. Double right ventricular perforation could lead to extensive bleeding when the sheath is removed at the end of the case. Prompt diagnosis, assessment of extent of bleeding and strategy for containing or fixing the cause is critical and can be life-saving. As such, ICE plays a crucial role for identifying and managing this complication in our laboratory (Figure 1). ICE can identify the location

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Ablation for Epicardial Ventricular Tachycardia of guidewire when gaining initial access. Inadvertent puncture of the right ventricle is easily diagnosed when the guidewire is seen in RV with ICE. Most bleeding with RV punctures from the access needle stop bleeding without any intervention as long as the sheath is not advanced over the guidewire into the RV. Lacerations are more likely to continue to bleed and require surgical intervention. Similarly, most small vessel punctures or adhesion disruptions also stop bleeding without major intervention other than aspiration of the blood from the pericardial space. Major vessel puncture or chamber laceration requires cardiac surgery or interventional cardiology. For these reasons we recommend epicardial ablation to be done only when surgical backup is available. Each electrophysiology (EP) laboratory needs to have rapid anticoagulation reversal and blood transfusion protocols in anticipation of potential major bleeding complications. Despite taking all the necessary precautions, occasionally surgical rescue is warranted to fix a complication. Electrophysiologists are advised to take this opportunity to perform intraoperative surgical ablation once the acute bleeding problem is managed and stability is restored. Prior coronary artery bypass surgery is a relative contraindication for epicardial ablation unless coronary anatomy is well defined and access to the VT circuit on the opposite side of the heart is possible. Prior cardiac valvular surgery is also a relative contraindication given the potential for significant adhesions that limit access and even if obtained, limits the ability to map freely.29 Repeated epicardial ablations and history of myopericarditis can lead to significant adhesions as well.29 Pericardial window by surgeons might be a safer approach when significant adhesions are anticipated.30 Hypotension during epicardial ablation requires close attention. The differential for hypotension includes tamponade, ECG changes or new wall motion abnormalities suggestive of coronary artery damage, drug reaction or anaesthesia-related complications. Intra-abdominal bleeding should be suspected when all of these are ruled out.

The course of the left phrenic nerve needs to be identified prior to performing epicardial ablation. High output pacing, 20–50 mA at 2 ms pulse width, is used to identify the region of phrenic nerve capture on the electroanatomical map.31 When the critical region for VT circuit is adjacent to the phrenic nerve, the phrenic nerve in the parietal pericardium can be displaced by inflating a pericardial balloon prior to ablation.32 Instillation of air or saline can also displace the phrenic nerve from the ablation target site.32 The left phrenic nerve can be captured by pacing from the left subclavian vein.33 Constant phrenic capture can be demonstrated and monitored while ablating in proximity to the nerve but persistent capture with pacing at low output warrants manipulation of the phrenic nerve away from the epicardial surface.

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Ablating close to coronary arteries may lead to acute or chronic damage to these vessels.34 A coronary angiogram is routinely performed to outline the location of major epicardial vessels relative to the region of interest. The EHRA/ESC/ACC/HRS/AHA consensus statement on VT ablation recommends a distance of at least 5 mm away from coronary vessel for ablation before ablation is considered.24 Multiple angiographic views are recommended to assess the distance appropriately. Realtime integration of multidetector CT-derived coronary anatomy and CARTO-UNIVU has been utilised to better integrate the coronary anatomy with the electroanatomical map.

Pericarditis Pericarditis is the most common adverse event of epicardial ablation. Adequate pain control immediately post procedure is required to minimise patient discomfort. Intrapericardial steroid injection at the end of the case has minimised pericarditis in in vivo animal studies35 and is commonly administered at a dose of 2–3 mg/kg of triamcinolone.

Conclusion Epicardial ablation is frequently required to control VTs in patients who harbour epicardial substrate and VT circuit. It can be safely performed by experienced electrophysiologists with adequate surgical backup to manage uncommon bleeding emergencies. Preprocedure planning is mandatory to anticipate when to perform epicardial ablation and possible challenges and contraindications for the procedure. Awareness of procedure-related complications and techniques for their management including haemopericardium, intra-abdominal bleeding, damage to intra-abdominal organs, phrenic nerve injury, damage to coronary vessels and pericarditis helps to prevent these complications and manage patients safely during ablation when these complications do occur. n

Clinical Perspective

Phrenic Nerve

 app JL, Wells GA, Parkash R, et al. Ventricular tachycardia S ablation versus escalation of antiarrhythmic drugs. N Engl J Med 2016;375:111–21. https://doi.org/10.1056/NEJMoa1513614; PMID: 27149033. 2. Connolly SJ, Dorian P, Roberts RS, et al. Comparison of beta-blockers, amiodarone plus beta-blockers, or sotalol for prevention of shocks from implantable cardioverter defibrillators: the OPTIC Study: a randomized trial. JAMA 2006;295:165–71. https://doi.org/10.1001/jama.295.2.165; PMID: 16403928. 3. Gula LJ, Doucette S, Leong-Sit P, et al. Quality of life with ablation or medical therapy for ventricular arrhythmias: A substudy of VANISH. J Cardiovasc Electrophysiol 2018;29:1–14. https://doi.org/10.1111/jce.13419; PMID: 29316012. 4. Deyell MW, Steinberg C, Doucette S, et al. Mexiletine or catheter ablation after amiodarone failure in the VANISH trial. J Cardiovasc Electrophysiol 2018;1–6. https://doi.org/10.1111/

Epicardial Coronary Arteries

5.

6.

7.

1. P  reprocedural planning and preparation may identify the need for epicardial ablation for successful control of ventricular tachycardia with catheter ablation especially in patients with non-ischaemic cardiomyopathy. 2. Twelve-lead electrocardiogram of ventricular tachycardia and ventricular bipolar and unipolar voltage maps contain valuable information to suggest epicardial exit and/or site of origin of ventricular tachycardia. 3. Understanding, anticipating and preventing potential complications is vital for a successful and safe procedure when epicardial mapping and ablation is performed.

jce.13431; PMID: 29356207. Tung R, Vaseghi M, Frankel DS, et al. Freedom from recurrent ventricular tachycardia after catheter ablation is associated with improved survival in patients with structural heart disease: an international VT ablation center collaborative group study. Heart Rhythm 2015;12(9):1997–2007. https://doi.org/10.1016/j.hrthm.2015.05.036; PMID: 26031376. Santangeli P, Zado ES, Supple GE, et al. Long-term outcome with catheter ablation of ventricular tachycardia in patients with arrhythmogenic right ventricular cardiomyopathy. Circ Arrhythm Electrophysiol 2015;8:1413–21. https://doi.org/10.1161/ CIRCEP.116.004333; PMID: 27516457. 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:pii: e004328. https://doi.org/10.1161/

CIRCEP.116.004328; PMID: 27733494. Hsia HH, Callans DJ, Marchlinski FE. Characterization of endocardial electrophysiological substrate in patients with nonischemic cardiomyopathy and monomorphic ventricular tachycardia. Circulation 2003;108:704–10. https://doi. org/10.1161/01.CIR.0000083725.72693.EA; PMID: 12885746. 9. Cano O, Hutchinson M, Lin D, et al. Electroanatomic substrate and ablation outcome for suspected epicardial ventricular tachycardia in left ventricular nonischemic cardiomyopathy. J Am Coll Cardiol 2009;54:799–808. https://doi.org/10.1016/j. jacc.2009.05.032; PMID: 19695457. 10. Garcia FC, Bazan V, Zado ES, et al. Epicardial substrate and outcome with epicardial ablation of ventricular tachycardia in arrhythmogenic right ventricular cardiomyopathy/ dysplasia. Circulation 2009;120:366–75. https://doi.org/10.1161/ CIRCULATIONAHA.108.834903; PMID: 19620503. 11. Soto-Becerra R, Bazan V, Bautista W, et al. Ventricular 8.

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tachycardia in the setting of chagasic cardiomyopathy: Use of voltage mapping to characterize endoepicardial nonischemic scar distribution. Circ Arrhythm Electrophysiol 2017;10:pii: e004950. https://doi.org/10.1161/CIRCEP.116.004950; PMID: 29133379. Berte B, Sacher F, Cochet H, et al. Postmyocarditis ventricular tachycardia in patients with epicardial-only scar: A specific entity requiring a specific approach. J Cardiovasc Electrophysiol 2015;26:42–50. https://doi.org/10.1111/jce.12555; PMID: 25257774.   Dukkipati SR, d’Avila A, Soejima K, et al. Long-term outcomes of combined epicardial and endocardial ablation of monomorphic ventricular tachycardia related to hypertrophic cardiomyopathy. Circ Arrhythm Electrophysiol 2011;4:185–94. https://doi.org/10.1161/CIRCEP.110.957290; PMID: 21270104.   Lim PCY, Nademanee K, Lee ECY, et al. Epicardial ablation utilizing remote magnetic navigation in a patient with Brugada syndrome and inferior early repolarization. Pacing Clin Electrophysiol 2018;41:214–17. https://doi.org/10.1111/ pace.13175; PMID: 28842979. Valles E, Bazan V, Marchlinski FE. ECG criteria to identify epicardial ventricular tachycardia in nonischemic cardiomyopathy. Circ Arrhythm Electrophysiol 2010;3:63–71. https://doi.org/10.1161/CIRCEP.109.859942; PMID: 20008307.    Berruezo A, Mont L, Nava S, et al. Electrocardiographic recognition of the epicardial origin of ventricular tachycardias. Circulation 2004;109:1842–7. https://doi.org/10.1161/01. CIR.0000125525.04081.4B; PMID: 15078793.    Hayashi T. Santangeli P, Pathak R, et al.  Outcomes of catheter ablation of idiopathic outflow tract ventricular arrhythmias with an R wave pattern break in lead V2: A distinct clinical entity. J Cardiovasc Electrophysiol 2017;May;28:504–14. https://doi.org/10.1111/jce.13183; PMID: 28233951.    Hutchinson MD, Gerstenfeld EP, Desjardins B, et al. Endocardial unipolar voltage mapping to detect epicardial ventricular tachycardia substrate in patients with nonischemic left ventricular cardiomyopathy. Circ Arrhythm Electrophysiol 2011;4:49–55. https://doi.org/10.1161/ CIRCEP.110.959957; PMID: 21131557. Polin GM, Haqqani H, Tzou W, et al. Endocardial unipolar voltage mapping to identify epicardial substrate in arrhythmogenic right ventricular cardiomyopathy/dysplasia. Heart Rhythm 2011;8:76–83. https://doi.org/10.1016/j.

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hrthm.2010.09.088; PMID: 20933099. 20. B  etensky BP, Kapa S, Desjardins B, et al. Characterization of trans-septal activation during septal pacing: criteria for identification of intramural ventricular tachycardia substrate in nonischemic cardiomyopathy. Circ Arrhythm Electrophysiol 2013; 6:1123–30. https://doi.org/10.1161/CIRCEP.113.000682; PMID: 24106241. 21. Jauregui Abularach ME, Campos B, Park KM, et al. Ablation of ventricular arrhythmias arising near the anterior epicardial veins from the left sinus of Valsalva region: ECG features, anatomic distance, and outcome. Heart Rhythm 2012;9:865–73. https://doi.org/10.1016/j.hrthm.2012.01.022; PMID: 22306618. 22. Santangeli P, Marchlinski FE, Zado ES, et al. Percutaneous epicardial ablation of ventricular arrhythmias arising from the left ventricular summit: outcomes and electrocardiogram correlates of success. Circ Arrhythm Electrophysiol 2015; 8:337–43. https://doi.org/10.1161/ CIRCEP.114.002377; PMID: 25637596.   23. Aliot EM, Stevenson WG, Almendral-Garrote JM, et al. EHRA/ HRS expert consensus on catheter ablation of ventricular arrhythmias: developed in a partnership with the European Heart Rhythm Association (EHRA), a registered branch of the European Society of Cardiology (ESC), and the Heart Rhythm Society (HRS); in collaboration with the American College of Cardiology (ACC) and the American Heart Association (AHA). Heart Rhythm 2009;6:886–933. https://doi.org/10.1016/j. hrthm.2009.04.030; PMID: 19467519. 24. Page SP, Duncan ER, Thomas G, et al. Epicardial catheter ablation for ventricular tachycardia in heparinized patients. Europace 2013;15:284–9. https://doi.org/10.1093/europace/ eus258; PMID: 23002196.    25. Sawhney V, Breitenstein A, Ullah W, et al. Epicardial catheter ablation for ventricular tachycardia on uninterrupted warfarin: A safe approach for those with a strong indication for peri-procedural anticoagulation? Int J Cardiol 2016; 222:57–61. https://doi.org/10.1016/j.ijcard.2016.07.113; PMID: 27454616. 26. Sosa E, Scanavacca M, d’Avila A, et al. A new technique to perform epicardial mapping in the electrophysiology laboratory. J Cardiovasc Electrophysiol 1996;7:531–6. https://doi.org/10.1111/j.1540-8167.1996.tb00559.x; PMID: 8743758. 27. D’Avila A. Epicardial catheter ablation of ventricular

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tachycardia. Heart Rhythm 2008;5:S73–S75. https://doi. org/10.1016/j.hrthm.2008.01.035; PMID: 18456208. Tung R, Michowitz Y, Yu R, et al. Epicardial ablation of ventricular tachycardia: an institutional experience of safety and efficacy. Heart Rhythm 2013;10:490–8. https://doi. org/10.1016/j.hrthm.2012.12.013; PMID: 23246598. Tschabrunn CM, Haqqani HM, Cooper JM, et al. Percutaneous epicardial ventricular tachycardia ablation after noncoronary cardiac surgery or pericarditis. Heart Rhythm 2013;10:165–169. https://doi.org/10.1016/j.hrthm.2012.10.012; PMID: 23059131. Soejima K, Couper G, Cooper JM, et al. Subxiphoid surgical approach for epicardial catheter-based mapping and ablation in patients with prior cardiac surgery or difficult pericardial access. Circulation 2004;110:1197–1201. https://doi. org/10.1161/01.CIR.0000140725.42845.90; PMID: 15337702.   Fan R, Cano O, Ho SY et al. Characterization of the phrenic nerve course within the epicardial substrate of patients with nonischemic cardiomyopathy and ventricular tachycardia. Heart Rhythm 2009;6:59–64. https://doi.org/10.1016/j. hrthm.2008.09.033; PMID: 19121801. Di Biase L, Burkhardt JD, Pelargonio G, et al. Prevention of phrenic nerve injury during epicardial ablation: comparison of methods for separating the phrenic nerve from the epicardial surface. Heart Rhythm 2009;6:957–61. https://doi.org/10.1016/j. hrthm.2009.03.022; PMID: 19560084. Santangeli P, Marchlinski FE. Left phrenic nerve pacing from the left subclavian vein: Novel method to monitor for left phrenic nerve injury during catheter ablation. Circ Arrhythm Electrophysiol 2015;8:241–2. https://doi.org/10.1161/ CIRCEP.114.002302; PMID: 25691560. D’Avila A, Gutierrez P, Scanavacca M, et al. Effects of radiofrequency pulses delivered in the vicinity of the coronary arteries: implications for nonsurgical transthoracic epicardial catheter ablation to treat ventricular tachycardia. Pacing Clin Electrophysiol 2002;5:1488–95. https://doi.org/10.1046/j.14609592.2002.01488.x; PMID: 12418747. D’Avila A, Neuzil P, Thiagalingam A, et al. Experimental efficacy of pericardial instillation of anti-inflammatory agents during percutaneous epicardial catheter ablation to prevent postprocedure pericarditis. J Cardiovasc Electrophysiol 2007;18:1178–83. https://doi.org/10.1111/j.15408167.2007.00945.x; PMID: 17887979.

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Clinical Review: Electrophysiology & Ablation

Source Determination in Atrial Fibrillation Rakesh Latchamsetty and Fred Morady Michigan Medicine, University of Michigan, Ann Arbor, MI, USA

Abstract Techniques to ablate persistent atrial fibrillation (AF) continue to evolve. Recent technological and strategic innovations have included a focus on mapping and ablating AF sources. These attempts have not yet yielded a consistent improvement in clinical outcomes following AF ablation. Advancements in these techniques in the next few years, however, may enhance our ability to map and ablate AF as well as further our understanding of the mechanisms behind AF initiation, perpetuation, and recurrence.

Keywords Atrial fibrillation, catheter ablation, intracardiac mapping, ablation strategy, atrial fibrillation rotors, source mapping, ablation outcomes Disclosure: Dr Latchamsetty has no conflict of interest to declare. Dr Morady is on the scientific advisory board of Acutus Medical. Received: 9 April 2018 Accepted: 5 June 2018 Citation: Arrhythmia & Electrophysiology Review 2018;7(3):165–8. DOI: https://doi.org/10.15420/aer:2018:25:2 Correspondence: Dr Rakesh Latchamsetty, CVC, SPC 5853, 1500 East Medical Center Dr, Ann Arbor, MI 48109-5853, US. E: rakeshl@med.umich.edu

Catheter ablation of AF has shown steady growth over the past two decades with a nearly 15 % annual increase in the US.1 This growth can be attributed in large part to four factors: an increase in operators and institutions performing the procedure;2 a steady rise in AF prevalence, which is predicted to reach 12 million in the US by 2030;3 a larger spectrum of AF patients with more complex atrial substrates being offered ablation;4 and the development of technologies such as the cryoballoon catheter, that have facilitated the ablation process. The increase in patients with persistent and long-term persistent AF undergoing ablation has highlighted the complexities and heterogeneity of AF mechanisms and challenged operators to optimise ablation strategies. While pulmonary vein isolation (PVI) alone has yielded favourable results for ablation of paroxysmal AF, success rates with PVI alone for patients with persistent AF have been significantly lower.5 Bolstered by advances in mapping technology, recent searches for alternative or adjunctive ablation strategies have included real-time mapping and ablation of potential AF sources. While some initial studies have described promising results utilising this strategy, randomised controlled trials evaluating its effectiveness are lacking. Appreciating the potential advantages and limitations of this strategy requires a fundamental knowledge of the mechanisms behind the initiation and perpetuation of AF. In this review, we will begin with a description of the current understanding of mechanisms driving AF, then discuss the challenges behind real-time AF mapping and signal analysis, and conclude with an evaluation of existing systems and strategies to target AF sources during ablation.

areas identified to harbour focal drivers include the superior vena cava and the coronary sinus.11 While focal triggers may be the dominant mechanism in paroxysmal AF, multiple mechanisms often coexist in patients with persistent AF, with variable mechanisms accounting for the initiation and perpetuation of AF. While focal sites of automaticity may be responsible for initiating episodes of AF, the explanations for maintenance of AF are largely divided into two general theories: ‘spatially distributed disorganisation’ versus ‘localised sources’. In the former, AF episodes are maintained by wavelets that continuously collide and generate other wavelets in a random and disorganised manner. This is in contrast to the ‘localised sources’ theory in which one or more discrete drivers are responsible for the perpetuation of AF.12 While settling this debate is beyond the scope of this review, enough evidence supports the presence of sustained rotors or organised atrial activity during most cases of AF to validate an investigation into the effects of their ablation.13

AF Mechanisms

Among the challenges to distinctly visualise AF mechanisms are the limitations of traditional electrogram activation mapping using conventional catheters. This technology suffers from limited spatial and temporal resolution, the small region of atrial tissue able to be simultaneously recorded, and vulnerability to corruption from farfield signals.12 After signal acquisition, further analysis is necessary to identify potential ablation targets. Alternative mapping techniques can overcome some of these limitations to better understand AF mechanisms, although some of these technologies are not practical to utilise in vivo during ablation.

The proposed mechanisms of AF dating to the early 1900s include focal automaticity, organised re-entry or multiple re-entrant wavelets.6–9 Technological advances since then have allowed us to better conceptualise these principles. Focal triggers and drivers within the pulmonary vein muscle sleeves and in the antral regions of the pulmonary veins have been found to be the predominant mechanism of paroxysmal AF and wide-area PVI has yielded favourable results in patients with paroxysmal AF.10 In addition to the pulmonary veins, other

Utilising optical mapping with high spatial resolution in sheep hearts in which AF was induced, Jalife et al. characterised discrete high frequency re-entrant circuits during AF.14,15 These rotors consisted of circulating areas of conduction that spawned spiralling wavefronts of activation at their periphery (Figure 1). Although the concept of rotors and their contribution to sustained episodes of AF have now been well described, their properties and viability as effective ablation targets

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Clinical Review: Electrophysiology & Ablation Figure 1: Isochrone Maps and Pseudo-Electrograms During an Episode of AF A

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Figure 2: Complex Fractionated Atrial Electrogram and Dominant Frequency Maps During AF

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Comparison of the regional distribution of the FI and DF in a patient with paroxysmal AF in the right anterior oblique view of the LA. In panel A, the shortest FI, consistent CFAE site (white coloured area), and highest DF site (blue coloured area) were located in the left superior pulmonary vein (LSPV) (DF = 11 Hz), where termination of the AF was obtained during pulmonary vein isolation. The functional CFAE site was located in the right inferior pulmonary vein (RIPV) ostium with the second-highest DF sites (DF = 8 Hz). CFAE = complex fractionated atrial electrograms; DF = dominant frequency; FI = fractionation interval; LA = left atrium. Source: Lin, et al., 2008.18 Reprinted with permission from Elsevier.

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Isochrone maps and pseudo-electrograms (pseudo-EGs) constructed from left atrial (LA) and right atrial (RA) optical recordings of an episode of atrial fibrillation (AF). A: Isochrone map of a single rotation of a stable rotor located in the LA; B: Pseudo-EG of this signal, which is monomorphic. C: Two sequential RA isochrone maps during AF; D: RA pseudo-EG. Despite uniform activation in the LA, the RA is highly heterogeneous in both activation sequence (see isochrone maps) and electrical activity (see pseudo-EG). E: Bipolar EG is consistent with AF. Source: Jalife, 2002.15 Reprinted with permission from John Wiley and Sons.

remain controversial. Initially, the spatiotemporal stability of these rotors was challenged. However, their reproducibility in experimental and clinical studies suggests their relative stability when appropriate mapping techniques are utilised.16 Whether these sources can be accurately and reproducibly identified during ablation and whether they represent practical and effective ablation targets to reduce longterm AF recurrences remains to be seen.

Early Mapping and Targeting of AF Sources Early attempts to target AF sources were based on complex fractionated atrial electrograms (CFAEs) or dominant frequency (DF). Targeting of CFAEs was introduced by Nademanee et al. in 2004.17 The explanation for the effectiveness of targeting CFAEs is that rapidly conducting rotors give rise to adjacent areas of fibrillatory conduction that manifest as fractionated or continuous electrograms (Figure 2).18 Ablation at areas of CFAEs could therefore have the ability to eliminate local drivers of AF, and this was supported by the observation of AF termination with ablation at some CFAE sites. However, AF termination could also result simply from debulking of the atria or by ablation at sites modifying atrial autonomic innervation. A major limitation of CFAE ablation is its non-specificity in localising AF rotors. Furthermore, with the often extensive ablation that elimination of CFAEs may require, there is a risk of proarrhythmia in the form of atrial flutter/tachycardia. While still employed by some as an adjunctive strategy to PVI in ablation of persistent AF, data supporting this strategy are equivocal.19,20

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Another attempt to identify drivers during AF used spectral analysis of intracardiac electrograms to identify sites with high dominant frequency (Figure 2). Atrial locations with the highest DF values were believed to represent sites of high frequency rotors. Propagation from these locations led to a surrounding gradient of decreasing DFs. Clinical trials subsequently evaluated attempts at either directly targeting high DF sites or ablating with an endpoint of reducing global DF values. The results of these studies did not reveal an overall clinical benefit of ablation targeting high DF locations.21 Since then, technological advances have facilitated attempts to directly map wavefront propagation during AF instead of using secondary markers to localise AF sources. One such tool, called electrocardiographic imaging (ECGI), is a non-invasive system integrating a high-resolution surface ECG with up to 250 electrodes to a real-time computed tomography image of the heart. Body surface obtained electrograms are mapped to the epicardial surface of the heart to provide real-time activation mapping.22 Other strategies utilising intracardiac mapping technologies to directly map AF sources during catheter ablation are described below.

Recent Mapping Strategies A recent technology for mapping and ablation of AF sources called the focal impulse and rotor modulation (FIRM) system was introduced by Narayan et al. The details of the signal processing utilised with this system remain proprietary, but important features include realtime electrogram acquisition with high spatial resolution, multielectrode basket catheters placed simultaneously in both atria, use of a monophasic action potential catheter to define the dynamics of atrial repolarisation and use of local atrial conduction properties to reduce erroneous or far-field electrogram components.23 Sources of AF using this system were defined as either rotors (stable circular activation patterns around a centre with outward propagation), or focal impulses (centrifugal activation from a focal site of origin). To improve

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Source Determination in Atrial Fibrillation Figure 3: Computational Mapping of Electrical Rotor During AF AF Rotor in Low Left Atrium Right Atrium Left Atrium Superior Vena Cava Superior Mitral

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A: ECG and intracardiac signals in an 85-year-old man during paroxysmal AF. B: Fluoroscopy shows a 64-pole catheter in each atrium, an implanted continuous electrocardiography (ECG) monitor, diagnostic catheters in the coronary sinus and left atrium and an oesophageal temperature probe at the inferior left atrium. C: Left atrial rotor during AF, showing clockwise revolution (coded red to blue based on activation time scale) around a precessing centre for three cycles (AF1 to AF3). The right atrium depicts the superior and inferior vena cavae above and below, and lateral and medial tricuspid annuli at left and right. The left atrium depicts superior and inferior mitral annuli above and below, and pulmonary vein pairs. Electrodes are labelled A to H. The right atrium depicts the superior and inferior vena cavae above and below, and lateral and medial tricuspid annuli at left and right. The left atrium depicts superior and inferior mitral annuli above and below, and pulmonary vein pairs. Electrodes are labelled A to H1 to 8, respectively. (D) Computationally processed and filtered intracardiac signals show sequential activation over the rotor path for cycles AF1 to AF3 (arrowed). The focal impulse and rotor modulation (FIRM) ablation at this rotor terminated AF to sinus rhythm in <1 min. Source: Narayan, et al., 2014.24 Reprinted with permission from Elsevier.

the specificity of the targets, sources were required to show stability with limited precession over a period of 10 minutes before they were targeted with ablation (Figure 3).24 Early results utilising this method during 107 ablations performed at two centres showed AF termination in 56 % of cases (and AF slowing in an additional 30 %) after targeting a mean of 2.1 sources per patient. In this study, FIRM-guided ablation plus conventional ablation showed higher freedom from AF after a median of 273 days of follow-up (82.4 % versus 44.9 %; p<0.001) compared to conventional ablation alone after a single procedure.24 A recent single-centre registry of 170 patients undergoing FIRM-guided ablation showed termination of AF with ablation to sinus rhythm or atrial tachycardia in 59 % of patients with paroxysmal AF, 37 % of patients with persistent AF and 19 % of patients with long-standing persistent AF.25 Right atrial ablation terminated AF in 22 % of cases. Freedom from atrial arrhythmias at 1 year was 77 % for paroxysmal AF, 75 % for persistent AF and 57 % for long-term persistent AF. Further publications from other centres have had mixed results.26,27 A recent meta-analysis comparing 511 patients undergoing AF ablation utilising a strategy of PVI plus FIRM to 295 patients undergoing PVI alone suggested similar 1-year success rates off antiarrhythmic medications between the PVI plus FIRM versus PVI alone groups (50 % versus 58 %, p=0.21).28 Another meta-analysis comparing ablation targeting drivers for AF to conventional strategies across 30 studies showed a higher rate of freedom from atrial arrhythmias at one year (RR 1.34, 95 % CI [1.05â&#x20AC;&#x201C;1.70]; p=0.02) when targeting AF sources.29 The majority of the studies in this analysis, however, were not randomised

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and the strategies employed in both the study and control arm were varied. These analyses highlight the necessity for a large-scale randomised controlled trial directly comparing ablation targeting AF sources to conventional strategies. While FIRM-guided ablation likely represents the most rigorous attempt to directly map and ablate AF sources, other studies have evaluated alternative techniques. One recent study looked at a much simpler electrogram activation map-guided approach.30 In this study, a 20-pole high-density mapping catheter was used to visually identify sites of centrifugal activity presumed to be AF sources. These sites were ablated along with sites where there was defragmentation. Only a minority of patients (9 %) experienced AF termination after ablating the presumed sources and the improvement in freedom from AF at 1 year (57 % versus 38 %, p=0.009) compared with a traditional step-wise approach was driven by a reduction in recurrences of atrial tachycardia. Another panoramic mapping system using a 64-pole basket catheter (CARTOFINDER, Biosense Webster) was recently introduced for mapping and ablation of AF sources. An initial study reported identifying AF sources in 19 of 20 patients, with AF termination during ablation at 12 of 26 identified drivers and AF slowing at an additional 10 locations.31 Long-term clinical results utilising this system are pending. Ablation targeting AF sources presents an exciting new technology that warrants further investigation as a potential adjunctive ablation strategy. However, clinical studies to date have not yielded sufficient evidence to substantiate superiority to conventional ablation strategies. Several

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Clinical Review: Electrophysiology & Ablation explanations may account for this. Existing mapping technology may identify some but not all AF sources responsible for maintaining AF. The ability to effectively ablate identified sources may also be limited, either in terms of the precise localisation of ablation lesions or the ability to provide durable, transmural lesions. The most significant reason, however, may be that even durable ablation of current AF sources may not sufficiently alter the atrial substrate to prevent the emergence of other drivers. This problem is compounded by the fact that the atrial substrate itself often changes over time, promoting recurrences of AF despite effective ablation of previous drivers.

Summary The mechanisms driving the initiation and perpetuation of AF remain complex and incompletely understood. Experimental and clinical mapping technologies have demonstrated the ability to identify local and stable sources that may contribute to the perpetuation of AF. Ablation of these sources has not yet consistently and reproducibly translated to improved clinical outcomes. This is probably due to multiple reasons, including limitations in the currently available

1.

 neeland PP, Fang MC. Trends in catheter ablation for atrial K fibrillation in the United States. J Hosp Med 2009;4:E1–5. https://doi.org/10.1002/jhm.455; PMID: 19753578. 2. Deshmukh A, Patel NJ, Pant S, et al. In-hospital complications associated with catheter ablation of atrial fibrillation in the United States between 2000 and 2010: analysis of 93 801 procedures. Circulation 2013;128:2104–12. https://doi.org/10.1161/CIRCULATIONAHA.113.003862; PMID: 24061087. 3. Colilla S, Crow A, Petkun W, et al. Estimates of current and future incidence and prevalence of atrial fibrillation in the U.S. adult population. Am J Cardiol 2013;112:1142–7. https://doi.org/10.1016/j.amjcard.2013.05.063; PMID: 23831166. 4. Cappato R, Calkins H, Chen SA, et al. Updated worldwide survey on the methods, efficacy, and safety of catheter ablation for human atrial fibrillation. Circ Arrhythm Electrophysiol 2010;3:32–8. https://doi.org/10.1161/CIRCEP.109.859116; PMID: 19995881. 5. Latchamsetty R, Morady F. Long-term benefits following catheter ablation of atrial fibrillation. Circ J 2013;77:1091-6. https://doi.org/10.1253/circj.CJ-13-0298; PMID: 23546473. 6. Mitteilung I. Über die Wirkung des N. vagus und accelerans auf das Flimmern des Herzens. Pflügers Arch Physiol 1907;117:223–56 [in German]. https://doi.org/10.1007/BF01677310. 7. Mines GR. On dynamic equilibrium in the heart. J Physiol 1913;46:349–83. https://doi.org/10.1113/jphysiol.1913; PMID: 16993210. 8. Moe GK. A conceptual model of atrial fibrillation. J Electrocardiol 1968;1:145–6. https://doi.org/ :10.1152/ajpheart.00456.2005; PMID: 5707064. 9. Mann I, Sandler B, Linton N, Kanagaratnam P. Drivers of atrial fibrillation: theoretical considerations and practical concerns. Arrhythm Electrophysiol Rev 2018;7:49–54. https://doi.org/10.15420/aer.2017.40.3; PMID: 29636973. 10. Haïssaguerre M, Jaïs P, Shah DC, et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med 1998;339:659–66. https://doi.org/10.1056/NEJM199809033391003; PMID: 9725923. 11. Oral H, Chugh A, Good E, et al. A tailored approach to catheter ablation of paroxysmal atrial fibrillation. Circulation 2006;113:1824–31. https://doi.org/10.1161/CIRCULATIONAHA.105.601898; PMID: 16606789.

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mapping and ablation technologies and our incomplete understanding of the most reliable strategy for the long-term elimination of AF. These issues are being addressed by many investigators and it seems likely that improvements in our ability to identify and ablate current and future AF sources will improve over the next few years. n

Clinical Perspective • M  echanisms of AF initiation and perpetuation, particularly in patients with persistent AF, are complex and heterogeneous. • Advanced mapping techniques in animal and human models have demonstrated the presence of high frequency circuits during AF with relative spatiotemporal stability. •  Observational studies have demonstrated the potential of available mapping technologies to map and target ongoing AF sources. • Prospective randomised controlled trials establishing improved outcomes associated with mapping and ablating AF sources are not yet available.

12. Z aman JAB, Baykaner T, Schricker AA, et al. Mechanistic targets for the ablation of atrial fibrillation. Glob Cardiol Sci Pract 2017:e201707. https://doi.org/10.21542/gcsp.2017.7; PMID: 28971106. 13. Narayan SM, Krummen DE. Targeting stable rotors to treat atrial fibrillation. Arrhythm Electrophysiol Rev 2012;1:34–8. https://doi.org/10.15420/aer.2012.1.1.34; PMID: 26835027. 14. Jalife J, Berenfeld O, Mansour M. Mother rotors and fibrillatory conduction: a mechanism of atrial fibrillation. Cardiovasc Res 2002;54:204–16. https://doi.org/10/1016/S0008-6363(02)00223-7; PMID: 12062327. 15. Jalife J. Rotors and spiral waves in atrial fibrillation. J Cardiovasc Electrophysiol 2003;14:776–80. https://doi.org/10.1046/j.1540-8167.2003.03136.x; PMID: 12930260. 16. Guillem MS, Climent AM, Rodrigo M, et al. Presence and stability of rotors in atrial fibrillation: evidence and therapeutic implications. Cardiovasc Res 2016;109:480–92. https://doi.org/10.1093/cvr/cvw011; PMID: 26786157. 17. Nademanee K, McKenzie J, Kosar E, et al. A new approach for catheter ablation of atrial fibrillation: mapping of the electrophysiologic substrate. J Am Coll Cardiol 2004;43:2044–53. https://doi.org/10.1016/j.jacc.2003.12.054. 18. Lin YJ, Tai CT, Kao T, et al. Consistency of complex fractionated atrial electrograms during atrial fibrillation. Heart Rhythm 2008;5:406–12. https://doi.org/10.1016/j.hrthm.2007.12.009; PMID: 18313599. 19. Providência R, Lambiase PD, Srinivasan N, et al. Is there still a role for complex fractionated atrial electrogram ablation in addition to pulmonary vein isolation in patients with paroxysmal and persistent atrial fibrillation? Meta-analysis of 1415 patients. Circ Arrhythm Electrophysiol 2015;8:1017–29. https://doi.org/ 10.1161/CIRCEP.115.003019; PMID: 26082515. 20. Li WJ, Bai YY, Zhang HY, et al. Additional ablation of complex fractionated atrial electrograms after pulmonary vein isolation in patients with atrial fibrillation: a meta-analysis. Circ Arrhythm Electrophysiol 2011;4:143–8. https://doi.org/10.1161/CIRCEP.110.958405; PMID: 21303900. 21. Gadenz L, Hashemi J, Shariat MH, et al. Clinical role of dominant frequency measurements in atrial fibrillation ablation – a systematic review. J Atr Fibrillation 2017;9:1548. https://doi.org/10.4022/jafib.1548; PMID: 29250291. 22. Rudy Y. Noninvasive imaging of cardiac electrophysiology and arrhythmia. Ann N Y Acad Sci 2010;1188:214–21. https://doi.org/10.1111/j.1749-6632.2009.05103.x; PMID: 20201906.

23. N  arayan SM, Baykaner T, Clopton P, et al. Ablation of rotor and focal sources reduces late recurrence of atrial fibrillation compared with trigger ablation alone: extended follow-up of the CONFIRM trial (Conventional Ablation for Atrial Fibrillation With or Without Focal Impulse and Rotor Modulation). J Am Coll Cardiol 2014;63:1761–8. https://doi.org/10.1016/j.jacc.2014.02.543; PMID: 24632280. 24. Narayan SM, Krummen DE, Shivkumar K, et al. Treatment of atrial fibrillation by the ablation of localized sources: CONFIRM (Conventional Ablation for Atrial Fibrillation With or Without Focal Impulse and Rotor Modulation) trial. J Am Coll Cardiol 2012;60:628–36. https://doi.org/10.1016/j.jacc.2012.05.022; PMID: 22818076. 25. Miller JM, Kalra V, Das MK, et al. Clinical benefit of ablating localized sources for human atrial fibrillation: the Indiana University FIRM Registry. J Am Coll Cardiol 2017;69:1247–56. https://doi.org/10.1016/j.jacc.2016.11.079; PMID: 28279291. 26. Steinberg JS, Shah Y, Bhatt A, et al. Focal impulse and rotor modulation: acute procedural observations and extended clinical follow-up. Heart Rhythm 2017;14:192–7. https://doi.org/10.1016/j.hrthm.2016.11.008; PMID: 27826130. 27. Buch E, Share M, Tung R, et al. Long-term clinical outcomes of focal impulse and rotor modulation for treatment of atrial fibrillation: a multicenter experience. Heart Rhythm 2016;13:636–41. https://doi.org/10.1016/j.hrthm.2015.10.031; PMID: 26498260. 28. Mohanty S, Mohanty P, Trivedi C, et al. Long-term outcome of pulmonary vein isolation with and without focal impulse and rotor modulation mapping: insights from a meta-analysis. Circ Arrhythm Electrophysiol 2018;11:e005789. https://doi.org/10.1161/CIRCEP.117.005789; PMID: 29545360. 29. Ramirez FD, Birnie DH, Nair GM, et al. Efficacy and safety of driver-guided catheter ablation for atrial fibrillation: A systematic review and meta-analysis. J Cardiovasc Electrophysiol 2017;28:1371–8. https://doi.org/10.1111/jce.13313; PMID: 28800192. 30. Takahashi Y, Yamashita S, Suzuki M, et al. Efficacy of catheter ablation of focal sources in persistent atrial fibrillation. J Cardiovasc Electrophysiol 2018. https://doi.org/10.111/jce13415; PMID: 29315991. 31. Honarbakhsh S, Schilling RJ, Dhillon G, et al. A novel mapping system for panoramic mapping of the left atrium: application to detect and characterize localized sources maintaining atrial fibrillation. JACC Clin Electrophysiol 2018;4:124–34. https://doi.org/10.1016/j.jacep.2017.09.177; PMID: 29387810.

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Clinical Reviews: Electrophysiology and Ablation

The Impact of Advances in Atrial Fibrillation Ablation Devices on the Incidence and Prevention of Complications Fehmi Keçe, Katja Zeppenfeld and Serge A Trines Department of Cardiology, Leiden University Medical Centre, University of Leiden, Leiden, the Netherlands

Abstract The number of patients with atrial fibrillation currently referred for catheter ablation is increasing. However, the number of trained operators and the capacity of many electrophysiology labs are limited. Accordingly, a steeper learning curve and technical advances for efficient and safe ablation are desirable. During the last decades several catheter-based ablation devices have been developed and adapted to improve not only lesion durability, but also safety profiles, to shorten procedure time and to reduce radiation exposure. The goal of this review is to summarise the reported incidence of complications, considering device-related specific aspects for point-bypoint, multi-electrode and balloon-based devices for pulmonary vein isolation. Recent technical and procedural developments aimed at reducing procedural risks and complications rates will be reviewed. In addition, the impact of technical advances on procedural outcome, procedural length and radiation exposure will be discussed.

Keywords Atrial fibrillation, ablation devices, ablation catheters, pulmonary vein isolation, complications Disclosure: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The Heart Lung Centre of the Leiden University Medical Centre received unrestricted research grants from Medtronic, Biotronik, Boston Scientific, Lantheus Medical Imaging, St Jude Medical, Edwards Lifesciences and GE Healthcare, and unrestricted educational grants from Medtronic, Edwards Lifesciences and St Jude Medical. The authors have no conflicts of interest to declare. Received: 31 May 2018 Accepted: 17 July 2018 Citation: Arrhythmia & Electrophysiology Review 2018;7(3):169–80. DOI: https://doi.org/10.15420/aer.2018.7.3 Correspondence: Serge A Trines, Leiden University Medical Centre, Department of Cardiology, C5-P, PO Box 9600; 2300 RC Leiden, the Netherlands. E: s.a.i.p.trines@lumc.nl

Catheter ablation is an effective strategy to maintain sinus rhythm in patients with symptomatic atrial fibrillation (AF), which has evolved from a highly specialised technique to a first-line therapy.1–3 The cornerstone of ablation is pulmonary vein isolation (PVI).4 Over the last decade, ablation devices have undergone technical improvements, aiming for better lesion durability and ablation outcomes. However, significant complications have been reported in survey studies and patient safety remains of concern.4–9 Although operators have become more experienced, technical advances with improved energy transfer may increase procedural risk. As a consequence, catheter design and ablation protocols have been adapted to prevent complications. For individualised patient care and device selection, knowledge of potential risks and benefits for the different available devices is important. The aim of this review is to provide an overview of type and incidence of complications and strategies for prevention for singletip and multi-electrode radiofrequency catheter ablation (RFCA) and balloon-based ablation devices.

and improved outcome,20 with a current AF free survival of 46–94 % at 1-year follow-up (Table 1a/Table 1b). The introduction of threedimensional electro-anatomical mapping systems (CARTO, Biosense Webster Inc., Diamond Bar, CA, USA and Ensite, Abbot, St Paul, MN, USA) and image-integration tools has been associated with improved efficacy.21–25 Contact-force (CF) measurement during ablation has been developed to improve lesion formation (Thermocool Smarttouch, Biosense and Tacticath, Abbot; Figure 1) with a reported one-year AF free survival between 52 and 94  % (Table 1a/Table 1b). There are conflicting reports whether CF improves ablation outcome (Table  1b),26,27 suggesting that CF parameters need to be validated.26 Data from a recent meta-analysis suggest that ablation guided by CF is associated with improved median outcome at 12-months follow-up.28 Recent developments focus on improved nearfield resolution by combining recordings from large-tip electrodes with recordings from micro-electrodes (QDOT-micro technology for Biosense Webster Inc.).

Point-by-Point Radiofrequency Ablation

Procedure Time

After evidence that the pulmonary veins (PVs) are the primary source of AF,10,11 non-cooled radiofrequency ablation of ectopic beats from the PVs has been introduced.12,13 Due to the high incidence of PV stenosis,14 ablation has evolved from segmental ablation of the PVs guided by a circular mapping catheter4,15,16 to wide-area circumferential PV isolation.17

Procedural length has been associated with higher complication rates.29 Although radiation exposure can be reduced with 3D mapping systems,24 point-by-point ablation often requires longer procedure times compared with single-shot techniques. Reported mean procedural times range between 101 and 284 minutes (Table 1a/Table 1b). Contact-force has been associated with reduced procedure, ablation and fluoroscopy times28 and high-power-short-duration radiofrequency applications to further reduce procedure time are currently under investigation.30–32 Fluoroscopy time for RFCA, however, approaches

Historical Overview Catheter irrigation resulted in a lower risk for coagulum formation, allowing for higher energy transfer with larger and deeper lesions18,19

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Clinical Reviews: Electrophysiology and Ablation Table 1a: Overview of Literature on Radiofrequency Ablation Author, year

Number of

AAD free

Procedural and

(study type)

patients and type

survival (1

ablation time

of ablation device

year) (%)

(min)

PAF (%)

Preventive techniques

Complications (%)

Aryana, 2015 (retrospective)

n=423 RF

76

Power reduction (40 W anterior, 30 W posterior)

60 (p<0.001) 188 (p<0.001) 66 (p<0.001)

Pericardial effusion/cardiac tamponade 1.7 Transient ST elevation 0.2 Vascular access 0.2 Venous thromboembolism 0.2 Other: pacemaker insertion 0.2

Chun, 2017122 (registry)

n=1559 RF n=556 RFA

43

Power reduction (40 W anterior and 30 W posterior and inferior)

NA

101 (p=0.004) NA

Cardiac tamponade 0.5 (p=0.024) Stroke/TIA 0.2 Atrial-oesophageal fistula 0.05 Vascular access 2.6 Other: hemothorax 0.1

Khoueiry, 201686 (observational)

n=376 RFA

100

Power reduction (30 W anterior, 25 W posterior). Temperature limitation 48°C

86

114 NA

Pericarditis/cardiac tamponade 1.6 Thromboembolic events 0.3 Transient phrenic palsy 0.3 (p=0.016) Upper digestive bleeding 0.3 Vascular access/major bleeding 3.2 Other 1.0 (haematuria, haemoptysis, and anaphylactic shock)

Kuck, 201687 (multicentre RCT)

n=284 RF n=93 RFA

100

Power reduction (40 W anterior and inferior, 30 W posterior)

64

124 (p<0.001) NA

Pericardial effusion/cardiac tamponade 1.3 Transient neurologic complication 0.8 and stroke/TIA 0.5 Gastrointestinal complications 0.5 Vascular access 4.3 Other 2.7 (pulmonary or bronchial complication 1.1, dyspnea 0.5, contrast media reaction 0.3, contusion 0.3, hematuria 0.3 and local oedema 0.3)

Luik, 2015161 (RCT)

n=159 RF

100

N.A

60

174 (IQR 147–218) Pericardial effusion 1.9 NA Vascular access 3.1

Mugnai, 201488 (retrospective)

n=260 RF

100

Power reduction (35 W 63 anterior and 25 W posterior); Temperature limit 48°C

192 (p<0.001) NA 36

Pericardial effusion/cardiac tamponade 10/1.5 Vascular access 0.8 Other: third degree AV-block/sinus arrest 0.8; contrast reaction 0.4

Providencia, 2017162 (multicentre retrospective)

n=467 RF

100

Power reduction (30 W anterior and 25 W posterior)

46–79 at 18 months

136 (p=0.001) NA

Pericardial effusion 1.7 (p=0.036) TIA 0.2 Oesophageal bleeding 0.2 Vascular access 1.9 Other 0.9 (haemoptysis, haematuria, anaphylactic shock and temporary myocardial sideration)

Schmidt, 201490 (multicentre retrospective)

n=2870 RF

100

Centre’s preference

NA

165 (IQR 120–210) Cardiac tamponade 1.4 33 (IQR 21–50) Phrenic nerve palsy 0.0 (p=0.001) (p<0.001) Vascular access 1.1 and 1.1 Other: pneumothorax 0.3, hemothorax 0.2; sepsis 0.0 and surgical accident 0.1

Squara, 201591 (multicentre retrospective)

n=178 RFA

100

Power reduction (30–35 W anterior and 20 W posterior) Oesophageal monitoring (discretion of the operator 38.5°C cut-off)

83 DC testing

123 (p=0.003) NA

Cardiac tamponade 1 Embolic events 1 Oesophageal complication 0.5 Vascular access 4

Straube, 201692 (multicentre observational)

n=180 RF

100

NA

61

180 (p<0.001) 38 (p<0.001)

Cardiac tamponade 2.5 Stroke 0.6 Transient PNP 0.6 Vascular access 7.5 and severe bleeding 0.6

Wasserlauf, 201596 (retrospective)

n=100 RF

100

NA

61

284 (p<0.001) NA

Cardiac tamponade 4 Vascular access 1 Other: respiratory arrest during extubation 1

82

Only observational/retrospective studies and randomised clinical trials with n>100 are included in patients with paroxysmal atrial fibrillation, showing the use of different radiofrequency ablation devices, outcomes, the use of preventive techniques and complication rates. AAD = anti-arrhythmic drugs, DC = dormant conduction, IQR = interquartile range, PAF = paroxysmal atrial fibrillation, PNP = phrenic nerve palsy, RF = radiofrequency ablation, RFA = radiofrequency advanced with CF technology and TIA = transient ischaemic attack. p-values indicated significant differences between catheters from the same technology (Table 1) or between catheters from different technologies (Table 1 versus Table 2).

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Advances in Atrial Fibrillation Ablation Devices Table 1b: Overview of Literature on Radiofrequency Ablation With and Without Contact-Force Author, year

Number of

AAD free

Procedural and

(study type)

patients and type

survival (1

ablation time

of ablation device

year) (%)

(min)

2016165

PAF (%)

Preventive techniques

Complications (%)

Itoh, (prospective, nonrandomised)

n=50 RF n=50 RFA

100

Power reduction (30 W anterior, 25 W posterior)

78 versus 94 245 versus 165 (p<0.001) NA

No major complications in either group

Jarman, 2015166 (multicentre, retrospective)

n=400 RF n=200 RFA

46

Power reduction (30–35 W anterior, posterior 25 W)

46 versus 59 (p=0.05)

Pericardial effusion/cardiac tamponade 1.2 RFA Stroke 0.2 RF TIA 0.2 RFA AE fistula 0.2 RF Pulmonary vein stenosis 0.2 RF Vascular access 1.8 (RF/RFA)

Lee, 2016167 (retrospective, observational, cohort)

n=418 RF n=238 RFA

47 versus 41 Power limitation (30 W)

NA

200 versus 240 (p<0.001) 43 versus 35

Pericardial effusion/cardiac tamponade 0.8 versus 1.0

Nair, 2017168 (observational cohort)

n=99 RF n=68 RFA

100

Power reduction (<40 W anterior and <25 W posterior)

51 versus 66 (p=0.06) (3-year follow- up)

347 versus 257 (p<0.001) 57 versus 43 (p<0.001)

Cardiac tamponade 3 versus 0 Vascular access 1 RF Other: oesophageal tear during temperature probe insertion 1 RFA, traumatic Foley catheter insertion 1 RF

Reddy, 201541 (multicentre RCT)

n=143 RF n=152 RFA

100

NA

68 versus 69 NA 27 versus 23. (p=0.044)

Cardiac tamponade 2.7 versus 2.1 and pericarditis 1.3 RFA Pulmonary vein stenosis 0.7 RF Vascular access 2 versus 2.1 Other: pulmonary oedema 1.3 versus 1.4

Sigmund, 2015169 (prospective, case matched)

n=99 RF n=99 RFA

65 versus 63 Power reduction (30–35 anterior, 25 posterior) Temperature limitation (43°C)

73 versus 82 216 versus 178 (p<0.001) 48 versus 38 (p=0.001)

Cardiac tamponade 3.0 versus 2.0 Vascular access 2 versus 1

Ullah, 201627 (multicentre RCT)

n=59 RF n=59 RFA

100

49 versus 52 39 [IQR 32–46] versus 41 [IQR 34–50]

Pericardial effusion/cardiac tamponade 1.7 versus 3.4 Vascular access 6.8 versus 3.9 Other: pericarditis 3.4 RFA

Wutzler, 2014170 (prospective, non-randomised)

n=112 RF n=31 RFA

76 versus 61 Power limitation (35 W) Temperature limitation (43°C)

63 versus 84 158 versus 128 (p=0.031)

Pericardial effusion/cardiac tamponade 0.9 RF Vascular access 2.7 versus 3.2

Power limitation (30 W) Temperature limitation (48°C)

Ablation (only observational/retrospective studies and randomised clinical trials with n>100 are included in patients with paroxysmal atrial fibrillation, showing use of different radiofrequency ablation devices, outcomes, the use of preventive techniques and complication rates. AAD = anti-arrhythmic drugs, DC = dormant conduction, IQR = interquartile range, PAF = paroxysmal atrial fibrillation, PNP = phrenic nerve palsy, RF = radiofrequency ablation, RFA = radiofrequency ablation advanced with CF technology and TIA = transient ischaemic attack. p-values indicates significant differences between catheters with and without contact force (RF versus RFA).

to zero under increasing experience of 3D mappings systems and intracardiac electrocardiography.33,34

Complications The use of image integration and electro-anatomical mapping has been associated with fewer complications.20–24,35,36 Whether CF-guided ablation improves safety requires additional investigation. In a recent meta-analysis, the overall complication and tamponade rates were 3.8 % and 0.5  % for CF and 3.9  % and 0.9  % for non-CF ablation.28 Irrigated catheters (Thermocool™, Biosense and Coolpath™, Abbot) have been introduced to prevent endothelial charring in particular at sites with low blood flow.19 Indeed, with irrigation, less micro-embolic signals have been detected with trans-cranial Doppler.37 Advanced irrigation technology (Thermocool Surround Flow and Abbot FlexAbility) reduces irrigation volume with maintenance of the safety profile.38 Thromboembolic event rates (stroke and transient ischaemic attack) range between 0.2 and 1 % for irrigated catheters. Phrenic nerve palsy (PNP) is rare (0.01–0.6  %) and mainly transient. Similar, the reported incidence of oesophageal and vagal injury is low, ranging between

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0.05 and 0.5 % (Table 1). However, a study focusing specifically on gastrointestinal complications reported an 11 % incidence of thermal oesophageal lesions and a 17  % incidence of gastroparesis.39 In the Manufacturer and User Facility Device Experience database of 2689 ablations, the incidence of atrial-oesophageal fistula as a percentage of all reported complications for CF catheters was higher (5.4  %: 65 of 1202 cases) compared with non-CF catheters (0.9  %: 13 of 1487 cases).40 These numbers do not reflect the absolute incidence however. Pulmonary vein stenosis (PVS) after CF-guided ablation was only reported in one study with an incidence of 0.7 %.41

Multi-electrode Catheters Historical Overview Multi-electrode RF catheters have the potential to reduce ablation and procedural time. The pulmonary vein ablation catheter (PVAC, Medtronic, Minneapolis, MN, USA) can deliver RF energy in different duty-cycled unipolar/bipolar modes. One-year AF-free survival off AAD with the first-generation device was 61 % in patients with paroxysmal AF.42 To reduce the embolic risk potentially associated with non-irrigated RF

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Clinical Reviews: Electrophysiology and Ablation Figure 1: Radiofrequency Ablation Devices with CF and Multi-electrode Ablation Catheters A

B

C

7.5 F 3.5 mm CF ablation catheter

Unique braiding structure at distal tip increases shaft pliability compared to proximal shaft3-5

Catheter shaft 3 Location sensors

Three fiber optic sensing cables

Precision spring

Electrodes

Tip electrode Magnetic transmitter coil Irrigation ports

2-2-2 Ring Spacing for evenly spaced bipole pairs Electrode magnetic sensor for seamless integration with EnSite PrecisionTM cardiac mapping system

Contact force sensor located behind the distal tip

(A) Thermocool Smarttouch, from Lin et al.164 (B) Tacticath Catheter, from Abbott (www.sjmglobal.com). (C) PVAC Gold – the non-irrigated multi-electrode catheter, reproduced with permission of Medtronic, Inc.

catheters, submerging the catheter in saline before introduction and maintaining an activated-clotting time (ACT) above 350 seconds have been recommended. As interaction of electrodes 1 and 10 was associated with occurrence of asymptomatic cerebral embolism,43 the current generation catheter (PVAC-Gold; Figure 1) has only nine electrodes with a larger inter-electrode spacing and different electrode composition (from platinum to gold) for better heat conductivity. Reported one-year AF free survival with PVAC-Gold ranges from 60 to 71 %.44–46 Studies comparing the efficacy of PVAC and PVAC-Gold found no significant difference at 1-year follow-up (64–65 % and 68–70 %, respectively).45,47 Other (irrigated) multi-electrode catheters in the past were withdrawn because of safety concerns (e.g. new multipolar irrigated radiofrequency ablation catheter, Biosense Webster Inc., Multi-array septal catheter/Multi-array ablation catheter, Medtronic Inc. and High Density Mesh ablator, Bard Electrophysiology, Lowell, MA, USA).48

Procedure Time Ablation with a smaller number of simultaneously activated electrodes to reduce thrombo-embolic risk has significantly prolonged procedure times (159±39 versus 121±15 minutes) with the first generation PVAC.49 For the PVAC-Gold catheter shorter procedure times (94–117 minutes) have been reported.45,47

Complications Asymptomatic cerebral embolisms were significantly higher with PVAC (incidence 38–39 %) than with irrigated RFCA and cryoballoon ablation.50–53 The potentially high embolic risk is supported by studies on micro-embolic signals recorded with transcranial Doppler ultrasonography.54–56 However, after technical modifications to eliminate electrode 1–10 interactions, the duration of microembolic signals was reduced with only 33 %.57,58 The clinical relevance of asymptomatic cerebral embolism detected on MRI and transcranial Doppler remains, however, unclear.59,60 Despite technical improvements, the second-generation PVAC-Gold catheter still showed a high incidence of asymptomatic cerebral embolism (20  % versus none, p=0.011) and a higher amount and duration of microembolic signals compared with irrigated RFCA in a randomised clinical trial from our centre.58 PNP is uncommon after PVAC ablation. It was first reported in 201061 and occurred in only 1/272 (0.4 %) consecutive patients.62 PVAC ablation is usually performed at the ostium of the PVs

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and a detectable narrowing of the PV diameter has been reported in 23 % of patients and 7 % of veins.14,63,64

Balloon-based Devices Several balloon-based devices have been developed for PVI (Figure 2), including the cryoballoon, the hotballoon, the endoscopic laserballoon and the high-intensity focused ultrasound balloon. The latter is no longer available (for safety reasons) and will not be discussed in this review. A potential limitation of these devices is the more distal PVI compared with point-by-point isolation.65 However, over the last decade, balloon-based devices have undergone important technical improvements.

Cryoballoon Historical Overview First animal studies with cryoballoon ablation were published in 2005.66,67 A double-lumen balloon is cooled by expansion of NO2.66 The second-generation cryoballoon (Arctic Front Advance, Medtronic Inc., Minneapolis, MN, USA) has an increased gas flow, improved temperature uniformity and a more proximal cooling of the balloon with more internal injection ports compared with the first-generation.68 The broader cooling zone, together with easier positioning of the balloon with the second-generation steerable sheath (Flexcath Advance) and real-time assessment of PV isolation with the intraluminal spiral catheter (Achieve) has resulted in enhanced lesion durability and more antral ablation.69,70 Recent studies reported success rates (off AAD) of 76–86 % after 1–2 years for the first and second generation cryoballoon (Table 2).71–78 Freedom of AF off drugs was reported in 48–74  % of patients for the first-generation cryoballoon and in 65–83  % for the second-generation cryoballoon at 1-year follow-up. In a retrospective study comparing the two balloons, no significant differences in outcome were observed (78 versus 83  % at 1-year follow-up).79 The third-generation cryoballoon with a shorter tip to facilitate better PV-signal recordings is still being developed.

Procedure Time With the development of the second-generation cryoballoon, the ablation protocol has been adapted with reduced cryo-application times (180 seconds instead of two-times 300 seconds).79,80 Recent studies evaluating shorter application times based on the time-toisolation showed a similar efficacy at 1-year follow-up.72–77, 81

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Atrial Fibrillation Ablation Devices and Complications Complications The reported incidence of complications is low and not significantly different between the first and second-generation cryoballoons.79,82–96 Specifically, the reduction in ablation time was not associated with lower complication rates (Table 2). Cardiac tamponade occurred in 0.7 % (47 of 6672 procedures) and was similar for first and secondgeneration balloons (Table 2). The incidence of phrenic and vagal nerve damage is, however, of concern. In a series of 66 patients, asymptomatic gastroparesis was reported in 9  %, transient PNP in 8  % and symptomatic inappropriate sinus tachycardia in 1  %.97 The reported incidence of PNP ranged between 2 and 28  % for the first-generation and between 1 and 16  % for the second-generation cryoballoon (Table 2). An association between cryoballoon use and any oesophageal injury has been reported in up to 17 %.98,99 However, atrialoesophageal fistulae are rare and have only been case-reported.100–102 Stroke and transient ischaemic attacks are reported in 0.3–0.5  % of patients (Table 2). Of importance, the risk for PVS is also low. In a recent study, 0.4 % of the patients showed only mild (25–50 %) PVS.103

Hotballoon Historical Overview The hotballoon (HotBalloon catheter, Sataka, Toray Industries, Tokyo, Japan) is a compliant RF-based balloon (25–35 mm) that is filled with saline and contrast. The balloon can be heated to a temperature of 65–75°C through a coil electrode inside the balloon. Energy delivery is based on thermal conduction to the tissue in contact with the balloon surface. The first human study has shown that 2–3 applications of 2–3 minutes duration were required to achieve PVI resulting in AF free survival of 92 % off AAD during a mean follow-up of 11±5 months.104 In consecutive studies, reported outcome off AAD was 78, 59 and 65 % after 1, 6.3 and 3.6 years, respectively.105–107 Randomised studies comparing the hotballoon with other ablation technologies are lacking.

Figure 2: Different Balloon-based Ablation Devices for Pulmonary Vein Isolation A

B

C

The second and third-generation cryoballoon (with a shorter tip indicated with arrows for better pulmonary vein recordings) (A) with a spiral catheter catheter inside the balloon. The hot balloon (B): the inflated balloon with a thermocouple and radiofrequency electrode inside and a central lumen for a guide wire. The laser balloon (C) with an endoscope and arc generator in the catheter shaft inside the balloon. Images are respectively derived from Chierchia et al.163 Sohara et al.109 and Reddy et al.110

endoscope, the intra-cardiac anatomy and adequate tissue contact can be visualised real-time. The arc generator delivers laser energy to perform PVI.110 Similar to other balloon-based devices, superior caval vein pacing and oesophageal temperature monitoring (39°C cut off) is recommended to minimise the risk for PNP and oesophageal injury. After ablation, PV isolation needs to be evaluated with a separate spiral catheter. In the next-generation balloon (HeartLight, Cardiofocus, Inc., Marlborough, MA, USA), the arc of the laser was decreased from 90–150° to 30° to improve safety. In addition, the balloon material was modified allowing variable sizing and deformation to prevent mismatch between the balloon size and the PV diameter.111 Based on data from nine studies including 1021 patients, the efficacy of the HeartLight balloon procedure ranged between 58 and 88 % at 1–1.5 year follow-up (off AAD).112 A more compliant laserballoon is currently being developed (HeartLight Excalibur Balloon™, Cardiofocus Inc.).

Complications In an early animal study published in 2001, no major complications were reported.108 In a human feasibility study, oesophageal injury, however, occurred in three of the first six cases. After introduction of oesophageal cooling with saline, consisting of repeated injections of 10–20 ml mixture of contrast medium and saline, cooled at 10°C during applications, only one additional injury was observed in the next 58 patients.109 In a series of 502 patients, the incidence of oesophageal injury could be further reduced by adapting the oesophageal temperature cut-off (39°C instead of 41°C).107 Additional procedural-related complications included PNP and PVS. In a series of 319 ablations performed in 238 patients, 16 major complications occurred: >70 % PV stenosis in 4 (1.7  %), temporary PNP in 8 (3.4 %) and oesophageal injury in 4 (1.7 %).105 In a randomised controlled trial comparing hotballoon with AADs, for paroxysmal AF major complications were reported in 15 (11 %) patients: PV stenosis of >70  % in 5  % and transient PNP in 3.7  %.106 The hotballoon is still under investigation and optimal ablation energy and duration needs to be determined.

Laserballoon Historical Overview The first-generation laserballoon (Endoscopic ablation system, Cardiofocus Inc. Marlborough, MA, USA) was available in three diameters (20, 25 and 30 mm). It consists of a delivery sheath with an endoscope and arc generator inside a balloon. With the

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Procedure Time The first-generation laserballoon was initially constructed as a twooperator device for positioning the balloon and directing the laser ablation.113 The second-generation laserballoon can be used by a single-operator. In addition, energy delivery has been modified leading to a shorter procedural duration from 334 minutes during first use110 to 133–236 minutes in the improved laserballoon.112,114

Complications A paper providing pooled data of eight small studies (total 308 patients) reported PNP in 2.3 % and cardiac tamponade in 1.9 % of the patients.113 In a multicentre study including 200 patients with paroxysmal AF, similar complication rates were observed (2  % cardiac tamponade and 2.5  % PNP.115 However, in a recent multicentre prospective study 1 patient out of 68 showed PNP and 1 patient developed a stroke (both 1.5  %).114 Of concern, the incidence of asymptomatic cerebral embolism with the laserballoon was 24 %, but not significantly higher (p=0.8) than for the cryoballoon (18  %) and irrigated RFCA (24  %) in a randomised study.116 In a clinical trial comparing laserballoon with irrigated RFCA (178 versus 175 patients), the incidence of all adverse events was also similar (12 % versus 15 %).111 However, the incidence of PNP was significantly higher with the laserballoon (3.5  % versus 0.6  %). PNP was also the major complication in another study with an incidence of 5.8  %. Cardiac tamponade was reported in 3.5  % of patients.117 In these studies PVS was not reported.

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Clinical Reviews: Electrophysiology and Ablation Table 2: Overview of Literature on Ablation with the Cryoballoon Complications (%)

Author, year

Number of

AAD free

Procedural,

(study type)

patients, ablation

survival (1

ablation time

device and

year) (%)

and fluoroscopy

PAF (%)

Preventive techniques

protocol*

time (min)

Aryana, 2014 (retrospective)

n=140; CB 3×5

86

Temperature balloon (-60) Phrenic nerve pacing (20 mA, 1500 ms)

78 DC testing

209 (p<0.001) 61 (p<0.001) 42 (p<0.001)

Transient PNP 12.1 and permanent PNP 0.7 Vascular access 0.7 Other: myocardial infarction 0.7 (after 8 weeks)

Aryana, 201479 (retrospective)

n=200; CBA 2×3-4

72

Temperature balloon (-60) Phrenic nerve pacing (20 mA, 1500 ms)

83 DC testing

154 (p<0.001) 47 (p<0.001) 27 (p<0.001)

Pericardial effusion/cardiac tamponade 1.5 Transient PNP 16 and permanent PNP 0.5 Gastroparesis 0.5 (symptoms resolved after 2 months) Vascular access 0.5 and haemorrhage requiring blood transfusion 0.5 Other: myocardial infarction 0.5

Aryana, 201582 (retrospective)

n=773; CBA 1-3×2-4

77

Temperature balloon (-65) Phrenic nerve pacing (20–25 mA, 800–1500 ms)

77 (p<0.001)

145 (p<0.001) 40 (p<0.001) 29 (p<0.001)

Pericardial effusion/cardiac tamponade 0.6 Transient ST-elevation 0.1 Transient PNP 7.6 and permanent PNP 1.2 Gastroparese 0.1 Vascular access 0.3 and venous thromboembolism 0.3

Aytemir, 201383 (observational)

n=236; CBA 2×5

80

Phrenic nerve pacing

Median 81 (IQR 6–27)

72 Median 2 (IQR 2–5) 14

Cardiac tamponade 0.8 Transient PNP 1.2 Vascular access 3.8

Chun, 2017122 (registry)

n=589 CB(A); n=286 Laserballoon CB 2×5; CBA 2×4

100

Oesophageal temperature monitoring

NA

106 (p=0.004) NA 13 (p<0.001)

Cardiac tamponade 0.1 (p=0.024) Stroke/TIA 0.4 Permanent PNP 1.7 (p=0.001) Vascular access 2.9 Other: haemothorax 0.2

Ciconte, 201584 (observational)

n=143; CBA 1×3

79

Phrenic nerve pacing

83

95 NA 14

Transient PNP 6.3; permanent PNP 3.5 (recovery <1 year) Vascular access 1.4

Defaye, 201185 (observational)

n=117; CB 2×4

79

Phrenic nerve pacing

69

155 NA 35

Pericardial effusion 1.7/cardiac tamponade 0.9 Transient ST elevation 0.9 Transient PNP 3.4 Other: chest pain/haemoptysis 0.9

Khoueiry, 201686 (observational)

n=208 CB; n=103 CBA; CB(A) 2×4 minutes

100

Phrenic nerve pacing

83

133 (p=0.001) NA 26 (p=0.005)

Pericarditis/cardiac tamponade 0.3 Thromboembolic events 0.3 Transient phrenic palsy 2.3 (p=0.016) Gastroparesis 0.3, oesophageal ulcer 0.3 Vascular complications/major bleeding 2.3 Other: 0.7 (haemoptysis and haemomediastin)

Kuck, 201687 (multicentre RCT)

n=90 CB; n=279 CBA; CB 1×5; CBA 1×4

100

Phrenic nerve pacing

65

141 (p<0.001) N.A 17 (p<0.001)

Cardiac tamponade/effusion 0.3 Stroke/TIA 0.5 and transient neurologic complications 0.3 Transient and permanent PNP 2.7 (p=0.001) and 0.3 Gastrointestinal complication 0.3; oesophageal ulcer 0.3 Vascular access 1.9 Other: pulmonary or bronchial complication 0.5; other cardiac complications 0.8, anxiety 0.3

Luik, 2015161 (RCT)

n=156; CB 2×5; CBA 2×4

100

NA

61

161 (IQR 133–193) (p=0.006) NA 25 (IQR 18–31)

Pericardial effusion 1.3 Transient and permanent PNP 3.8 (p=0.002) and 1.9 Vascular access 5.1

Mugnai, 201488 (retrospective)

n=136; CB 2×5

100

Phrenic nerve pacing (12 mA, 1000 ms)

57

112 (p<0.001) NA

Pericardial effusion/cardiac tamponade 7.3/0.7 Transient ST-elevation 1.5 Phrenic nerve palsy 8.1 (p<0.001); 0.7 at 12 months Vascular access 1.5

79

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Atrial Fibrillation Ablation Devices and Complications Table 2: Cont. Author, year

Number of

AAD free

Procedural,

(study type)

patients, ablation

survival (1

ablation time

device and

year) (%)

and fluoroscopy

PAF (%)

Preventive techniques

protocol* Neumann, 2008 (observational)

Complications (%)

time (min)

n=346; CB2×5

85

NA

74

170 (IQR 140–195) Cardiac tamponade 0.6 46 (IQR 26–60) Transient PNP 7.5 40 (IQR 30–57) Vascular access 2.3

Providencia, 2017162 (multicentre retrospective)

n=393; CB 2×4

100

NA

68–80 at 18m

120 (p<0.001) NA 23

Pericardial effusion 0.3 (p=0.036) Stroke/TIA 0.3/0.5 and coronary gas embolism 0.3 PNP 1.8 (p=0.004) Vascular access 2.0 Other: 1.0 (haemoptysis and hemothorax)

Schmidt, 201490 (multicentre retrospective)

n=905 CB; (discretion of the physician)

100

Phrenic nerve pacing

NA

160 (IQR 130–200) 45 (IQR 40–57) (p<0.001) 34 (26-46) (p<0.001)

Cardiac tamponade 0.8 Stroke/TIA 0.3 and myocardial infarction 0.1 Permanent PNP 2.1 (p<0.001) Vascular access 1.4 Other: third-degree AV-block 0.1

Squara, 201591 (multicentre retrospective)

n=198 CBA; 2×4

100

NA

82 DC testing

110 (p=0.003) NA 18

Transient PNP 5.6 (p=0.001) Vascular access 1.7

Straube, 201493

n=224 CB; n=308 CBA; CB 2×5 CBA 2×4

100

Temperature balloon Oesophageal temperature monitoring

NA

185 versus. 175 (p=0.038) NA 34 versus 29 (p<0.001)

Pericardial effusion/cardiac tamponade 0.27/0.27 versus none Stroke/TIA 0.27/0.27 versus none and transient amaurosis fugax none versus 0.83 Transient PNP 27.5 versus 27.5 and permanent PNP 1.1 versus 1.67 Gastroparesis 0.27 versus none. Vascular access 1.10 versus 0.83

Straube, 201692 (multicentre observational)

n=193 (86 % CBA; n=164) NA

100

NA

71

112 (p<0.001) 32 (p<0.001) 16

Cardiac tamponade 0.4 Stroke 0.5 Transient/permanent PNP 1.6/0.5 Vascular access 7.5

Van Belle, 200894 (observational)

CB=141; NA

100

NA

48 (58 after second)

207 NA 50

Transient PNP 4 Vascular access 4 Other: haemoptysis 2

Vogt, 201395 (prospective observational)

n=605 CB; CB 2×6 (LSPV 3×5)

96

NA

62 (24 (IQR 12-42)

156 NA 25

Pericardial effusion/Cardiac tamponade 0.2/0.2 Stroke 0.3 Transient PNP 2.5 Asymptomatic pulmonary vein stenosis 0.3 Other: hemoptysis 1.7

Wasserlauf, 201596 (retrospective)

n=31 CB; n=70 CBA; 1×3-4

101

NA

60

193 (P<0.001) NA 46 (P<0.001)

Transient PNP 1 Vascular access 1 Other: urinary tract infections 3

89

Only observational/retrospective studies and randomised clinical trials with n>100 are included) in patients with paroxysmal atrial fibrillation, showing the use of different radiofrequency ablation devices, outcomes, the use of preventive techniques and complication rates. AAD = anti-arrhythmic drugs, CB = cryoballoon (first-generation), CBA = cryoballoon advanced (secondgeneration), DC = dormant conduction, IQR = interquartile range, PAF = paroxysmal atrial fibrillation, PNP = phrenic nerve pacing and TIA = transient ischaemic attack. p-values indicated significant differences between catheters from the same technology (Table 2) or between catheters from different technologies (Table 2 versus Table 1). *protocol (number of freeze cycles × duration in minutes).

Comparison of Ablation Devices Ablation Technology and Efficacy Outcome after cryoballoon ablation versus point-by point RFCA has been well studied, also in randomised trials: a recent meta-analysis of 10 studies (total of 6473 patients; 3 randomised trials) showed similar efficacy.118 Data comparing other single-shot techniques with RFCA are limited. Smaller studies suggest no significant differences in efficacy. A randomised multicentre clinical trial comparing the laserballoon with RFCA (178 versus 175 patients) reported a 61 versus 62 % AF free survival at 1 year off AAD.111 Also in another multicentre prospective trial comparing the laserballoon (n=68) with RFCA (n=66) there was no difference in outcome (71 versus 69 %, p=0.40) at 1-year follow-up

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(off AAD).114 In a study comparing the laserballoon with the cryoballoon (n=140) the efficacy at 1 year off AAD was comparable between the two techniques (73. versus 63 %).119

Ablation Technology and Procedural Time The reported procedure times for cryoballoon ablation are significantly shorter compared with point-by-point RFCA (Tables 1 and 2).118 Similarly, procedural times using multi-electrode ablation catheters (PVAC) are shorter if compared with point-by-point RFCA, while the efficacy was similar.120,121 Although in an early study longer procedural times were reported for laserballoon ablation compared with cryoballoon ablation and point-by-point RFCA,116 a recent study demonstrated

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Clinical Reviews: Electrophysiology and Ablation similar procedural duration (laserballoon 144 minutes, cryoballoon 136 minutes).119 This was also applicable when comparing laserballoon with RFCA (128 versus 135 minutes).114

Pericardial Effusion/Cardiac Tamponade Radiofrequency ablation compared with balloon-based devices is associated with an increased risk for cardiac tamponade (1.5 versus 0.1 %).122 This risk was higher in PVI plus additional lesion sets compared with PVI only (0.8 versus 0.1 %, p=0.024).122 For CF catheters, the reported incidences are higher (2.5–8 %).123–125 Based on published data (Tables 1 and 2), the estimated incidence of pericardial effusion/ cardiac tamponade is approximately 1.9  % (144 of 9793; range 1–12 %) for point-by-point RFCA and 0.7 % (47 of 6772; range 0–8 %) for the cryoballoon.

Stroke/TIA Cryoballoon ablation has been associated with a lower risk for thrombus formation compared with RFCA.126 In line with this data is the observed lower incidence of silent cerebral embolism compared with irrigated RFCA and PVAC.51,52,127 However, in a randomised study comparing laserballoon (n=33), cryoballoon (n=33) and irrigated RFCA (n=33), the incidence of asymptomatic cerebral lesions was not significantly different (24 %, 18  % and 24  %, respectively).116 For PVAC, a higher rate of micro-embolic signals and asymptomatic cerebral embolism has been observed compared with cryoballoon or RFCA.51,53,56 However, the incidence of symptomatic cerebral events (stroke/TIA) is similar (0.3 versus 0.2 %).

Phrenic Nerve Palsy and Oesophageal/Vagal Nerve Injury The incidence of PNP is significantly higher with the cryoballoon compared with RF, occurring in 3.9 % of the ablations (264 of 6772 cases; range 0–15  %), with permanent paralysis in <1  % (Tables 1 and 2). Similarly, laserballoon ablations are complicated by PNP in 5.8 % of patients.111 In contrast, the reported risk for oesophageal injury is lower with cryoballoon compared with RFCA.128

Pulmonary Vein Stenosis In a clinical trial comparing laserballoon versus RFCA, the incidence of PV stenosis was lower (0 versus 3 %).111 In a study comparing the laserballoon with RFCA and cryoballoon, only mild stenosis was seen in 18, 10 and 3.6 % of the PVs, respectively.129

Groin Complications and Bleeding Based on the published data summarised in Tables 1 and 2, there were no significant differences in groin-related complications between cryoballoon ablation and RFCA: total reported cases for cryoballoon are 139 (1.8 %) versus 179 (1.8 %) for RFCA.

Patient Characteristics Related to Complications The majority of patients included in ablation studies are male.130 Bleeding complications (groin-related) after catheter ablation were reported in 2.1 % of female patients (total 3265 patients, n=518 females) undergoing AF ablation. These numbers exceed those reported in males (n=27; 0.9 %).130 Both female gender and higher age have been associated with major adverse events.29 In a large nationwide survey, significant predictors for complications were female gender, high burden of comorbidity and low ablation volume of the hospital (<50 procedures/per year).131 In addition, patients with diabetes are at risk specifically for thrombotic or haemorrhagic complications.132

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Prevention of Complications Knowledge of all potential complications is important for prevention. Technical advances may help to improve safety. Three-dimensional electro-anatomical mapping and image integration can minimise radiation exposure. Careful procedural planning, close cooperation of different medical specialities (e.g. in hybrid AF treatment) and patient monitoring can further reduce complications.133

Pericardial Effusion/Tamponade For prevention of cardiac tamponade, limiting of radiofrequency power to 30–40 watts in the anterior wall and 20–30 watts in the posterior wall has been applied in most studies (Table 1a/Table 1b). Previous studies demonstrated that power limitation from 45–60 to ≤42 watts in linear lesions during AF ablation limited the incidence of cardiac tamponade.134 With the introduction of force-sensing catheters, RF power adjustment according to CF parameters became possible. However optimal values remain to be established.135

Stroke/TIA Trans-oesophageal echocardiography, computed tomography or cardiac magnetic resonance imaging may be used to exclude the presence of a left atrial thrombus.4 Symptomatic cerebral thromboembolic events are relatively rare (0.8 %).136 Independent risk factors are a CHADS2 score ≥2 and a history of stroke.137 Accurate sheath management can reduce the risk of air embolism (incidence <1  %). Continued oral anticoagulation (INR ≥ 2) during the procedure and maintenance of an adequate ACT (>300) should be considered to impact catheter thrombogenicity and the risk for (asymptomatic) cerebral embolism.138 A meta-analysis of 13 studies comparing non-vitamin K antagonists (NOAC) with vitamin-k antagonists (including 3 randomised controlled trials) could demonstrate that NOACs are safe and effective, but adequately-powered randomised controlled trials are required to confirm these results.139

Phrenic Nerve Palsy Superior caval vein phrenic nerve pacing with palpation of diaphragmatic excursions may allow discontinuation of ablation before permanent injury.140 Diaphragmatic compound motor action potential (CMAP) monitoring is a relatively new technique to prevent PNP.141 To measure the CMAP signal, the left and right arm electrocardiogram leads are placed, respectively, 5 cm above the xiphoid and 16 cm along the right costal margin. Peak-to-peak measurement is performed of the CMAP signal with each phrenic nerve capture during superior vena cava pacing with a decapolar catheter. CMAP signals were amplified using a bandpass filter between 0.5 and 100 kHz and recorded on a recording system (Prucka, GE Healthcare, Milwaukee, WI, USA). The technique is well described with figures by Lakhani et al.142 The ablation is terminated after reaching a 30 % reduction in CMAP, which resulted in a faster recovery of phrenic nerve injury compared with manual palpation.143 Abortion of the freeze cycle during cryoballoon ablation (“double stop” technique: immediate ablation termination with direct balloon deflation) is an important additional manoeuvre to prevent permanent nerve injury.143,144 Measuring of CMAP has reduced PNP incidence to 1  % compared to 4–11  % with manual palpation.145

Oesophageal/Vagal Nerve Injury Reduction of radiofrequency power to 20–25 watts aims to prevent oesophageal injury, atrial-oesophageal fistulae and vagal nerve injury causing gastric hypo-motility.146 Oesophagus and/or vagal nerve damage can be prevented by monitoring of the oesophageal temperature

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Atrial Fibrillation Ablation Devices and Complications during ablation,147–149 with a reduction from 36 % to 6 % in RFCA150 and from 18.8 % to 3.2 % in cryoballoon ablation.148 Temperature cut-offs that may be considered safe are >38.5°C for RFCA and <15°C for cryoballoon procedures.148,150 However, the use of temperature monitoring during RFCA is still under debate. Employment of temperature probes during RFCA has been associated with a higher incidence of oesophageal injury (30 versus 2.5 %; p<0.01) and using the temperature probe has been identified as an independent predictor.151 It has been hypothesised that the probe may act as an antenna drawing RF energy to the oesophagus.152 Other methods for prevention of oesophageal damage are active cooling with saline,153 changing the oesophagus position with a deviation tool and visualisation of the posterior wall and oesophagus with image-integration and electro-anatomical mapping.154–157 Whether prescription of prophylactic proton-pump inhibitors can prevent oesophageal damage needs further investigation.

Pulmonary Vein Stenosis Pulmonary vein stenosis is likely an underdiagnosed complication after AF ablation which may be due to the lack of specific symptoms.158 The most important step to reduce the risk of PV stenosis is to avoid ablation inside the PVs by careful determination of the PV ostia before ablation.

Groin Complications and Bleeding Management of coagulation is important to prevent vascular complications. In addition, a three-point strategy tested in 324 patients with continued warfarin during ablation, a smaller needle for access (18G instead of 21G) and avoiding arterial access has resulted in a reduction in vascular access complications (3.7 % versus 0  %; p=0.03), while the rates of thromboembolic complications and cardiac tamponade were similar.159 Ultrasound-guided versus conventional femoral puncture did not reduce major complication rate (0.6 versus 1.9  %; p=0.62) in 320 patients, however it was associated with significantly lower puncture time, higher rate of first pass success and less extra or arterial punctures.160

1.

2.

3.

4.

5.

6.

7.

8.

 alkins H, Reynolds MR, Spector P, et al. Treatment of atrial C fibrillation with antiarrhythmic drugs or radiofrequency ablation: two systematic literature reviews and metaanalyses. Circ Arrhythm Electrophysiol 2009;2:349–61. https://doi.org/10.1161/CIRCEP.108.824789; PMID: 19808490. Hakalahti A, Biancari F, Nielsen JC, Raatikainen MJ. Radiofrequency ablation vs. antiarrhythmic drug therapy as first line treatment of symptomatic atrial fibrillation: systematic review and meta-analysis. Europace 2015;17:370–8. https://doi.org/10.1093/europace/euu376; PMID: 25643988. Raatikainen MJ, Hakalahti A, Uusimaa P, et al. Radiofrequency catheter ablation maintains its efficacy better than antiarrhythmic medication in patients with paroxysmal atrial fibrillation: On-treatment analysis of the randomized controlled MANTRA-PAF trial. Int J Cardiol 2015;198:108–14. https://doi.org/10.1016/j.ijcard.2015.06.160; PMID: 26163901. Calkins H, Kuck KH, Cappato R, et al. 2012 HRS/EHRA/ ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design. J Interv Cardiac Electrophysiol 2012;33:171–257. https://doi. org/10.1007/s10840-012-9672-7; PMID: 22382715. Cappato R, Calkins H, Chen SA, et al. Updated worldwide survey on the methods, efficacy, and safety of catheter ablation for human atrial fibrillation. Circ Arrhythm Electrophysiol 2010;3:32–8. https://doi.org/10.1161/CIRCEP.109.859116; PMID: 19995881. Raviele A, Natale A, Calkins H, et al. Venice Chart international consensus document on atrial fibrillation ablation: 2011 update. J Card Electrophysiol 2012;23:890–923. https://doi. org/10.1111/j.1540-8167.2012.02381.x; PMID: 22953789. Chen J, Dagres N, Hocini M, et al. Catheter ablation for atrial fibrillation: results from the first European Snapshot Survey on Procedural Routines for Atrial Fibrillation Ablation (ESS-PRAFA) Part II. Europace 2015;17:1727–32. https://doi. org/10.1093/europace/euv315; PMID: 26462700. Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ ECAS/APHRS/SOLAECE expert consensus statement

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9.

10.

11.

12.

13.

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Conclusion Several ablation devices have been developed over the last 15 years to increase procedural efficacy. Improvement of safety profiles is often initiated after the occurrence of complications. Knowledge of potential and device-specific complications and awareness of currently considered asymptomatic procedure related events (e.g. cerebral emboli) is important for patient counselling and selection – primum non nocere. n

Clinical Perspective • C  ardiac tamponade remains an important complication and is more frequently observed in irrigated contact-force guided radiofrequency catheter ablation (RFCA) compared with balloon-based techniques. •  Compared with single-shot techniques, the procedural duration of point-by-point RFCA is longer, while fluoroscopy duration is usually shorter due to three-dimensional navigation. High-power short-duration ablation methods are in development to reduce procedural duration with limited data on the safety profile. •  Procedural duration for multi-electrode catheters is short. A potential drawback is the association with asymptomatic cerebral embolism, the clinical significance of which is not clarified yet. • Improvement of cryoballoon technology has led to shorter procedural and fluoroscopy times with similar efficacy and complication rates. Outcome and complications compared with RFCA are similar, except for a higher incidence of phrenic nerve palsy. Other balloon-based devices are in development with unknown safety profiles. •  Pre-procedural patient evaluation, appropriate device selection, optimisation of energy delivery and intraprocedural monitoring is important to balance efficacy and safety.

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ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

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J Cardiovasc Electrophysiol 2012;23:346–51. https://doi. org/10.1111/j.1540-8167.2011.02219.x; PMID: 22081875. 98. Ahmed H, Neuzil P, d’Avila A, et al. The esophageal effects of cryoenergy during cryoablation for atrial fibrillation. Heart Rhythm 2009;6:962–9. https://doi.org/10.1016/j. hrthm.2009.03.051; PMID: 19560085. 99. D’Avila A, Dukkipati S. Esophageal damage during catheter ablation of atrial fibrillation: is cryo safer than RF? PACE 2009;32:709–10. https://doi.org/10.1111/j.15408159.2009.02355.x; PMID: 19545331. 100. John RM, Kapur S, Ellenbogen KA, Koneru JN. Atrioesophageal fistula formation with cryoballoon ablation is most commonly related to the left inferior pulmonary vein. Heart Rhythm 2017;14:184–9. https://doi.org/10.1016/j.hrthm.2016.10.018; PMID: 27769853. 101. Lim HW, Cogert GA, Cameron CS, et al. Atrioesophageal fistula during cryoballoon ablation for atrial fibrillation. J Cardiovasc Electrophysiol 2014;25:208–13. https://doi.org/10.1111/ jce.12313; PMID: 24172231. 102. Stockigt F, Schrickel JW, Andrie R, Lickfett L. Atrioesophageal fistula after cryoballoon pulmonary vein isolation. J Cardiovasc Electrophysiol 2012;23:1254–7. https://doi.org/10.1111/j.15408167.2012.02324.x; PMID: 22486804. 103. Coutino HE, Takarada K, Sieira J, et al. Anatomical and procedural predictors of pulmonary vein stenosis in the setting of second-generation cryoballoon ablation. J Cardiovasc Med (Hagerstown) 2018;19:290–6. https://doi.org/10.2459/ JCM.0000000000000646; PMID: 29601309. 104. Satake S, Tanaka K, Saito S, et al. Usefulness of a new

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radiofrequency thermal balloon catheter for pulmonary vein isolation: a new device for treatment of atrial fibrillation. J Card Electrophysiol 2003;14:609–15. https://doi.org/10.1046/j.15408167.2003.02577.x; PMID: 12875422. 105. Yamaguchi Y, Sohara H, Takeda H, et al. Long-term results of radiofrequency hot balloon ablation in patients with paroxysmal atrial fibrillation: safety and rhythm outcomes. J Cardiovasc Electrophysiol 2015;26:1298–306. https://doi. org/10.1111/jce.12820; PMID: 26331460. 106. Sohara H, Ohe T, Okumura K, et al. Hotballoon ablation of the pulmonary veins for paroxysmal AF: a multicenter randomized trial in Japan. J Am College Cardiol 2016;68:2747–57. https://doi.org/10.1016/j.jacc.2016.10.037; PMID: 28007137. 107. Sohara H, Satake S, Takeda H, et al. Prevalence of esophageal ulceration after atrial fibrillation ablation with the hot balloon ablation catheter: what is the value of esophageal cooling? J Cardiovasc Electrophysiol 2014;25:686–92. https://doi. org/10.1111/jce.12394; PMID: 24576252. 108. Tanaka K, Satake S, Saito S, et al. A new radiofrequency thermal balloon catheter for pulmonary vein isolation. J Am Coll Cardiol 2001;38:2079–86. https://doi.org/10.1016/S07351097(01)01666-7; PMID 11738318. 109. Sohara H, Takeda H, Ueno H, et al. Feasibility of the radiofrequency hot balloon catheter for isolation of the posterior left atrium and pulmonary veins for the treatment of atrial fibrillation. Circ Arrhythm Electrophysiol 2009;2:225–32. https://doi.org/10.1161/CIRCEP.108.817205; PMID: 19808472. 110. Reddy VY, Neuzil P, Themistoclakis S, et al. Visually-guided balloon catheter ablation of atrial fibrillation: experimental feasibility and first-in-human multicenter clinical outcome. Circulation 2009;120:12–20. https://doi.org/10.1161/ CIRCULATIONAHA.108.840587; PMID: 19546385. 111. Dukkipati SR, Cuoco F, Kutinsky I, et al. Pulmonary vein isolation using the visually guided laser balloon: a prospective, multicenter, and randomized comparison to standard radiofrequency ablation. J Am Coll Cardiol 2015;66:1350–60. https://doi.org/10.1016/j.jacc.2015.07.036; PMID: 26383722. 112. Bhardwaj R, Reddy VY. Visually-guided laser balloon ablation of atrial fibrillation: a “real world” experience. Revista espanola de cardiologia (English ed) 2016;69:474–6. https://doi. org/10.1016/j.rec.2016.02.006; PMID: 27062677. 113. Bordignon S, Chun KR, Gunawardene M, et al. Endoscopic ablation systems. Expert Rev Med Devices 2013;10:177–83. https://doi.org/10.1586/erd.12.86; PMID: 23480087. 114. Schmidt B, Neuzil P, Luik A, et al. Laser balloon or widearea circumferential irrigated radiofrequency ablation for persistent atrial fibrillation: a multicenter prospective randomized study. Circ Arrhythm Electrophysiol 2017;10:pii: https://doi.org/10.1161/CIRCEP.117.005767; PMID: 29217521. 115. Dukkipati SR, Kuck KH, Neuzil P, et al. Pulmonary vein isolation using a visually guided laser balloon catheter: the first 200-patient multicenter clinical experience. Circ Arrhythm Electrophysiol 2013;6(3):467–72. https://doi.org/10.1161/ CIRCEP.113.000431; PMID: 23559674. 116. Schmidt B, Gunawardene M, Krieg D, et al. A prospective randomized single-center study on the risk of asymptomatic cerebral lesions comparing irrigated radiofrequency current ablation with the cryoballoon and the laser balloon. J Cardiovasc Electrophysiol 2013;24:869–74. https://doi. org/10.1111/jce.12151; PMID: 23601001. 117. Dukkipati SR, Woollett I, McElderry HT, et al. Pulmonary vein isolation using the visually guided laser balloon: results of the US feasibility study. J Cardiovasc Electrophysiol 2015. https://doi. org/10.1111/jce.12727; PMID: 26080067. 118. Buiatti A, von Olshausen G, Barthel P, et al. Cryoballoon vs. radiofrequency ablation for paroxysmal atrial fibrillation: an updated meta-analysis of randomized and observational studies. 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Complications in catheter ablation of atrial fibrillation in 3,000 consecutive procedures. balloon versus radiofrequency current ablation. JACC Clin Electrophysiol 2017;3:154–61. https://doi.org/10.1016/j. jacep.2016.07.002; PMID: 29759388. 123. Kautzner J, Neuzil P, Lambert H, et al. EFFICAS II: optimization of catheter contact force improves outcome of pulmonary vein isolation for paroxysmal atrial fibrillation. Europace 2015;17:1229–35. https://doi.org/10.1093/europace/euv057; PMID: 26041872. 124. Natale A, Reddy VY, Monir G, et al. Paroxysmal AF catheter ablation with a contact force sensing catheter: results of the prospective, multicenter SMART-AF trial. J Am Coll Cardiol

2014;64:647–56. https://doi.org/10.1016/j.jacc.2014.04.072; PMID: 25125294. 125. Kuck KH, Reddy VY, Schmidt B, et al. A novel radiofrequency ablation catheter using contact force sensing: Toccata study. Heart Rhythm 2012;9:18–23. https://doi.org/10.1016/j. hrthm.2011.08.021; PMID: 21872560. 126. Khairy P, Chauvet P, Lehmann J, et al. Lower incidence of thrombus formation with cryoenergy versus radiofrequency catheter ablation. Circulation 2003;107:2045–50. https://doi. org/10.1161/01.CIR.0000058706.82623.A1; PMID: 12668527. 127. Neumann T, Kuniss M, Conradi G, et al. MEDAFI-Trial (Microembolization during ablation of atrial fibrillation): comparison of pulmonary vein isolation using cryoballoon technique vs. radiofrequency energy. Europace 2011;13:37–44. https://doi. org/10.1093/europace/euq303; PMID: 20829189. 128. Ripley KL, Gage AA, Olsen DB, et al. Time course of esophageal lesions after catheter ablation with cryothermal and radiofrequency ablation: implication for atrio-esophageal fistula formation after catheter ablation for atrial fibrillation. J Cardiovasc Electrophysiol 2007;18:642–6. https://doi.org/10.1111/ j.1540-8167.2007.00790.x; PMID: 17428270. 129. Nagase T, Bordignon S, Perrotta L, et al. Low risk of pulmonary vein stenosis after contemporary atrial fibrillation ablation – lessons from repeat procedures after radiofrequency current, cryoballoon, and laser balloon. Circulation 2018;82:1558–65. https://doi.org/10.1253/circj.CJ-17-1324; PMID: 29618679. 130. Patel D, Mohanty P, Di Biase L, et al. Outcomes and complications of catheter ablation for atrial fibrillation in females. Heart Rhythm 2010;7:167–72. https://doi.org/10.1016/j. hrthm.2009.10.025; PMID: 20022814. 131. Tripathi B, Arora S, Kumar V, et al. Temporal trends of in-hospital complications associated with catheter ablation of atrial fibrillation in the United States: An update from Nationwide Inpatient Sample database (2011–2014). J Cardiovasc Electrophysiol 2018;29:715–24. https://doi.org/10.1111/ jce.13471; PMID: 29478273. 132. Tang RB, Dong JZ, Liu XP, et al. Safety and efficacy of catheter ablation of atrial fibrillation in patients with diabetes mellitus – single center experience. J Interv Card Electrophysiol 2006;17:41–6. https://doi.org/10.1007/s10840-006-9049-x; PMID: 17235682. 133. Umbrain V, Verborgh C, Chierchia GB, et al. Onestage approach for hybrid atrial fibrillation treatment. Arrhythm Electrophysiol Rev 2017;6:210–6. https://doi. org/10.15420/2017.36.2; PMID: 29326837. 134. Hsu LF, Jais P, Hocini M, et al. Incidence and prevention of cardiac tamponade complicating ablation for atrial fibrillation. PACE 2005;28 Suppl 1:S106-9. https://doi.org/10.1111/j.15408159.2005.00062.x; PMID: 15683473. 135. Ullah W, Schilling RJ, Wong T. Contact force and atrial fibrillation ablation. J Atr Fibrillation 2016;8:1282. https://doi. org/10.4022/jafib.1282; PMID: 27909471. 136. Patel D, Bailey SM, Furlan AJ, et al. Long-term functional and neurocognitive recovery in patients who had an acute cerebrovascular event secondary to catheter ablation for atrial fibrillation. J Cardiovasc Electrophysiol 2010;21:412–7. https://doi. org/10.1111/j.1540-8167.2009.01650.x; PMID: 19925610. 137. Scherr D, Sharma K, Dalal D, et al. Incidence and predictors of periprocedural cerebrovascular accident in patients undergoing catheter ablation of atrial fibrillation. J Cardiovasc Electrophysiol 2009;20:1357–63. https://doi.org/10.1111/j.15408167.2009.01540.x; PMID: 19572951. 138. Di Biase L, Gaita F, Toso E, et al. Does periprocedural anticoagulation management of atrial fibrillation affect the prevalence of silent thromboembolic lesion detected by diffusion cerebral magnetic resonance imaging in patients undergoing radiofrequency atrial fibrillation ablation with open irrigated catheters? Results from a prospective multicenter study. Heart Rhythm 2014;11:791–8. https://doi. org/10.1016/j.hrthm.2014.03.003; PMID: 24607716. 139. Elgendy AY, Mahtta D, Barakat AF, et al. Meta-analysis of safety and efficacy of uninterrupted non-vitamin K antagonist oral anticoagulants versus vitamin K antagonists for catheter ablation of atrial fibrillation. Am J Cardiol 2017;120:1830–6. https://doi.org/10.1016/j.amjcard.2017.07.096; PMID: 28882334. 140. Bunch TJ, Bruce GK, Mahapatra S, et al. Mechanisms of phrenic nerve injury during radiofrequency ablation at the pulmonary vein orifice. J Cardiovasc Electrophysiol 2005;16:1318– 25. https://doi.org/10.1111/j.1540-8167.2005.00216.x; PMID: 16403064. 141. Kowalski M, Ellenbogen KA, Koneru JN. Prevention of phrenic nerve injury during interventional electrophysiologic procedures. Heart Rhythm 2014;11:1839–44. https://doi. org/10.1016/j.hrthm.2014.06.019; PMID: 24952147. 142. Lakhani M, Saiful F, Parikh V, et al. Recordings of diaphragmatic electromyograms during cryoballoon ablation for atrial fibrillation accurately predict phrenic nerve injury. Heart Rhythm 2014;11:369–74. https://doi.org/10.1016/j. hrthm.2013.11.015; PMID: 24252287. 143. Miyazaki S, Kajiyama T, Watanabe T, et al. Characteristics of phrenic nerve injury during pulmonary vein isolation using a 28-mm second-generation cryoballoon and short freeze strategy. J Am Heart Assoc 2018;7:pii: e008249. https://doi. org/10.1161/JAHA.117.008249; PMID: 29574457. 144. Ghosh J, Sepahpour A, Chan KH, et al. Immediate balloon deflation for prevention of persistent phrenic nerve palsy during pulmonary vein isolation by balloon cryoablation. 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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. 154. Koruth JS, Reddy VY, Miller MA, et al. Mechanical esophageal displacement during catheter ablation for atrial fibrillation. J Cardiovasc Electrophysiol 2012;23:147–54. https://doi. org/10.1111/j.1540-8167.2011.02162.x; PMID: 21914018. 155. Nair GM, Nery PB, Redpath CJ, et al. Atrioesophageal fistula in the era of atrial fibrillation ablation: a review. Can J Cardiol 2014;30:388–95. https://doi.org/10.1016/j.cjca.2013.12.012; PMID: 24582720. 156. 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;pii: S1547-5271(18)30362-X. https://doi.org/10.1016/j. hrthm.2018.04.017; PMID: 29678784; epub ahead of press. 157. Chugh A, Rubenstein J, Good E, et al. Mechanical displacement of the esophagus in patients undergoing left atrial ablation of atrial fibrillation. Heart Rhythm 2009;6:319–22. https://doi.org/10.1016/j.hrthm.2008.12.010; PMID: 19251204. 158. Edriss H, Denega T, Test V, Nugent K. Pulmonary vein stenosis complicating radiofrequency catheter ablation for atrial fibrillation: A literature review. Resp Med 2016;117:215–22. https://doi.org/10.1016/j.rmed.2016.06.014; PMID: 27492534. 159. Abhishek F, Heist EK, Barrett C, et al. Effectiveness of a strategy to reduce major vascular complications from catheter ablation of atrial fibrillation. J Interv Card Electrophysiol 2011;30:211–5. https://doi.org/10.1007/s10840-010-9539-8; PMID: 21336618. 160. Yamagata K, Wichterle D, Roubicek T, et al. Ultrasound-guided versus conventional femoral venipuncture for catheter ablation of atrial fibrillation: a multicentre randomized efficacy and safety trial (ULTRA-FAST trial). Europace 2018;20:1107–14. https://doi.org/10.1093/europace/eux175; PMID: 28575490 161. Luik A, Radzewitz A, Kieser M, et al. cryoballoon versus open irrigated radiofrequency ablation in patients with paroxysmal atrial fibrillation: the prospective, randomized, controlled, noninferiority FreezeAF study. Circulation 2015;132:1311–9. https://doi.org/10.1161/CIRCULATIONAHA.115.016871;

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Clinical Reviews: Clinical Arrhythmias

Arrhythmogenic Inflammatory Cardiomyopathy: A Review Brenton S Bauer, Anthony Li and Jason S Bradfield UCLA Cardiac Arrhythmia Center, David Geffen School of Medicine at UCLA, Los Angeles, USA

Abstract Arrhythmogenic inflammatory cardiomyopathy is a recent clinical description of a subgroup of patients with non-ischaemic cardiomyopathy who are referred to electrophysiologists for evaluation and management of ventricular arrhythmias and are found to have evidence of active cardiac inflammation. The identification of these patients is key, since the aetiology of their arrhythmic burden is likely both related to scar-mediated and direct inflammatory mechanisms, which may have different treatment approaches. Evaluation of these patients starts with a full clinical history and physical examination along with echocardiography, as with most patients with cardiomyopathy, however, additional imaging with fluorodeoxyglucose PET-CT and cardiac MRI is crucial. Medical treatment is aimed at targeting traditional neurohumeral mediators to achieve recovery of ejection fraction, in addition to immunosuppressant medication to directly treat inflammation. While medical treatment alone is successful in many patients, some will require further invasive management with electrophysiologic study and radiofrequency catheter ablation.

Keywords Arrhythmogenic inflammatory cardiomyopathy, computed tomography, ejection fraction, fluorodeoxyglucose, implantable cardioverterdefibrillator, ischemic cardiomyopathy, non-ischaemic cardiomyopathy, ventricular arrhythmia, ventricular tachycardia Disclosure: The authors have no conflicts of interest to declare. Received: 12 April 2018 Accepted: 26 June 2018 Citation: Arrhythmia & Electrophysiology Review 2018;7(3):181–6. DOI: https://doi.org/10.15420/aer.2018.26.2 Correspondence: Jason S Bradfield MD, UCLA Cardiac Arrhythmia Center, 100 Medical Plaza, Suite 660, Los Angeles, CA, USA, E: JBradfield@mednet.ucla.edu

Ventricular arrhythmias (VA) are commonly associated with structural heart disease and have substantial impact on patient outcomes and health system costs. Within the realm of cardiomyopathy (CM), there has been substantial progress with respect to ischaemic CM (ICM) in the understanding of infarct related scar biology and scar-mediated ventricular tachycardia (VT). This has led to interventions to decrease VT recurrence and associated ICD shocks, including radiofrequency catheter ablation therapy.1 However, these advances have not translated into the same long-term successes for patients who present with VT in the setting of nonischaemic CM (NICM).2 Yet, it has been increasingly recognised in VT referral centres that there is a growing number of patients referred for consideration of VT ablation secondary to NICM.3 NICM comprises a heterogeneous group of disorders and in a majority of patients the underlying cause is not identified, leading to a label of idiopathic. This is problematic for a variety of reasons since, in many instances, patients are not offered a uniform diagnostic approach and ultimately the absence of a causal entity may impair the ability to provide optimal care. Active myocardial inflammation is becoming better understood as a frequent finding in NICM and a potential contributor to poorly controlled VA.4

Definition Arrhythmogenic inflammatory cardiomyopathy (AIC) is a recent clinical description encompassing a broad group of patients with NICM, who are referred to electrophysiologists for management of VA and are found to have evidence of active myocardial inflammation of unclear aetiology (Figure 1).5

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Proposed diagnostic criteria for AIC are: •  Non-ischaemic cardiomyopathy with an left ventricular ejection fraction (LVEF) of <50 %. • The presence of documented VA – monomorphic or polymorphic VT, ventricular fibrillation or frequent premature ventricular contractions. • Patchy focal or focal on diffuse fluorodeoxyglucose (FDG) uptake on PET imaging. Diffuse uptake was eliminated from the diagnostic criteria, given the potential for inadequate fasting/physiologic uptake with limitation of specificity.6 AIC can be further categorised according to perfusion/ metabolism mismatch by inflammation in the presence of scar (late AIC) and in the absence of scar (early AIC) with or without extra cardiac involvement (AIC+; Figure 2). AIC as a classification schema provides a useful framework for conceptualising this particular group of patients and as a reminder to the potential role that chronic inflammation plays in mediating this disease process.

Epidemiology The prevalence of NICM is difficult to determine due to the variety of pathologies that contribute and the regional and geographic variability of those conditions. A study by Lipshultz et al. reviewed the US paediatric CM registry from 1996 to 2003 and determined that the incidence of CM was 1.13 per 100,000 children.7 In adults, one of the largest ongoing registries is the Sarcomeric Human Cardiomyopathy Registry (SHaRe) which has reported an overall prevalence of approximately 2.4 million adults living with either hypertrophic or dilated cardiomyopathy in the US and Europe. A variety of national and international registries exist for both children and adults with specific types of CM, but there is a

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Clinical Reviews: Clinical Arrhythmias Figure 1: Diagnostic Criteria for Arrhythmogenic Inflammatory Cardiomyopathy

viruses that cause CM include echoviruses, Epstein-Barr, hepatitis C, HIV and influenza A.

Bacterial Nonischemic (no presence of coronary artery disease)

Cardiomyopathy (EF <50 %)

Arrhythmogenic Inflammatory Cardiomyopathy

Ventricular arrhythmias

Myocardial Inflammation

Bacteria are usually considered in the aetiology of endocarditis, but many bacterial species are known to cause myocarditis. Most lead to acute myocarditis that tends to recover, but some bacterial entities linger as unrecognised chronic myocarditis. Bacterial involvement tends to occur via direct inoculation, seeding from bacteraemia, or the effects of toxins produced by bacteria during the course of their lifecycle in the human host.11 Some prominent bacteria species that must be considered in the appropriate patient are Chlamydia, Corynebacterium diphtheriae, Legionella, Mycobacterium tuberculosis, Mycoplasma, Staphylococcus, Streptococcus A and S pneumoniae.

Other paucity of data on the prevalence of NICM overall and more specifically on chronic myocarditis/inflammatory cardiomyopathy given the lack of large studies in these areas. The key finding from the paper by Tung et al. was that in a cohort of 103 patients with NICM and VA 49 % had underlying myocardial inflammation.5 This study is limited by referral bias given the highly sub-selected group of patients included. Nevertheless, there is likely a significant population of patients with NICM that have unrecognised chronic inflammation that requires further study.

Pathology The pathophysiologic basis of AIC is not well understood and there has not been sufficient investigation into this newly described entity. Some patients with NICM and VA have alternative diagnoses that are made after further diagnostics are considered. An example of this would be in a patient identified as having AIC+ after evaluation of PET-CT imaging, but is reclassified as systemic sarcoidosis with cardiac involvement after intrathoracic lymph node biopsy confirms the presence of noncaseating granulomas and chronic inflammation on histology.8 In the Tung et al. study, 60 % of the patients who underwent biopsy demonstrated evidence of chronic lymphocytic infiltration and inflammation. The significance of this finding is not clear. It is likely that a role is played by an inflammatory trigger in a person with an underlying genetic predisposition towards chronic inflammation and autoimmunity, but this hypothesis will require further scientific evaluation.9

Differential Diagnoses AIC is considered an aetiology of NICM that exists within the realm of chronic inflammatory CM. It is imperative to consider other causes of chronic inflammatory CM to ensure patients receive the appropriate diagnostic and therapeutic possibilities.

Infectious Viral Infectious aetiologies of chronic inflammatory CM are the most studied, with viral myocarditis being the best understood. The most common viruses associated with cardiotropism are the enteroviruses, with coxsackie B virus being the most highly implicated. A study by Donoso Mantke et al. evaluated the prevalence of cardiotropic viruses in explanted hearts of patients who underwent transplantation and found enteroviruses (mostly coxsackie B) and adenoviruses, followed by parvovirus B19, human herpes virus 6 and cytomegalovirus.10 Other

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Other organisms that may be considered usually depend on risk factors such as living in or travel to endemic locations, diet, age and immunosuppression status. Some of the more notable infectious agents are fungal (Aspergillus, Cryptococcus and Candida), helminthic (Trichinella spiralis) and protozoal (Toxoplasma gondii and Trypanosoma cruzi).9

Autoimmune Diseases There are a variety of autoimmune conditions that can involve chronic myocarditis as either a primary or secondary feature and affect the heart by differing mechanisms. The various autoimmune diseases that should be considered include sarcoidosis, Churg-Strauss and eosinophilic myocarditis, giant cell myocarditis, dermatomyositis, inflammatory bowel disease, systemic lupus erythematosus, rheumatoid arthritis, scleroderma, and chronic lymphocytic myocarditis.

Drug Reactions Drug reactions can occur by predominantly two different mechanisms: hypersensitivity/immunologic mediate and direct toxic effects. Drugs to be considered as implicated in hypersensitivity/immunologic class include penicillin, ampicillin, cephalosporins, tetracyclines, sulphonamides, benzodiazepines, clozapine, loop/thiazide diuretics, methyldopa and tricyclic antidepressants. Drugs that may have a direct toxic effect on the myocardium include amphetamines, cocaine, anthracyclines, cyclophosphamide, 5-fluorouracil, trastuzumab and phenytoin.9

Risk of Ventricular Arrhythmia/Sudden Cardiac Death and Myocardial Inflammation Structural changes in the ventricular myocardium are implicated in the risk of VA and sudden cardiac death (SCD) in NICM. Numerous studies have implicated the degree of systolic dysfunction as having stepwise higher risks, with an EF of <35 % appropriate for primary prevention ICD implantation in most patients. Yet, in patients with AIC and other chronic inflammatory CM, data suggest that foci of inflammation and local fibrosis portend a significant risk of VA and SCD despite potentially normal or only mildly reduced systolic function.12 Mueller et al. showed that in patients with NICM with mean EF >35 %, inducibility of VA during programmed ventricular stimulation correlated significantly with areas of late gadolinium enhancement on cardiac MRI.13 A meta-analysis by Scott et al. reviewed the utility of scar quantification by cardiac MRI and identified it as a possible valuable tool in determining need for ICD therapy for primary prevention of SCD in patients with EF >35 %.14 Furthermore, the degree and localisation of inflammation as identified on PET-CT imaging has been shown to have

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Arrhythmogenic Inflammatory Cardiomyopathy prognostic value. Blankstein et al. demonstrated that patients with inflammation on PET-CT involving the right ventricle (RV) secondary to cardiac sarcoidosis had worse outcomes including a fivefold higher event rate with respect to malignant VA and death. This finding was postulated to be a result of a variety of possible mechanisms including RV involvement indicating greater burden of inflammatory disease and the possibility of RV inflammation being a more arrhythmogenic substrate.15 Furthermore, their study also demonstrated that areas of inflammation with concurrent perfusion defects also portend a graver prognosis. This finding mirrors the finding of Tung et al. that patients with late AIC/AIC+ had more recurrent VT despite treatment with immunosuppressive therapy and/or ablation therapy, which is likely to be related to the presence of scar.5

Figure 2: Classification Schema of Arrhythmogenic Inflammatory Cardiomyopathy Based on PET-CT Imaging

Diagnosis History and Physical The completion of a thorough history and physical examination should be the first step in assessment of patients with possible AIC. Given the nonspecific systemic manifestations of AIC, the utility of the history and physical is to identify more specific features of other disease processes (e.g. rheumatologic or autoimmune) that will guide further diagnostic testing, including laboratory and imaging.

Categorisation of arrhythmogenic inflammatory cardiomyopathy (AIC) according to perfusion/ metabolism mismatch by inflammation in the presence of scar (late AIC) and in the absence of scar (early AIC) with or without extra cardiac involvement (AIC +). Source: Tung, et al., 2015.5 Reprinted with permission from Elsevier.

Laboratory Testing Laboratory tests which identify non-specific inflammation (e.g. ESR and C-reactive protein) and myocardial damage (e.g. troponin) are important both during the initial diagnostic phase and for subsequent follow up of response to therapy. Further laboratory testing should be guided based upon clinical suspicion as determined by the history and physical.

Echocardiography Two-dimensional transthoracic echocardiography is an important diagnostic modality in AIC. While the majority of the echo findings are nonspecific, it is crucial to rule out other causes of NICM that do have more specific echo diagnostic criteria (e.g. hypertrophic cardiomyopathy). The main characteristic is systolic dysfunction with global hypokinesis. However, more specific regional wall motion abnormalities can be identified in a non-coronary artery distribution. Speckle tracking echocardiography is likely to be a useful tool as it has recently been demonstrated to identify abnormal myocardial strain patterns in early cardiac sarcoidosis, but this will require further study in AIC.16

Cardiac MRI Cardiac MRI provides a highly specific tool for imaging inflammation and scar in patients with AIC. Cine imaging utilising steady state free precession (also known as bright blood imaging) sequences allows for evaluation of segmental wall motion abnormalities in addition to quantification of function.17 Late gadolinium enhancement (LGE) images are obtained with a pulsed inversion sequence taken 10 minutes after gadolinium contrast administration. LGE allows for identification of necrosis and replacement of viable myocardium by scar.17 Localisation patterns of LGE are important in helping to determine the potential type of AIC at play. For example, LGE in a diffuse subepicardial localisation suggests viral myocarditis, patchy basal predominant uptake suggests cardiac sarcoidosis, and endomyocardial apical predominance in eosinophilic myocarditis.18 Active inflammation can be identified utilising T2-weighted sequences to demonstrate associated oedema.19 However, there are many

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limitations with current T2-weighted sequences in cardiac MRI that make it less widely utilised including but not limited to: low signal to noise ratio, high dependence on magnetic field homogeneity, loss of signal due to cardiac motion in black blood preparation, motion artifact susceptibility and subjective inter-reader variability.20 Development of new magnetic resonance techniques and sequences are being investigated to minimise these limitations since cardiac MRI is the only modality to be able to noninvasively evaluate myocardial oedema, which represents early phase of myocardial inflammation. Furthermore, identification of active inflammation as compared to a preponderance of scar is likely to be important in both its prognostic value and for determination of ideal therapy (e.g. immunosuppressive therapy versus ablation), but further data are needed. Lastly, cardiac MRI is crucial in helping to identify other causes of NICM that have a preponderance towards VA. Arrhythmogenic right ventricular dysplasia (ARVD) is commonly misdiagnosed in patients with RV involvement caused by cardiac sarcoidosis or AIC. ARVD is a predominantly hereditary condition with mutations in genes encoding for myocardial intercalated discs, most commonly desmosomal proteins.21 These abnormalities eventually lead to fibrofatty infiltration and replacement of normal myocardial tissue, predominantly in the RV, with resultant cardiomyopathy, clinical heart failure, and significant predisposition towards VA. Cardiac MRI is helpful in confirming the diagnosis of ARVD based upon the assessment of RV structure and kinetics, in addition to fibrofatty infiltration as determined utilising fat suppression sequences (e.g. fat saturation and triple inversion recovery).22

PET-CT PET-CT imaging can be utilised with a high degree of sensitivity to identify patients with AIC.23 As previously discussed, in the Tung et al. study, nearly half of the study population were noted to have myocardial inflammation and/or perfusion defects on 18-FDG-PET-CT imaging. PET-CT cardiac imaging utilises both perfusion imaging with radiotracers 13-N NH3 or 82Rb and metabolism imaging with

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Clinical Reviews: Clinical Arrhythmias radiotracer 18-F FDG.24 Furthermore, CT is used for attenuation correction and improved anatomic localisation, but at the expense of increased radiation exposure with this modality. 18-FDG uptake within myocardium in the setting of no perfusion abnormality signifies a mismatch, which represents early inflammation without fibrosis. This is in contrast to 18-F FDG uptake in setting of perfusion defect or absence of 18-F FDG uptake, which represents late stage and burned out disease respectively. Recent data in cardiac sarcoidosis have demonstrated that pattern of 18-FDG uptake and perfusion defect are not only diagnostic, but can be prognostic, both in the natural course of the disease in addition to response to therapy.15, 25 This may also be true for AIC as a whole but warrants further investigation.

Endomyocardial Biopsy Endomyocardial biopsy is an invasive approach to obtain tissue for histopathologic assessment and is still considered to be the gold standard with respect to diagnosis of myocarditis overall (infectious, autoimmune, etc). While specificity is excellent, sensitivity is poor for a variety of inflammatory CMs because of sampling error or bias.

Treatment Currently there are no prospective or randomised controlled clinical trials specifically investigating therapies in patients with AIC. Thus, best practice for management of AIC patients is based upon literature and therapy better studied in cohorts with other aetiologies of NICM.

Beta Blockers Beta blockers are an important class of medications in the management of chronic heart failure with reduced ejection fraction (HFrEF). Furthermore, it has been found in a small number of studies that the specific agent chosen may play an important role. In a rat model with inflammatory CM, carvedilol was demonstrated to be cardioprotective due to suppression of inflammatory cytokines whereas both metoprolol and propranolol were not.26 Beta blockers have also been noted to have an independent survival advantage in patients with VA who don’t already have an ICD, which is likely to be a large proportion of AIC patients.27

ACE Inhibitors and ARBs Angiotensin-converting enzyme (ACE) inhibitor and angiotensin-receptor blocker (ARB) therapy are well established in HFrEF management, with early initiation helpful in minimising maladaptive ventricular remodelling and have demonstrated substantial survival advantage. There are small mouse model studies that have demonstrated this in autoimmune myocarditis for ACE inhibitors and ARBs, but further studies are warranted specifically in patients with AIC.28,29

Aldosterone Antagonists Aldosterone antagonists have an increasing role in the management of HFrEF patients both for ischemic and non-ischaemic aetiologies of disease. There are small mouse model studies that demonstrate anti-inflammatory benefits in viral myocarditis, but there have not been studies in our review of these agents in virus negative chronic myocarditis or for AIC patients in particular.

Immunosuppressive Therapy Immunosuppressive therapy has been a controversial topic in the management of inflammatory CM overall. There have been a variety of trials using heterogeneous methods, study populations, and outcome measures that have provided little further clarification. In 1989, Parrillo

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et al. published one of the earliest trials evaluating prednisone in idiopathic dilated CM.30 This was a randomised controlled trial of 102 patients with idiopathic dilated CM and endomyocardial biopsy demonstrating inflammatory features on histopathology. Patients were assigned to prednisone or placebo, with the prednisone arm demonstrating a statistically significant 2.2 % absolute improvement in LVEF. The improvement in LVEF was the primary outcome measurement, as the study was not powered to evaluate survival benefit. Subsequently, the 1995 European Study of Epidemiology and Treatment of Cardiac Inflammatory Disease (ESETCID) examined 182 acute or chronic myocarditis patients with LVEF <45  %.31 Patients with a cytomegalovirus, enterovirus or adenovirus were given antiviral or immunoglobulin versus placebo. Subjects with virus negative myocarditis were administered prednisolone and azathioprine or placebo. The primary outcome was reduction in inflammation, but no statistically significant benefit was seen in either the virus positive or virus negative arms versus placebo . The Myocarditis Treatment Trial (MTT), published in the same year as the ESETCID trial, was a multicentre randomised controlled trial of 111 patients with myocarditis and LVEF <45  % assigned to conventional heart failure therapy or immunosuppressive therapy with prednisone plus cyclosporine or azathioprine.32 This study was designed to evaluate mortality benefit, but there was no benefit demonstrated at the conclusion of the trial. In 2009, the Tailored Immosuppression in Inflammatory Cardiomyopathy (TIMIC) study was published, which was a randomised controlled trial of 85 patients with biopsy proven virus negative inflammatory CM assigned to prednisone and azathioprine or placebo over a 6-month period.33 The immunosuppression arm of this trial did demonstrate a statistically significant improvement in LVEF and reduction in LV chamber dimensions as compared to the placebo arm. In the Tung et al. study of AIC patients, it was retrospectively discovered that subjects with early AIC and AIC+ demonstrated greater benefit with respect to reduction in recurrent VT with the use of immunosuppressive therapy compared to late AIC over a 6-month period.5 This may be explained by immunosuppressive therapy having greater benefit in the setting of active inflammation before the development of scar later in the disease course. There are significant limitations with past studies due to heterogeneity of included patients with acute, subacute, and chronic myocarditis; issues with interpretation of endomyocardial biopsy results within certain studies; and choice of immunosuppressive therapy. Further studies are warranted to tease out specific groups of patients including AIC patients that may in fact benefit from early and/or long-term immunosuppressive therapy. Despite these limitations, a trial of immunosuppressive therapy could be considered in patients with suspected AIC as determined by clinically proposed criteria and supported by advanced imaging (PET-CT and/or cardiac MRI). Based upon the work of Tung et al., patients presenting with VT storm can be induced with two doses of methylprednisolone 1g IV, followed by 40 mg oral prednisone daily. Patients without VT storm can be started on daily prednisone without pulsed IV dose. After 8 weeks, repeat PET-CT imaging to assess for response in addition to clinical assessment of reduction in arrhythmia burden. If improvement noted, then consideration

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Arrhythmogenic Inflammatory Cardiomyopathy for tapering dose of prednisone by 10 mg every 1−2 months with gradual transition to a steroid sparing immunosuppressant agent (e.g. azathioprine, etc.).5

Implantable cardioverter-defibrillator therapy ICD therapy has been a cornerstone of HFrEF management since pivotal trials such as the Multicenter Automatic Defibrillator Implantation Trials (MADIT and MADIT-II), and Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) had demonstrated reduced mortality over 1−5 years follow-up.34−36 Those studies were a composite of both ICM and NICM and thus difficult to ascertain the benefit for NICM and more specifically AIC. Most recently, the Danish Study to Assess the Efficacy of ICDs in Patients with Non-ischemic Systolic Heart Failure on Mortality (DANISH) study of 556 patients with NICM and symptomatic heart failure found that there was an insignificant reduction in the primary outcome of all-cause mortality, but with a statistically significant reduction in SCD with ICD over control.37 While this trial provided more specific data as to the benefit of ICD therapy in patients with NICM, a major limitation with this study and a reflection of the field in general, is the lack of stratification of types of NICM. The field cannot be oversimplified into ICM versus NICM without missing the mark on how best to manage patients with specific forms of NICM. For instance, hypertrophic CM and AIC are both considered specific types of NICM that can manifest with malignant VA. In the field of hypertrophic CM, there are fairly strict evidence-based guidelines as to the use of ICD therapy. However, these data and guidelines cannot be used in patients with AIC given the significant differences in their pathophysiology and clinical manifestations. Even within the field of inflammatory cardiomyopathies there exists significant differences between specific causes based upon the natural course of the disease process that makes risk stratification of sudden cardiac death difficult. Giant cell myocarditis is a very rare form of inflammatory CM that is usually fatal within 6 months without heart transplantation. Therefore, while ICD therapy in these cases may avert SCD, it would not be expected to change the long-term expectation and survivability of the underlying disease. In addition, other diseases such as cardiac sarcoidosis and likely AIC, can have relapsing/remitting courses and the natural progression may be affected by immunosuppressive therapy. Thus, it is not known how ICD therapy would benefit these individuals with respect to improving long-term survival. There is a significant paucity of data in the field of ICD therapy in subgroups of NICM and at this time clinicians must use currently published guidelines and their best clinical judgement to have a discussion with their patients about using this particular therapy.

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 jijola OA, Tung R, Shivkumar, K. Ventricular tachycardia in A ischemic heart disease substrates. Indian Heart J 2014; 66(Suppl 1):S24−34. https://doi.org/10.1016/j.ihj.2013.12.039; PMID: 24568826. Dinov B, Fiedler L, Schonbauer R, et al. Outcomes in catheter ablation of ventricular tachycardia in dilated nonischemic cardiomyopathy compared with ischemic cardiomyopathy: results from the Prospective Heart Centre of Leipzig VT (HELP-VT) Study. Circulation 2014;129:728−36. https://doi.org/10.1161/circulationaha.113.003063; PMID: 24211823. Sacher F, Tedrow UB, Field ME, et al. Ventricular tachycardia ablation: evolution of patients and procedures over 8 years. Circ Arrhythm Electrophysiol 2008;1):153−61. https://doi. org/10.1161/CIRCEP.108.769471; PMID: 19808409. Wu AH. Management of patients with non-ischaemic cardiomyopathy. Heart 2007;93:403−8. https://doi.org/10.1136/

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Ablation Therapy The role of radiofrequency ablation in patients with AIC is not well studied or understood. It has been reported in the literature that there is a clear discordance between long-term ablation outcomes in ICM and NICM. This difference is thought to be due to a lack of modifiable substrate (scar) in NICM patients. NICM patients may have a combination of scar-based re-entrant VT and functional VT not directly related to myocardial scar or fibrosis. Kumar et al. investigated the characterisation of substrate and outcomes after ablation in 435 patients with cardiac sarcoidosis. They identified that the mechanism of cardiac sarcoid-related VT is likely to be a result of re-entry involving confluent regions of scarring in the RV endocardium and epicardium along with patchy LV endocardial scarring affecting the basal septum, anterior wall and perivalvular regions. Furthermore, catheter ablation was able to terminate VT storm and >1 inducible VT in the majority of patients, resulting in reduction in ICD shock burden, but recurrences were common and failure to abolish all VT was predominantly attributable to intramural circuits.38 Patients with AIC may be prone to VA related to scar, but possibly also VA directly caused by inflammation. Since patients with AIC can develop VA across the spectrum of early to late disease, it will be of great importance to further study the outcomes of these patients to best determine the safety and efficacy of an ablation versus ablation plus immunosuppressive strategy for management during various stages of the disease process.

Conclusion AIC is a recent clinical description encompassing a broad group of patients with NICM, who are referred to electrophysiologists for management of VAs.5 These are a unique group of patients who suffer from long standing chronic myocardial inflammation and myocardial scar formation that leads to congestive heart failure and the development of malignant ventricular arrhythmias. Currently, much of the literature to help diagnose and manage these patients is extrapolated from patients with NICM and sarcoidosis, so it is of paramount importance that further effort is made to investigate patients with AIC and to establish optimal diagnostic and treatment paradigms. n

Clinical Perspective • A  significant number of patients with non-ischaemic cardiomyopathy and ventricular arrhythmias have been referred to electrophysiologists with underlying myocardial inflammation of unclear aetiology. •  Arrhythmogenic inflammatory cardiomyopathy is a newly described entity encompassing this group of patients to catalyse a paradigm shift in clinical care and promote the need for further research in the field.

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Clinical Reviews: Clinical Arrhythmias

Long-QT Syndrome and Competitive Sports Frédéric Schnell 1 , Nathalie Behar 2 and François Carré 1 1. University of Rennes, Department of Sports Medicine University Hospital of Rennes, Inserm, LTSI-UMR 1099 Rennes, France; 2. University of Rennes, Department of Cardiology University Hospital of Rennes, Inserm, LTSI-UMR 1099 Rennes, France

Abstract Long QT syndrome (LQTS) is an inherited channelopathy which exposes athletes to a risk of sudden cardiac death. Diagnosis is more difficult in this population because: the QT interval is prolonged by training; and the extreme bradycardia frequently observed in athletes makes the QT correction formula less accurate. Based on limited clinical data which tend to demonstrate that exercise, especially swimming, is a trigger for cardiac events, participation in any competitive sports practice is not supported by 2005 European guidelines. However, based on recent retrospective studies and adopting a different medical approach, involving the patient-athlete in shared decision making, the 2015 US guidelines are less restrictive, especially in asymptomatic genotype-positive/phenotype-negative athletes. These guidelines also consider giving medical clearance to competitive sport participation in asymptomatic athletes with appropriate medical therapy.

Keywords Long QT syndrome, arrhythmia, sudden death, sport, athlete Disclosure: The authors have no conflict of interest to declare. Received: 2 June 2018 Accepted: 17 July 2018 Citation: Arrhythmia & Electrophysiology Review 2018;7(3):187–92. DOI: https://doi.org/10.15420/aer.2018.39.3 Correspondence: Frédéric Schnell, Department of Sports Medicine, Pontchaillou Hospital. 2 rue Henri le Guilloux, 35000 Rennes, France; E: frederic.schnell@chu-rennes.fr

Congenital long QT syndrome (LQTS) is an inherited cardiac ion channelopathy characterised by a variable degree of QT interval prolongation on ECG and an increased susceptibility to life-threatening ventricular arrhythmias (torsades de pointes and ventricular fibrillation) in the absence of morphological cardiac disease. LQTS is estimated to affect one in 2,000 individuals.1 It is usually diagnosed in children and young adults, with a mean age at presentation of 14 years2; the annual rate of sudden cardiac death (SCD) in untreated patients is estimated to be between 0.33  %3 and 0.9  %,4 and the rate of syncope is 5 %.4 Mutations in 17 genes have been associated with LQTS5. The subtypes of LQTS can be grouped into three categories: • Thirteen genes have been reported in autosomal dominant forms of Romano-Ward syndrome (LQT1–6 and 9–15), which are characterised by an isolated prolongation of the QT interval. Among them, LQT1 (KCNQ1 gene), LQT2 (KCNH2 gene) and LQT3 (SCN5A gene) account for the majority (75 %) of genetically identifiable cases.6 • Two autosomal dominant forms of LQTS are associated with a phenotype extending beyond cardiac arrhythmia. In addition to the prolonged QT interval, associations include muscle weakness as well as facial dysmorphism in Andersen-Tawil syndrome (LQTS7) and hand/foot, facial and neurodevelopmental features in Timothy syndrome (LQTS8). • There are also two autosomal-recessive forms of LQTS (Jervell and Lange–Nielsen syndrome: JLN 1–2), which are associated with profound sensorineural hearing loss.6 There is a variable penetrance in patients with genotype-positive LQTS, resulting in variation in both clinical and ECG manifestations, as well as between family members with the same genotype.7

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In general, the QT interval is longer in athletes than in non-athletic controls because of the lower resting heart rates associated with athletic training, while the corrected QT (QTc) of the athletic group is within normal limits, although toward the upper limit.8-10 Intense sports participation is considered to be a potential risk-taking behaviour for patients with LQTS in general and those with LQT1 in particular. Therefore, correct diagnosis and risk stratification is fundamental to advising patients appropriately about sports practice. This review will discuss the effect of sport on QT prolongation, the best way to diagnose patients and to attempt accurate risk stratification in athletes. Finally, this study will discuss current evidence on competitive sports participation in athletes with LQTS.

Challenges of QT Measurement in Athletes Studies have suggested that the ability of cardiologists and even heart rhythm specialists to accurately measure the QTc is suboptimal.11 The accuracy of computer-generated QTc values is approximately 90 –95 %; the duration of the QT interval therefore should be measured manually from the beginning of the QRS complex to the end of the T wave. The first difficulty is to define the end of the T wave. This is usually done by drawing the tangent line to the steepest part of the descending portion of the T wave, chosen in a lead where the T wave has the greatest amplitude, taking its intercept with the isoelectric line as the end of the T wave (Figure 1).12,13 This ‘teach the tangent, avoid the tail’ method will help to exclude low amplitude U waves, which are common in athletes. QT interval should be preferably measured using lead II or V5; the longest value should be considered.

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Clinical Reviews: Clinical Arrhythmias Figure 1: Measure of QT Using The ‘Teach the Tangent, Avoid-the-Tail’ Method

Figure 2: QT Corrected Interval with Bazett’s Formula According to Heart Rate 500

QTc (Bazett) = QT/√RR

As the QT changes with the heart rate, there are several formulas to correct QT interval with the heart rate, the most used is Bazett’s formula – QTc = QT/√RR – using the RR interval preceding the QT interval measured.14 As the majority of the available data for congenital LQTS are derived from studies using Bazett’s formula, this is still the recommended way to adjust QT in athletes.15 Using Bazett’s formula, the QTc interval represents the value of the QT interval normalised for a heart rate of 60 BPM, i.e. a RR interval of 1000 ms. In case of a significant fluctuation in heart rate, as seen in respiratory arrhythmia, it is important to calculate the average QT interval and average RR interval to improve accuracy15. The response of the QT interval to a change in heart rate is not instantaneous, with full adaptation taking 1–3 minutes.16 Bazett’s formula has been criticised as inaccurate, especially at extreme heart rates of ≤40 BPM and >120 BPM15. At slow heart rates, which frequently occur in athletes (due to change in the automatic balance with a lower sympathetic activity and a higher vagal tone at rest), the QTc interval may be underestimated if Bazett’s formula is used (Figure 2).2,15 If the heart rate is too slow, the ECG should therefore be repeated after a mild aerobic activity to achieve a heart rate closer to 60 BPM where the formula is most accurate; conversely, if the heart rate is too fast, repeating the ECG after a longer resting period should be considered. Holter ECG monitoring is also useful to measure QT interval at a stable heart rate of 60 BPM, where no adjustment for heart rate is needed. An alternative solution, to avoid using correction formulas, is to use QT/RR scatter diagrams obtained from individual athletes.17 Using such a diagram might make it easier to measure the QT interval and corresponding RR value of an individual athlete to ascertain if they are in the normal range (Figure 3).

Which Cut-off Should be Used in Athletes? Clinical observations have shown that training can increase and detraining decrease the QT interval duration in athletes.8 Vagal stimulation is increased in athletes, which prolongs the QT interval, independently of the induced bradycardia.12 An isolated long QT interval in an athlete may result from the effect of delayed repolarisation as a result of increased left ventricular mass.10 The cut-off values used to identify whether a QTC interval is prolonged vary in the literature. Incomplete penetration (i.e. where people who carry a genetic mutation do not show the pathological phenotype) has been clearly demonstrated in LQTS. Consequently, there is a remarkable overlap of QT values between normal subjects and those carrying an LQTS mutation at the upper values of QT

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Bazett’s corrected QT interval (ms)

480 460 440 420 400 380 360 340 320 300 280 260

0

≤5

0

–6

50

0

–7

60

0

–8

70

0

–9

80

0

>9

Source: personal data from a cohort of 5,092 French elite athletes

distribution. Therefore, no screening programme will identify all persons with LQTS.18,19 The QTc cut-off value used to decide whether further evaluation is needed must be chosen carefully to balance the frequency of abnormal results with the positive predictive value when LQTS is detected incidentally. QT interval is modulated by sex so different cut-off values are used after puberty.20 The latest ECG recommendations in athletes consider that QTc values of >470 ms in men and >480  ms in women are the thresholds of QT prolongation that warrant further assessment in asymptomatic athletes.15 These cut-off values are around the 99th percentile and are consistent with thresholds defined by the 36th Bethesda Conference.21 However, not only the duration of QT interval should be considered. Recent European Society of Cardiology (ESC) guidelines2 emphasised that a Schwartz score of >3 might also be used to diagnose LQTS.22 This score includes QT interval duration on a resting ECG, occurrence of torsades de pointes, T wave alternans, morphology of the QT, low heart rate for age (which might be difficult to identify in an athlete); clinical history of symptoms such as syncope (especially if occurring during stress), congenital deafness; family history (definite LQTS or unexplained SCD below the age of 30 years among immediate family members) (Table 1). LQTS is also diagnosed, irrespective of the QT duration, in the presence of a confirmed pathogenic LQTS mutation.

Complementary Exploration for LQTS Diagnosis Before considering congenital LQTS as a diagnosis, acquired causes of prolongation of QT interval should be excluded. The most frequent causes are the use of QT-prolonging medication, metabolic changes and electrolyte disorders (such as hypokalemia).23 This abnormality might also be encountered in athletes. It might be valuable to repeat resting ECG measurements for several days, especially if the QT value is borderline. In endurance athletes, because of the frequent occurrence of bizarre T-wave shapes, it could be useful to repeat resting ECG after a period (2–4 weeks) of complete detraining.

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Long-QT Syndrome and Competitive Sports Figure 3: Scatter Diagram of QT/RR

Table 1: Schwartz score LQTS diagnostic criteria and their values in athletes

550 525

QT interval (ms)

500

Men Women Athlete assessed

Schwartz Score

Electrocardiographic findings

450

A

424

3

460–470

2

x

450 (in males)

1

x

B

Torsades de pointes*

2

C

T-wave alternans

1

D

Notched T wave in three leads

1

E

Low heart rate for age

0.5

375 350 325 300 800

1,000

1,200 1,400 RR (ms)

1,600

1,800

Source: personal data obtained from individual athletes

increase of an uncorrected QT interval during infusion of low-dose epinephrine has been demonstrated in patients with LQT1.28,29 The response of the QT interval to the brief tachycardia provoked by standing suddenly is another way to assess QT dynamics.30 Viskin et al. demonstrated that, in response to brisk standing, patients with LQTS and untrained control subjects responded with similar heart rates, but the response of the QT interval to this tachycardia differed. On average, the QT interval of controls shortened by 21±19 ms whereas the QT interval of LQTS patients increased by 4±34  ms (p<0.001). Since the RR interval shortened more than the QT interval, during maximal tachycardia the corrected QT interval increased by 50±30  ms in the control group and by 89±47  ms in the LQTS group (p<0.001). A similar experiment was performed by Pressler et al., which found that in healthy elite athletes, the QT interval shortened in all athletes by 40±17  ms, so QTc increased by 12±22  ms.31 Unfortunately, the authors are not aware of a study that assessed athletes with LQTS.

x

Clinical history A

Evaluating the QT dynamic can improve diagnostic accuracy in some patients. An exercise test is useful to identify ventricular arrhythmias related to LQTS and to assess the evolution of QT during recovery.15 Indeed, a QT duration at 4 minutes of recovery from exercise stress above 480 ms is included in the 2011 update of the Schwartz score.24–26 Holter ECG monitoring, which is useful to measure QT at a HR of 60 BPM to avoid having to use QT correction formulas, is also used to depict ventricular arrhythmias and to assess the dynamic evolution of QT.27 Pharmacological tests might also be performed; a paradoxical

QTc duration (ms) (Bazett formula) ≥480

400

600

Questionable in Athletes

475

275

Points

B

Syncope* With stress

2

Without stress

1

Congenital deafness

0.5

Family history A

Family members with definite LQTS

1

B

Unexplained sudden cardiac death below the age of 30 among immediate family members

0.5

*Mutually exclusive. Source: Schwartz PJ, et al.22 With permission from Wolters Kluver.

(adults) on serial ECG analysis, genetic testing is recommended. In case of QTc values >460 ms (prepuberty) or >480  ms (adults), this might also be considered. As the HRS/EHRA guidelines are not specific to athletes, ECGs should be interpreted with common athlete-specific findings in mind.15 Nevertheless, LQTS genetic testing should not be performed systematically without any evidence of LQTS and should be interpreted with caution if diagnosis is borderline. Indeed, the significant rate of rare variants of uncertain significance in the LQT 1–3 genes complicates correct mutation identification and shows that LQTS genetic testing should be carried out based upon clinical suspicion rather than being ordered indiscriminately.32 A cascade familial genetic screening should be performed if the index athlete has a positive genotype.

Risk Stratification in Athletes As LQTS is hereditary, clinical familial screening should be considered if the condition is strongly suspected. Because penetrance varies,7 it might be helpful to assess first degree relatives as well in case of borderline phenotype (with history, clinical examination and a resting ECG) to increase the diagnostic accuracy in the index athlete.

Risk stratification is difficult, especially in the setting of competitive sport. In the general adult population, the most important predictors of outcome are QT interval duration (≥500 ms), male sex in childhood but female sex in adulthood, and a history of cardiac events including syncope.

The Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA) have issued a statement on genetic testing in LQTS.6 They recommend genetic testing in any patient where there is a strong clinical suspicion for LQTS based on clinical history, family history and expressed electrocardiographic phenotype (resting 12–lead ECGs and/or provocative stress testing with exercise or catecholamine infusion). In a patient with a QTc>480 ms (prepuberty) or >500  ms

Genotype is also associated with outcome and with different arrhythmia triggers. LQT1 genotype seems to be associated with a more positive prognosis, especially with a better response to beta-blocker therapy.3,33,34 Exercise is the most important trigger of arrhythmia in this form of LQTS. Schwartz et al. demonstrated that exercise, especially swimming, was the trigger in 62 % of cardiac events in LQT1, 13 % of LQT2 and 13 % of LQT3. Furthermore, exercise

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Clinical Reviews: Clinical Arrhythmias was found to be the trigger of 68 % of lethal cardiac events in LQT1. Emotional stress and auditory stimuli were specific triggers of cardiac events in LQT2, and events were most likely to occur at sleep or at rest in LQT3.35 These differences in triggers of cardiac events make competitive sport disqualification more questionable in LQT2–3. Patients with LQT1 with malfunctioning IKs channels are expected to shorten their QT intervals during tachycardia less effectively than normal individuals. A major catecholamine release, as happens during intense exercise, without a proper QT adaptation sets the stage for early afterdepolarisations, which may then lead to torsades de pointes via re-entry.35 This concept is supported by an experimental model for LQT1 in which IKs blockade greatly increases the probability of torsades de pointes in the presence of catecholamines. This study also demonstrated the protective effect of beta-blockers, as they prevent the actions of isoproterenol to increase transmural dispersion of repolarization and to induce torsades de pointes.36 The exact mechanism of the specific arrhythmogenic effect of swimming in people with LQT1 is unclear. The hypothesis is that autonomic conflict plays a role. The sympathetic nervous system is activated because of physical effort and the cold shock response, while the parasympathetic nervous system is activated by the diving response induced by face immersion and voluntary apnoea. This concomitant activation of both sympathetic and parasympathetic autonomic systems may explain why swimming seems to precipitate premature ventricular contractions.37 Epinephrine QT stress testing29 and coldwater face immersion38 demonstrate a paradoxical prolongation in the QT interval in LQT1. Furthermore, the consequences of a syncope during swimming are more severe that one during dry land activities because of the risk of drowning.39 Because people with LQT1 are more susceptible to cardiac events during exercise than those with LQT2–3, genotype identification might be relevant to assess risks related to sports. The correlation between genotype and ST–T morphologies on the ECG is not always clear. Zhang et al. demonstrated that typical ST–T patterns were present in 88 % of LQT1 and LQT2 gene carriers but in only in 65 % of those carrying LQT3; with ECG analysis, the mean sensitivity/specificity for LQT1, LQT2 and LQT3 was 61 %/71 %, 62 %/87 % and 33 %/98 % respectively40. Therefore, genotyping might be used to improve risk stratification, keeping in mind that in about one-third of cases there is a failure to identify mutations.40 Complicating our interpretation of genotype is the complexity of variable penetrance and modifier genes that are relatively poorly understood, which may account for the pleiotropy between different families with the same mutation. Nevertheless, recent retrospective studies temper previous conclusions. Johnson and Ackerman demonstrated the absence of any lethal sport-related event in a cohort of 353 athletes whose LQTS syndrome was well managed. However, the majority of patients did not participate in competitive sports or chose to discontinue sport (63 %). The remaining 130 patients (37  %) chose to continue competitive sports; most of them (87  %) were treated with beta-blockers and 20 (15 %) had an ICD implanted. Just one 9-year-old child experienced two sport-related events and an appropriate ICD shock was delivered; there was non-adherence to beta-blocker medication.41 Another retrospective study was conducted by Chambers et al.,42 in 172 children with LQTS, of whom 66 (38 %) exercised on a recreational

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basis and 106 (62 %) competitively. No syncopal events were reported during competitive exercise, and no cardiac arrests or deaths were reported during recreational or competitive exercise, but four patients experienced exertional syncope during recreational sport. The same results were demonstrated by Aziz et al. on a retrospective cohort of 103 children with LQTS involved in recreational (75  %) or competitive sport practice (25 %). No patients experienced LQTS symptoms during sports participation.43 These studies had limitations. They were retrospective, involved young subjects, and sports with the highest cardiovascular demand were poorly represented (only a few class IIIB and IIIC sports), with few subjects practising at a national/professional level. Assessing the suitability of competitive/professional sport to young adults with LQTS might be a different task from advising children regarding participation in normal sport activities. As these studies state, optimal treatment is warranted. As the ESC guidelines recommend, beta-blockers are the cornerstone of treatment and are recommended in patients with a diagnosis of LQTS; they should also be considered in carriers of a causative LQTS mutation who have a normal QT interval. ICD implantation with the use of betablockers is recommended in those with LQTS with previous cardiac arrest, and should be considered in patients who have experienced syncope and/or ventricular tachycardia while receiving an adequate dose of beta-blockers.2

Eligibility for Competitive Sport Participation According to European and US Guidelines Several guidelines on the eligibility of athletes with LQTS for competitive sport exist, and conclusions by different experts are not the same on both sides of the Atlantic. The ESC recommendations for competitive sport participation, published in 2005, are the most restrictive44. These state that congenital LQTS is a contraindication for any type of sports, even without documented major arrhythmic events. In 2015, ESC guidelines for the management of ventricular arrhythmia and prevention of SCD recommended the avoidance of strenuous swimming, especially in LQT1, but no other kinds of sports were mentioned.2 The more recent US guidelines on suitability and disqualification recommendations for competitive athletes in cardiac channelopathies, proposed in 2015, are less restrictive.45 Of course, experts recommend symptomatic athletes should not compete and that a comprehensive evaluation should be performed by a heart rhythm specialist or genetic cardiologist with sufficient experience and expertise with LQTS. For an athlete with symptomatic LQTS or an ECG with manifest LQTS, competitive sports participation (except competitive swimming in a previously symptomatic person with LQT1) may be considered after treatment has been implemented and appropriate precautionary measures taken, assuming the athlete has been asymptomatic on treatment for at least 3 months. Athletes and their families should be given information on the potential risks of competitive sports participation. In asymptomatic genotype-positive/phenotype-negative athletes, the experts concluded that it was reasonable for them to participate in all competitive sports as long as they took precautionary measures. These include the avoidance of QT-prolonging drugs, electrolyte/hydration replenishment and avoidance of dehydration, avoidance or treatment

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Long-QT Syndrome and Competitive Sports of training-related heat exhaustion or heat stroke, as well as acquiring a personal automatic external defibrillator (AED) and establishing an emergency action plan with school or team officials. Pundi et al. evaluated retrospectively the efficacy of AEDs for prevention of sudden cardiac arrest in children with LQTS. The rate of needing an external defibrillator rescue was relatively low (three AED rescues in 1,700 patient-years). Irrespective of the external defibrillator used (personal, community or hospital AED) or the person delivering the shock (medical provider or parent/school personnel), the AED was successful in recognising and treating the LQTS-triggered ventricular arrhythmia appropriately.46 Furthermore, Drezner et al. demonstrated that survival rates were higher in schools with an established emergency action plan for sudden cardiac arrest than in those without (79 % against 44  %; odds ratio 4.6) and if an onsite AED was used compared to an offsite AED provided by emergency medical services (80  % versus 50 %; OR 4.0).47 Why are the guidelines so different? It may be argued that the European guidelines were written before the most recent studies on LQTS and sport.41,42 The variation might also reflect a cultural contrast between the US and Europe regarding personal freedom to pursue life’s goals versus the role of the state to ensure the safety of its population.48 What is acceptably safe is not solely a medical decision – it is also a social and ethical question.49 In some European countries, for example France or Italy, physicians are asked to certify that an athlete is fit to compete without any restriction. This legal position will lead to a paternalistic model, where the athlete’s autonomy is limited to what the physician will consider for the good of the patient, regardless of the will of the athlete. In the US, the physician is asked for medical advice on risk stratification, and the athlete is responsible for the final decision after having received thorough information, which

1.

 chwartz PJ, Stramba-Badiale M, Crotti L, et al. Prevalence of S the congenital long-QT syndrome. Circulation 2009;120:1761–7. https://doi.org/10.1161/CIRCULATIONAHA.109.863209. PMID:19841298; PMCID:PMC2784143. 2. Priori SG, Blomstrom-Lundqvist C, Mazzanti A, et al. 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Eur Heart J 2015;36:2793–867. https://doi.org/10.1093/eurheartj/ ehv316. PMID:26320108. 3. Priori SG, Schwartz PJ, Napolitano C, et al. Risk stratification in the long-QT syndrome. N Engl J Med 2003;348:1866–74. https:// doi.org/10.1056/NEJMoa022147. PMID:12736279. 4. Moss AJ, Schwartz PJ, Crampton RS, et al. The long QT syndrome. Prospective longitudinal study of 328 families. Circulation 1991;84:1136–44. https://doi.org/10.1161/01. CIR.84.3.1136. PMID:1884444. 5. Nakano Y, Shimizu W. Genetics of long-QT syndrome. J Hum Genet 2016;61:51-5. https://doi.org/10.1038/jhg.2015.74. PMID:26108145. 6. Ackerman MJ, Priori SG, Willems S, et al. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies. Heart Rhythm 2011;8:1308–39. https://doi.org/10.1016/j.hrthm.2011.05.020. PMID:21787999. 7. Priori SG, Napolitano C, Schwartz PJ. Low penetrance in the Long-QT syndrome: clinical impact. Circulation 1999;99:529–33. https://doi.org/10.1161/01.CIR.99.4.529. PMID:9927399. 8. Napolitano C, Bloise R, Priori SG. Long QT syndrome and short QT syndrome: how to make correct diagnosis and what about eligibility for sports activity. J Cardiovasc Med 2006;7:250–6. https://doi.org/10.2459/01.JCM.0000219317.12504.5f. PMID:16645398. 9. Kapetanopoulos A, Kluger J, Maron BJ, et al. The congenital long QT syndrome and implications for young athletes. Med Sci Sports Exerc 2006;38:816–25. https://doi.org/10.1249/01. mss.0000218130.41133.cc. PMID:16672832. 10. Basavarajaiah S, Wilson M, Whyte G, et al. Prevalence and significance of an isolated long QT interval in elite athletes. Eur Heart J 2007;28:2944–9. https://doi.org/10.1093/eurheartj/ ehm404. PMID:17947213. 11. Viskin S, Rosovski U, Sands AJ, et al. Inaccurate electrocardiographic interpretation of long QT: The majority of physicians cannot recognize a long QT when they see one. Heart Rhythm 2005;2:569–74. https://doi.org/10.1016/j. hrthm.2005.02.011. PMID:15922261.

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lead to a more modern shared decision-making or informed decision model.50 In the US, under the latest US guidelines, the return to play of an athlete with LQTS will have to involve the school and or team official, who can refuse to accept a medical decision.51

Conclusion There is still only a paucity of firm prospective data that can guide practitioners in making decisions about sports participation in athletes with LQTS. Nevertheless, current ESC guidelines are probably too restrictive. In the era of precision medicine, the recommendation of disqualifying every single athlete with LQTS athlete, regardless of any risk stratification or even genotype-positive/phenotype-negative athletes, is probably too restrictive. n

Clinical Perspective • A  ppropriate LQTS cut-off values in athletes are 470 ms in men and 480 ms in women •  Beta-blockers are the cornerstone therapy for patients with a clinical diagnosis of LQTS and should also be considered in genotype-positive/phenotype-negative patients. • A comprehensive evaluation, with risk stratification according to age, sex, genotype and symptoms should be performed, with referral to a cardiologist with specialist skills in LQTS and/or sports cardiology. • Current European guidelines (2005) recommend that patients with LQTS should be excluded from any competitive sports. The more recent US guidelines (2015) are less restrictive, especially in athletes who are genotype-positive/phenotype-negative and asymptomatic.

12. F  unck-Brentano C, Jaillon P. Rate-corrected QT interval: techniques and limitations. Am J Cardiol 1993;72:17B–22B. https://doi.org/10.1016/0002-9149(93)90035-B. PMID: 8256750. 13. Lepeschkin E, Surawicz B. The measurement of the Q-T interval of the electrocardiogram. Circulation 1952;6:378–88. https://doi.org/10.1161/01.CIR.6.3.378. PMID:14954534. 14. Bazett HC. An analysis of the time relations of electrocardiograms. Heart 1920;7:355–70. 15. Sharma S, Drezner JA, Baggish A, et al. International recommendations for electrocardiographic interpretation in athletes. Eur Heart J 2017;39:1466–80. https://doi.org/10.1093/ eurheartj/ehw631. PMID:28329355. 16. Toivonen L. More light on QT interval measurement. Heart 2002;87:193–4. https://doi.org/10.1136/heart.87.3.193. PMID:11847147; PMCID:PMC1767027. 17. Malik M, Färbom P, Batchvarov V, et al. Relation between QT and RR intervals is highly individual among healthy subjects: implications for heart rate correction of the QT interval. Heart 2002;87:220–8. https://doi.org/10.1136/heart.87.3.220. PMID:11847158; PMCID:PMC1767037. 18. Johnson JN, Ackerman MJ. QTc: how long is too long? Br J Sports Med 2009;43:657–62. https://doi.org/10.1136/ bjsm.2008.054734. PMID:19734499; PMCID:PMC3940069. 19. Taggart NW, Haglund CM, Tester DJ, et al. Diagnostic miscues in congenital long-QT syndrome. Circulation 2007;115:2613–20. https://doi.org/10.1161/CIRCULATIONAHA.106.661082. PMID:17502575 20. Rautaharju PM, Zhou SH, Wong S, et al. Sex differences in the evolution of the electrocardiographic QT interval with age. Can J Cardiology 1992;8:690–5. PMID:1422988. 21. Maron BJ, Zipes DP. Eligibility recommendations for competitive athletes with cardiovascular abnormalities. J Am Coll Cardiol 2005;45:1318–1375. https://doi.org/10.1016/j. jacc.2005.02.006. PMID:15837280. 22. Schwartz PJ, Moss AJ, Vincent GM, et al. Diagnostic criteria for the long QT syndrome. An update. Circulation 1993;88:782–4. https://doi.org/10.1161/01.CIR.88.2.782. PMID:8339437. 23. Ernstene AC, Proudfit WL. Differentiation of the changes in the Q-T interval in hypocalcemia and hypopotassemia. Am Heart J 1949;38:260–72. https://doi.org/10.1016/00028703(49)91334-4. PMID: 18133358. 24. Chattha IS, Sy RW, Yee R, et al. Utility of the recovery electrocardiogram after exercise: a novel indicator for the diagnosis and genotyping of long QT syndrome? Heart Rhythm

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

2010;7:906-11. https://doi.org/10.1016/j.hrthm.2010.03.006. PMID:20226272. Sy RW, van der Werf C, Chattha IS, et al. Derivation and validation of a simple exercise-based algorithm for prediction of genetic testing in relatives of LQTS probands. Circulation 2011;124:2187–94. https://doi.org/10.1161/ CIRCULATIONAHA.111.028258. PMID:22042885. Schwartz PJ, Crotti L. QTc Behavior during exercise and genetic testing for the Long-QT Syndrome. Circulation 2011;124:2181–4. https://doi.org/10.1161/ CIRCULATIONAHA.111.062182. PMID:22083145. Mauriello DA, Johnson JN, Ackerman MJ. Holter Monitoring in the evaluation of congenital long QT syndrome. Pacing Clin Electrophysiol 2011;34:1100–4. https://doi.org/10.1111/j.15408159.2011.03102.x. PMID:21507020. Vyas H, Hejlik J, Ackerman MJ. Epinephrine QT stress testing in the evaluation of congenital Long-QT syndrome: diagnostic accuracy of the paradoxical QT response. Circulation 2006;113:1385–92. https://doi.org/10.1161/ CIRCULATIONAHA.105.600445. PMID:16534005. Shimizu W, Noda T, Takaki H, et al. Diagnostic value of epinephrine test for genotyping LQT1, LQT2, and LQT3 forms of congenital long QT syndrome. Heart Rhythm 2004;1:276–83. https://doi.org/10.1016/j.hrthm.2004.04.021. PMID:15851169. Viskin S, Postema PG, Bhuiyan ZA, et al. 1 The response of the QT interval to the brief tachycardia provoked by standing: a bedside test for diagnosing long QT syndrome. J Am Coll Cardiol 2010;55:1955–61. https://doi.org/10.1016/j.jacc.2009.12.015. PMID:20116193; PMCID:PMC2862092. Pressler A, Vogel A, Scherr J, et al. Applying the ‘Viskin test’: QT interval in response to standing in elite athletes. Int J Cardiol 2012;154:93–4. https://doi.org/10.1016/j.ijcard.2011.10.034. PMID:22056043. Kapa S, Tester DJ, Salisbury BA, et al. Genetic testing for long-QT syndrome: distinguishing pathogenic mutations from benign variants. Circulation 2009;120:1752–60. https://doi. org/10.1161/CIRCULATIONAHA.109.863076. PMID:19841300; PMCID:PMC3025752. Sauer AJ, Moss AJ, McNitt S, et al. Long QT syndrome in adults. J Am Coll Cardiol 2007;49:329–37. https://doi. org/10.1016/j.jacc.2006.08.057. PMID:17239714. Goldenberg I, Moss AJ. Long QT syndrome. J Am Coll Cardiol 2008;51:2291–300. https://doi.org/10.1016/j.jacc.2008.02.068. PMID:18549912.

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Clinical Reviews: Clinical Arrhythmias 35. S  chwartz PJ, Priori SG, Spazzolini C, et al. genotype-phenotype correlation in the long-qt syndrome: gene-specific triggers for life-threatening arrhythmias. Circulation 2001;103:89–95. https://doi.org/10.1161/01.CIR.103.1.89. PMID:11136691. 36. Shimizu W, Antzelevitch C. Cellular basis for the ECG features of the LQT1 form of the Long-QT syndrome: effects of β-Adrenergic agonists and antagonists and sodium channel blockers on transmural dispersion of repolarization and torsade de pointes. Circulation 1998;98:2314–22. https://doi. org/10.1161/01.CIR.98.21.2314. PMID:9826320. 37. Shattock MJ, Tipton MJ. ‘Autonomic conflict’: a different way to die during cold water immersion? J Physiol 2012;590:3219–30. https://doi.org/10.1113/jphysiol.2012.229864. PMID:22547634; PMCID:PMC3459038. 38. Yoshinaga M, Kamimura J, Fukushige T, et al. Face immersion in cold water induces prolongation of the QT interval and T-wave changes in children with nonfamilial long QT syndrome. Am J Cardiol 1999; 83:1494-7. https:// doi.org/10.1016/S0002-9149(99)00131-9. PMID:22547634; PMCID:PMC3459038. 39. Choi G, Kopplin LJ, Tester DJ, et al. Spectrum and frequency of cardiac channel defects in swimming-triggered arrhythmia syndromes. Circulation 2004;110:2119–24. https://doi. org/10.1161/01.CIR.0000144471.98080.CA. PMID:15466642. 40. Zhang L, Timothy KW, Vincent GM, et al. Spectrum of ST-T– Wave patterns and repolarization parameters in congenital Long-QT syndrome: ECG findings identify genotypes. Circulation

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2000;102:2849–55. https://doi.org/10.1161/01.CIR.102.23.2849. PMID:11104743. Johnson JN, Ackerman MJ. Return to play? Athletes with congenital long QT syndrome. Br J Sports Med 2012;47:28– 33. https://doi.org/10.1136/bjsports-2012-091751. PMID:23193325. Chambers KD, Beausejour Ladouceur V, Alexander ME, et al. Cardiac events during competitive, recreational, and daily activities in children and adolescents with long QT syndrome. J Am Heart Assoc 2017;6(9):e005445. https://doi.org/10.1161/ JAHA.116.005445. PMID:28935680; PMCID:PMC5634250. Aziz PF, Sweeten T, Vogel RL, et al. Sports participation in genotype positive children with long QT syndrome. JACC Clin Electrophysiol 2015;1:62–70. https://doi.org/10.1016/j. jacep.2015.03.006. PMID:26301263; PMCID:PMC4540361. Pelliccia A, Fagard R, Bjørnstad HH, et al. Recommendations for competitive sports participation in athletes with cardiovascular disease: a consensus document from the Study Group of Sports Cardiology of the Working Group of Cardiac Rehabilitation and Exercise Physiology and the Working Group of Myocardial and Pericardial Diseases of the European Society of Cardiology. Eur Heart J 2005; 26:1422–45. https://doi.org/10.1093/eurheartj/ehi325. PMID:15923204. Ackerman MJ, Zipes DP, Kovacs RJ, et al. Eligibility and disqualification recommendations for competitive athletes with cardiovascular abnormalities: Task Force 10: the cardiac

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channelopathies. J Am Coll Cardiol 2015;66:2434-28. https://doi. org/10.1016/j.jacc.2015.09.042. PMID:26542662. Pundi KN, Bos JM, Cannon BC, et al. Automated external defibrillator rescues among children with diagnosed and treated long QT syndrome. Heart Rhythm 2015;12:776–81. https://doi.org/10.1016/j.hrthm.2015.01.002. PMID:25576780. Drezner JA, Toresdahl BG, Rao AL, et al. Outcomes from sudden cardiac arrest in US high schools: a 2-year prospective study from the national registry for AED use in sports. Br J Sports Med 2013;47:1179–83. https://doi. org/10.1136/bjsports-2013-092786. PMID:24124037. Pew Research Center. The American-western European values gap. Pew Research Centers Global Attitudes Project 2011;1–25. Pelliccia A. Long QT syndrome, implantable cardioverter defibrillator (ICD) and competitive sport participation: when science overcomes ethics. Br J Sports Med 2014;48:1135–6. https://doi.org/10.1136/bjsports-2013-092441. PMID:23729177. Providencia R, Teixeira C, Segal OR, et al. Empowerment of athletes with cardiac disorders: a new paradigm. Europace 2017;339:1623–9. https://doi.org/10.1093/europace/eux268. PMID: 29016796. Turkowski KL, Bos JM, Ackerman NC, et al. Return-to-play for athletes with genetic heart diseases. Circulation 2018;137:1086– 8. https://doi.org/10.1161/CIRCULATIONAHA.117.031306. PMID:29507000.

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Clinical Reviews: 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 One: Physiology and Methods Nikhil Singh 1 , Kegan James Moneghetti 2,3 , Jeffrey Wilcox Christle 3 , David Hadley 4 , Daniel Plews 5 and Victor Froelicher 3 1. Department of Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA, USA; 2. Department of Medicine, St Vincent’s Hospital, University of Melbourne, Melbourne, Australia; 3. The Division of Cardiovascular Medicine, Department of Medicine, Stanford School of Medicine, Stanford, CA, USA; 4. Cardiac Insight Inc, Seattle, WA, USA; 5. Sports Performance Research Institute New Zealand, AUT University, AUT-Millennium, 17 Antares Place, Mairangi Bay, New Zealand

Abstract The autonomic nervous system plays a major role in optimising function of the cardiovascular (CV) system, which in turn has important implications for CV health. Heart rate variability (HRV) is a measurable reflection of this balance between sympathetic and parasympathetic tone and has been used as a marker for cardiac status and predicting CV outcomes. Recently, the availability of commercially available heart rate (HR) monitoring systems has had important CV health implications and permits ambulatory CV monitoring on a scale not achievable with traditional cardiac diagnostics. The focus of the first part of this two-part review is to summarise the physiology of HRV and to describe available technologies for HRV monitoring. Part two will present HRV measures for assessing CV prognosis and athletic training.

Keywords Heart rate variability, ambulatory monitoring, wearable devices Disclosure: Dr Hadley and Dr Froelicher are partial owners of Cardiac Insight, Inc and developers of its ECG analysis software. There is no mention of their products in this review. The remaining authors have no conflicts of interest to declare. Received: 16 April 2018 Accepted: 19 June 2018 Citation: Arrhythmia & Electrophysiology Review 2018;7(3):193–8. DOI: https://doi.org/10.15420/aer.2018.27.2 Correspondence: Victor Froelicher, MD, 870 Quarry Road, Falk Cardiovascular Research Building, MC-5406/Room CV-285, Stanford, CA 94305-5406, USA. E: victorf@stanford.edu

Considerable evidence supports the importance that the autonomic nervous system (ANS) has regarding cardiovascular health and prognosis.1 Specific variables derived from heart rate (HR) and heart rate variability (HRV) at rest and with exercise help assess the status of the ANS. Interest has also peaked on the use of HRV to assess the quality of an exercise programme. Among the athletic population, HRV has been recommended to warn of over-training and to optimise performance. The wide availability of mHealth2 HR-monitoring devices (wellness and medical devices) for both health status and exercise training assessment provided motivation for this systematic review.

Autonomic Nervous System The ANS is predominantly an efferent system transmitting impulses from the central nervous system (CNS) to peripheral organs. Its effects include control of HR and force of heart contraction, constriction and dilatation of blood vessels, contraction and relaxation of smooth muscle in various organs, and glandular secretions. Autonomic nerves constitute all the efferent fibres that leave the CNS, except those that innervate skeletal muscle. There are some afferent autonomic fibres (i.e. from the periphery to the CNS) that innervate the baroreceptors and chemoreceptors in the carotid sinus and aortic arch, which are important in the control of HR, blood pressure and respiratory activity. The ANS is divided into the parasympathetic and sympathetic systems, based on anatomical and functional differences (Figure 1).

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Parasympathetic Nervous System The preganglionic outflow of the parasympathetic nervous system (PNS) arises from the brain stem and is known as the craniosacral outflow. The vagus nerve (or 10th cranial nerve) carries fibres to the heart and lungs (as well as other organs) and is the primary parasympathetic innervation of these organs. Vagal tone declines with ageing, and the major stimulus that increases vagal tone is regular aerobic exercise.1 The PNS is largely concerned with conservation and restoration of energy by causing a reduction in HR and blood pressure and by facilitating digestion and absorption of nutrients and discharge of waste. The chemical transmitter at synapses in the PNS is acetylcholine (ACh); thus, nerve fibres that release ACh from their endings are described as cholinergic. Postganglionic parasympathetic nerve endings not only respond to ACh, but also to muscarine (muscarinic ACh receptors) or nicotine (nicotinic ACh receptors).

Sympathetic Nervous System The cell bodies of the sympathetic preganglionic fibres are in the lateral horns of spinal segments T1 to L2, which comprise the thoracolumbar outflow of the sympathetic ganglionic chains. The adrenal medulla is innervated by preganglionic fibres, and adrenaline is released from the gland by stimulation of nicotinic ACh receptors. In situations involving physical or psychological stress, adrenaline is released. The specific ACh receptors have been further subdivided pharmacologically by the actions of the alkaloids muscarine and nicotine on these receptors.

Access at: www.AERjournal.com

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Clinical Reviews: Clinical Arrhythmias Figure 1: Anatomy of Parasympathetic and Sympathetic Nervous System with Connections and Effects on Various Organ Systems Parasympathetic system

Nerve

Sympathetic system

III erve

Constricts pupils

DIiates pupils

Stimulates flow of saliva

Inhbits salivation

Constricts bronchi

Relaxes bronchi

N VII

Nerve IX Nerve X (vagus)

Slows heartbeat

Accelerates heartbeat T1

Stimulates peristalsis and secretion Stimulates bile release

Inhibits peristalsis and secretion Stimulates glucose production and release

T12

Secretion of adrenaline and noradrenaline

Table 1: Sympathetic and Parasympathetic Effects on Target Organs Through Various Receptor Interactions Sympathetic

Parasympathetic

Organ

Receptor Subtype

Effect

Receptor Subtype

Effect

Heart

Beta-1, beta-2 ? also alpha and DA1

↑ Heart rate ↑ Force of contraction ↑ Conduction velocity ↑ Automaticity (beta-2) ↑ Excitability ↑ Force of contraction

M2

↓ Heart rate ↓ Force of contraction ↓ Conduction velocity

M

Vasodilatation in skin, skeletal muscle, pulmonary and coronary circulations

M 1, M 3

Bronchoconstriction Stimulation of secretions

Alpha-1

DA1, beta-2

Coronary vasodilatation Vasodilatation (skeletal muscle) Vasoconstriction (coronary, pulmonary, renal and splanchnic circulations, skin and skeletal muscle) Splanchnic and renal vasodilatation

Veins

Alpha-1, also alpha-2 Beta-2

Vasoconstriction Vasodilatation

Lungs

Beta-2

Bronchodilation Inhibition of secretions Bronchoconstriction

Arteries

Beta-1

Alpha-1

DA1 = dopaminergic receptors; M/M1 /M2 /M3 = muscarinic receptors.

In contrast to the parasympathetic system, the sympathetic system enables the body to respond to challenges to survival (fight or flight) or situations of haemodynamic collapse or respiratory failure. Sympathetic responses include an increase in HR, blood pressure and cardiac output, a diversion of blood flow from the skin and splanchnic vessels to those supplying skeletal muscle, bronchiolar dilation, and a decline in metabolic activity. The actions of catecholamines are mediated by alpha and beta receptors. Beta-1-adrenoceptor-mediated effects in the heart, which include increased force and rate of contraction, are differentiated from those producing smooth muscle relaxation in the bronchi and blood vessels, which are beta-2-mediated effects. Table 1 summarises the various cardiovascular and pulmonary responses to parasympathetic and sympathetic stimulation.

Measuring Heart Rate Variability HRV is defined as the physiological variation in the duration of intervals between sinus beats. It reflects the combined activity of sympathetic

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and parasympathetic tone on HR and serves as a measurable indicator of cardiovascular integrity and prognosis. Formal criteria for HRV and comparison of variables were developed by a joint task force between the European Society of Cardiology and the North American Society of Pacing and Electrophysiology in 1996 and updated in 2015.3,4 The update added newer methods, including fractal and chaos analysis, and highlighted the disconnection between biomedical engineering developments and their application to clinical disease states. The major methods of analysis can be divided into time-domain (subdivided into statistical and geometric approaches) and frequency-domain methods.5 

Time-domain Measures of Heart Rate Variability We will concentrate on statistical methods, since clinical studies have used them the most. Time-domain statistical methods assess the difference between normal R-R intervals (NN), excluding ectopic beats. Units of measurement include the standard deviation of NN intervals

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HRV and mHealth Table 2: Frequency-domain Variable Ranges and the Components of the Autonomic Nervous System They Reflect Event Heart beat

Per minute

Hertz (per second)

Autonomic nervous system

60 (range 40–200)

1 (1.4–0.67)

Sympathetic and parasympathetic

Respiration (respiratory sinus arrhythmia)

High frequency

15 (range 10–20)

0.25 (0.17–0.33)

Vagal, parasympathetic

Baroreflex activity

Low frequency

6 (range 4–10)

0.1 (0.07–0.17)

Sympathetic and parasympathetic (with slow respiration)

Thermoregulation

Very low frequency

2 (range 4–0.1)

0.03 (0.07–0.002)

Probably circadian, neuroendocrine and thermoregulation

(SDNN), the standard deviation of the average R-R intervals (SDANN), the root mean square of the differences in successive R-R intervals (RMSSD), and the percentage of normal R-R intervals that differ by 50 ms (pNN50). Other difference values, including the proportion of R-R intervals that differ by 20 ms (pNN20), have been found to have better discriminatory value.6 Variance of HRV is related to the length of analysed recordings, so comparison of different SDNN values must be standardised to the same duration of recording length.7 With an increasing number of devices on the market, standardisation is becoming increasingly important. The RMSSD method is preferred because it is more sensitive and less affected by respiratory rate, HR or recording duration, and because it reflects largely parasympathetic activity.8

Frequency-domain Measures of Heart Rate Variability Frequency-domain methods allow for the distinction between high frequency (HF) and low frequency (LF) components (Table 2). HF components (between 0.14 and 0.40 Hz) reflect the activity of the PNS, while LF components (between 0.04 and 0.15 Hz) are generally accepted to reflect the activity of the sympathetic nervous system. The aetiology of LF remains in question, with some studies suggesting it is primarily under sympathetic control; others suggest it is the result of both sympathetic and parasympathetic influences. Goldstein and colleagues have proposed that LF power reflects underlying baroreflex function rather than sympathetic tone.9 They note that patients with congestive heart failure and resultant increases in sympathetic tone tend to have decreased LF power levels. Additionally, pharmacological manipulation through blockade of preganglionic sympathetic outflow does not seem to affect LF, while beta-adrenergic stimulation with isoprenaline results in a decrease of LF power. Goldstein and colleagues concluded that LF power results from baroreflex function, and manipulations that affect LF power may do so not by directly affecting cardiac autonomous outflows but through modulation of those outflows by baroreflexes. Roach and Sheldon hypothesised that HRV in the LF band is due to transient fluctuations of about 10 seconds in HRV sequences, associated with blood pressure fluctuations.10 Ten healthy subjects, mean age 36 years, had HRV and blood pressure measured for 10 minutes. Non-random HRV fluctuations lasting 6.7–20 seconds were detected using time-scrambled surrogate sequences as controls. These fluctuations were 99 ± 40 ms in amplitude, in concatenates 23.4 ± 7.4 seconds long. The HRV fluctuations correlated with blood pressure fluctuations of 5 ± 5 mmHg (correlation r2 = 0.68 ± 0.10). A second HRV structure consisting of transient tachycardias of 140 ± 53 ms lasting 15.1 ± 6.1 seconds occurred singly. Together, the two occurrences contributed 84 % of the total power in the LF band. Mini bursts were noted independently of blood pressure changes and were thought to be due to muscle mechanoreceptor activation and

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contraction of small muscle groups. The authors concluded that HRV is due to a clustering of transient events, with the LF component being the result of the two types of HRV structures. Due to the small study size, further investigation assessing the effect of ageing and disease will be required to validate the authors’ findings. The LF/HF ratio serves as an index to assess the relationship between sympathetic and parasympathetic (vagal tone) activity (Figure 2). This ratio is subject to marked variation depending on type and delivery of stress. During tilt and other physical stress the LF component becomes dominant to HF (LF>HF, LF/HF=3), while during rest the absolute power of LF is less than HF (LF<HF, LF/HF=0.8). During emotional/ mental stress, the HF component becomes dominant to LF. At very low respiratory rates (<7–8 breaths per minute or deep breaths), parasympathic activity can drive LF power. This translates to changes in all frequency-domain methods favouring vagal tone: higher HF power, lower LF and LF/HF power.11 Therefore, respiratory rate must be considered, since it is a confounder of these methods.

Autonomic Nervous System Regulation of Heart Rate Variability HRV refers to the beat-to-beat alteration of the HR, i.e. the RR interval. The ECG of a healthy individual measured under resting conditions exhibits an obvious high frequency (0.14–0.4 Hz) periodic variation known as respiratory sinus arrhythmia (RSA). This can be identified on a 10-second ECG recording, since two or more HF cycles can be observed, while no more than one LF cycle could occur which is imperceptible. RSA fluctuates with the phase of respiration, with HR increasing during inspiration and HR decreasing during expiration. Vagal efferent trafficking to the sinus node occurs primarily in expiration and is attenuated during inspiration (bronchodilatation). During inhalation, intra-thoracic pressure lowers due to the contraction and downward movement of the diaphragm and the expansion of the chest cavity. Atrial pressure is also lowered because of this, enabling more blood to return to the heart. As more blood enters the heart, the vasculature and atria expand, triggering baroreceptors which suppress vagal tone, and, subsequently, HR increases. During exhalation, the diaphragm relaxes, moving upwards, and decreases the size of the chest cavity, causing an increase in intra-thoracic pressure. This increased pressure inhibits venous return to the heart, and thus less atrial expansion and activation of baroreceptors occurs. As these baroreceptors are no longer acting to suppress vagal tone, HR decreases. RSA is predominantly mediated by respiratory gating of parasympathetic efferent activity to the heart, making HRV a response to dynamic and cumulative cardiac workloads. As a dynamic marker of loads, HRV appears to be sensitive and responsive to acute stress. Mental load (i.e. making complex decisions, public speaking) decreases HRV.12 As a marker of chronic changes, HRV is also reduced

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Clinical Reviews: Clinical Arrhythmias Figure 2: Illustration of the High and Low Frequency Amplitudes and Ratio and How they Respond to Tilt Table Testing

HF

LF

0

Tilt

Power (BPM2/Hz)

Power (BPM2/Hz)

Rest

0.1

0.2

0.3

0.4

0.5

0.6

Frequency (Hz)

6

12

18

24

30

36

Cycles/Min

LF

HF

0

0.1

0.2

0.3

0.4

0.5

0.6

Frequency (Hz)

6

12

18

24

30

36

Cycles/Min

LF

LF

HF

HF

HF= high frequency; LF = low frequency.

with the ageing, sedentary lifestyle and, perhaps, over-training. Resting HR (average 72 BPM for decades 20 and above) does not change with ageing, and a reduction of HRV is attributed to a decrease in efferent vagal tone and reduced beta-adrenergic responsiveness. By contrast, aerobic exercise training increases resting HRV by increasing vagal tone. Therefore, HRV is considered a marker of frequent activation (short dips in HRV in response to acute stress) and the inadequate response (long-term vagal withdrawal, resulting in the over-activity of the counter-regulatory system), leading to the sympathetic control of HR.

Devices for Monitoring Heart Rate Variability A wide range of ambulatory medical and fitness devices are available that use sensors to detect heartbeats. These have been based on sensors for auscultation of the heart (sound), blood pressure measurement (pressure or oscillographic),13 pulse oximetry (optical), photoplethysmography (optical) and ECGs. The ECG device can consider the entire ECG or just the fiducial point of the QRS complex. There are currently no clinical studies using ambulatory auscultation or pulse oximetry for HRV studies, but such are possible. In clinical use since 1970, Holter ECG recorders have evolved by incorporating advances in electronic amplifiers, processors, solid state memory, batteries and wireless communications.14 Other advances have included single-lead ECG adhesive recorders, implantable loop recorders, smartphone attachments, and wearables, including watches and straps for the chest or wrist. The implication is that extended periods of continuous HR and rhythm monitoring are possible with minimal cost. Guidelines on how to optimise the use of these data need refining. Recordings for HRV measurements can be short term (10–20 seconds or a few minutes) or long term (days). Short-term recordings should have specific situations identified regarding position (supine, standing), state, time of day and breathing; for instance, morning, relaxed, supine or erect, spontaneous and/or controlled breathing (10 breaths/min). These situations can be identified or annotated during prolonged recordings.

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Pulse Oximeter A pulse oximeter is frequently used in exercise studies. Pulse oximetry works by passing a beam of red and infrared light through a pulsating capillary bed, usually an ear or finger. The ratio of red to infrared light transmitted gives a measure of the oxygen saturation of the blood. The oximeter works on the principle that the oxygenated blood is a brighter red than the deoxygenated blood, which is more blue-purple. The oximeter measures the sum of the intensity of both shades of red, representing the fractions of the blood with and without oxygen. The oximeter detects the pulse and then subtracts the intensity of colour detected when the pulse is absent. The remaining intensity of colour represents only the oxygenated red blood. This is displayed on the electronic screen as a percentage of oxygen saturation in the blood, along with the HR.

Photoplethysmography Photoplethysmography (PPG) is an optical technique that detects blood volume changes in the microvascular bed of tissue under the skin surface.15 The PPG waveform comprises a pulsatile (‘AC’) physiological waveform attributed to changes in the blood volume with each heart beat and a ‘DC’ baseline with various lower frequency components associated with respiration, sympathetic activity and thermoregulation. The AC waveforms can be corrupted by motion artifact and affected by skin characteristics. Numerous groups are working to overcome these limitations, often by incorporating accelerometers and spectral analysis.16,17 Validation of PPG for the assessment of HRV has been limited, but interest in the technique has increased substantially in recent years. Although there are issues related to motion artifact, the accuracy and wearability of PPG devices make them an attractive option for HRV monitoring. With PPG-HRV, SDNN and SD2 seem to have the greatest stability, with relative error compared with ECG between 2 % and 2.5  %, whereas pNN50 seems to be unstable, with relative error ~30  %.18 HRV estimation using PPG through Bayesian learning algorithms may improve. PPG has the potential to assess ultra-shortterm analysis in a free-living environment. In one study, Baek et al. reported a 5-minute PPG-HRV procedure in which HR, HF, LF, VLF, LF/

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HRV and mHealth HF, RMSSD, pNN50 and SDNN required 10, 20, 90, 270, 90, 30, 60 and 240 seconds, respectively.19 In response to the rapid uptake in usage of PPG-based wellness devices, Shcherbina et al. compared five commercially available wrist-worn devices that measure HR using PPG.20 Sixty participants wore devices while being simultaneously assessed with continuous telemetry when sitting, walking, running and cycling. Error in HR was computed for each subject–device–activity combination. Devices reported the lowest error for cycling and the highest for walking. Device error was higher for males, greater body mass index, darker skin tone and walking. Six of the devices achieved a median error for HR below 5 % during cycling. Shcherbina et al. concluded that most wrist-worn devices adequately measure HR in laboratory-based activities. HRV was not part of this study. To establish the validity of smartphone PPG and HR sensors in the measurement of HRV, Plews et al. studied 29 healthy subjects.21 An app called HRV4Training uses a smartphone’s light and camera as a PPG sensor. RR intervals were measured at rest during 5 minutes of guided breathing and normal breathing using the smartphone PPG, ECG chest strap (H10 Polar, which uses the R wave peak to send RR data via Bluetooth to a smartphone) and ECG. The root mean sum of the squared differences between R–R intervals (rMSSD) was determined from each device. Both PPG- and HR-sensor-derived measures had almost perfect correlations with ECG (R = 1.00 [0.99; 1.00]). Plews et al. concluded that PPG and HR sensors provide an acceptable agreement for the measurement of rMSSD when compared with ECG. Lu et al. enrolled 42 subjects, comparing ECG-measured parameters with ear-clip contact-based PPG methods for HRV analysis.22 After 5 minutes of analysis at rest, they found highly significant correlations in SDNN, LF power, HF power and LF/HF ratio. Similarly, in a study of 30 subjects, Peng et al.23 used a smartphone-based PPG to compare HRV measurements with ECG while at rest. They found good correlation between the average of all NN intervals. LF parameters were in greater agreement than HF parameters, consistent with HF measurements being more prone to noise. Perrotta et al. compared Elite HRV, a commercially available mobile app, to an established software program for ECG analysis (Kubios HRV 2.2).24 Thirty-seven subjects (average age 30.8 years) were enrolled, recording HRV measurements (RMSSD) for 14 consecutive days upon waking. There was a significant correlation between Elite HRV and Kubos HRV 2.2 measurements (r=0.92, p<0.0001). However, when using Bland–Altman analysis to assess for agreement, 6.4 % of RMSSD values fell outside the 95 % confidence interval. This was thought to be due to the prolonged time of measurement – many participants recorded data for more than 10 minutes – and longer sampling lengths have been shown to increase variance in R-R intervals in vagal-related indicies.3 For this reason, most studies choose a sampling time of between 3 and 5 minutes. While these studies have established a high correlation between PPG and ECG for HRV at rest, few studies have assessed HRV parameters with exercise. Lin et al. enrolled eight healthy subjects, comparing PPG and ECG HRV parameters at rest and with exercise.25 While LF coherence was demonstrated throughout, HF coherence decreased after exercise, again demonstrating the susceptibility of these measurements to noise when used in the general community.

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ECG Devices ECG devices offer the most accurate way to measure ambulatory HRV, either by using only the fiducial point of the QRS complex or, better yet, by using the entire ECG complex processed by computer algorithms to account for arrhythmias.

Single-lead ECG Adhesive Recorder In one of the earliest reports of an adhesive recorder, Lemmert et al. reported the comparative ability of a three-channel ECG recorder to detect premature ventricular contractions and ventricular fibrillation.26 Ackermans et al evaluated the feasibility of an adhesive monitor.27 They found that the new monitor could be worn by most participants for at least 6 days, and that skin irritation and comfort rating were comparable and impact on the quality of life was low compared with the control. The NUVANT was a single-lead ECG adhesive recorder paired with a portable transmitter.28 To minimise noise, Lee and colleagues created a wearable device that utilised R and S wave amplitudes for QRS detection, as well as a temporal period of at least 200 ms between successive R-R intervals to decrease noise. This patch device showed improved signal-to-noise ratio when compared with Holter for ambulation at speeds greater than 1 km/h.29 There are other ambulatory ECG solutions with software providing HRV analysis.30 A more complicated method of ECG analysis with potential for assessing sympathetic nervous system activity requires 3D highresolution ECG recordings.31 ST and T wave portions of the ECG are subject to rhythmic modulations in the LF range (≤0.1 Hz). Periodic repolarisation dynamics likely reflect the response of the myocardium to sympathetic activation and are a strong and independent predictor of mortality. This could be applied to ECG signals gathered by an ambulatory device.

Wearables: Watches and Wrist or Chest Bands Most wrist-worn wearables depend upon PPG to estimate HR and cardiac rhythm, although some have an added ECG sensor. Chest straps with ECG electrodes that record ECG signals are more accurate. One such device is the H10 Polar, which uses the R wave peak to send RR data via wireless technology to a smartphone. The actual ECG waveform is not visualised with this device. Samsung has developed several prototypes of a band that includes a single-channel ECG (built-in electrodes for right and left hand), multiwavelength PPG, and tri-axial accelerometry recording simultaneously at 128 Hz. In a published study, ambulatory pulsatile and movement data were recorded from 46 subjects and the ECG was recorded for 3.5–8.5 minutes.32 Pulse detection was performed on the PPG waveforms, and 11 features were extracted based on HRV and waveform signal quality. Google’s health division Verily recently announced the launch of a new smartwatch called the Study Watch, which will be focused on use in medical research studies.33 It will be able to capture and store up to a week’s worth of raw encrypted data, including ECG, movement data and electrodermal activity.34

Conclusion Given the recent trend towards incorporating health assessment into wearable and other mobile technologies, efforts are being put into

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Clinical Reviews: Clinical Arrhythmias establishing the validity of these devices for HRV measurements. While multi-lead ambulatory ECG devices have served as the gold standard, multiple alternative devices, mainly based on single-lead ECG and PPG, are more convenient and practical for measuring HRV parameters. Their validity must continue to be studied, particularly in cohorts needing risk stratification, and decisions made regarding which measurements are the most accurate and reproducible. Part two will deal with prognostic studies and training studies applying HRV technologies and methods. n

1.

 reeman JV, Dewey FE, Hadley DM, et al. Autonomic nervous F system interaction with the cardiovascular system during exercise. Prog Cardiovasc Dis 2006;48:342–62. https://doi. org/10.1016/j.pcad.2005.11.003; PMID: 16627049.  2. Eapen Z, Turakhia M, McConnell M, et al. Defining a mobile health roadmap for cardiovascular health and disease. J Am Heart Assoc 2016;5:e003119. https://doi.org/10.1161/ JAHA.115.003119; PMID: 27405809. 3. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Heart rate variability: standards of measurement, physiological interpretation, and clinical use. Eur Heart J 1996;17:354–81. https://doi.org/10.1093/oxfordjournals. eurheartj.a014868; PMID: 8737210.  4. Sassi R, Cerutti S, Lombardi F, et al. Advances in heart rate variability signal analysis: joint position statement by the e-Cardiology ESC Working Group and the European Heart Rhythm Association co-endorsed by the Asia Pacific Heart Rhythm Society. Europace 2015;17:1341–53. https://doi. org/10.1093/europace/euv015; PMID: 26177817. 5. Xhyheri B, Manfrini O, Mazzolini M, et al. Heart rate variability today. Prog Cardiovasc Dis 2012;55:321–31. https://doi. org/10.1016/j.pcad.2012.09.001; PMID: 23217437. 6. Mietus JE, Peng CK, Henry I, et al. The pNNx files: re-examining a widely used heart rate variability measure. Heart 2002;88:378–80. https://doi.org/10.1136/heart.88.4.378; PMID: 12231596. 7. Saul JP, Albrecht P, Berger RD, Cohen RJ. Analysis of long term heart rate variability: methods, 1/f scaling and implications. Comput Cardiol 1988;14:419–22. PMID: 11542156. 8. Penttilä J, Helminen A, Jartti T, et al. Time domain, geometrical and frequency domain analysis of cardiac vagal outflow: effects of various respiratory patterns. Clin Physiol 2001;21:365–76. https://doi.org/10.1046/j.13652281.2001.00337.x; PMID: 11380537. 9. Goldstein DS, Bentho O, Park MY, Sharabi Y. Low‐frequency power of heart rate variability is not a measure of cardiac sympathetic tone but may be a measure of modulation of cardiac autonomic outflows by baroreflexes. Exp Physiol 2011;96:1255–61. https://doi.org/10.1113/ expphysiol.2010.056259; PMID: 21890520. 10. Roach D, Sheldon R. Origins of the power of the low frequency heart rate variability bandwidth. J Electrocardiol 2018;51:422–7. https://doi.org/10.1016/j. jelectrocard.2018.02.008; PMID: 29486899.  11. Chang Q, Liu R, Shen Z. Effects of slow breathing rate on blood pressure and heart rate variabilities. Int J Cardiol 2013;169:e6–8. https://doi.org/10.1016/j.ijcard.2013.08.121; PMID: 24063918. 12. Castaldo R, Melillo P, Bracale U, et al. Acute mental stress assessment via short term HRV analysis in healthy adults:

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13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

Clinical Perspective • It is important to understand the balance between sympathetic and parasympathetic control over HR variability. •  New ambulatory monitoring technologies permit ambulatory cardiovascular monitoring on a scale not achievable with traditional techniques. • Part two of this review will focus on implications of these new devices for training and prognostic purposes.

a systematic review with meta-analysis. Biomedical Signal Processing and Control 2015;18:370–7. https://doi.org/10.1016/j. bspc.2015.02.012 Kane S, Blake J, McArdle F, et al. Opportunistic detection of atrial fibrillation using blood pressure monitors: a systematic review. Open Heart 2016;12:e000362. https://doi.org/10.1136/ openhrt-2015-000362; PMID: 27099760. Khairuddin AM, Azir KNF, Kan PE. Limitations and future of electrocardiography devices: a review and the perspective from the Internet of Things. In: 2017 International Conference on Research and Innovation in Information Systems (ICRIIS), 2017 International IEEE Conference, 16 July 2017. https://doi. org/10.1109/ICRIIS.2017.8002506 Allen J. Photoplethysmography and its application in clinical physiological measurement. Physiol Meas 2007;28:R1. https://doi.org/10.1088/0967-3334/28/3/R01; PMID:17322588. Mullan P, Kanzler CM, Lorch B, et al. Unobtrusive heart rate estimation during physical exercise using photoplethysmographic and acceleration data. Conf Proc IEEE Eng Med Biol Soc 2015:6114–7. https://doi.org/10.1109/ EMBC.2015.7319787 Salehizadeh SM, Dao, D, Bolkhovsky J, et al. A novel timevarying spectral filtering algorithm for reconstruction of motion artifact corrupted heart rate signals during intense physical activities using a wearable photoplethysmogram sensor. Sensors (Basel) 2015;16:10. https://doi.org/10.3390/ s16010010; PMID: 26703618. Jeyhani V, Mahdiani S, Peltokangas M, Vehkaoja A. Comparison of HRV parameters derived from photoplethysmography and electrocardiography signals. Conf Proc IEEE Eng Med Biol Soc 2015;2015:5952–5. https://doi. org/10.1109/EMBC.2015.7319747; PMID: 26737647. Baek HJ, Shin J. Effect of missing inter-beat interval data on heart rate variability analysis using wrist-worn wearables. J Med Syst 2017;41:147. https://doi.org/10.1007/s10916-0170796-2; PMID: 28812280. Shcherbina A, Mattsson C, Waggott D, et al. Accuracy in wrist-worn, sensor-based measurements of heart rate and energy expenditure in a diverse cohort. J Pers Med 2017;7:3. https://doi.org/10.3390/jpm7020003; PMID: 28538708. Plews DJ, Scott B, Altini M, et al. Comparison of heart-ratevariability recording with smartphone photoplethysmography, Polar H7 chest strap, and electrocardiography. Int J Sports Physiol Perform 2017;12:1324–8. https://doi.org/10.1123/ ijspp.2016-0668; PMID: 28290720. Lu G, Yang F, Taylor J, Stein J. A comparison of photoplethysmography and ECG recording to analyse heart rate variability in healthy subjects. J Med Eng Technol

2009;33:634–41. https://doi.org/10.3109/03091900903150998; PMID: 19848857. 23. Peng R, Zhou X, Lin W, Zhang Y. Extraction of heart rate variability from smartphone photoplethysmograms. Comput Math Methods Med 2015;2015:516826. https://doi. org/10.1155/2015/516826; PMID: 25685174. 24. Perrotta A, Jeklin A, Hives B, et al. Validation of the Elite HRV smartphone application for examining heart rate variability in a field-based setting. J Strength Cond Res 2017;31:2296– 302. https://doi.org/10.1519/JSC.0000000000001841; PMID: 28195974. 25. Lin W, Wu D, Li C, et al. Comparison of heart rate variability from PPG from that from ECG. In: The International Conference on Health Informatics IFMBE Proceedings 2015. 26. Lemmert M, Janata A, Erkens P, et al. Detection of ventricular ectopy by a novel miniature electrocardiogram recorder. J Electrocardiol 2011;44:222–8. https://doi.org/10.1016/j. jelectrocard.2010.10.028; PMID: 21145065. 27. Ackermans P, Solosko T, Spencer E, et al. A user-friendly integrated monitor-adhesive patch for long-term ambulatory electrocardiogram monitoring. J Electrocardiol 2012;45:148–53. https://doi.org/10.1016/j.jelectrocard.2011.10.007; PMID: 22153334. 28. Engel J, Mehta V, Fogoros R, Chavan A. Study of arrhythmia prevalence in NUVANT mobile cardiac telemetry system patients. Conf Proc IEEE Eng Med Biol Soc 2012:2440–3. 29. Lee WK, Yoon H, Park KS. Smart ECG monitoring patch with built-in R-peak detection for long-term HRV analysis. Ann Biomed Eng 2016;44:2292–301. https://doi.org/10.1007/s10439015-1502-5; PMID: 26558395.  30. Derkac W, Finkelmeier J, Horgan D, Hutchinson M. Diagnostic yield of asymptomatic arrhythmias detected by mobile cardiac outpatient telemetry and autotrigger looping event cardiac monitors. J Cardiovasc Electrophysiol 2017;28:1475–8. https://doi.org/10.1111/jce.13342; PMID: 28940881. 31. Rizas KD, Hamm W, Kääb S, et al. Periodic repolarisation dynamics: a natural probe of the ventricular response to sympathetic activation. Arrhythm Electrophysiol Rev 2016;5:31–6. https://doi.org/10.15420/aer.2015:30:2; PMID: 27403291 32. Nemati S, Ghassemi M, Ambai V, et al. Monitoring and detecting atrial fibrillation using wearable technology. Conf Proc IEEE Eng Med Biol Soc 2016:3394–7. 33. Heater B. Alphabet’s Verily offers a more serious take on health monitoring wearables with the Study Watch. TechCrunch 14 April 2017. Available at: http://tcrn.ch/2ofNo7Z (accessed 06 July 2018) 34. Dorsey E, Marks W. Verily and its approach to digital biomarkers. Digital Biomarkers 2017;1:96–9. https://doi. org/10.1159/000476051

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Clinical Reviews: Drugs and Devices

Mechanisms Underlying the Actions of Antidepressant and Antipsychotic Drugs That Cause Sudden Cardiac Arrest Serge Sicouri 1 and Charles Antzelevitch 1,2,3 1. Lankenau Institute for Medical Research, Wynnewood, PA, USA; 2. Lankenau Heart Institute, Wynnewood, PA; 3. Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, PA, USA

Abstract A number of antipsychotic and antidepressant drugs are known to increase the risk of ventricular arrhythmias and sudden cardiac death. Based largely on a concern over the development of life-threatening arrhythmias, a number of antipsychotic drugs have been temporarily or permanently withdrawn from the market or their use restricted. While many antidepressants and antipsychotics have been linked to QT prolongation and the development of torsade de pointes arrhythmias, some have been associated with a Brugada syndrome phenotype and the development of polymorphic ventricular arrhythmias. This article examines the arrhythmic liability of antipsychotic and antidepressant drugs capable of inducing long QT and/or Brugada syndrome phenotypes. The goal of this article is to provide an update on the ionic and cellular mechanisms thought to be involved in, and the genetic and environmental factors that predispose to, the development of cardiac arrhythmias and sudden cardiac death among patients taking antidepressant and antipsychotic drugs that are in clinical use.

Keywords Sudden cardiac death, cardiac arrhythmias, long QT syndrome, Brugada syndrome, J wave syndromes, genetics Disclosure: The authors acknowledge financial support from the National Heart, Lung, and Blood Institute (NHLBI) (Grant #HL47678) and from the Martha and Wistar Morris Fund. Received: 25 April 2018 Accepted: 19 June 2018 Citation: Arrhythmia & Electrophysiology Review 2018;7(3):199–209. DOI: https://doi.org/10.15420/aer.2018.29.2 Correspondence: Charles Antzelevitch, Professor and Executive Director, Cardiovascular Research, Lankenau Institute for Medical Research, Wynnewood, PA 19096, USA, Director of Research, Lankenau Heart Institute, Wynnewood, PA 19096, USA, E: cantzelevitch@gmail.com

The link between sudden unexplained death in individuals with mental health problems who are administered antipsychotic drugs has been recognised for over a century.1 A clear relationship has emerged over the past 25 years between antipsychotic drugs, prolongation of the QT interval of the ECG, atypical polymorphic tachycardia known as torsade de pointes (TdP) and sudden cardiac death (SCD). A number of antipsychotic drugs have been temporarily or permanently withdrawn from the market – or their use restricted – because of a concern over QT and QT corrected for heart rate (QTc) prolongation and development of TdP. In some cases, close follow-up with an ECG has been recommended or a modification of label imposed. The list of antipsychotic drugs implicated includes pimozide, sertindole, thioridazine, mesoridazine, promazine, triflupromazine, droperidol, moperone, pipamperone, sultopride and ziprasidone. A link between clinical use of antidepressants and the development of arrhythmias was first suggested following the Cardiac Arrhythmia Suppression Trial (CAST),2 based on the sodium channel-blocking properties of a number of antidepressant drugs including imipramine. Tricyclic antidepressants were subsequently shown to inhibit potassium channels and thus to prolong the QT interval and induce TdP. These effects of tricyclic antidepressants are generally observed when combined with other QT-prolonging agents or in cases of overdose. In addition, a number of case reports have linked tricyclic antidepressants as well as antipsychotic drugs to drug-induced Brugada syndrome (BrS), leading to syncope and SCD as a result of the development of rapid polymorphic ventricular tachycardia (VT) and VF.

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Our focus in this article is on mechanisms and predisposing factors underlying the development of cardiac arrhythmias and SCD associated with antidepressant and antipsychotic drugs in clinical use.

Drug-induced Long QT Syndrome and Torsade de Pointes by Antidepressant and Antipsychotic Agents The QT interval is a measure of the time interval between the start of depolarisation and the end of repolarisation. QTc intervals above 450 ms in men and 460 ms in women are considered to be abnormally prolonged. TdP, from the French for ‘twisting of the points’, is an atypical VT characterised by oscillations of the points or R wave peaks (‘pointes’) around the main axis of the ECG, giving rise to a unique morphology. Since the original work of François Dessertenne,3 it has been well recognised that many conditions are capable of causing prolonged or abnormal repolarisation, giving rise to QT prolongation, abnormal T/U wave morphologies and the development of TdP.4 Although a prolonged QT interval is essential for the development of TdP, it is generally not considered sufficient to induce TdP. An increased risk for TdP is recognised when the QTc exceeds 500 ms and whenever a drug increases QTc by >60–70 ms, especially when the increase develops rapidly.4–6 In addition to QTc prolongation, the risk of TdP is associated with the dispersion of transmural repolarisation and excitability. TdP arrhythmias can degenerate into VF, leading to SCD. TdP can be caused by either congenital or acquired long QT syndrome (LQTS). Congenital LQTS is subdivided into 10 genotypes distinguished

Access at: www.AERjournal.com

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Clinical Reviews: Drugs and Devices Table 1: Drugs that Prolong the QT Interval and Induce Torsade de Pointes Drug

Clinical Use

TdP

References

by mutations in at least 17 different genes encoding for cardiac ion channels and structural anchoring proteins. In the different genotypes, cardiac events may be precipitated by physical or emotional stress (LQT1), a startle (LQT2), or may occur at rest or during sleep (LQT3).

Category Antidepressants

14, 92

Tricyclic Antidepressants

136–141

Amitriptyline

Depression

CR

Amoxapine

Depression

CR

Clomipramine

Depression

CR

Desipramine

Depression

CR

Citalopram

Depression

CR

Doxepin

Depression

CR

Imipramine

Depression

PR

Nortriptyline

Depression

CR

Protriptyline

Depression

CR

Trimipramine

Depression

PR

Isradipine

Depression

PR

Lithium

Depression

PR

Fluoxetine

Depression

CR

Sertraline

Depression

CR

Venlafaxine

Depression

PR

Citalopram

Depression

KR

Escitalopram

Depression

KR

Promethazine

Depression

PR

Chlorpromazine Levomepromazine

Schizophrenia Schizophrenia

KR KR

Clozapine

Schizophrenia

PR

Haloperidol Droperidol

Schizophrenia Schizophrenia

KR KR

Pimozide

Tourette’s tic Women>Men

KR

Quetiapine

Schizophrenia

CR

Risperidone

Schizophrenia

PR

Sertindole*

Schizophrenia

PR

Thioridazine

Schizophrenia

KR

Flupentixol

Schizophrenia

KR

Ziprasidone

Schizophrenia

PR

Cyamemazine

Schizophrenia

KR

Dromperidone

Schizophrenia

KR

Sulpiride

Schizophrenia

KR

Levosulpiride

Schizophrenia

KR

Sultopride

Schizophrenia

KR

Zotepine

Schizophrenia

KR

Prothipendyl

Schizophrenia

PR

Pimavanserin

Schizophrenia

PR

Benperidol

Schizophrenia

PR

Other Antidepressants

Antipsychotics

17–19, 142

*Withdrawn from the market. Risk Category: Drug List KR: These drugs prolong the QT interval and are clearly associated with a known risk of TdP, even as taken as recommended. Drug List PR: These drugs cause QT prolongation but lack evidence for a risk of TdP when taken as recommended. Drug List CR: These drugs are associated with TdP but only under certain conditions (for example, excessive dose, in patients with conditions such as hypokalemia, or when taken with interacting drugs) or by creating conditions that facilitate or induce TdP (for example, by inhibiting metabolism of a QT-prolonging drug or by causing an electrolyte disturbance that facilitates the development of TdP). (Table 3). CR = conditional risk; KR = known risk; PR = possible risk; TdP = torsade de pointes. Source: Modified from www.crediblemeds.org.

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Acquired LQTS refers to a syndrome caused by circumstances other than genetic factors, including exposure to drugs that prolong the duration of the ventricular action potential (AP),7 or secondary to cardiomyopathies such as dilated or hypertrophic cardiomyopathy, as well as to abnormal QT prolongation associated with bradycardia or electrolyte imbalance.8–13 The acquired form of the disease is far more prevalent than the congenital form, and in some cases may have a genetic predisposition. Table 1, modified from www.CredibleMeds.org, lists the antidepressant and antipsychotic drugs that have been shown to prolong QT interval and induce TdP. Among the antidepressant agents, amitriptyline, imipramine, and maprotiline are the agents most commonly associated with TdP the greatest prolongation of QT interval is observed with maprotiline).14 Table 1 shows the relative risk of TdP for distinct antidepressants and antipsychotics by classifying the drugs in TdP risk categories ranging from the highest risk of TdP; known risk of TdP (KR), to possible risk of TdP (PR) and conditional risk of TdP (CR). As shown in Table 1, most antidepressants are classified as CR, with a low risk of TdP. Vieweg and Wood14 reported 13 cases of TdP induced by antidepressants. As is typical of acquired LQTS, most cases (12 of 13) involved women. One case involved a child. In addition to female sex, risk factors include age (peaking in adolescence), bradycardia, metabolic inhibitors, hypokalemia, hypomagnesaemia, drug overdose and co-administration of QT-prolonging drugs (Table 2). QRS duration of the ECG, measured in five of 13 cases, showed prolongation in two and no change in three, suggesting that QT prolongation with antidepressants may be a result of sodium as well as potassium channel blockade. In a recent study, Danielsson and colleagues confirmed that antidepressants with KR or PR of TdP were associated with a higher risk than those classified as CR of TdP.15 Selective serotonin reuptake inhibitors (SSRIs), including citalopram, escitalopram, fluoxetine, paroxetine, sertraline and venlafaxine have been shown to exhibit a higher risk than tricyclic antidepressants, especially considering that an increase in dose of SSRIs, but not that of tricyclic antidepressants, markedly increases the risk of sudden death.16 For the most commonly used antidepressants in the elderly, the following risk ranking was observed, from highest to lowest; mirta zapine;citalopram;sertraline;amitriptyline.15 In 2011, the Food and Drug Administration (FDA) issued a warning concerning the antidepressant citalopram (Celexa®, Allergan) and its potential risk for TdP at doses greater than 40 mg (FDA, drug safety communication). Providers were asked to use doses less than 20 mg in patients over 60 years of age with hepatic dysfunction, as well as in poor CYP2C19 metabolisers or those taking concomitant CYP2C19 inhibitors. The maximum daily dosage of citalopram is now 40 mg in the non-elderly adult population. Most studies show that – in contrast to antipsychotics – antidepressants, including SSRIs, induce QT prolongation and TdP arrhythmias in cases of overdose, but rarely at therapeutic concentrations. However, QT prolongation may occur in elderly patients at therapeutic doses.16 Among the newer non-SSRIs, QT prolongation has rarely been reported with venlafaxine at therapeutic doses or with overdose. Bupropion has been linked to QT prolongation in overdose situations. In elderly patients with a number of high-risk comorbidities, mirtazapine demonstrated higher risk of SCD and ventricular arrhythmias than paroxetine.16 Jasiak

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SCD Caused by Antidepressants and Antipsychotics et al. concluded that, based on the current literature, risk of QT/QTc prolongation with most newer non-SSRI antidepressants at therapeutic doses is low.16 The highest risk for QT prolongation appears to exist in overdose situations with venlafaxine and bupropion. They note that, given the few controlled studies and confounding variables in case reports, it is difficult to draw conclusions on QT prolongation risk with many of the newer non-SSRI antidepressants. Antipsychotic drugs, especially those in the phenothiazine group, can also induce QT prolongation and TdP. Mehtonen et al. surveyed cases of sudden death by antidepressant or antipsychotic drugs and found 49 cases of sudden death (31 women and 18 men) associated with the use of these agents.17 A therapeutic dose of phenothiazine was involved in 46 of the 49 cases. Thioridazine was the only antipsychotic drug administered in 15 of the 49 cases. Figure 1 displays a case of a marked QT prolongation and TdP induced by the antipsychotic agent flupentixol. Antipsychotic drugs generally have a higher torsadogenic potential (category KR and PR) than antidepressants (category CR) (Tables 1 and 3). As a consequence, antidepressant-induced TdP is more typically observed in the presence of drug combinations. Ray et al. conducted a retrospective cohort study of half a million Medicaid patients between 1988 and 1993, before the introduction of atypical antipsychotics, and observed that the risk for sudden death increased 2.39 times in individuals receiving antipsychotic drugs compared with those who did not receive these agents.18 Although the study did not demonstrate causality, it suggested that the potential adverse cardiac effects of antipsychotics should be considered in clinical practice, particularly for patients with cardiovascular disease. Hennessy et al. in a study of 90,000 patients, observed that those treated for schizophrenia had a higher incidence of cardiac arrest and ventricular arrhythmias than nonschizophrenia patients.19 The drugs used were clozapine, haloperidol, risperidone, and thioridazine. In a study of nursing home residents in six states, Liperoti et al. observed that the use of conventional antipsychotics led to a twofold increase in risk of hospitalisation for ventricular arrhythmias and cardiac arrest, especially in patients with pre-existing cardiac disease.20 In the elderly, haloperidol has been associated with high risk of TdP.15 The IV form of haloperidol is thought to carry a higher risk of QTc prolongation and TdP than the oral form.21,22 In 11 cases of fatal TdP, eight occurred with IV haloperidol. The FDA now recommends cardiac monitoring for all patients receiving haloperidol.

Table 2: Risk Factors for Torsade de Pointes and Brugada Syndrome by Antidepressant and Antipsychotic Drugs Risk Factor

Increased Risk

Increased Risk

for TdP

for BrS

Sex

Female

Male

Bradycardia

+

+

Hypokalemia

+

-/+

Hypomagnesaemia

+

-

Drug interaction (QT-prolonging agents)

+

-

Drug interaction (sodium or calcium channel blockers, parasympathetic agonists)

-

+

Drug interaction (slow metabolism by CYP inhibitors 2D6,1A2,3A4)

+

+

Hepatic dysfunction (increased drug concentration)

+

+

Genetic predisposition

Congenital LQTS

Congenital BrS

TdP: torsade de pointes; BrS: Brugada syndrome; CYP: cytochrome 450; LQTS: long QT syndrome.

Figure 1: Flupentixol-induced Marked QT Prolongation and Torsade de Pointes

Marked prolongation of the QT interval leading to episodes of polymorphic VT displaying features of TdP. TdP = torsade de pointes; VT = ventricular tachycardia.

BrS was introduced as a new clinical entity by Pedro and Josep Brugada in 1992.23 The syndrome has been associated with a high risk of sudden death, especially in men as they enter their third and fourth decades of life. A consensus report published in 2002 delineated diagnostic criteria for the syndrome.24,25 A second consensus conference report published in 2005 focused on risk stratification schemes and approaches to therapy.26,27 The most recent expert consensus report focused on emerging concepts, advances in risk stratification and approaches to therapy for both Brugada and early repolarisation syndrome (ERS), the so-called J wave syndromes.28

Three types of repolarisation patterns in the right precordial leads are recognised.24,25 Type 1 ST-segment elevation is diagnostic of BrS and is characterised by a coved ST-segment elevation ≥2 mm (0.2 mV) followed by a negative T wave. Type 2 ST-segment elevation has a saddleback appearance with a high take-off ST-segment elevation of ≥2 mm, followed by a trough displaying ≥1 mm ST elevation, followed by either a positive or biphasic T wave. Type 3 ST-segment elevation has either a saddleback or coved appearance with an ST-segment elevation of <1 mm. These three patterns may be observed sequentially in the same patient or following the introduction of specific drugs, particularly sodium channel blockers. Type 2 and type 3 ST-segment elevation are not considered to be diagnostic of BrS. BrS is definitively diagnosed only when a type 1 ST-segment elevation (Brugada ECG) is observed in more than one right-precordial lead (V1–V3), in the presence or absence of sodium channel-blocking agent, and in conjunction with one or more of the following; documented VF, polymorphic VT; a family history of SCD (<45 years old); coved type ECGs in family members; inducibility of VT with programmed electrical stimulation; syncope; or nocturnal agonal respiration.24–27

BrS is characterised by an electrocardiographic pattern of right bundle brunch in right precordial leads, ST-segment elevation in the right precordial leads, relatively normal QTc interval, coupled with syncope and sudden death caused by VT/VF in patients with no or minimal structural disease.

The average age at the time of cardiac arrest in patients with BrS is approximately 45 years, but most develop symptoms between 20 and 65 years.29–31 BrS in children is rare, but sudden death in this population is reported.32,33 Men are at increased risk for development of a spontaneous type I Brugada ECG and SCD.34,35

Drug-induced Brugada Syndrome Phenotype by Antidepressant and Antipsychotic Agents

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Clinical Reviews: Drugs and Devices Table 3: Drugs that Induce Brugada ECG Pattern (Type 1 ST-Segment Elevation) and that Should be Avoided in Patients with Brugada Syndrome Drug

Class

Clinical use

References

Amitriptyline

IIA

Depression

85, 87

Desipramine

IIA

Depression

70, 86

Nortriptyline

IIA

Depression

72, 88

Clomipramine

IIA

Depression/ obsessive compulsive disorder

Imipramine

IIA

Depression/ anxiety

Tetracyclic Antidepressant

Maprotiline

IIA

Depression/ anxiety

87

Others

Lithium

IIB

Depression

82

Bupropion Cyamemazine Dosulepin Doxepin Fluoxetin Fluvoxamine Maprotiline Paroxetine Lamotrigine

IIB

Depression Depression Depression Depression Depression Depression Depression Depression Depression Epilepsy, bipolar disorder

143

related variants in SCN5A, the gene encoding the alpha subunit of the cardiac sodium channel, have been reported.37–40 Loss-of-function mutations in SCN5A contribute to the development of both BrS and ERS, as well as to various conduction diseases, Lenegre’s disease and sick sinus syndrome.

Antidepressants Tricyclic Antidepressant

Antipsychotics

Antiepileptic

New susceptibility genes proposed and awaiting confirmation include the transient receptor potential melastatin protein 4 gene (TRPM4)61 and the KCND2 gene. Variants in KCNH2, KCNE5, SEMA3A, although not causative, have been identified as capable of modulating the substrate for the development of BrS.62–65 KCNE4 has recently been added to

Trifluoperazine IIA

IIA

Anxiety, psychotic disorders

85

Loxapine

IIA

Psychotic conditions including hallucinations, delusions, and confusion

144

Clotiapine Cyamemazine Thioridazine

IIB

Psychotic disorders

Propofol

IIA

Sedative, hypnotic and antiepileptic

83, 84

Recommendation class: Class I: There is evidence and/or general agreement that a given drug is potentially arrhythmic in BrS patients. Class IIA: There is conflicting evidence and/or divergence of opinion about the drug, but the weight of evidence/opinion is in favour of a potentially arrhythmic effect in BrS patients. Class IIB: There is conflicting evidence and/or divergence of opinion about the drug, and the potential arrhythmic effect in BrS patients is less well established by evidence/opinion. BrS = Brugada syndrome. Source: Modified from www.brugadadrugs.org.

In a recent study, women comprised 42 % of a cohort of 542 patients who presented with a spontaneous or drug-induced Brugada type  1 pattern on the ECG.36 Women with BrS present more benign clinical characteristics, less spontaneous type  1 ECG pattern, and are more likely to be asymptomatic than men.35 BrS has been associated with variants in 19 different genes. The gene most often associated with BrS is SCN5A, accounting for 11–28  % of cases, depending largely on geographic location. Over 300 BrS-

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Variants in genes encoding the calcium channels including CACNA1C (Cav1.2), CACNB2b (Cavbeta2b) and CACNA2D1 (Cavalpha2delta) have been reported in up to 13 % of probands.41–44 Mutations in glycerol-3phosphate dehydrogenase 1-like enzyme gene (GPD1L), SCN1B (beta1subunit of sodium channel), KCNE3 (MiRP2), SCN3B (beta3-subunit of soduim channel), KCNJ8 (Kir6.1), KCND3 (Kv4.3), RANGRF (MOG1), SLMAP, ABCC9 (SUR2A), (Navbeta2), PKP2 (plakophillin-2), FGF12 (FHAF1), HEY2, SEMA3A (semaphorin) and KCNAB2 (Kvbeta2) are relatively rare.45–56 An association of BrS with SCN10A, a gene encoding a neuronal sodium channel, was first reported in 2014.56–58 There is controversy as to the pathogenicity of many SCN10A mutations with yields ranging from 5.0 % to 16.7 %.57–59 Mutations in all of these genes lead to loss of function in sodium (INa) and calcium (ICa) channel currents, as well as to a gain of function in transient outward potassium current (Ito) or ATP-sensitive potassium current (IK-ATP).58,60

this group (unpublished observation, Clatot and Antzelevitch). Loss-offunction mutations in HCN4 (prominently expressed in the sinus node) have been associated with BrS but may be modulatory by acting to unmask BrS by reducing heart rate.66 A large number of factors modulate the electrocardiographic and arrhythmic manifestations of BrS. ST-segment elevation in BrS is often dynamic. The Brugada ECG may be concealed, but can be unmasked or modulated by sodium channel blockers, a febrile state, vagotonic agents, alpha adrenergic agonists, beta adrenergic blockers, tricyclic or tetracyclic antidepressants, first generation antihistamines (dimenhydrinate), a combination of glucose and insulin, hyperkalemia, hypokalemia, hypercalcaemia, and by alcohol and cocaine toxicity.67–77 These agents may also induce acquired forms of BrS. Propafenone, typically prescribed for the treatment of AF, is a common example of a drug that can unmask BrS.78–81 Lithium, a widely used antidepressant agent, has been recently added to the list of drugs to avoid in patients with BrS. Lithium is a potent blocker of cardiac sodium channels and can unmask a type 1 ECG in patients with BrS.82 Propofol, a short-acting, IV-administered sedativehypnotic and antiepileptic agent with anaesthetic properties, may cause a rare condition called propofol infusion syndrome, characterised by unexplained lactic acidosis, lipaemia, rhabdomyolysis, cardiovascular collapse and Brugada-like ECG pattern following high-dose propofol infusion over prolonged periods of time.83,84 Table 3 lists the antidepressants and antipsychotic agents reported to induce the Brugada ECG pattern. All cases of BrS pattern induced by antidepressants and antipsychotics displayed a type 1 ST-segment elevation (Figure 2). A study of 98 patients experiencing an overdose of tricyclic antidepressants reported that 15 of these displayed an ECG consistent with BrS.71 The overall mortality was 3.0 % among all patients, but 6.7 % among patients who displayed a Brugada phenotype. Rouleau et al. described three cases of psychotropic drug-induced Brugada

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SCD Caused by Antidepressants and Antipsychotics ECG,85 occurring during concomitant administration of amitriptyline and a phenothiazine (case 1), overdose of fluoxetine (case 2), and co-administration of trifluoperazine and loxapine (case 3). Babaliaros and Hurst described a Brugada pattern in patients receiving increasing doses of imipramine.70 Akhtar and Goldschlager reported a case of BrS following massive ingestion of desipramine and clonazepam.77 Chow et al. reported a similar case involving desipramine.86 Bolognesi et al. described a Brugada ECG pattern following overdose of amitriptyline and with maprotiline.87 Additional cases of BrS were reported following overdose with nortriptyline72,88 or lithium.82,89

Figure 2: Brugada Syndrome Phenotype in a 42-year-old Man Treated with Lithium

The available data suggest that most cases of antidepressant and antipsychotic-induced BrS phenotype occur as a consequence of drug overdose or drug combination.

Effects of antidepressants and antipsychotics on ion channels Antidepressants and antipsychotics are reported to modulate the cardiac AP by blocking a variety of cardiac ion channels. In the ventricle they inhibit the fast sodium channel inward current (INa), the inward calcium current (ICa), and one or more outward potassium currents (IK), particularly the rapidly activating delayed rectifier current (IKr). Druginduced IKr block has attracted considerable attention in recent years because of the association of IKr block with QT interval prolongation in the ECG and life-threatening cardiac arrhythmias such as TdP. Druginduced INa and ICa block underlie the development of the BrS phenotype in experimental models of BrS.90,91 Table 4 illustrates the IC50 values for block of IKr, ICa and INa derived from heterologous expression systems (for example, HEK and CHO cells) and/or native cardiac myocytes for a number of antidepressants and antipsychotics that have been shown to induce arrhythmias.92 The available studies suggest that most antidepressants inhibit both inward and outward currents, these include imipramine, amitriptyline, and fluoxetine, all of which block both IKr and ICa. Imipramine and amitriptyline also block INa. The ability of antidepressants to block both outward and inward currents is associated with lack of correlation between the degree of IKr block and QT prolongation because calcium and/or sodium channel inhibition limit the effects of IKr block to prolong AP duration (APD) and thus to prolong the QT interval. In contrast to antidepressants, antipsychotic drugs produce more of an outward current inhibition. QT prolongation is most commonly secondary to inhibition of IKr. A 30-fold difference between the effective plasma concentration and the IC50 for inhibition of IKr has been suggested as an adequate margin of safety for avoiding the development of TdP as an adverse effect.93

Mechanisms of Arrhythmias in Long QT Syndrome Amplification of spatial dispersion of repolarisation within the ventricular myocardium has been identified as the principal arrhythmogenic substrate in both acquired and congenital LQTS. The accentuation of spatial dispersion – typically secondary to an increase of transmural, trans-septal or apico-basal dispersion of repolarisation – and the development of early afterdepolarisation (EAD)-induced triggered activity, underlie the substrate and trigger, respectively, for the development of TdP arrhythmias observed under LQTS conditions.94,95 Models of the LQT1, LQT2, LQT3, LQT5, LQT6, LQT7, and LQT8 forms of the LQTS have been developed using the canine arterially-perfused left ventricular wedge preparations.96–99 These models suggest that in

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ECG displays downsloping ST elevation (type 1) in leads V1–V2. Lithium plasma concentration was 1.4 mEq/l (reference range 0.8–1.4 mEq/l). Source: Modified from Pirotte, et al., 200889, with permission from Elsevier.

Table 4: IC Values for Block of I , I and I by Antidepressant and Antipsychotic Drugs 50

Drug

Kr

Ca

Na

IKr IC50

ICa IC50

INa IC50

(μM)

(μM)

(μM)

References

Antidepressants Amitriptyline*

4.78

3.75

>1.0

92, 145–148

Imipramine*

3.4

4.0

5.0

92, 147, 149

Fluoxetine*

1.5–3.1

2.8

Citalopram

3.97

92, 147, 150, 151 92

Antipsychotics Chlorpromazine

1.47 ± 0.03

152, 153

Clozapine

2.63 ± 0.12

152, 153

Haloperidol

1.0

154

Sertindole†

2.9

154

Thioridazine

1.07 ± 0.06

152, 153

*Drugs with mixed ion channel block92. † Drug withdrawn.

the first three forms of LQTS preferential prolongation of the M cell APD leads to an increase in the QT interval, as well as an increase in transmural dispersion of repolarisation (TDR), which contributes to the development of TdP (Figure 3).100–102 The unique characteristics of the M cells are at the heart of the LQTS. The hallmark of the M cell is the ability of its AP to prolong more than that of endocardium or epicardium in response to a slowing of rate.103–105 This feature of the M cell is a result of weaker repolarising current during phases two and three of the AP, secondary to a smaller IKs and a larger late INa and INa-Ca.106–108 These ionic distinctions also sensitise the M cells to a variety of pharmacological agents. Agents that block IKr (such as antidepressants and antipsychotics), IKs, or increase ICa or late INa, generally produce a much greater prolongation of the APD of the M cell than that of epicardial or endocardial cells. The duration of the M cell AP therefore determines the QT interval, whereas the duration of the epicardial AP generally determines the QT peak interval. Figure 4 presents our working hypothesis of the mechanisms underlying LQTS-related TdP. The hypothesis presumes the presence of electrical heterogeneity in the form of spatial dispersion of repolarisation in the form of transmural and trans-septal dispersion of repolarisation under baseline conditions, and the amplification of

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Clinical Reviews: Drugs and Devices Figure 3: Polymorphic VT Displaying Features of Torsade de Pointes Induced by D-sotalol (100 μM) in an Arterially Perfused Canine Left Ventricular Wedge Preparation

50 mV

M Cell

50 mV

EPi

ECG

2 mV S1

S1

2 sec Each trace shows action potentials simultaneously recorded from M and epicardial (Epi) cells together with a transmural ECG. The preparation was paced from the endocardial surface at a basic cycle length of 2000 ms (S1). Spontaneous TdP occurred in this model. The first groupings show spontaneous ventricular premature beat (or couplets) that fail to induce TdP, and a second grouping show spontaneous premature beats that succeed. The premature response appears to originate in the deep subendocardium (M or Purkinje cells). TdP = torsade de pointes; VT = ventricular tachycardia. Source: Modified from Shimzu and Antzelevitch., 2000102, with permission from Elsevier.

Figure 4: Proposed Mechanisms of Arrhythmogenesis in Models of Congenital or Drug-induced Long QT Syndrome Intrinsic Heterogeneity

Antidepressants or Antipsychotics

Net Repolarizing Current IKr

IKs Prolongation of APD (Homogeneous)

APD Prolongation preferentially in M cells (Heterogeneous)

Long QT Interval Dispersion of Refractoriness

EAD- or DAD-induced triggered beat (Purkinje or M cell ?)

Long QT Interval Transmural Dispersion of Repolarization

ß adrenergic Torsade de Pointes (Reentry) Source: Modified from Antzelevitch and Shimizu., 2000,95 with permission.

TDR by agents that reduce net repolarising current via a reduction in IKr or IKs (or augmentation of ICa or late INa). Pharmacological agents or other conditions that cause a reduction in IKr lead to a preferential prolongation of the M cell AP. As a consequence, the QT interval prolongs and is accompanied by a dramatic increase in TDR, creating a vulnerable window for the development of re-entry. The reduction in net repolarising current also predisposes to the development of EAD-induced triggered activity and, in rare cases, delayed afterdepolarisation-induced, triggered activity in M and Purkinje cells, which provide the extrasystole that triggers TdP when it falls within the vulnerable period. Betaadrenergic agonists further amplify transmural heterogeneity in the case of IKs block, as well as (transiently) in the case of IKr block, but reduce it in the case of INa agonists.102,109 Inhibition of IKr is the most common cause of reduction in net outward current by antidepressant and antipsychotic drugs. The presence of other IKr blockers (combination of an antidepressant and antipsychotic drug) or agents that reduce IKs or augment ICa or late

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INa can accentuate the reduction in repolarisation forces and increase the probability of arrhythmia.

Mechanisms of Arrhythmia in Brugada Syndrome The development of prominent J waves, appearing as ST-segment elevation in the right precordial leads of BrS patients, is believed to be a result of accentuation of the right ventricular (RV) epicardial AP notch secondary to an outward shift in the balance of currents active at the end of phase 1.110 A spike and dome morphology, displaying a prominent notch in ventricular epicardium but not endocardium, generates a transmural voltage gradient that results in the electrocardiographic J wave.111 The cellular basis for BrS is thought to involve an outward shift of net transmembrane current active at the end of phase 1 of the RV epicardial AP. The Ito has been shown to be most prominent in the right ventricle, particularly in the region of the RV outflow tract (RVOT).112 Such a shift can accentuate the AP notch and lead to allor-none repolarisation at the end of phase 1 (Figures 5 and 6). When phase 1 repolarises beyond the voltage range at which L-type Ca+2 channels activate, the Ca+2 channels fail to activate, resulting in loss of the AP dome. Conduction of the AP dome from epicardial sites at which it is maintained to sites at which it is lost gives rise to phase 2 re-entry that generates a closely coupled extrasystole that precipitates VT/VF.110,113,114 Although genetic mutations are equally distributed between sexes, the clinical phenotype is 8– to10–times more prevalent in men than in women. The basis for this sex-related distinction is a more prominent Ito in the RV epicardium of men versus women.115 The more prominent Ito-mediated AP notch causes the end of phase 1 of the RV epicardial AP to repolarise to more negative potentials in tissue and arteriallyperfused wedge preparations from men, facilitating loss of the AP plateau and the development of phase 2 re-entry and polymorphic VT. The cellular mechanisms underlying BrS have long been a matter of debate.116,117 Two principal hypotheses have been proposed; the repolarisation hypothesis and the depolarisation hypothesis. The repolarisation hypothesis described above maintains that an outward shift in the balance of currents in RV epicardium can lead to repolarisation abnormalities, resulting in the development of the substrate for re-entrant activity as well as the development of phase 2 re-entry, which generates closely coupled premature beats capable of precipitating VT/VF. The depolarisation hypothesis suggests that slow conduction in the RVOT, as a result of fibrosis, reduces Cx43 expression leading to discontinuities in conduction. Conduction slowing is not necessarily limited to the RVOT area. Leong et al. recently reported a study in which the magnitude of ST elevation correlated with the degree of ajmaline-induced conduction delay in the RVOT of patients with type I Brugada ECG, seemingly supporting the depolarisation hypothesis.118 The study included 11 patients with concealed type I BrS ECG and two healthy controls undergoing ECG imaging before and after ajmaline infusion. Activation maps and activation recovery intervals were derived from electrograms recorded from the epicardial surface of the heart, including the RV, RVOT, and left ventricle (LV). Conduction time was recorded from 3.5 cm segments within these regions of the heart before and after ajmaline and correlated with J point (ST-segment) elevation observed in the surface

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SCD Caused by Antidepressants and Antipsychotics Figure 5: Amitriptyline (0.2 μM)-induced Brugada Phenotype in the Presence of the Transient Outward Potassium Channel Current Agonist NS5806 Control

NS5806

NS5806 + Amitriptyline

Figure 6: Brugada Syndrome Brugada Syndrome Intrinsic Heterogeneity

INa, ICa Ito, IKr, IKs, IK-ATP, ICI(Ca)

LOSS of APD Dome in Epicardium

QT interval ST Segment

Epi1

Phase 2 reentry

0

50 mV

200 ms 4 3 12

0

Transmural Dispersion of Repolarization

0

Phase 2 Reentry in RV Epicardium

0

50 mV

Phase 2 Reentry-induced VT/VF

200 ms

Extrasystole

VT/VF (Reentry) 50 mV

Epi2

ECG

Endo

M 0

0

Dispersion of Repolarization Epicardial Transmural

Endo

Epi 0

1 mV

1 mV

200 ms

0.5 mV 1s

Each panel shows transmembrane APs simultaneously recorded from 1 endocardial (Endo) and 2 epicardial (Epi) sites together with a pseudo-ECG. NS5806 (8 μM) accentuates the AP notch and J wave, but does not induce arrhythmic activity. Addition of amitriptyline (0.2 μM) leads to the development of a closely coupled phase 2 re-entrant extrasystole. The phase 2 re-entrant extrasystole with the briefer coupling interval precipitates polymorphic VT. AP = action potential; VT = ventricular tachycardia. Source: Modified from Minoura, et al., 2012,120 with permission.

ECGs. Ajmaline increased conduction delay by 5.4 ± 2.8 ms in the RVOT, 2.0 ± 2.8 ms in RV free wall and 1.1 ± 1.6 ms in LV free wall. Conduction delay in the RVOT, but not RV or LV, correlated with the degree of J point elevation in BrS patients. The authors’ conclusion that the magnitude of J point (ST-segment) elevation in patients with the type I BrS pattern is attributable to conduction delay in the RVOT was challenged by Antzelevitch and Patocskai who demonstrated that ajmaline can induce prominent ST-segment elevation by accentuation of the RV epicardial AP notch.119 They further pointed out that according to the depolarisation hypothesis for ST-segment elevation associated with BrS, RVOT activation delay, relative to activation of the RV, must be roughly equivalent to the duration of the ST segment elevation (typically >200 ms)116 and that the 3.4 ms reported by Leong et al. falls far short of that requirement, thus discounting the depolarisation hypothesis as a cause. Figure 5 displays an example of amitriptyline-induced BrS phenotype in the presence of the Ito agonist NS5806 in a canine right ventricular wedge model.120 Amitriptyline (0.2 μm) caused loss of the AP dome in the AP of Epi1 but not in that of Epi2. Phase 2 re-entry developed as the epicardial AP dome propagated from sites at which it was maintained to sites at which it was lost. This mechanism generates closely coupled extrasystoles and the development of a polymorphic VT.

Genetic Predisposition The degree to which a genetic predisposition contributes to the clinical manifestation of antidepressant- and antipsychotic-induced arrhythmogenesis is not well defined. Congenital LQTS has been associated with 17 different genes (Table 5). Drugs are by far the most common cause of acquired forms, including drug-induced forms, of LQTS. Mounting evidence suggests that drug-induced LQTS also has a significant heritable component,

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50 mV

Epi 1 Epi 2

50 mV

ECG

0.5 mV 500 ms

Proposed mechanism for the BrS. A shift in the balance of currents serves to amplify existing heterogeneities by causing loss of the AP dome at some epicardial, but not endocardial, sites. A vulnerable window develops as a result of the dispersion of repolarisation and refractoriness within epicardium, as well as across the wall. Epicardial dispersion leads to the development of phase 2 re-entry, which provides the extrasystole that captures the vulnerable window and initiates VT/VF via a circus movement re-entry mechanism. AP = action potential; BrS = Brugada syndrome; VF = Ventricular tachycardia. Source: Modified from Antzelevitch., 2001,110 with permission from Oxford University Press and the European Society of Cardiology.

and recent studies have made advances in identifying the genetic substrate underlying drug-induced LQTS. Advances in next-generation sequencing technology and molecular biology techniques have identified genetic variants underlying the acquired form of LQTS.121 Acquired LQTS characterised by QT prolongation and TdP triggered by drugs, hypokalemia or bradycardia are usually reversed upon elimination of the triggers. In some cases the LQTS phenotype persists, suggesting the presence of an underlying genetic substrate. Itoh et al. reported that a third of acquired LQTS patients carry congenital LQTS mutations, with variants in KCNH2 being the most common.122 In a recent study, Strauss et al. demonstrated that a genetic QT score comprising 61 common genetic variants can account for a significant proportion of the variability in drug-induced QT prolongation and is a significant predictor of drug-induced TdP.123 The authors indicate that these findings highlight an opportunity for such genetic discoveries to improve individualised risk–benefit assessment for pharmacologic therapies. Of note, replication of these findings in larger samples is needed to more precisely identify the individual variants that drive these effects.123 Abbott et al. were among the first to show that a polymorphism (a genetic variation that is present in greater than 1 % of the population) in an ion channel gene is associated with a predisposition to druginduced TdP.124 They identified a polymorphism (T8A) of the KCNE2 gene encoding for MiRP, a beta subunit of the IKr channel, that is present in 1.6 % of the population and is associated with TdP related to quinidine and to sulfamethoxazole/trimethoprim administration. This finding suggests that common genetic variations may increase the risk for development of drug-related arrhythmias. Yang et al. showed that DNA variants in the coding regions of congenital long QT disease genes predisposing to acquired LQTS can be identified in approximately 10–15  % of affected subjects, predominantly in genes encoding ancillary subunits, providing further support for the hypothesis that subclinical mutations and polymorphisms may

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Clinical Reviews: Drugs and Devices Table 5: Genes Associated with Congenital Long QT Syndrome Chromosome

Gene

trafficking of the channel to the surface membrane, thus mimicking the effects of some KCNH2 variants.132

Ion Channel

LQT1

11

KCNQ1, KvLQT1

LQT2

7

LQT3

3

LQT4

↓IKs

30–35 %

KCNH2, HERG

↓IKr

20–25 %

SCN5A, Nav1.5

↑Late INa

5–10 %

4

Ankyrin-B, ANK2

↑Cai, ↑Late INa ?

1–2 %

LQT5

21

KCNE1, MinK

↓IKs

1%

LQT6

21

KCNE2, MiRP1

↓IKr

Rare

LQT7 *

17

KCNJ2, Kir 2.1

↓IK1

Rare

LQT8 †

6

CACNA1C, Cav1.2

↑ICa

Rare

LQT9

3

CAV3, Caveolin-3

↑Late INa

Rare

LQT10

11

SCN4B, NavB4

↑Late INa

Rare

LQT11

7

AKAP9, Yatiao

↓IKs

Rare

LQT12

20

SNTA1, a1 Syntrophin

↑Late INa

Rare

LQT13

11

KCNJ5, Kir 3.4

↓IK-ACh

Rare

LQT14

14

CALM1, Calmodulin

↑ICa, ↑Late INa Rare

LQT15

2

CALM2, Calmodulin

↑ICa, ↑Late INa Rare

LQT16

19

CALM3, Calmodulin

↑ICa, ↑Late INa Rare

LQT17

19

TRPM4, Transient receptor potential cation channel

↓Inon-selctive cation

Rare

channel

*Andersen-Tawill Syndrome, † Timothy Syndrome. LQT = Long QT. Source: Modified from Obeyesekere, et al., 2015.155

predispose to drug-induced TdP.125 Splawski et al. further advanced this concept by identifying a heterozygous polymorphism involving substitution of serine with tyrosine in codon 1103 (S1103Y) in the sodium channel gene SCN5A (S1102Y in the shorter splice variant of SCN5A) among Africans and African-Americans that increases the risk for acquired TdP.126 The polymorphism was present in 57 % of 23 patients with pro-arrhythmic episodes, but in only 13 % of controls. Another common polymorphism that has been associated with acquired forms of LQTS and TdP is K897T in KCNH2.127 Most functional expression studies have reported that K897T reduces IKr,128–130 although one study has reported an increase in hERG current.131 Antidepressant drugs have been shown to induce acquired LQTS via both direct inhibition of the hERG or IKr channel or via impaired

The action of antidepressants to precipitate the BrS may also have a genetic disposition. For example, the SCN5A promoter haplotype (so-called Hap B) has been shown to be associated with longer PR and QRS intervals as well as with a more exaggerated response to sodium channel blockers.133 Genetic defects can also contribute to drug-induced channelopathies by influencing the metabolism of drugs. In the case of relatively pure IKr blockers, there is a clear relationship between plasma levels of drug and the incidence of TdP. Genetic variants of the genes encoding for enzymes responsible for drug metabolism could alter pharmacokinetics so as to cause wide fluctuations in plasma levels, thus exerting a significant proarrhythmic influence.134,135 For example, in the case of cytochrome CYP2D6, which is involved in the metabolism of some QT-prolonging drugs (terodiline, thioridazine), multiple polymorphisms have been reported that reduce or eliminate its function; 5–10 % of Caucasians and African-Americans lack a functional CYP2D6. Numerous proteins, including drug transport molecules and other drug metabolising enzymes, are involved in drug absorption, distribution and elimination, and genetic variants of each of these has the potential to modulate drug concentrations and effects. Multiple substrates and inhibitors of the cytochrome P450 enzymes have been identified. A comprehensive database can be found at http://medicine.iupui.edu/flockhart Antipsychotic drugs are more commonly associated with QT prolongation and TdP than antidepressants are. Most cases of antidepressantinduced TdP occur following drug overdose or when administered in combination with other QT-prolonging agents or conditions. Antidepressants, on the other hand, are more likely to predispose to BrS phenotype. These proclivities are because antipsychotic drugs generally exert a predominant effect to inhibit outward currents, IKr block in particular, whereas antidepressants exert a predominant effect to inhibit inward currents, such as INa and ICa. Commonly used antipsychotic and antidepressant drugs should be used with great care in cases of long QT or BrS,or when combined with agents known to prolong QT intervals or to predispose to acquired forms of BrS.

Acknowledgements The authors acknowledge Gan-Xin Yan, Lin Wu and Subramanian Krishnan’s assistance in providing us with ECGs of patients administered with antipsychotic and antidepressant drugs. n

Clinical Perspective • S  ome antipsychotic and antidepressant drugs increase the risk of ventricular arrhythmias and SCD by prolonging the QT interval and inducing Torsade de Pointes arrhythmias. These include typical antipsychotics such as chlorpromazine; tricyclic antidepressants such as amitriptyline and other antidepressants such as fluoxetine. • Other antipsychotic and antidepressant drugs increase the risk of ventricular arrhythmias and SCD by inducing a Brugada Syndrome phenotype. These include antipsychotics such as trifluoperazine; tricyclic antidepressants such as amitriptyline or desipramine; and other antidepressants such as maprotiline or lithium. • Antipsychotic drugs can increase cardiac risk even at low doses, whereas antidepressant drugs generally do it at high doses or in combination with other drugs. • The newer atypical antipsychotics, including olanzapine, risperidone, quetiapine, prothipendyl, pimavanserin and benperidol display a lower level of risk than the older typical antipsychotics, especially those in the phenothiazine category. • Antipsychotic and antidepressant drugs should be used with great care in cases of long QT or BrS or when combined with agents known to prolong QT intervals or to predispose to acquired forms of BrS.

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• In the case of drugs categorised as having a potential to cause significant QT prolongation and/or TdP, ECG monitoring is advisable, particularly where the FDA-approved label recommends ECG monitoring. Review of specific antipsychotic or antidepressant therapy, including cessation and change of medication should be considered if the ECG shows major prolongation of the QT interval (QTc >500 ms), QTc prolongation >60 ms, T wave abnormalities, marked bradycardia, or a BrS phenotype. • Finally, high-risk antipsychotics and antidepressants should be avoided in patients with acute systemic disease, including acute MI and renal or hepatic disease.

1.

2.

3. 4.

5.

6.

7. 8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

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104. Antzelevitch C, Shimizu W, Yan GX, et al. The M cell: its contribution to the ECG and to normal and abnormal electrical function of the heart. J Cardiovasc Electrophysiol 1999;10:1124–52. https://doi.org/10.1111/j.1540-8167.1999. tb00287.x; PMID: :10466495. 105. Anyukhovsky EP, Sosunov EA, Gainullin RZ and Rosen MR. The controversial M cell. J Cardiovasc Electrophysiol 1999;10:244–60. https://doi.org/10.1111/j.1540-8167.1999.tb00667.x; PMID:10090229. 106. Zygmunt AC, Goodrow RJ and Antzelevitch C. INaCa contributes to electrical heterogeneity within the canine ventricle. Am J Physiol Heart Circ Physiol 2000;278:H1671-8. https://doi. org/10.1152/ajpheart.2000.278.5.H1671; PMID: 10775148. 107. Zygmunt AC, Eddlestone GT, Thomas GP, et al. Larger late sodium conductance in M cells contributes to electrical heterogeneity in canine ventricle. Am J Physiol 2001;281: H689–97. https://doi.org/10.1152/ajpheart.2001.281.2.H689; PMID: 11454573. 108. Liu DW and Antzelevitch C. Characteristics of the delayed rectifier current (IKr and IKs) in canine ventricular epicardial, midmyocardial, and endocardial myocytes. A weaker IKs contributes to the longer action potential of the M cell. Circ Res 1995;76:351–65. https://doi.org/10.1161/01.RES.76.3.351; PMID: 7859382. 109. Li GR, Feng J, Yue L and Carrier M. Transmural heterogeneity of action potentials and Ito1 in myocytes isolated from the human right ventricle. Am J Physiol 1998;275:H369–77. https:// doi.org/10.1152/ajpheart.1998.275.2.H369 PMID: 9683422. 110. Antzelevitch C. The Brugada syndrome: diagnostic criteria and cellular mechanisms. Eur Heart J 2001;22:356–63. https:// doi.org/10.1053/euhj.2000.2461; PMID: 11207076. 111. Yan GX and Antzelevitch C. Cellular basis for the electrocardiographic J wave. Circulation 1996;93:372–9. https:// doi.org/10.1161/01.CIR.93.2.372; PMID: 8548912. 112. Volders PG, Sipido KR, Carmeliet E, et al. Repolarizing K+ currents ITO1 and IKs are larger in right than left canine ventricular midmyocardium. Circulation 1999;99:206–10. https://doi.org/10.1161/01.CIR.99.2.206; PMID: 9892584. 113. Antzelevitch C. State of the art: overview of brugada syndrome. Circulation Journal 2006;70:12. 114. Badri M, Patel A and Yan G. Cellular and ionic basis of J-wave syndromes. Trends Cardiovasc Med 2015;25:12–21. https://doi. org/10.1016/j.tcm.2014.09.003; PMID: 25446046. 115. Di Diego JM, Cordeiro JM, Goodrow RJ, et al. Ionic and cellular basis for the predominance of the Brugada syndrome phenotype in males. Circulation 2002;106:2004–11. https://doi. org/10.1161/01.CIR.0000032002.22105.7A; PMID: 12370227. 116. Wilde AA, Postema PG, Di Diego JM, et al. The pathophysiological mechanism underlying Brugada syndrome: depolarization versus repolarization. J Mol Cell Cardiol 2010;49:543–53. https://doi.org/10.1016/j.yjmcc.2010.07.012; PMID: 20659475. 117. Morita H, Zipes DP and Wu J. Brugada syndrome: insights of ST elevation, arrhythmogenicity, and risk stratification from experimental observations. Heart Rhythm 2009;6:S34–43. https://doi.org/10.1016/j.hrthm.2009.07.018; PMID: 19880072. 118. Leong KM, Ng FS, Yao C, et al. ST-Elevation Magnitude Correlates With Right Ventricular Outflow Tract Conduction Delay in Type I Brugada ECG. Circ Arrhythm Electrophysiol 2017;10:e005107. https://doi.org/10.1161/CIRCEP.117.005107; PMID: 29038102. 119. Antzelevitch C and Patocskai B. Ajmaline-Induced Slowing of Conduction in the Right Ventricular Outflow Tract Cannot Account for ST Elevation in Patients With Type I Brugada ECG. Circ Arrhythm Electrophysiol 2017;10:e005775. https://doi. org/10.1161/CIRCEP.117.005775; PMID: 29038108. 120. Minoura Y, Di Diego JM, Barajas-Martinez H, et al. Ionic and cellular mechanisms underlying the development of acquired Brugada syndrome in patients treated with antidepressants. J Cardiovasc Electrophysiol 2012;23:423–32. https://doi. org/10.1111/j.1540-8167.2011.02196.x; PMID: 22034916. 121. Mahida S, Hogarth AJ, Cowan C, et al. Genetics of congenital and drug-induced long QT syndromes: current evidence and future research perspectives. J Interv Card Electrophysiol 2013;37:9–19. https://doi.org/10.1007/s10840-013-9779-5; PMID: 23515882. 122. Itoh H, Crotti L, Aiba T, et al. The genetics underlying acquired long QT syndrome: impact for genetic screening. Eur Heart J 2016;37:1456–64. https://doi.org/10.1093/eurheartj/ehv695; PMID: 26715165. 123. Strauss DG, Vicente J, Johannesen L, et al. Common Genetic Variant Risk Score Is Associated With Drug-Induced QT Prolongation and Torsade de Pointes Risk: A Pilot Study. Circulation 2017;135:1300–10.https://doi.org/10.1161/ CIRCULATIONAHA.116.023980; PMID: 28213480. 124. Abbott GW, Sesti F, Splawski I, et al. MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia. Cell 1999;97:175–87. https://doi.org/10.1016/ S0092-8674(00)80728-X; PMID: 10219239. 125. Yang P, Kanki H, Drolet B, et al. Allelic variants in long-QT disease genes in patients with drug-associated torsades de pointes. Circulation 2002;105:1943–8. https://doi. org/10.1161/01.CIR.0000014448.19052.4C; PMID: 11997281. 126. Splawski I, Timothy KW, Tateyama M, et al. Variant of SCN5A sodium channel implicated in risk of cardiac arrhythmia. Science 2002;297:1333–6. https://doi.org/10.1126/ science.1073569; PMID:12193783. 127. Pollevick GD, Oliva A, Viskin S, et al. Genetic predisposition to post-myocardial infarction long QT intervals and torsade de

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SCD Caused by Antidepressants and Antipsychotics pointes. Heart Rhythm 2007;4:S121. 128. Crotti L, Lundquist AL, Insolia R, et al. KCNH2-K897T is a genetic modifier of latent congenital long-QT syndrome. Circulation 2005;112:1251–8.https://doi.org/10.1161/ CIRCULATIONAHA.105.549071; PMID: 16116052. 129. Anson BD, Ackerman MJ, Tester DJ, et al. Molecular and functional characterization of common polymorphisms in HERG (KCNH2) potassium channels. Am J Physiol Heart Circ Physiol 2004;286:H2434–41. https://doi.org/10.1152/ ajpheart.00891.2003; PMID: 14975928. 130. Paavonen KJ, Chapman H, Laitinen PJ, et al. Functional characterization of the common amino acid 897 polymorphism of the cardiac potassium channel KCNH2 (HERG). Cardiovasc Res 2003;59:603–11. https://doi.org/10.1016/ S0008-6363(03)00458-9; PMID: 14499861. 131. Bezzina CR, Verkerk AO, Busjahn A, et al. A common polymorphism in KCNH2 (HERG) hastens cardiac repolarization. Cardiovasc Res 2003;59:27–36. https://doi. org/10.1016/S0008-6363(03)00342-0; PMID: 12829173. 132. Cubeddu LX. Drug-induced Inhibition and Trafficking Disruption of ion Channels: Pathogenesis of QT Abnormalities and Drug-induced Fatal Arrhythmias. Curr Cardiol Rev 2016;12:141–54. https://doi.org/10.2174/157340 3X12666160301120217; PMID: 26926294. 133. Bezzina CR, Shimizu W, Yang P, et al. Common sodium channel promoter haplotype in asian subjects underlies variability in cardiac conduction. Circulation 2006;113:338–44. https://doi.org/10.1161/CIRCULATIONAHA.105.580811; PMID: 16415376. 134. Ford GA, Wood SM and Daly AK. CYP2D6 and CYP2C19 genotypes of patients with terodiline cardiotoxicity identified through the yellow card system. BrJ Clin Pharmacol 2000;50:77– 80. https://doi.org/10.1046/j.1365-2125.2000.00230.x; PMID: 10886124. 135. Roden DM. Pharmacogenetics and drug-induced arrhythmias. Cardiovasc Res 2001;50:224–31. https://doi.org/10.1016/S00086363(00)00302-3; PMID: 11334826. 136. Dorsey ST and Biblo LA. Prolonged QT interval and torsades de pointes caused by the combination of fluconazole and amitriptyline. Am J Emerg Med 2000;18:227–9. https://doi.

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org/10.1016/S0735-6757(00)90027-5; PMID: 10750939. 137. Davison ET. Amitriptyline-induced Torsade de Pointes. Successful therapy with atrial pacing. J Electrocardiol 1985;18:299–301. https://doi.org/10.1016/S00220736(85)80055-8; PMID: 4031733. 138. Jerjes Sánchez Díaz C, García Hernández N, González Carmona VM, Rosado Buzzo A. [Helicoidal ventricular tachycardia caused by amitriptyline. Presentation of a case]. Arch Inst Cardiol Mex 1985;55:353–6 [in Spanish]. PMID: 2934037 139. Flugelman MY, Pollack S, Hammerman H, et al. Congenital prolongation of Q-T interval: a family study of three generations. Cardiology 1982;69:170–4. https://doi. org/10.1159/000173500; PMID: 7127350. 140. Strasberg B, Coelho A, Welch W, et al. Doxepin induced torsade de pointes. Pacing Clin Electrophysiol. 1982;5:873–7. https://doi.org/10.1111/j.1540-8159.1982.tb06570.x; PMID: 6184690. 141. Alter P, Tontsch D and Grimm W. Doxepin-induced torsade de pointes tachycardia. Ann Intern Med 2001;135:384–5. https:// doi.org/10.7326/0003-4819-135-5-200109040-00026; PMID: 11529713. 142. Stollberger C, Huber JO and Finsterer J. Antipsychotic drugs and QT prolongation. Int Clin Psychopharmacol 2005;20:243–51. https://doi.org/10.1097/01.yic.0000166405.49473.70; PMID: 16096514. 143. Alampay MM, Haigney MC, Flanagan MC, et al. Transcranial magnetic stimulation as an antidepressant alternative in a patient with Brugada syndrome and recurrent syncope. Mayo Clin Proc 2014;89:1584–7. https://doi.org/10.1016/j. mayocp.2014.08.010; PMID: 25444490. 144. Yap YG and Camm AJ. Drug induced QT prolongation and torsades de pointes. Heart. 2003;89:1363–72. https://doi. org/10.1136/heart.89.11.1363; PMID:14594906. 145. Teschemacher AG, Seward EP, Hancox JC and Witchel HJ. Inhibition of the current of heterologously expressed HERG potassium channels by imipramine and amitriptyline. Br J Pharmacol 1999;128:479–85. https://doi.org/10.1038/ sj.bjp.0702800; PMID: 10510461. 146. Jo SH, Youm JB, Lee CO, et al. Blockade of the HERG human

cardiac K(+) channel by the antidepressant drug amitriptyline. Br J Pharmacol 2000;129:1474–80. https://doi.org/10.1038/ sj.bjp.0703222; PMID: 10742304. 147. Park KS, Kong ID, Park KC and Lee JW. Fluoxetine inhibits L-type Ca2+ and transient outward K+ currents in rat ventricular myocytes. Yonsei Med J 1999;40:144–51. https://doi.org/10.3349/ymj.1999.40.2.144; PMID: 10333718. 148. Barber MJ, Starmer CF and Grant AO. Blockade of cardiac sodium channels by amitriptyline and diphenylhydantoin. Evidence for two use-dependent binding sites. Circ Res 1991;69:677–96. https://doi.org/10.1161/01.RES.69.3.677; PMID: 1651817. 149. Curtis LH, Ostbye T, Sendersky V, et al. Prescription of QT-prolonging drugs in a cohort of about 5 million outpatients. Am J Med 2003;114:135–41.https://doi.org/10.1016/ S0002-9343(02)01455-9; PMID: 12586234. 150. Witchel HJ, Hancox JC and Nutt DJ. Psychotropic drugs, cardiac arrhythmia, and sudden death. J Clin Psychopharmacol 2003;23:58–77. https://doi.org/10.1097/00004714-20030200000010; PMID: 12544377. 151. Thomas D, Gut B, Wendt-Nordahl G and Kiehn J. The antidepressant drug fluoxetine is an inhibitor of human ether-a-go-go-related gene (HERG) potassium channels. J Pharmacol Exp Ther 2002;300:543–8. https://doi.org/10.1124/ jpet.300.2.543; PMID: 11805215. 152. Tie H, Walker BD, Valenzuela SM, et al. The heart of psychotropic drug therapy. Lancet 2000;355:1825. https://doi.org/10.1016/ S0140-6736(05)73083-X; PMID: 10832858. 153. Tie H, Walker BD, Singleton CB, et al. Clozapine and sudden death. J Clin Psychopharmacol 2001;21:630–2. https://doi.org/10.1097/00004714-200112000-00023; PMID: 11763021. 154. Tamargo J. Drug-induced torsade de pointes: from molecular biology to bedside. Jpn J Pharmacol 2000;83:1–19. https://doi. org/10.1254/jjp.83.1; PMID: 10887935. 155. Obeyesekere MN, Antzelevitch C and Krahn AD. Management of ventricular arrhythmias in suspected channelopathies. Circ Arrhythm Electrophysiol 2015;8:221–31. https://doi.org/10.1161/ CIRCEP.114.002321; PMID: :25691556.

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Clinical Reviews: Drugs and Devices

Transvenous Lead Extractions: Current Approaches and Future Trends Adryan A Perez, 1 Frank W Woo, 1 Darren C Tsang 1 and Roger G Carrillo 2 1. University of Miami Miller School of Medicine, Miami, FL, USA; 2. Palmetto General Hospital, Hialeah, FL, USA

Abstract The use of cardiac implantable electronic devices (CIEDs) has continued to rise along with indications for their removal. When confronted with challenging clinical scenarios such as device infection, malfunction or vessel occlusion, patients often require the prompt removal of CIED hardware, including associated leads. Recent advancements in percutaneous methods have enabled physicians to face a myriad of complex lead extractions with efficiency and safety. Looking ahead, emerging technologies hold great promise in making extractions safer and more accessible for patients worldwide. This review will provide the most up-to-date indications and procedural approaches for lead extractions and insight on the future trends in this novel field.

Keywords Transvenous, lead, extraction, management, cardiac, implantable, electronic, device, infection, indications, complications Disclosure: Darren Tsang, Adryan Perez and Frank Woo have no conflicts of interest to declare. Roger Carrillo reports receiving personal fees from Spectranetics, personal fees from Sensormatic, grants from St Jude Medical, personal fees from Medtronic, personal fees from St Jude Medical, and personal fees from The Sorin Group outside the submitted work. Received: 22 May 2018 Accepted: 16 July 2018 Citation: Arrhythmia and Electrophysiology Review 2018;7(3):210–7. DOI: https://doi.org/10.15420/aer.2018.33.2 Correspondence: Roger Carrillo, Palmetto General Hospital, 7150 W 20th Avenue, Suite 615, Hialeah, FL, 33016. E: Rogercar@aol.com

The use of cardiovascular implantable electronic devices (CIEDs) has increased dramatically, with approximately 1.2–­1.4 million CIEDs implanted annually worldwide.1 In the US alone, there are more patients with CIEDs than registered nurses.2,3 CIEDs use leads that connect a generator to cardiac tissue to treat patients with many conditions including symptomatic bradycardia, morbid tachycardia and advanced heart failure. However, CIEDs can become infected, and leads can occasionally fail – this affects approximately 1–2 % of cases – potentially leading to adverse clinical outcomes.4 Therefore, safe, innovative techniques for lead removal are emerging to aid in the complex management of patients with CIEDs. Once implanted, leads are held in place by scar tissue in the major veins and surrounding cardiac structures, making their withdrawal challenging. The degree of endothelial fibrosis is proportional to the length of time the lead has been implanted and the patient’s vascular inflammatory reactivity. While open heart surgery was initially used to remove leads in the 1980s, transvenous lead extraction has evolved as the premier method over the past three decades. Compared with median sternotomy, transvenous lead extraction is an endovascular intervention more amenable for patients with several comorbidities necessitating lead removal. This review discusses indications for transvenous lead extraction, describes each step and potential complications, and concludes by highlighting the future trends in this fascinating and ever-evolving field.

Indications for Lead Extraction The decision to perform a lead extraction should include a consideration of many factors such as extractor and team experience, risks versus benefits, patient preference and the strength of the clinical indication

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for the procedure. With regards to strength of indication, the most recent Heart Rhythm Society (HRS) document divides indications into class I, IIa, IIb, or III recommendations1. Class I indications are strong and signify solid evidence or general agreement in favour of the procedure being useful and effective. Class IIa indications are considered moderate and reasonably supported by evidence, while class IIb indications are weak. The weakest strength of recommendation is class III, in which there is a general agreement that the procedure would not be useful or effective and may even be harmful.1 The following discussion expands on a variety of clinical scenarios in which lead extraction may be indicated. For simplicity, these have been divided into infectious (a class I recommendation) and non-infectious indications (Table 1).

Infectious CIED infections have become increasingly prevalent because of the rise in CIED implantation, an ageing population, the existence of multiple comorbidities, and the increase in cardiac pacing centres where staff experience is inadequate.5–7 According to the recent European Lead Extraction ConTRolled registry (ELECTRa) study, infections make up 52.8 % (19.3  % systemic and 33.1  % local) of the indications for lead extractions.8 Unfortunately, infected devices are associated with significant financial burden, morbidity and mortality and require aggressive treatment.9,10 This aggressive treatment includes the complete removal of all hardware and antimicrobial therapy. CIED infections (Table 1) have been categorised into four common clinical scenarios where complete hardware removal is required. These infections include a pocket infection with or without bacteraemia (Figure  1), left-sided endocarditis in a CIED carrier, CIED-related endocarditis and occult bacteraemia with probable CIED infection. An

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Transvenous Lead Extractions Table 1: Infectious and Non-infectious Clinical Scenarios for Lead Extraction Infectious

Clinical Scenarios (Class I Indications)

Pocket infection with or without bacteraemia

L ocalised signs of inflammation such as erythema, swelling, pain, tenderness, warmth or drainage with positive or negative blood cultures

Left-sided endocarditis in a CIED carrier

Left heart vegetations with or without tricuspid valve or CIED involvement, and positive blood cultures

CIED-related endocarditis

Positive blood cultures and lead or valvular vegetation(s), without local signs of pocket infection

Occult bacteraemia with probable CIED infection

Bacteraemia without an alternative source, resolves after CIED extraction

Non-infectious

Clinical Scenarios (Class I, IIa, And IIb Indications)

Thrombosis/vascular Issues

 linically significant thromboembolic events attributable to thrombus on a lead or a lead fragment that cannot be C treated by other means (class I) Superior vena cava (SVC) stenosis or occlusion that prevents implantation of a necessary lead (class I) Planned stent deployment in a vein already containing a transvenous lead to avoid entrapment of the lead (class I) Maintaining patency of SVC stenosis or occlusion with limiting symptoms (class I) Ipsilateral venous occlusion preventing access to the venous circulation for required placement of an additional lead (class IIa)

Chronic pain

 evere chronic pain at the device or lead insertion site or believed to be secondary to the device, which causes S significant patient discomfort, is not manageable by medical or surgical techniques, and for which there is no acceptable alternative17 (Class IIa)

Other

Life-threatening arrhythmias secondary to retained leads (class I) Lead removal can be useful for patients with a CIED location that interferes with the treatment of a malignancy18 (class IIa) CIED implantation requires more than four leads on one side or more than five leads through the SVC (class IIa) Abandoned lead(s) that interfere with the operation of a CIED system (class IIa) Leads that pose a potential future threat to the patient if left in place, because of their design or failure (class IIb) Lead removal may be considered to facilitate access to MRI18 (class IIb) T he setting of normally functioning, non-recalled pacing or defibrillation leads for selected patients after a shared decision-making process (class IIb)

Sources: Kusumoto et al.,1 2017; Durante-Mangoni et al.,7 2013; Bongiorni et al., 201816

additional type of infection is a superficial incisional infection; here, all the hardware should not be removed because involvement is localised in the skin and subcutaneous tissue.

extraction (rather than lead abandonment) because of the higher incidence of major complications and increased difficulty of extraction in the future.12

Symptoms of lead-associated endocarditis (LAE) may differ, according to the most recent CIED research. A study analysing patient outcomes from the Multicenter Electrophysiologic Device Cohort (MEDIC) registry determined that patients with early LAE (defined as signs and symptoms occurring within 6 months of the most recent CIED procedure) presented more frequently with signs of local pocket infection, which included erythema, pain, swelling, warmth and pus or drainage from the pocket. However, patients with late LAE (defined as signs and symptoms occurring after 6 months of the most recent CIED procedure) typically presented with signs of systemic infection, such as fever, chills, sweats and signs of sepsis.11 This discrepancy often complicates the ability to make a diagnosis. Therefore, a diligent, pre-procedural approach should be implemented to ensure the best opportunity for clinical success.

In addition to lead malfunction, some important non-infectious indications for extraction include manufacturer recall, lead redundancy and a device upgrade being required because of venous occlusion.13-15 Notably, lead extractions carried out during generator change or upgrade have been reported to have fewer complications than lead-only extractions performed without a concomitant generator change.15 Table 1 sets of the most recent classification of non-infectious indications.

Non-infectious The decision to perform an extraction in some non-infectious scenarios requires a complicated weighing up of the risks, benefits and long-term prognosis. For example, if a 20-year-old patient and a 90-year-old patient present with the issue of removing an abandoned lead, the management strategies will differ, considering the shorter life expectancy in the 90-year-old patient: the 20-year-old would benefit more from an

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Facilities, Equipment and Personnel Lead extractions are performed in operating theatres, catheterisation/ electrophysiology (EP) labs and hybrid labs. A hybrid lab is a surgical suite with a movable, high-quality fluoroscopy system. The ability to provide immediate surgical intervention in cases of major complications make the operating theatre and the hybrid labs the best options to perform lead extractions. Major vascular injuries or cardiac perforations requiring surgical or endovascular intervention are rare, and these procedures may carry a higher mortality in EP laboratories than in operating theatres.12,19 Ultimately, the best location to perform lead extractions should be based on the individual facility and its team members. It is essential that the facility provides the necessary equipment to perform lead extractions and manage complications safely.1,20,21 This should be in the room at the start of every procedure and includes

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Clinical Reviews: Drugs and Devices Figure 1: Pocket Infection with Localised Signs of Inflammation

Pre-procedure Phase A thorough patient history should be documented including age, height, weight, current medications, New York Heart Association class and previous surgeries. There should be an evaluation of cardiac and non-cardiac conditions that could affect the procedure outcome such as diabetes, reduced left ventricular ejection fraction and out atrial fibrillation.12,16,25. Implanted devices and information about their leads (including number, location, construction, fixation type and implantation dates) should be documented. The patient’s intrinsic rhythm and dependency should be checked by CIED interrogation.26,27

Imaging

equipment for transoesophageal echocardiography (TEE), fluoroscopy and arterial blood pressure monitoring, as well as a crash cart, pericardiocentesis kit, sternal saw, cardiopulmonary bypass machine, cell-saver and matched blood on standby. Most facilities have an extraction cart with all materials pertinent to the procedure.22,23 A lead extraction team typically includes a physician (who performs the extraction), a cardiothoracic surgeon (if not the primary operator), an individual in charge of providing anaesthesia support, an X-ray technician (for fluoroscopy) and assistants.23 The operator and the team must have the experience and training necessary to maximize patient safety and clinical success. The operator should have handson experience of a minimum of 40 lead extractions as the primary operator, with exposure to various lead types and be familiar with employing different extraction tools and approaches.1,22 The surgeon must be immediately available and be able perform an emergent thoracotomy within 5–10 minutes. Although data from a National Cardiovascular Data Registry of 11,304 ICD extractions revealed that only 0.36 % patients required urgent cardiac surgery, these emergent procedures had a 34 % mortality rate.15 Therefore, it is critical that the team is properly trained to recognise the need for surgical intervention to avoid any delays and maximise the likelihood that patients will survive any potential complications. Virtual reality training tools offering simulation have been found to enhance the skills necessary to perform extractions.24 This supplementary training method could be further implemented in the future to assess competency with the growing number of new extraction equipment.

Various imaging techniques are used to determine procedural approach and the risk of complications. First, a chest X-ray should be performed for lead localisation, lead analysis and to determine the existence of calcifications. It should be noted whether the implanted leads are passively or actively fixated, given that passive fixation and dual-coil lead design may correlate with fibrous adhesions.28 The type of fixation is easily determined on chest X-ray as passively fixated leads use tines, fins or conical structures at the tip of the lead, while actively fixated leads use a corkscrew helix to screw into the myocardium.29 The X-ray is also useful to determine the presence of undocumented leads or devices that may pose issues during the extraction. Second, a TEE is recommended for patients with suspected systemic CIED infection to determine any cardiac abnormalities including reduced ejection fraction, vegetations, tricuspid regurgitation, intracardiac shunts and pre-existing pericardial effusions.16,30–33. If large vegetations (>2.5 cm) are present, the procedure may require an alternative approach such as an open extraction.20 Because of thromboembolic risk, the presence of vegetations and their relative size should be accounted in management of antithrombotic therapy.34,35 Third, a gated cardiac CT scan is taken in some centres to check for venous stenosis or the presence of extravascular lead segments.16

Procedural Definitions

Last, fluorine–18–fluorodeoxyglucose (18F–FDG) PET and CT can be used to identify infections in patients where this is suspected but not clearly evident using other imaging modalities.36,37 A recent meta-analysis with 14 studies involving 492 patients determined high sensitivity (83 %) and specificity (89 %) in the evaluation of CIED infection using PET/CT.38 The 18F–FDG PET/CT scan has been evaluated for diagnostic accuracy in other studies and its use should be considered before creating a treatment regimen where infection is suspected.39-41

To allow for better discussion of the topic, specific terminologies and definitions have been established.

Blood Tests

Lead extraction is a procedure where the removal of the lead requires equipment not typically employed during lead implantation or where at least one lead has been implanted for longer than 1 year.1,20 Lead explantation is as a procedure in which a lead is removed without specialised tools and all leads have been implanted for less than 1 year.1 In addition, clinical success for a lead extraction is defined by the removal of all targeted leads and lead material from the vascular space or retention of a small portion (<4 cm) that does not negatively affect the outcome goals of the procedure.1,16

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Before the procedure, blood samples should be collected to assess renal function, coagulation and haemoglobin, and for platelet count tests. These results should be compared with the post-procedure values.16 A minimum of two sets of blood cultures should be drawn before antibiotic therapy is started for patients with suspected CIED infection.33 For patients with infections, the firstline antibiotic should be vancomycin until the causative organism has been identified.42 The most common cause of CIED infections are Staphylococcus aureus and coagulasenegative staphylococcus.43 Nearly half of the staphylococci that cause infections are meticillin resistant which is why vancomycin is the antibiotic of choice.43

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Transvenous Lead Extractions Anticoagulation Many patients with CIEDs are prescribed oral anticoagulation or dual antiplatelet therapy. Unfortunately, lead extraction procedures carry the risk of severe and life-threatening haemorrhagic events – such as vascular tears involving the SVC, tamponade and haemothorax – and may involve thromboembolic events.20 Periprocedural management of anticoagulant therapy is essential for these patients. Anticoagulation strategies should be considered after thromboembolic risk has been assessed. A lead extraction anticoagulation protocol should account for clinical predictors of thrombotic/thromboembolic events such as mechanical valve prostheses, out atrial fibrillation, duration of confinement to bed and length of hospitalisation.34 In the authors’ experience, continuing anticoagulation is usual practice when the patient is undergoing lead extraction.15,44,45

Extraction Approach The extraction is conducted through the subclavian vein, the femoral vein or the internal jugular or using a combination of methods.46,47 The subclavian approach allows the complete procedure to be performed through a single incision and permits ipsilateral access to the implanting vein; it is therefore the most popular approach. Open surgical approaches are rare and usually reserved for complex and high-risk cases that preclude percutaneous methods. Such cases usually necessitate a hybrid approach that combines open heart surgery and transvenous lead extraction to remove the intracardiac and intravascular portions of the leads respectively. Recently, minimally invasive approaches have been introduced that provide an alternative to median sternotomy.48–53

Procedure Phase First, the patient is prepped and draped in the same manner as for an open-heart procedure. Then, general anaesthesia is administered, and a TEE is carried out.1 Next, an incision is made through the original CIED implantation site to gain access to the device pocket. If there is a localised pocket infection, the pocket is debrided and microbial cultures of the pocket tissue obtained.54 If no infection is present, minimal debridement should be performed while freeing the lead from the fibrotic constraints in the pocket. The leads are then removed from the header and are dissected away from the fibrous tissue. To prevent the lead from unraveling and to apply traction across the whole length of it, the components are often secured to a lead-locking device using suture ties or a compression coil. If the lead locking device cannot be inserted, a lead extender can be used.22

Table 2: Specialised Sheaths: Types and Uses Type of Specialised

Useful For

Less Useful For

Fibrous adhesions

Dense fibrotic or heavily calcified lesions

Laser sheaths58, 59

Fibrous lesions and scar tissue

Heavily calcified lesions

Rotational mechanical

Dense calcified fibrotic lesions

Scar tissue

Sheath Non-powered telescoping sheaths56,57

cutters60–63

retained sheath to maintain venous access.22 In special circumstances such as venous occlusion and leads with minimal adhesions, femoral snaring can aid in maintaining traction while the sheath breaks through the occluded veins. In addition, a femoral approach is also useful for removing lead fragments that may break off during the extraction procedure. Furthermore, if the subclavian approach fails due to an intravascular lead break, extraction can be performed via the femoral or the internal jugular approach.55

Postprocedure Phase After the procedure, the patient should be checked for any complications – early and late – using a chest X-ray, transthoracic echocardiogram (TTE) and physical examination.16 First, it is useful to take a chest X-ray within 24 hours of the procedure to rule out an occult haemothorax or pneumothorax. Second, a TTE after the procedure is used to assess for tricuspid valve injury, pericardial effusion and intracardial masses such as retained fragments.1 Third, physical examinations should include checking for the presence of arteriovenous fistulas from the upper arm to the subclavian area.1 Moreover, in patients with infections, additional post-procedure considerations include antibiotic selection and wound care management.1

CIED Reimplantation After the procedure, patients are often reassessed for the clinical need for CIED reimplantation. Reimplantation may not be necessary in patients who demonstrate sufficient improvement in ejection fraction, recovery of sinus function or resolution of symptomatic bradycardia. In patients with CIED infection, reimplantation timing is not associated with risk of a second infection; second infections have been noted in patients with specific risk factors including haemodialysis, malignancy, pocket haematomas or S aureus bacteraemia.64

Complications

The next step depends on the degree of fibrosis, which is proportional to the age of the lead. If the lead was implanted recently, simple traction (or mild pulling with no specialised extraction tools besides a standard stylet) was found to be effective in removal of 27 % of the leads in the ELECTRa registry.8 On the other hand, if simple traction alone is unsuccessful, a specialised sheath can be used on the intravascular adhesions around the lead. The choice of sheath depends on the nature of the lesions as well as the experience, training and preference of the operator. Because of this, different sheaths may be used throughout the course of a single lead extraction depending on the circumstances (Table 2).

Overwhelmingly, transvenous lead extraction has been shown to be a safe and effective method to remove problematic leads. Poor outcomes are exceedingly rare, with several large registries reporting mortality rates from 0.2–1.2 %.1,15,19 However, serious complications that require emergent intervention may still arise in 0.2–1.8 % of cases in even the most experienced hands. There has therefore been a concerted effort to identify factors associated with complications to help clinicians stratify patients as high risk for endovascular perforations and other adverse outcomes.1,8,12,19,22,65–68 Notable risk factors identified include:

The sheath is advanced coaxially to reach the distal end of the lead (at the myocardial interface). Once the sheath is close to the myocardial interface, the lead is gently pulled in a traction-countertraction motion to release and remove the lead tip from the myocardium (Figure 2). If a new lead implant is required, a guide wire is threaded through the

• • • • •

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longer lead implant duration (>6 years);8,12,19,20,66,67 female sex;8,20,68 low BMI or body surface area;12,66 number of implanted leads (three or more);8,67 infectious indication for extraction;1,22

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Clinical Reviews: Drugs and Devices Figure 2: Representation of Forces Involved In Lead Removal Telescoping: Combined use of inner and outer sheaths, with alternating clockwise and counter clockwise motion

Traction: Backward force on the lead away from the lead tip

Counter pressure: Forward force on sheath towards lead tip

Extraction sheath tip

Countertraction: Forward force on sheath toward lead tip at myocardial interface

Table 3: Extraction Procedure-related Complications 1 Complications

Incidence (%)

Major

0.19–1.80

Death

0.19–1.20

Cardiac avulsion

0.19–0.96

Vascular laceration

0.19–0.96

Respiratory arrest

0.20

Pericardial effusion requiring intervention

0.23–0.59

Haemothorax requiring intervention

0.07–0.20

Massive pulmonary embolism

0.08

Minor

0.60–6.20

Haematoma requiring evacuation

0.90–1.60

Pneumothorax requiring chest tube

1.10

Bleeding requiring blood transfusion

0.08–1.00

Worsening tricuspid valve function

0.32–0.59

Pulmonary embolism

0.24–0.59

Venous thrombosis requiring medical intervention

0.10–0.21

Migrated lead fragment without sequelae

0.20

Pericardial effusion without intervention

0.07–0.16

Source: Kusumoto et al, 2017. With permission from Elsevier 1

• • • • • • • • • • • • • •

presence of dual-coil ICD lead;20,67 aggressive calcified adhesions;22,65 extravascular leads;65 venous occlusions;65 femoral extraction approach;8,19 use of powered sheaths8,19,20 renal disease (end-stage renal failure and dialysis);68 type 2 diabetes mellitus;68 congestive heart failure;68 cerebrovascular disease;68 anticoagulation or antiplatelet use;68 chronic pulmonary disease;68 corticosteroid use;65 non-target lead dislodgement;15

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• non-electively scheduled extraction;15,68 • low volume extraction centres;8,12,68 and • lack of operator experience (carrying out fewer than 30 cases per year).22 Major studies have reported conflicting results in the continuing effort to identify risk factors. For instance, the ELECTRa registry of 3,510 extractions from 73 European centres concluded that high volume centres, compared with low-volume centres, were associated with higher success rates and lower all-cause complication and mortality rates.8,69 However, a study of 11,304 extractions from 762 centres across the US subsequently reported that operator annual procedure volume was not associated with a lower incidence of major complications.15 This same study found no difference in complications between dual-coil and single-coil ICD leads, and no difference in outcomes between backfilled and expanded polytetrafluoroethylene coated leads. 15 That said, multiple factors may contribute to the risk of complications, including patient/lead profile and centre/operator experience. Collectively, these factors should be considered to stratify accurately for risk, prepare for complications and improve patient outcomes. Major complications associated with lead extraction primarily arise from damage to the venous vasculature or myocardium (Table  3).1 These complications include death, vascular laceration, cardiac avulsion, pericardial tamponade, haemothorax and thromboembolic events (such as pulmonary embolism and paradoxical emboli in the presence of a patent foramen ovale or an atrial septal defect). In rare cases of rapid and massive blood loss, death is often the result. Pericardial tamponade is the most common major complication; it can be resolved if treated quickly using a sternotomy. SVC tears below the pericardial reflection may lead to pericardial effusion while tears above the reflection often result in a large haemothorax. These injuries may necessitate emergent sternotomy and surgical repair. Minor complications include bleeding, pocket haematoma, pneumothorax necessitating chest tube placement, venous thrombosis and migrated lead fragment. Although these events are significant and require rapid intervention, they are usually not life threatening. (Table 3). This potential for catastrophic complications underscores the importance of having a cardiac surgeon available and a competent operative team for both early recognition of injury and implementation of rapid response protocols. First, this necessitates all personnel and equipment to be available to perform an urgent sternotomy and repair, including a crash cart, sternal saw, cardiopulmonary bypass machine, cell-saver and matched blood on standby.70 Second, the operative team must be aware of the unique presentation of these injuries associated with lead extraction. When a sudden drop in blood pressure occurs, the team should immediately use fluoroscopy or TEE to identify the cause. A growing pericardial effusion, identified by the cessation of movement at the left heart border, suggests either a myocardial perforation or an SVC tear below the pericardial reflection. An empty ventricle on TEE and haemothorax on fluoroscopy suggests massive blood loss from a vascular tear above the pericardium.22 Clancy et al. demonstrated in a swine model that every second counts; a mere 2 cm tear along the SVC can rapidly haemorrhage at a rate of 500 cm3/minute, leading to complete exsanguination in less than 10 minutes.71 Finally, the nature of these injuries resembles major trauma surgery, and the operative team must be prepared to emergently manage massive bleeding to rescue the patient.

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Transvenous Lead Extractions Rescue devices such as the occlusion balloon (Bridge™; Spectranetics Corporation) (Figure 3) can be rapidly deployed to help stem the loss of blood in the event of an SVC tear. The device is a compliant, endovascular balloon that occludes the SVC from the innominate veins to the right atrium and can be deployed in less than two minutes. Inflation times can be reduced to less than 15 seconds by prophylactically placing the device in the inferior vena cava of high-risk patients before extraction65. In the event of a suspected tear, the occlusion balloon can be threaded up a prepositioned wire and inflated to provide temporary haemostasis and haemodynamic stability, thereby facilitating a more controlled surgical repair. Comparative analysis of early clinical data has demonstrated that proper employment of the occlusion balloon can improve the likelihood of patients surviving these injuries.72

Figure 3: Endovascular Occlusion Balloon

Future Directions Over the past three decades, the rise in CIED implantation has been paralleled by a remarkable increase in lead extractions. As indications for therapy expand and patients with CIEDs live longer, it is likely that demand for lead extraction will only continue to grow.73 Today, methods to reduce the number of extracted leads are being explored, whether by investigating novel infection control strategies or refining alternative device therapies to transvenous systems. Additionally, recent advances in cardiac imaging modalities hold promise in making lead extraction safer.74 Above all, as lead extraction becomes safer and easier to perform, it will likely become accessible to a wider variety of clinicians and patients.

Prevention of Infection Given that a substantial portion of lead extractions are indicated because of infection, methods to reduce rates of infection are being explored. A promising technique under study is the use of an antibioticeluting mesh (TYRX™ Anti-bacterial Envelope; Medtronic plc) to reduce CIED infections in high-risk patients.33,75 This bio-absorbable mesh is placed in the CIED pocket at the time of implantation and releases minocycline and rifampicin for a 7-day period. Meta-analyses have revealed significant reductions in CIED infections, and cost-effectiveness analysis has shown a reduction in healthcare resource utilisation.76,77 Over the long term, randomised controlled studies, such as the Worldwide Randomized Antibiotic Envelope Infection Prevention Trial (WRAP–IT), are in progress.78 Another important area of investigation is the use of perioperative antibiotics after CIED implantation. Currently, no guideline recommendations support the use of post-procedural antibiotic prophylaxis.79–81 A 2017 HRS survey suggested that real-world prescribing patterns vary considerably, and that post-procedural antibiotics are administered after 22–50  % of CIED surgeries.82 Moreover, the recent Prevention of Arrhythmia Device Infection Trial (PADIT), involving 19,603 patients in Canada, found that increased postoperative antibiotics after CIED implantation had no substantial effect on infections.83,84 Future analyses may help identify effective post-procedure prophylactic antibiotics strategies.

Leadless Alternatives While transvenous pacing and defibrillating systems remain the premier strategy for treating cardiac conduction abnormalities, a few emerging device therapies may mitigate the rise in leads requiring extraction. Leadless pacemakers (Micra™ Transcatheter Pacing System, Medtronic plc) and subcutaneous ICD systems (S–ICDTM System, Boston Scientific Corp) are attractive alternatives that supplant the need for transvenous

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Picture courtesy of Bridge™, Spectranetics Corporation, Colorado Springs, CO

leads altogether.85 Several large, multicentre trials for both modalities have demonstrated consistently high implant success rates and lower complication rates than conventional systems.86–92 Moreover, recent advances in operator experience, preparation and implantation techniques have led to further improvements in infection rates and wider use around the world.75,93–95 Currently, leadless pacemaker and subcutaneous ICD systems are limited to a few clinical indications. As these emerging technologies continue to develop, the leadless pacemaker and the S–ICD could play a more prominent role in the management of cardiac arrhythmias.

Advances in Imaging Novel imaging modalities have the potential to make lead extraction even safer through better preprocedural planning and intraoperative navigation. The use of three-dimensional (3D) reconstruction of gated cardiac CT provides an unparalleled ability to visualize the CIED system in relation to intravascular and intracardiac structures. Colour 3D Doppler echocardiography of the SVC was used by a team at Drexel University to predict lead fibrosis. This demonstrated the feasibility of a low-cost, noninvasive screening method to predict whether complex procedures would be needed.96 These modalities have enabled lead extractors to better risk stratify patients and prepare for otherwise unforeseen problems. Additionally, recent advancements in 3D imaging technology (CartoSound™, Biosense Webster Inc) have allowed for real-time assessment of binding sites during transvenous lead extraction97. By integrating real-time, two-dimensional intracardiac echocardiography into the Carto® electroanatomic mapping system environment (Biosense Webster Inc), Nguyen et al. demonstrated that this novel imaging modality yielded better visualization of binding site volume and morphology than fluoroscopy.98 Moreover, this resulted in a significantly

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Clinical Reviews: Drugs and Devices improved procedural success rate and reductions in complications, procedural times and radiation exposure. Future studies are needed to continue evaluating these technologies and their integration before they can be adopted into routine clinical practice.

intervention. To attain this vision, practitioners must remain committed to fostering a culture of both steadfast innovation and collaboration, while ensuring that safety and efficacy remain at the forefront of this exciting arena in medicine. n

Prospective Innovation

Clinical Perspective

The future of lead extraction will likely include more intuitive, effective tools to break adhesions and safely extract leads. We predict these tools will be simpler to use and reduce the steep learning curve currently required to gain competence in lead extraction. For example, these novel technologies may be completely different from today’s laser and mechanical techniques and may include expanding balloon or mechanical vibratory sheaths that break adhesions with ease.

• M  ulticenter, real-world registries have demonstrated that lead extraction is a safe and effective procedure to address problematic cardiac implantable electronic device leads. • The decision to perform a lead extraction should consider the updated guidelines from both Europe and the US, extractor and team experience, risks versus benefits and patient preference. • Transvenous lead extraction approach and risk of complications may be determined using imaging modalities, such as chest x-ray, transesophageal echocardiogram, gated cardiac CT and fluorine–18-fluorodeoxyglucose (18F–FDG) PET and CT. •  Published clinical registries for lead extraction have offered insight into potential complications and strategies to improve patient safety. •  Recent advances regarding infection control, imaging, and equipment offer promise of increasingly safer procedures and better outcomes.

As the field of lead extraction and management continues to evolve, efforts should be made to increase the use of lead extraction. Even with current guidelines, lead extractions are not carried out as much as they could be, as one third of patients with device infections do not receive the proper lead removal therapy and only 15 % of patients with abandoned leads have these extracted in the US.98,99 Ultimately, the goal of these new technologies is to reduce the burden of CIED complications and ensure all patients receive the appropriate

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Positron emission tomography and single-photon emission computed tomography imaging in the diagnosis of cardiac implantable electronic device infection. Circ Cardiovasc Imaging 2017;10(4):pii:e005772. https://doi.org/10.1161/ CIRCIMAGING.116.005772. PMID:28377468. 40. Ahmed FZ, James J, Cunnington C, et al. Early diagnosis of cardiac implantable electronic device generator pocket infection using 18F–FDG–PET/CT. Eur Heart J Cardiovasc Imaging 2015;16(5):521–30. https://doi.org/10.1093/ehjci/jeu295. PMID:25651856; PMCID:PMC4407104. 41. Granados U, Fuster D, Pericas JM, et al. Diagnostic accuracy of 18F–FDG PET/CT in infective endocarditis and implantable cardiac electronic device infection: a cross-sectional study. J Nucl Med 2016;57(11):1726–32. https://doi.org/10.2967/ jnumed.116.173690. PMID:27261514. 42. Tarakji KG, Chan EJ, Cantillon DJ, et al. Cardiac implantable electronic device infections: Presentation, management, and patient outcomes. 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PMID:16403159. 55. Bongiorni MG, Segreti L, Di Cori A, et al. Safety and efficacy of internal transjugular approach for transvenous extraction of implantable cardioverter defibrillator leads. Europace 2014;16(9):1356–62. https://doi.org/10.1093/europace/ euu004. PMID:24696221. 56. Gaubert M, Giorgi R, Franceschi F, et al. Outcomes and costs associated with two different lead-extraction approaches: a single-centre study. Europace 2017;19(10):1710–6. https://doi. org/10.1093/europace/euw254. PMID:27733470.

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Safety and efficacy of the new bidirectional rotational Evolution® mechanical lead extraction sheath: results from a multicentre Italian registry. Europace 2018;20(5):829–34. https://doi.org/10.1093/europace/ eux020. PMID:28339758. 62. Aytemir K, Yorgun H, Canpolat U, et al. Initial experience with the TightRail Rotating Mechanical Dilator Sheath for transvenous lead extraction. Europace 2016;18(7):1043–8. https://doi.org/10.1093/europace/euv245. PMID:26467403. 63. Hussein AA, Wilkoff BL, Martin DO, et al. Initial experience with the Evolution mechanical dilator sheath for lead extraction: safety and efficacy. Heart Rhythm 2010;7(7): 870–3. https://doi.org/10.1016/j.hrthm.2010.03.019. PMID:20346418. 64. Boyle TA, Uslan DZ, Prutkin JM, et al. Reimplantation and repeat infection after cardiac-implantable electronic device infections: experience from the MEDIC (Multicenter Electrophysiologic Device Infection Cohort) database. Circ Arrhythm Electrophysiol 2017;10(3). https://doi.org/10.1161/ CIRCEP.116.004822. PMID:28292753. 65. Tsang DC, Azarrafiy R, Pecha S, et al. Long-term outcomes of prophylactic placement of an endovascular balloon in the vena cava for high-risk transvenous lead extractions. Heart Rhythm 2017;14(12):1833–8. https://doi.org/10.1016/j. hrthm.2017.08.003. PMID:28797678. 66. Fu HX, Huang XM, Zhong LI, et al. Outcomes and complications of lead removal: can we establish a risk stratification schema for a collaborative and effective approach? Pacing Clin Electrophysiol 2015;38(12):1439–47. https:// doi.org/10.1111/pace.12736. PMID:26293652. 67. Bontempi L, Vassanelli F, Cerini M, et al. Predicting the difficulty of a transvenous lead extraction procedure: validation of the LED index. J Cardiovasc Electrophysiol 2017;28(7):811–8. https://doi. org/10.1111/jce.13223. PMID:28419604. 68. Deshmukh A, Patel N, Noseworthy PA, et al. Trends In use and adverse outcomes associated with transvenous lead removal in the United States. Circulation 2015;132(25):2363–71. https://doi.org/10.1161/CIRCULATIONAHA.114.013801. PMID:26534954. 69. 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(3):111–3. https://doi.org/10.15420/aer.2017.25.1. PMID:29018517; PMCID:PMC5610740. 70. Bashir J, Fedoruk LM, Ofiesh J, et al. Classification and surgical repair of injuries sustained during transvenous lead extraction. Circ Arrhythm Electrophysiol 2016;9(9). https://doi. org/10.1161/CIRCEP.115.003741. PMID:27625167. 71. Clancy JF, Carrillo RG, Sotak R, et al. Percutaneous occlusion balloon as a bridge to surgery in a swine model of superior vena cava perforation. Heart Rhythm 2016;13(11):2215–20. https://doi.org/10.1016/j.hrthm.2016.06.028. PMID:27343856. 72. Azarrafiy R, Tsang DC, Boyle TA, et al. Compliant endovascular balloon reduces the lethality of superior vena cava tears during transvenous lead extractions. Heart Rhythm 2017;14(9):1400–4. https://doi.org/10.1016/j. hrthm.2017.05.005. PMID:28506914. 73. Voigt A, Shalaby A, Saba A. Continued rise in rates of cardiovascular implantable electronic device infections in the United States: temporal trends and causative insights. Pacing Clin Electrophysiol 2010;33(4):414–9. https://doi.org/10.1111/ j.1540-8159.2009.02569.x. PMID:19793359. 74. Kondo Y, Ueda M, Kobayashi Y, Schwab JO. New horizon for infection prevention technology and implantable device. J Arrhythm 2016;32(4):297–302. https://doi.org/10.1016/j. joa.2016.02.007. PMID:27588153; PMCID:PMC4996843. 75. Kolek MJ, Patel NJ, Clair WK, et al. Efficacy of a bio-absorbable antibacterial envelope to prevent cardiac implantable electronic device infections in high-risk subjects. J Cardiovasc Electrophysiol 2015; 26(10):1111–6. https://doi.org/10.1111/ jce.12768. PMID:26222980; PMCID:PMC4607656. 76. Ali S, Kanjwal Y, Bruhl SR, et al. A meta-analysis of antibacterial envelope use in prevention of cardiovascular implantable electronic device infection. Ther Adv Infect Dis 2017;4(3):75–82. https://doi.org/10.1177/2049936117702317. PMID:28634537; PMCID:PMC5467856. 77. Kay G, Eby EL, Brown B, et al. Cost-effectiveness of TYRX absorbable antibacterial envelope for prevention of cardiovascular implantable electronic device infection. J Med Econ 2018;21(3):294–300. https://doi.org/10.1080/13696998.20 17.1409227. PMID:29171319. 78. Tarakji KG, Mittal S, Kennergren C, et al. Worldwide Randomized Antibiotic EnveloPe Infection PrevenTion Trial (WRAP–IT). Am Heart J 2016;180:12–21. https://doi. org/10.1016/j.ahj.2016.06.010. PMID:27659878.

79. D  a Costa A, Kirkorian G, Cucherat M, et al. Antibiotic prophylaxis for permanent pacemaker implantation: a meta-analysis. Circulation 1998;97(18):1796–801. https://doi. org/10.1161/01.CIR.97.18.1796. PMID:9603534. 80. Bratzler DW, Dellinger EP, Olsen KM, et al. Clinical practice guidelines for antimicrobial prophylaxis in surgery. Am J Health Syst Pharm 2013;70(3):195–283. https://doi.org/10.2146/ ajhp120568. PMID:23327981. 81. Padfield GJ, Steinberg C, Bennett MT, et al. Preventing cardiac implantable electronic device infections. Heart Rhythm 2015;12(11):2344–56. https://doi.org/10.1016/j. hrthm.2015.06.043. PMID:26142295. 82. Basil A, Lubitz SA, Noseworthy PA, et al. Periprocedural antibiotic prophylaxis for cardiac implantable electrical device procedures: results from a Heart Rhythm Society survey. JACC Clin Electrophysiol 2017;3(6):632–4. https://doi.org/10.1016/j. jacep.2017.01.013. PMID:28804785; PMCID:PMC5550102. 83. Krahn AD et al. B–LBCT01–01/B–LBCT01–01 – Prevention of Arrhythmia Device Infection Trial (PADIS). Presented at: Heart Rhythm Society. Boston, MA, USA, 9–12 May 2018. 84. Connolly SJ, Philippon F, Longtin Y, et al. Randomized cluster crossover trials for reliable, efficient, comparative effectiveness testing: design of the Prevention of Arrhythmia Device Infection Trial (PADIT). Can J Cardiol 2013;29(6):652–8. https://doi.org/10.1016/j.cjca.2013.01.020. PMID:23702356. 85. Reynolds D, Duray GZ, Omar R, et al. A leadless intracardiac transcatheter pacing system. N Engl J Med 2015;374(6):533–41. https://doi.org/10.1056/NEJMoa1511643. PMID:26551877. 86. Roberts PR, Clementy N, Al Samadi F, et al. A leadless pacemaker in the real-world setting: the Micra Transcatheter Pacing System Post-Approval Registry. Heart Rhythm 2017;14(9):1375–9. https://doi.org/10.1016/j. hrthm.2017.05.017. PMID:28502871. 87. Reddy VY, Knops RE, Sperzel J, et al. Permanent leadless cardiac pacing: results of the LEADLESS Trial. Circulation 2014;129(14):1466–71. https://doi.org/10.1161/ CIRCULATIONAHA.113.006987. PMCID:PMC4194270; PMID: 24664277. 88. Duray GZ, Ritter P, El-Chami M, et al. Long-term performance of a transcatheter pacing system: 12–month results from the Micra Transcatheter Pacing Study. Heart Rhythm 2017;14(5):702–9. https://doi.org/10.1016/j.hrthm.2017.01.035. PMID:28192207. 89. Tjong FVY, Reddy VY. Permanent leadless cardiac pacemaker therapy: a comprehensive review. Circulation 2017;135(15):1458–70. https://doi.org/10.1161/ CIRCULATIONAHA.116.025037. PMID:28396380. 90. Tjong FVY, Knops RE, Neuzil P, et al. Midterm safety and performance of a leadless cardiac pacemaker. Circulation 2018;137(6):633–5. https://doi.org/10.1161/ CIRCULATIONAHA.117.030106. PMID:29431664. 91. Basu-Ray I, Liu J, Jia X, et al. Subcutaneous versus transvenous implantable defibrillator therapy: a meta-analysis of case-control studies. JACC Clin Electrophysiol 2017;3(13):1475– 83. https://doi.org/10.1016/j.jacep.2017.07.017. PMID:29759827. 92. Pedersen SS, Mastenbroek MH, Carter N, et al. A comparison of the quality of life of patients with an entirely subcutaneous implantable defibrillator system versus a transvenous system (from the EFFORTLESS S–ICD Quality of Life Substudy). Am J Cardiol 2016;118(4):520–6. https://doi.org/10.1016/j. amjcard.2016.05.047. PMID:27353211. 93. Lenarczyk R, Boveda S, Haugaa KH, et al. Peri-procedural routines, implantation techniques, and procedure-related complications in patients undergoing implantation of subcutaneous or transvenous automatic cardioverterdefibrillators: results of the European Snapshot Survey on S–ICD Implantation (ESSS–SICDI). Europace 2018;20(7):1218–24. https://doi.org/10.1093/europace/euy092. PMID: 29762683. 94. 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(7):830–41. https://doi.org/10.1016/j.jacc.2017.06.040. PMID:28797351. 95. Honarbakhsh S, Providencia R, Srinivasan N, et al. A propensity matched case–control study comparing efficacy, safety and costs of the subcutaneous vs. transvenous implantable cardioverter defibrillator. Int J Cardiol 2017;228:280–5. https://doi.org/10.1016/j.ijcard.2016.11.017. PMID:27865198. 96. Yakish SJ, Narula A, Foley R, et al. Superior vena cava echocardiography as a screening tool to predict cardiovascular implantable electronic device lead fibrosis. J Cardiovasc Ultrasound 2015;23(1):27–31. https://doi.org/10.4250/ jcu.2015.23.1.27. PMID:25883753; PMCID:PMC4398781. 97. Nguyen BL, Nguyena BL, Persi A, Gang ES, et al. Threedimensional binding sites volume assessment during cardiac pacing lead extraction. Clin Trials Regul Sci Cardiol 2015;7:1–6. https://doi.org/10.1016/j.ctrsc.2015.08.006. 98. Sohail MR, Eby EL, Ryan MP, et al. Incidence, treatment intensity, and incremental annual expenditures for patients experiencing a cardiac implantable electronic device infection: evidence from a large US payer database 1–year post implantation. Circ Arrhythm Electrophysiol 2016;9(8). https:// doi.org/10.1161/CIRCEP.116.003929. PMID: 27506820. 99. Pokorney SD, Mi X, Lewis RK, et al. Outcomes associated with extraction versus capping and abandoning pacing and defibrillator leads. Circulation 2017;136(15):1387–95. https://doi. org/10.1161/CIRCULATIONAHA.117.027636. PMID:28830879.

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Letter to the Editor: His Bundle Pacing: A New Frontier in the Treatment of Heart Failure Theodoros Zografos

Citation: Arrhythmia & Electrophysiology Review 2018;7(3):218. DOI: https://doi.org/10.15420/aer.2018.7.3.L1 Correspondence: Theodoros Zografos, Research Associate, Athens Red Cross Hospital, 8 Artemidos Street, 16672, Vari, Athens, Greece.

Dear Sir, I read with great interest the elegant article by Ali et al.1 on His bundle pacing in issue 17.2 of AER. I do concur with the authors’ view and conclusions. However, there are two issues that may merit further attention. First, specific His-bundle pacing is indeed the reasonable option that mimics the natural ventricular excitation. However, no benefit of mid-septal over apical pacing has been shown in randomised comparisons.2,3 Is this because of the relatively shortterm follow-up that did not allow apical pacing to expose its deleterious effects on the ventricle or just reflects the fact that mid-septal is not equivalent to specific His pacing? Second, acute results of His-bundle pacing are comparable to these of cardiac resynchronisation therapy (CRT).4,5 Do the authors believe that we have enough data to implement this principle in clinical practice, even before a randomised trial confirms this notion? That should have a tremendous impact on cost and efficacy of pacing in the setting of intractable heart failure, especially in view of the cost and complications of CRT, as demonstrated in the BLOCK-HF trial.6

1. 2. 3. 4. 5. 6.

Ali N, Keene D, Arnold A, et al. His bundle pacing: a new frontier in the treatment of heart failure. Arrythm Electrophysiol Rev 2018;7:103–10. https://doi.org/10.15420/aer.2018.6.2; PMID: 29967682. Janousek J, van Geldorp IE, Krupičková S, et al. Permanent cardiac pacing in children: choosing the optimal pacing site: a multicenter study. Circulation 2013;127:613–23. https://doi.org/10.1161/CIRCULATIONAHA.112.115428; PMID: 23275383.    Kaye GC, Linker NJ, Marwick TH, et al. Effect of right ventricular pacing lead site on left ventricular function in patients with high-grade atrioventricular block: results of the ProtectPace study. Eur Heart J 2015;36:856–62. https://doi.org/10.1093/eurheartj/ehu304; PMID: 25189602.    Katritsis DG. Choice of ventricular pacing site: the end of non-physiological, apical ventricular pacing? Arrhythm Electrophysiol Rev 2017;6:159–60. https://doi.org/10.15420/ aer.2017.6.4:EO3; PMID: 29326829.   Vijayaraman P, Naperkowski A, Subzposh FA, et al. Permanent His bundle pacing: Recommendations from a Multicenter His Bundle Pacing Collaborative Working Group for standardization of definitions, implant measurements, and follow-up. Heart Rhythm 2018;15:460–8. https://doi.org/10.1016/j.hrthm.2017.10.039; PMID: 29107697.    Curtis AB, Worley SJ, Adamson PB, et al. Biventricular pacing for atrioventricular block and systolic dysfunction. N Engl J Med 2013;368:1585–93. https://doi.org/10.1056/ NEJMoa1210356; PMID: 23614585.  

Authors’ Reply: His Bundle Pacing: A New Frontier in the Treatment of Heart Failure Ahran Arnold, Nadine Ali, Daniel Keene, Mathew Shun-Shin, Zachary Whinnett and SM Afzal Sohaib

Citation: Arrhythmia & Electrophysiology Review 2018;7(3):218–9. Correspondence: Dr Zachary I Whinnett, Senior Lecturer & Consultant Cardiologist, Imperial College London, 2nd Floor B Block South, Hammersmith Campus, Du Cane Road, London W12 0HS, UK. E: z.whinnett@imperial.ac.uk

Dear Sir, We read Dr Zografos’ response to our article1 with interest. He agrees with the findings of our review but highlights two important issues for further discussion, which we address below.

Right ventricular lead position Dr Zografos points out that randomised comparisons of different right ventricular lead positions have not shown superiority of septal pacing over apical pacing.2 This is important because right ventricular (RV) septal pacing is considered to be “more

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Letters physiological” than apical pacing due to its closer proximity to the bundle of His. It is therefore postulated that the activation of the ventricular myocardium has a pattern and duration closer to that of native conduction through the His–Purkinjie system. If more physiological pacing is not more beneficial, this might lead some to cast doubt on the efficacy of His bundle pacing. Dr Zografos speculates on two explanations for this: insufficient follow-up duration to detect differences between septal and apical pacing or important differences between His bundle pacing and septal pacing. A sceptical third view would suggest that increasingly physiological ventricular activation does not have clinically relevant benefits. We think that there is insufficient data in current literature to provide a definitive answer to this question due to the lack of randomised controlled trials for His bundle pacing. However, we believe his second explanation, that septal pacing and His bundle pacing are not equivalent, is the most plausible one. Regardless of whether pacing is performed from the right ventricular outflow tract, septum or apex, the activation of the left ventricle (LV) occurs via slow cell-to-cell myocardial activation. Therefore, although the severity may vary, any lead position that captures RV myocardium rather than conduction system tissue will result in deleterious intra-ventricular LV dyssynchrony. His bundle pacing, however, is thought to obviate pacing-induced intra-LV dyssynchrony, by its very nature, as activation occurs rapidly through the His–Purkinje network. An important caveat to this is non-selective His bundle capture, which is likely to induce intra-RV dyssynchrony and therefore a degree of inter-ventricular dyssynchrony. The clinical significance of this is not yet known. It is possible that study design has impacted the ability of randomised trials to detect a difference between septal and apical pacing, but this is not necessarily limited to follow-up duration (although this appears to be a factor3). Recruiting patients with preserved LV systolic function means that the trial is designed to prevent, rather than treat, pacing-induced cardiomyopathy. Although this might be a better clinical strategy for patients, it may underpower trials as some patients experience lifelong RV apical pacing without developing heart failure. Furthermore establishing a definition of high or mid septal pacing that differs from apical pacing, and is achievable in the vast majority of patients randomised to septal pacing, can be difficult. Irrespective of trial design, His bundle pacing differs from septal pacing in terms of implant technique. Septal pacing is based on a fluoroscopic, anatomical assessment of the position of the septum. Varying rotation of the heart can result in an apparently high septal lead position being, in actuality, relatively posterior/anterior, or even lateral.4 This is difficult to detect using fluoroscopy alone but is important because these alternative positions might be expected to have worse characteristics of ventricular activation than apical pacing. His pacing, however, is a combined electrophysiological and anatomical technique. The presence of a His signal, His injury current and formal ECG and electrogram criteria mean that His bundle pacing can be verified more robustly than septal pacing.

Randomised evidence for His bundle pacing Dr Zografos highlights the need for randomised trials to support routine use of His bundle pacing in clinical practice. He points out that while the acute benefits may be similar to cardiac resynchronisation therapy (CRT), this does not necessarily mean this will be the same for clinical outcomes. Randomised controlled trials (RCTs) remain the gold standard for evidence based medical interventions. For His bundle pacing in heart failure to be recommended for routine clinical practise, existing observational data are insufficient. Important confounders and biases that limit observational data may be responsible for the positive findings that existing studies report. There are potential pitfalls of His bundle pacing that have not been fully addressed by current technology, some of which may mitigate its efficacy, such as programming and long-term threshold issues. The absence of recommendation for routine His pacing limits the ability for operators to gain implant experience. This, combined with the encouraging acute and observational findings, mean that RCTs are now urgently required. We are currently addressing this in the HOPE-HF trial where we are objectively measuring differences in exercise capacity in individuals with PR prolongation and LV impairment where individuals are randomised to having AV optimised His bundle pacing and conventional back-up pacing in a crossover design.5 The results of the His-SYNC study should provide further information about the use of His pacing to reverse left bundle branch block (LBBB) (NCT 02700425). A trial for His bundle pacing for bradycardia indications is awaited.

1. 2. 3. 4. 5.

Ali N, Keene D, Arnold A, et al. His bundle pacing: a new frontier in the treatment of heart failure. Arrythm Electrophysiol Rev 2018;7:103–10. https://doi.org/10.15420/aer.2018.6.2; PMID: 29967682. Victor F, Leclercq C, Mabo P, et al. Optimal right ventricular pacing site in chronically implanted patients: a prospective randomized crossover comparison of apical and outflow tract pacing. JACC 1999;33:311–16. https://doi.org/10.1016/S0735-1097(98)00589-0; PMID: 9973008. Shimony A, Eisenberg MJ, Filion KB, Amit G. Beneficial effects of right ventricular non-apical vs. apical pacing: a systematic review and meta-analysis of randomized-controlled trials. Europace 2011;14:81–91. https://doi.org/10.1093/europace/eur240; PMID: 21798880. McGavigan AD, Roberts‐Thomson KC, Hillock RJ, et al. Right ventricular outflow tract pacing: radiographic and electrocardiographic correlates of lead position. Pacing and Clin Electrophysiol 2006;29:1063–8. https://doi.org/10.1111/j.1540-8159.2006.00499.x; PMID: 17038137.   Keene D, Arnold A, Shun‐Shin MJ et al. Rationale and design of the randomized multicentre His Optimized Pacing Evaluated for Heart Failure (HOPE‐HF) trial. ESC heart failure 2018.

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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 Reviewâ&#x20AC;&#x2122;s articles are free-to-access, and aim to support continuous learning for physicians within the field.

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Cardiology

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JOURNALS | LIVE STREAMS | WEBINARS ROUNDTABLES | CME COURSES

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Video

Education Streaming

CME Marketing

Vascular

Media

Radcliffe

Cardiology Online

Research

Courses

Medical

Digital

Publishing

Articles

Webinars

Healthcare Round Tables Surgeons

Journals Learning

Academic

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S AV E T H E D AT E

Please join us at the 40th Scientific Sessions in San Francisco, CA May 8 - 11, 2019 Learn more at HRSsessions.org

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ESC future congresses Covering the full spectrum of cardiology

ESC Congress Munich 2018 25-29 August

Where the world of cardiology comes together

ALL TOPICS Munich, Germany 25-29 August 2018

EuroEcho 2 0 Imaging 1 8 exercise and sport | valvular heart disease

LISBON PORTUGAL

1 7-1 9

MARCH

5/8

December

Milan

Implementing diagnostic and therapeutic innovations in daily practice

ITALY

22nd Annual Congress

www.escardio.org/EHRA-congress

of the European Association of Cardiovascular Imaging (EACVI), a registered branch of the ESC. www.escardio.org/EACVI

In conjunction with the 43rd Annual Meeting of the ESC Working Group on Cardiac Cellular Electrophysiology

INTERVENTION London, United Kingdom 9-11 September 2018

CARDIAC IMAGING Milan, Italy 5-8 December 2018

ACUTE CARDIAC CARE Malaga, Spain 2-4 March 2019

EuroHeartCare

EuroCMR 2019

Annual Congress of the Council on Cardiovascular Nursing and Allied Professions

extending the clinical value of cmr through quality and evidence

HEART RHYTHM Lisbon, Portugal 17-19 March 2019

2019

EuroPrevent European Congress on Preventive Cardiology

2-4 May 2019

Milan, Italy

2-4 May

Ve n i c e i

LISBON PORTUGAL

12-14 May 2019 w w w. i c n c 20 1 9.o rg

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a

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y

KEY FIGURES: 3 Days, 20 Sessions, 50 international faculty members, 200 abstracts, 500 delegates, 40 countries represented, 1 congress!

17th Annual Meeting

KEY DEADLINES: Abstract Submission: 10 January Early Registration fee: 27 February Late Registration fee: 2 April

on Cardiovascular Magnetic Resonance (CMR) of the European Association of Cardiovascular Imaging (EACVI)

11-13 April 2019 Lisbon, Portugal

www.escardio.org/EACVI www.escardio.org/EuroHeartCare #euroheartcare

NUCLEAR CARDIOLOGY AND CARDIAC CT Lisbon, Portugal 12-14 May 2019

#EuroCMR

NURSING Milan, Italy 2-4 May 2019

CARDIAC MAGNETIC RESONANCE Venice, Italy 2-4 May 2019

www.escardio.org/europrevent #europrevent

PREVENTION Lisbon, Portugal 11-13 April 2019

Heart Failure

&

Wo r l d Co ng ress o n Acute Hear t Failure

2019

2 5 -2 8 M AY AT H E N S g r e e c e

Organised by the Heart Failure Association of the ESC

heart failure from alpha to omega

www.escardio.org/heartfailure

INTERVENTION Paris, France 21-24 May 2019

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HEART FAILURE Athens, Greece 25-28 May 2019

BASIC SCIENCE Budapest, Hungary Spring 2020

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AER 7.3  

Arrhythmia & Electrophysiology Review Volume 7 Issue 3 Summer 2018

AER 7.3  

Arrhythmia & Electrophysiology Review Volume 7 Issue 3 Summer 2018