AER 5.1 by Radcliffe Cardiology

Volume 5 • Issue 1 • Summer 2016

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Differences in Left versus Right Ventricular Electrophysiological Properties in Cardiac Dysfunction and Arrhythmogenesis Cristina E Molina, Jordi Heijman and Dobromir Dobrev

Pharmacological Therapy of Tachyarrhythmias During Pregnancy Ameeta Yaksh, Lisette JME van der Does, Eva AH Lanters and Natasja MS de Groot A Novel Interventional Strategies for the Treatment of Atrial Fibrillation

Konstantinos C Siontis and Hakan Oral

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Henry Chubb, Mark O’Neill and Eric Rosenthal A

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CARDIOSTIM 2016 SATELLITE SYMPOSIUM @ EHRA EUROPACE PLEASE JOIN US AT BOOTH A15 Learning Objectives •

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Third party trademarks used herein are trademarks of their respective owners. Review all relevant Instruction for Use, with particular attention to the indications, contraindications, warnings and precautions, prior to use the medical device. This Satellite Symposium has been made possible by an educational grant from Biosense Webster and is intended for Healthcare professionals in Europe Middle East Africa only. © Johnson & Johnson Medical NV/SA 2016 052282-160429

Volume 5 • Issue 1 • Spring 2016

Editor-in-Chief Demosthenes Katritsis Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, US

Section Editor – Arrhythmia Mechanisms / Basic Science

Section Editor – Clinical Electrophysiology and Ablation

Section Editor – Implantable Devices

Andrew Grace

Karl-Heinz Kuck

Angelo Auricchio

University of Cambridge, UK

Asklepios Klinik St Georg, Hamburg, Germany

Fondazione Cardiocentro Ticino, Lugano, Switzerland

Charles Antzelevitch

Lankenau Institute for Medical Research, Wynnewood, US

Carsten W Israel

Carlo Pappone

JW Goethe University, Germany

IRCCS Policlinico San Donato, Milan, Italy

Warren Jackman

University of Oklahoma Health Sciences Center, Oklahoma City, US

Sunny Po

University Hospital Uppsala, Sweden

Johannes Brachmann

Pierre Jaïs

Antonio Raviele

Carina Blomström-Lundqvist

Klinikum Coburg, II Med Klinik, Germany

Pedro Brugada

University of Brussels, UZ-Brussel-VUB, Belgium

Bordeaux University Hospital, Electrophysiology and Heart Modelling Institute (LIRYC), France

Mark Josephson

Beth Israel Deaconess Medical Center, Boston, US

Alfred Buxton

Heart Rhythm Institute, University of Oklahoma Health Sciences Center, Oklahoma City, US ALFA – Alliance to Fight Atrial Fibrillation, Venice-Mestre, Italy

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

Beth Israel Deaconess Medical Center, Boston, US

Josef Kautzner

Hugh Calkins

John Hopkins Medical Institution, Baltimore, US

Institute for Clinical and Experimental Medicine, Prague, Czech Republic

A John Camm

Samuel Lévy

St George’s University of London, UK

Aix-Marseille University, France

Riccardo Cappato

Cecilia Linde

Brigham and Women’s Hospital, Harvard Medical School, US

Gregory YH Lip

Richard Sutton

IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy

Karolinska University, Stockholm, Sweden

Ken Ellenbogen

University of Birmingham, UK

Virginia Commonwealth University School of Medicine, US

Sabine Ernst

Royal Brompton and Harefield NHS Foundation Trust, London, UK

Andreas Götte

St Vincenz-Hospital Paderborn and University Hospital Magdeburg, Germany

Hein Heidbuchel

Francis Marchlinski

University of Pennsylvania Health System, Philadelphia, US

Richard Schilling

Barts Health NHS Trust, London Bridge Hospital, London, UK

William Stevenson

National Heart and Lung Institute, Imperial College, London, UK

Juan Luis Tamargo

University Complutense, Madrid, Spain

Jose Merino

Panos Vardas

Hospital Universitario La Paz, Madrid, Spain

Heraklion University Hospital, Greece

Fred Morady

Marc A Vos

Cardiovascular Center, University of Michigan, US

University Medical Center Utrecht, Netherlands

Sanjiv M Narayan

Katja Zeppenfeld

Hasselt University and Heart Center, Jessa Hospital, Hasselt, Belgium

Stanford University Medical Center, US

Leiden University Medical Center, Netherlands

Gerhard Hindricks

Mark O’Neill

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

Douglas P Zipes

University of Leipzig, Germany

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

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Published by Radcliffe Cardiology. All information obtained by Radcliffe Cardiology and each of the contributors from various sources is as current and accurate as possible. However, due to human or mechanical errors, Radcliffe Cardiology and the contributors cannot guarantee the accuracy, adequacy or completeness of any information, and cannot be held responsible for any errors or omissions, or for the results obtained from the use there of. Where opinion is expressed, it is that of the authors and does not necessarily coincide with the editorial views of Radcliffe Cardiology. Statistical and financial data in this publication have been compiled on the basis of factual information and do not constitute any investment advertisement or investment advice. Radcliffe Cardiology, Unit F, First Floor, Bourne End Business Park, Cores End Road, Bourne End, Buckinghamshire SL8 5AS © 2016 All rights reserved

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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-today 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 tri-annual 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

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.

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.

Frequency: Tri-annual

Current Issue: Summer 2016

• 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 Managing Editor for further details: managingeditor@radcliffecardiology.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@radcliffecardiology.com

Distribution and Readership Arrhythmia & Electrophysiology Review is distributed tri-annually 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 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 and European Cardiology Review. n

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Radcliffe Cardiology

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www.radcliffecardiology.com A free-to-access community supporting best practice in cardiovascular care

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The Role of Percutaneous Haemodynamic Support in High-risk Percutaneous Coronary Intervention and Cardiogenic Shock Dagmar M Ouweneel, Bimmer E Claessen, Krischan D Sjauw and José PS Henriques

Intravascular Ultrasound vs. Optical Coherence Tomography For Coronary Artery Imaging - Apples And Oranges? Krishnaraj S Rathod, Stephen M Hamshere, Daniel A Jones, and Anthony Mathur US Cardiology Review

Transcatheter Aortic Valve Replacement for Native Aortic Valve Regurgitation Roberto Spina, Chris Anthony, David WM Muller and David Roy

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Volume 4 • Issue 1 • Spring 2015

Volume 10 • Issue 1 • Spring 2016 • RELAUNCH ISSUE

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Percutaneous Closure of Patent Foramen Ovale – Data from Randomized Clinical Trials and Meta-Analyses Volume 10 • Issue 1 • Spring 2016 • RELAUNCH ISSUE

Stefan Stortecky and Stephan Windecker

Biology of the Sinus Node and its Disease Moinuddin Choudhury, Mark R Boyett and Gwilym M Morris

Optimal Anticoagulation Strategy for Cardioversion in Atrial Fibrillation Philipp Bushoven, Sven Linzbach, Mate Vamos and Stefan H Hohnloser

Role of Rotors in the Ablative Therapy of Persistent Atrial Fibrillation

Promising New Therapies in Heart Failure: Ivabradine and the Neprilysin Inhibitors Michelle Kittleson, MD, PhD

Ischemic Complications of Pregnancy: Who is at Risk? Sara C Martinez, MD, PhD and Sharonne N Hayes, MD

Optimizing Heart Rate and Controlling Symptoms in Atrial Fibrillation

Amir A Schricker, Junaid Zaman and Sanjiv M Narayan

Public Reporting of Cardiovascular Data: Benefits, Pitfalls, and Vision for the Future

Computer Modelling for Better Diagnosis and Therapy of Patients by Cardiac Resynchronisation Therapy

Gregory J Dehmer, MD, MACC, MSCAI, FAHA, FACP ISSN: 1756-1477

Marieke Pluijmert, Joost Lumens, Mark Potse, Tammo Delhaas, Angelo Auricchio and Frits W Prinzen

Intravascular ultrasound

Optical coherence tomography image of normal coronary arteries

Intra-procedural fluoroscopy and the animation of valve implantation process SNS

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RAAS

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Non-invasive Mapping of Atrial Fibrillation Re-entrant and Focal Driver Domains

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Voltage Map of the Left Atrium During Atrial Fibrillation Ablation

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RAAS Inhibitors

ACEI, ARB, MRA Left coronary artery

Angiotensin II → right AT1 receptor in the anterior-

oblique projection

Electrocardiogram rhythm strips

ARNIs Vasoconstriction Blood pressure Sympathetic tone Aldosterone Hypertrophy Fibrosis

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LIVE FROM THE HAMMERSMITH

Pragnesh Parikh, MD and KL Venkatachalam, MD

→ → →→ →

Arrhythmia & Electrophysiology Review Volume 4 • Issue 1 • Spring 2015

Interventional Cardiology Review Volume 10 • Issue 1 • Spring 2015

Volume 10 • Issue 1 • Spring 2015

C Academy C Webinars C Webinars

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Contents

Foreword

Consensus Document on Supraventricular Arrhythmias: A Valuable Initiative from EHRA

Demosthenes Katritsis, Editor-in-Chief

Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, US

EHRA Editorial

The European Heart Rhythm Association: On the Move Towards the Future of Electrophysiology

Gerhard Hindricks, EHRA President

Expert Opinion

12 Controversy Surrounding ROCKET-AF: A Call for Transparency,

But Should We Be Changing Practice?

Jason D Matos 1 and Peter J Zimetbaum 1,2

1. Cardiovascular Division, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston,

Massachusetts, US; 2. Harvard-Thorndike Electrophysiology Institute and Arrhythmia Service, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, US

Arrhythmia Mechanisms ifferences in Left Versus Right Ventricular Electrophysiological D Properties in Cardiac Dysfunction and Arrhythmogenesis

Cristina E Molina, 1 Jordi Heijman 2 and Dobromir Dobrev 1

1. Institute of Pharmacology, West German Heart and Vascular Center, Faculty of Medicine, University Duisburg-Essen, Essen, Germany; 2. Cardiovascular Research Institute Maastricht, Faculty of Health, Medicine, and Life Sciences, Maastricht University, Maastricht, The Netherlands

P ost-extrasystolic Potentiation: Link between Ca 2+ Homeostasis and Heart Failure?

David J Sprenkeler and Marc A Vos

University Medical Center Utrecht, Utrecht, The Netherlands

P ost-extrasystolic Blood Pressure Potentiation as a Risk Predictor in Cardiac Patients

Alexander Steger, Daniel Sinnecker, Petra Barthel, Alexander Müller, Josef Gebhardt and Georg Schmidt

1st Medical Clinic and Policlinic, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany

eriodic Repolarisation Dynamics: A Natural Probe of the Ventricular Response P to Sympathetic Activation

Konstantinos D Rizas, 1,2 Wolfgang Hamm, 1,2 Stefan Kääb, 1,2 Georg Schmidt 2,3 and Axel Bauer 1,2

1. Munich University Clinic, Munich, Germany; 2. Deutsches Zentrum für Herzkreislaufforschung (DZHK), Munich, Germany; 3. Technical University of Munich, Munich, Germany

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Contents

Arrhythmia Mechanisms

M icrovolt T-wave Alternans: Where Are We Now?

Aapo L Aro, 1 Tuomas V Kenttä, 2 Heikki V Huikuri 2

1. Helsinki University Hospital, Helsinki, Finland; 2. University Hospital of Oulu and University of Oulu, Oulu, Finland

Clinical Arrhythmias

Pharmacological Therapy of Tachyarrhythmias During Pregnancy

Ameeta Yaksh, Lisette JME van der Does, Eva AH Lanters and Natasja MS de Groot

Erasmus Medical Center, Rotterdam, The Netherlands

The Role of Flecainide in the Management of Catecholaminergic Polymorphic Ventricular Tachycardia

Krystien VV Lieve, 1 Arthur A Wilde, 1,2 Christian van der Werf 1

1. Heart Centre, Academic Medical Centre, Amsterdam, The Netherlands; 2. Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, Jeddah, Kingdom of Saudi Arabia

Diagnostic Electrophysiology & Ablation

Novel Interventional Strategies for the Treatment of Atrial Fibrillation

Konstantinos C Siontis and Hakan Oral

Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI, US

Device Therapy

Pacing and Defibrillators in Complex Congenital Heart Disease

Henry Chubb, 1,2 Mark O’Neill, 1,3 and Eric Rosenthal 2,3

1. Division of Imaging Sciences and Biomedical Engineering, King’s College London, London, UK; 2. Department of Congenital Heart Disease, Evelina Children’s Hospital, London, UK; 3. Adult Congenital Heart Disease Group, Departments of Cardiology at Guy’s and St Thomas’ NHS Foundation Trust and Evelina Children’s Hospital, London, UK

Cardiac Implantable Electronic Device Infection in Patients at Risk

Khaldoun G Tarakji, 1 Christopher R Ellis, 2 Pascal Defaye 3 and Charles Kennergren 4

1. Heart and Vascular Institute, Cleveland Clinic, Ohio, US; 2. Vanderbilt Heart and Vascular Institute at Vanderbilt University, Nashville, Tennessee, US; 3. Centre Hospitalier Universitaire de Grenoble, La Tronche, France; 4. Sahlgrenska University Hospital, Gothenburg, Sweden

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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.

Call for Submissions Arrhythmia & Electrophysiology Review publishes invited contributions from prominent experts, but also welcomes speculative submissions of a superior quality. For further information on submitting an article, or

In partnership with

for free online access to the journal, please visit:

www.AERjournal.com

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

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Foreword

Consensus Document on Supraventricular Arrhythmias: A Valuable Initiative from EHRA

upraventricular tachycardias (SVT) are common, with an estimated prevalence of 2.25/1,000 persons and an incidence of 35/100,000 person-years.1 Atrioventricular nodal reentrant tachycardia (AVNRT), in particular, represents the most common regular arrhythmia in the human, and its proportion

increases with age.2 However, the European Society of Cardiology has not published management guidelines for SVT since its original 2003 document,3 while our colleagues in the US did so in 2015.4 In this respect, the recent initiative of the European Heart Rhythm Association (EHRA) to produce a consensus document guiding the management of patients with SVT is most welcome. This will be presented in the forthcoming CARDIOSTIMEHRA EUROPACE congress in June, and is to be followed by formal ESC guidelines scheduled for 2019. The Task Force convened for this purpose by EHRA worked together with representatives from the Heart Rhythm Society (HRS), the Asia Pacific Heart Rhythm Society (APHRS) and the Sociedad Latinoamericana de Estimulación Cardíaca y Electrofisiología (SOLAECE). Thus, a global, rather than strictly European perspective, was ensured. The final document is aimed at summarising current developments in the field, with focus on new advances since the last ESC guidelines, and providing general recommendations for the management of these common clinical entities, based on the principles of evidence-based medicine. In addition, it presents a new concept of recommended diagnostic and therapeutic practices. Current systems of ranking levels of evidence are becoming complicated in such a way that their practical utility might be compromised.5 EHRA, APHRS and SOLAECE therefore, have opted for an easier system of ranking that classifies recommendations simply as recommended, may be recommended or not recommended. It is hoped that this user-friendly and straightforward approach will allow physicians to easily assess the current status of evidence and consequent guidance. Demosthenes Katritsis Editor-in-Chief, Arrhythmia & Electrophysiology Review Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, US

Orejarena LA, Vidaillet H, Jr, DeStefano F, et al. Paroxysmal supraventricular tachycardia in the general population. J Am Coll Cardiol 1998;31:150–7. DOI:10.1016/S07351097(97)00422-1; PMID: 9426034 Porter MJ, Morton JB, Denman R, et al. Influence of age and gender on the mechanism of supraventricular tachycardia. Heart Rhythm 2004;1:393–6. DOI: http://dx.doi.org/10.1016/j. hrthm.2004.05.007; PMID: 15851189 Blomstrom-Lundqvist C, Scheinman MM, Aliot EM, et al. ACC/AHA/ESC guidelines for the management of

patients with supraventricular arrhythmias – executive summary: A report of the American College of Cardiology/ American Heart Association task force on practice guidelines and the European Society of Cardiology committee for practice guidelines (writing committee to develop guidelines for the management of patients with supraventricular arrhythmias). Circulation 2003;108:1871–909. DOI: 10.1161/01. CIR.0000091380.04100.84; PMID: 14557344. Page RL, Joglar JA, Caldwell MA, et al. 2015 ACC/AHA/

HRS guideline for the management of adult patients with supraventricular tachycardia: A report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines and the Heart Rhythm Society. Circulation 2015;133:e506–74. DOI: 10.1161/ CIR.0000000000000311; PMID: 26399663. Benhorin J, Bodenheimer M, Brown M, et al. Improving clinical practice guidelines for practicing cardiologists. The Am J Cardiol 2015;115:1773–6. DOI: 10.1016/j. amjcard.2015.03.026; PMID: 25918027

DOI: 10.15420/AER.2016.5.1.ED1

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Be part of the leading network of European Cardiac Rhythm Management, connect with EHRA and access all these benefits: Registration discount on EHRA annual congresses: • CARDIOSTIM-EHRA EUROPACE 2016 & EHRA EUROPACE-CARDIOSTIM 2017

Reduced fee for the EP Europace Journal

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14/05/2016 18:41

EHRA Editorial

The European Heart Rhythm Association: On the Move Towards the Future of Electrophysiology

he Board of the European Heart Rhythm Association (EHRA) sends greetings and best regards to the readers of Arrhythmia &

Electrophysiology Review and expresses great

pleasure about the continuation of the co-operation between the journal and our Association. We greatly appreciate this new opportunity to share information and news from EHRA with the readership of Arrhythmia & Electrophysiology Review.

EHRA Executive Board 2015 â&#x20AC;&#x201C; 2017. From left to right : Karl-Heinz Kuck, A John Camm, Katja Zeppenfeld, Gerhard Hindricks, Hein Heidbuchel

EHRA has developed tremendously over the last decade and has continuously enlarged the scope of educational and scientific activities. EHRA has been a driving force for successful innovations and has evolved to become a role model for new projects within the family of the European Society of Cardiology (ESC) associations and beyond. One of the pioneering achievements was the introduction of the EHRA White Book, which was first published in 2008. The EHRA White Book documents the status and development of electrophysiology across Europe and provides unique and valuable data for scientists, healthcare economists and also for healthcare politicians. We expect the next edition summarising data for 2015 to be published in June this year. The EHRA Fellowship Programme has been running for 9 years and is the largest programme of its kind within the ESC. The programme offers many opportunities for education and exchange â&#x20AC;&#x201C; further information can be found at www.escardio.org/EHRA-training-fellowships We invite everyone to check the available options and apply for the next call in September, and also take the opportunity to learn more about EHRA Proctor Programme, which is open for application until 29 July 2016 on www.escardio.org/EHRA-proctor-prog The EHRA website is the best place to check for our educational courses in pacing, electrophysiology and catheter ablation. The portfolio has been recently updated and enriched with focus elements in the fields of AF ablation and VT ablation. Space on courses is limited and we encourage everyone to sign up early. Take a course first and then sign up for the EHRA Certification programme, which is available for physicians and allied professionals. The latest educational project is the Diploma of Advanced Studies in Cardiac Arrhythmia Management; the DAS CAM course is a joint activity by Maastricht University, the European Heart Academy and EHRA. The DAS CAM programme is designed as a premium 2-year educational event for the leaders of tomorrow. The programme will be available on our website early this summer. It is only a few weeks until the CARDIOSTIM-EHRA EUROPACE congress in Nice, France, opens its doors. This congress will be the leading event in Europe for science and education but also a unique chance for personal exchange with your colleagues from around the world.

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EHRA Editorial

In addition to premium offerings in science and education, we are increasingly focusing on strategic goals in the field of heart rhythm to improve EHRAâ&#x20AC;&#x2122;s recognition and influence. In February this year EHRA organised the first EHRA Innovation Forum at which key opinion leaders from the healthcare sector met and discussed strategies to improve the development, assessment and clinical implementation of innovative ideas and treatment options in the field of electrophysiology. EHRA has also undertaken intense activities in the field of clinical trials. We have extended our involvement in the Early Treatment of Atrial Fibrillation for Stroke Prevention Trial (EAST) and also started activities in the field of public sponsored clinical studies and trial supported by grants from the European Union. We believe that this is an important strategic move to extend the roles and responsibilities of the EHRA. The EHRA Spring Summit 2016 took place recently and had a focus on education. Together with representatives of more than 40 EP National Cardiac Societies and Working Groups, EHRA leadership discussed the future needs and future strategies to improve the quality and efficacy of our educational provision. For the first time the EHRA Summit was enriched by the EHRA Young EP Summit at which the EHRA Young Ambassadors gathered to meet with EHRA leadership. One key topic was the future of our EHRA EUROPACE congress in the light of the recent announcements by European industry (MedTech Europe) to change the rules and regulations for individual physician support for congress participation. While this is a significant change and a big challenge, we will come up with creative, innovative and effective solutions to maintain a high level of support for our congress guests. We believe that every challenge is also an opportunity â&#x20AC;&#x201C; always! Thus, EHRA leadership has taken strong action to turn this challenge into success together with our industry partners and of course our EP National Cardiac Societies. We need you with your ideas to support us. The new EHRA membership scheme offers multiple opportunities to become an active part of the leading European association in the field of heart rhythm. On behalf of the EHRA Board and the EHRA staff at European Heart House I wish you great and successful times. Gerhard Hindricks EHRA President www.escardio.org/EHRA

DOI: 10.15420/AER.2016.5.1.ED2

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Expert Opinion

Controversy Surrounding ROCKET-AF: A Call for Transparency, But Should We Be Changing Practice? Jason D Matos 1 and Peter J Zimetbaum 1,2 1. Cardiovascular Division, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, US; 2. Harvard-Thorndike Electrophysiology Institute and Arrhythmia Service, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, US

Disclosure: The authors have no conflicts of interest to declare. Received: 18 April 2016 Accepted: 4 May 2016 Citation: Arrhythmia & Electrophysiology Review 2016;5(1):12–3 Access at: www.AERjournal.com DOI: 10.15420/AER.2016.24.2 Correspondence: Dr Peter Zimetbaum, Harvard-Thorndike Electrophysiology Institute, Division of Cardiology, Beth Israel Deaconess Medical Center, Harvard Medical School, 185 Pilgrim Road, Baker 4, Boston, MA 02215, US. E: pzimetba@bidmc.harvard.edu

rior to the emergence of novel oral anticoagulants (NOACS), nearly all patients were prescribed vitamin K antagonists for thromboembolic prophylaxis in non-valvular atrial fibrillation (AF). Rivaroxaban (Xarelto, Bayer/Johnson & Johnson), an oral factor Xa inhibitor, is now one of the most frequently prescribed NOACs used for this indication.1,2

ROCKET-AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation), published in the New England Journal of Medicine in 2011, demonstrated the non-inferiority of rivaroxaban compared with warfarin for the primary prevention of stroke or systemic embolism in patients with AF. This double-blinded randomised trial, which included 14,264 patients across 45 countries, also showed no significant difference in the risk of major bleeding between these two groups.3 Rivaroxaban use in AF has become widespread since the publication of this trial and US Food and Drug Administration (FDA) approval. Two additional Factor Xa inhibitors, apixaban and edoxaban, have also been evaluated in similar randomised trials and have demonstrated non-inferiority to warfarin for stroke or systemic embolism prophylaxis in patients with non-valvular AF with no significant difference in major bleeding.4,5 In recent months, the results of ROCKET-AF have come into question after the FDA issued a recall notice for the device used to obtain International Normalised Ratio (INR) measurements in the warfarin control group. The FDA found that lower INR values were seen with the ‘point-of-care’ INRatio Monitor System (Alere) compared with a plasma-based laboratory in patients with certain medical conditions.2 These conditions included abnormal haemoglobin levels, abnormal bleeding and abnormal fibrinogen levels.6 Since the FDA recall of this device, there has been widespread concern that falsely low INR readings in ROCKET-AF may have led to warfarin overdosing. Inappropriately high warfarin dosing could have increased bleeding rates in the control group and therefore made the rivaroxaban arm appear falsely favourable.7 This point-of-care device recall also highlighted a lack of transparency of the specifics of devices used in large clinical trials. In response, the authors from ROCKET-AF released a correspondence in February 2016, citing the FDA recall. They also provided a post hoc analysis of patients who may have been affected by the recall. They found that major bleeding was greater in patients with conditions affected by the recall, but, reassuringly, the bleeding risk was greater in those who were on rivaroxaban and not warfarin.6 Despite this post hoc analysis, concern has arisen regarding the generalisability of ROCKET-AF given the faulty point-of-care INR readings. There has been a call for complete transparency of the data from this trial and a better explanation of the mechanism of the incorrect INR measurements.7 Once published, the data supporting an FDA-approved treatment should be available for independent analysis. One issue is that rivaroxaban was approved in the US prior to 1 January 2014, before a new transparency policy on clinical trial data sharing was approved by the European Federation of Pharmaceutical Industries and Associations (EFPIA) and the Pharmaceutical Research and Manufacturers of America (PhRMA).2 Drug companies are refusing to share any data on pharmaceuticals approved before 2014. A device malfunction in a large clinical trial also should raise concern, especially when that trial has altered clinical practice for millions of patients. On review of Patel et al’s correspondence regarding the point-of-care malfunction, there is inadequate explanation of the mechanism of these faulty readings. Why are they only seen only in patients with abnormal haemoglobin and fibrinogen levels? How

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Controversy Surrounding ROCKET-AF

inaccurate could the readings be – within 0.1 or 1.0 of a gold standard value? Most alarming is the revelation that the manufacturer had evidence of faulty readings in similar models dating back to 2002.2 Despite legitimate concerns regarding the absence of data transparency and the faulty point-of-care device, rivaroxaban need not be removed from clinical practice for AF patients. In ROCKET-AF, the drug demonstrated non-inferiority to warfarin in preventing thromboembolic events. In addition, data has shown that patients potentially affected by the faulty point-of-care device actually bled more on rivaroxaban than warfarin.6 Therefore, the original risk–benefit ratio presented in ROCKET-AF remains true. There are other, albeit smaller, randomised trials with shorter follow-up times that compare rivaroxaban and warfarin for thromboembolic prophylaxis.8,9 For example, Cappato et al in 2014, randomised 1,504 patients to show that oral rivaroxaban was non-inferior to warfarin in preventing a composite endpoint of stroke, transient ischaemic attack, peripheral embolism, myocardial infarction and cardiovascular death in patients with AF undergoing cardioversion. Major bleeding rates in the rivaroxaban and warfarin arms were similar (0.6 % versus 0.8 % respectively).8 The prospective observational trial XANTUS (Xarelto for Prevention of Stroke in Patients with Atrial Fibrillation) followed 6.784 patients on rivaroxaban for AF during a mean time of 329 days at 311 different hospitals. Major bleeding occurred in 128 patients (2.1 events/100 patient years) and 43 patients (0.7 events/100 patient years) suffered a stroke. These numbers are more reassuring than those seen in ROCKET-AF, though the patient population had a lower risk profile, with an average CHADS2 score of 2.0 compared with 3.5 in ROCKET-AF.10 To further mitigate concern regarding inaccuracies of bleeding rates in the ROCKET-AF control group, it is helpful to compare bleeding rates in the warfarin arms of the other major NOAC trials. The RE-LY (Randomised Evaluation of Long-Term Anticoagulation Therapy) trial, had a warfarin-arm major bleeding rate of 3.4%/year.11 The ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial, had a warfarin-arm major bleeding rate of 3.1%/year.4 The ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) trial, had a warfarin-arm major bleeding rate of 3.4 %/year.5 The warfarin arm of ROCKET-AF had a 3.4 %/year major bleeding rate, comparable to the other studies. Furthermore, the ROCKET-AF patients are known to be at higher risk for stroke and bleeding; their average CHADS2 score was highest among these studies (3.5 compared with 2.1–2.8).3 In addition, ROCKET-AF had a very high percentage of patients with a HAS-BLED score ≥3 (62 %) compared with the other studies (23 % in ARISTOTLE and 51 % in ENGAGE AF-TIMI 48).12–14 Several large randomised trials have compared the safety and efficacy of rivaroxaban versus warfarin for venous thromboembolic disease. The warfarin arm of the EINSTEIN-PE trial (Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients with Acute Symptomatic Pulmonary Embolism), which randomised patients with pulmonary embolism to warfarin or rivaroxaban, had a major bleeding rate of 2.2 %. The bleeding rate was lower in the rivaroxaban arm (1.1 %) and notably patients received a higher loading dose of rivaroxaban for the first 3 weeks (15 mg twice daily) compared with the daily 20 mg daily in ROCKET-AF.15 The recent uncertainties surrounding ROCKET-AF demonstrate the need for widespread data transparency for major trials with the capability of so greatly affecting patients’ lives. These are complicated issues both for the companies’ manufacturing products and the clinical trial organisations who carry out these studies and analyse the data. Ultimately the goal of full transparency to allow increased confidence in trial results should be sought. In this instance there is no compelling evidence of imminent danger of excessive bleeding with rivaroxaban. We should take notice of the recent findings, but there is no need to change practice. n

2. 3.

Kubitza D, Becka M, Wensing G, et al. Safety, pharmacodynamics, and pharmacokinetics of BAY 59-7939 – an oral, direct Factor Xa inhibitor – after multiple dosing in healthy male subjects. Eur J Clin Pharmacol 2005;61:873–80. PMID: 16328318 Cohen D. Rivaroxaban: can we trust the evidence? BMJ 2016;352:i575. DOI: 10.1136/bmj.i575; PMID: 26843102 Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883–91. DOI: 10.1056/NEJMoa1009638; PMID: 21830957 Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981–92. DOI: 10.1056/NEJMoa1107039; PMID: 21870978 Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013;369:2093–104. DOI: 10.1056/NEJMoa1310907; PMID: 24251359 Patel MR, Hellkamp AS, Fox KA, et al. Point-of-care warfarin monitoring in the ROCKET AF Trial. N Engl J Med 2016;374:785–8. DOI: 10.1056/NEJMc1515842;

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PMID: 26839968 Mandrola J. Rivaroxaban: It’s not time to cut the rope, yet. Medscape. 9 February 2016. Available at: www.medscape. com/viewarticle/858648 (accessed 6 May 2016). 8. Cappato R, Ezekowitz MD, Klein AL, et al. Rivaroxaban vs. vitamin K antagonists for cardioversion in atrial fibrillation. Eur Heart J 2014;35:3346–55. DOI: 10.1093/eurheartj/ehu367; PMID: 25182247 9. Cappato R, Marchlinski FE, Hohnloser SH, et al. Uninterrupted rivaroxaban vs. uninterrupted vitamin K antagonists for catheter ablation in non-valvular atrial fibrillation. Eur Heart J 2015;36:1805–11. DOI: 10.1093/eurheartj/ehv177; PMID: 25975659 10. Camm AJ, Amarenco P, Haas S, et al. XANTUS: a real-world, prospective, observational study of patients treated with rivaroxaban for stroke prevention in atrial fibrillation. Eur Heart J 2016;37:1145–53. DOI: 10.1093/eurheartj/ehv466; PMID: 26330425 11. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139–51. DOI: 10.1056/NEJMoa0905561; PMID: 19717844 7.

12. Sherwood MW, Nessel CC, Hellkamp AS, et al. Gastrointestinal bleeding in patients with atrial fibrillation treated With rivaroxaban or warfarin: ROCKET AF trial. J Am Coll Cardiol 2015;66:2271–81. DOI: 10.1016/j.jacc.2015.09.024; PMID: 26610874 13. Lopes RD, Al-Khatib SM, Wallentin L, et al. Efficacy and safety of apixaban compared with warfarin according to patient risk of stroke and of bleeding in atrial fibrillation: a secondary analysis of a randomised controlled trial. Lancet 2012;380:1749–58. DOI: 10.1016/S0140-6736(12)60986-6; PMID: 23036896 14. Eisen A, Giugliano RP, Ruff CT, et al. Edoxaban vs warfarin in patients with nonvalvular atrial fibrillation in the US Food and Drug Administration approval population: An analysis from the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) trial. Am Heart J 2016;172:144–51. DOI: 10.1016/j.ahj.2015.11.004; PMID: 26856226 15. EINSTEIN-PE Investigators, Buller HR, Prins MH, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;366:1287–97. DOI: 10.1056/ NEJMoa1113572. PMID: 22449293

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Arrhythmia Mechanisms

Differences in Left Versus Right Ventricular Electrophysiological Properties in Cardiac Dysfunction and Arrhythmogenesis Cristina E Molina, 1 Jordi Heijman 2 and Dobromir Dobrev 1 1. Institute of Pharmacology, West German Heart and Vascular Center, Faculty of Medicine, University Duisburg-Essen, Essen, Germany; 2. Cardiovascular Research Institute Maastricht, Faculty of Health, Medicine, and Life Sciences, Maastricht University, Maastricht, The Netherlands

Abstract A wide range of ion channels, transporters, signaling pathways and tissue structure at a microscopic and macroscopic scale regulate the electrophysiological activity of the heart. Each region of the heart has optimised these properties based on its specific role during the cardiac cycle, leading to well-established differences in electrophysiology, Ca2+ handling and tissue structure between atria and ventricles and between different layers of the ventricular wall. Similarly, the right ventricle (RV) and left ventricle (LV) have different embryological, structural, metabolic and electrophysiological features, but whether interventricular differences promote differential remodeling leading to arrhythmias is not well understood. In this article, we will summarise the available data on intrinsic differences between LV and RV electrophysiology and indicate how these differences affect cardiac function. Furthermore, we will discuss the differential remodeling of both chambers in pathological conditions and its potential impact on arrhythmogenesis.

Keywords Regional differences, ventricular function, right and left ventricle, cardiac remodeling, ventricular arrhythmias Disclosure: The authors have no conflicts of interest to declare. Acknowledgement: The authors’ current work is supported by the German Federal Ministry of Education and Research through DZHK (German Center for Cardiovascular Research, to DD). Received: 13 January 2016 Accepted: 24 March 2016 Citation: Arrhythmia & Electrophysiology Review 2016;5(1):14–9 Access at: www.AERjournal.com DOI: 10.15420/AER.2016.8.2 Correspondence: Prof Dr Dobromir Dobrev, Institute of Pharmacology, Hufelandstr 55, D-45122 Essen, Germany. E: dobromir.dobrev@uk-essen.de

Optimal cardiac function depends on appropriate rate and force of contraction, with specific cardiac regions having developed particular beat-to-beat properties depending on their individual functions. For example, isovolumetric contraction time is shorter in the right ventricle (RV) than in the left ventricle (LV). At the cellular level, cardiac function is regulated by regional cardiomyocyte electrophysiological and Ca2+handling properties (see Figure 1). Differences in these properties between nodal cells and working myocardium,1,2 atrial and ventricular cardiomyocytes1,3,4 and different layers of the LV wall (endo-, mid- and epicardium)5–7 have been well established. Although electrophysiological differences between left and right sides of the heart have been less extensively characterised there is evidence for clinically relevant left-toright differences in the atrium1,8–10 and the ventricle.1,5,11–14 Here, we review the known differences in LV and RV electrophysiology and Ca2+ handling at baseline and during pathophysiological conditions. Furthermore, we discuss the implications of these differences for arrhythmogenesis.

Basic Cardiac Electrophysiology and Arrhythmia Mechanisms Cardiac excitation–contraction (EC) coupling is a sequence of events occurring in cardiomyocytes upon electrical activation, resulting in the generation of an action potential (AP) and subsequent cardiomyocyte contraction (see Figure 2). This sequence shows many similarities between different cell types, notably between LV and RV cardiomyocytes. In this section we briefly summarise the common features.

AER 5.1_Dobrev_FINAL.indd 14

EC coupling involves an initial depolarisation of the membrane potential due to activation of Na+ channels and consequent opening of voltage-dependent K+ channels and L-type Ca2+ channels. The K+ channels consist of delayed-rectifier channels with distinct kinetics, underlying a transient-outward K+ current (Ito), as well as rapid and slow delayed-rectifier K+ currents (IKr and IKs, respectively). These currents play a major role in the AP repolarisation and critically determine AP duration (APD). The inward-rectifier K+ current (IK1) activates late during the AP and controls final repolarisation and resting membrane potential stability. L-type Ca2+ channels activate early during the AP and provide a depolarising current (ICa,L). Although the current subsequently declines due to voltage- and Ca2+-dependent inactivation, it supports the plateau phase of the ventricular AP (see Figure 2A). Moreover, the Ca2+ entering the cardiomyocyte through L-type Ca2+ channels plays a critical role initiating EC coupling by activating type-2 ryanodine receptor (RyR2) channels on the sarcoplasmic reticulum (SR) membrane, producing a much larger SR Ca2+ release. This process is termed Ca2+-induced Ca2+ release (CICR) and results in an increase in the cytoplasmic Ca2+ concentration sufficient to activate the contractile apparatus, initiating cardiomyocyte contraction.15 Subsequently, resequestration of Ca2+ in the SR by the SR Ca2+ ATPase type-2a (SERCA2a) and extrusion of Ca2+ to the extracellular space by the Na+-Ca2+ exchanger type-1 (NCX1) returns cytosolic Ca2+ to diastolic levels, promoting cellular relaxation. Finally, ionic homeostasis of intracellular Na+ and K+ is maintained by the Na+/

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Left Versus Right Ventricular Electrophysiological Differences

K+-ATPase and the resulting current (INaK) contributes to membrane repolarisation and stability of the resting membrane potential.

Figure 1: Schematic Representation of the Electrophysiological Properties of Different Regions in the Heart +20 0 mV

SA nodal

Cardiac arrhythmias can arise when normal impulse generation or impulse propagation is compromised.16 Abnormal impulse formation outside of the sinoatrial node (ectopic activity) generally results from instabilities of the membrane potential during or after the AP (termed early or delayed after depolarisations [EADs/DADs]). EADs are promoted by excessive APD prolongation (e.g., due to loss of repolarising K+ currents), resulting in ICa,L reactivation and secondary depolarisations.17 DADs, on the other hand, result from spontaneous SR Ca2+-release events that activate NCX1. Since NCX1 is electrogenic (exchanging one Ca2+ for three Na+), this produces a transient inward current and depolarisation of the membrane potential.18–20

Atrial

-100 +20 0 mV

-100

AV nodal

+20 0 mV

-100

When EADs or DADs of sufficient amplitude occur synchronised between a large enough number of cells, the electrical activity can propagate through the remainder of the myocardium as ectopic (triggered) activity. Impulse propagation is mainly determined by electrical cell-to-cell coupling through gap-junction channels, presence of non-conducting tissue (non-excitable cells, fibrosis), and the local source/sink balance (e.g., depending on INa availability). Slow, heterogeneous conduction and short effective refractory periods promote reentrant activity, the predominant arrhythmia maintaining mechanism.21,22 Both ectopic activity and reentry are promoted by electrical, structural and neurohumoral ventricular remodeling, occurring in both hereditary and acquired cardiovascular diseases.

+20 0 mV

LV Epi

M cells

Endo

Epi

M cells

Endo

-100 +20 0 mV

-100

Representative action potential waveforms from different regions of the heart are shown. AV = atrioventricular node; Endo = cardiomyocytes from endocardium; Epi = cardiomyocytes from epicardium; LV = left ventricle; M Cells = cardiomyocytes from midmyocardium; RV = right ventricle; SA = sinoatrial node. Adapted based on experimental traces from Diego et al.,27 Nerbonne et al.63 and Volders et al.64

Figure 2: Key Ion Currents Shaping the Cardiac Action Potential

Differences Between Left Ventricle and Right Ventricle Cellular Electrophysiology at Baseline and During Pathophysiological Remodeling

ICa,L / INCX / IKATP

0 mV

Differences in Ion Channel Properties The AP is generated by specific voltage-gated ion currents so it is logical that electrophysiological differences between heart chambers result in large part from differences in ion currents (see Figure 3).1 Indeed, electrophysiological specialisation of different regions of the heart has resulted in characteristic AP patterns for each region (see Figure 1).6

Ito

INa 3

IKr / IKs IK1

-80 mV

IK1 /INCX

INa

INaK

IKATP IK1

IKr

IKs

Ito Extracellular

PLM

Potential ionic differences between basal LV and RV cellular electrophysiology have been identified at the mRNA, protein and functional levels (see Table 1). In most species and experimental models, the RV myocardium shows a relative overexpression of Kv4.2, Kv4.3 and KChIP2,23,24 molecular components of Ito, as well as greater KCNQ1 expression,25,26 part of the IKs macromolecular complex. In agreement, a number of studies observed larger IKs and Ito in RV compared with LV.27–30 In addition, some studies have observed changes in the gene expression of Kir6.1/Kir6.2, underlying the ATP-sensitive K+ current (IKATP),31,32 NCX133 and Kir2.1/Kir2.3, molecular components of IK1.34,35 Consistent with these molecular data, IK1 density is larger in LV myocytes from guinea pigs, contributing to the stabilisation of the high-frequency rotors in LV.36,37 However, other studies in different animal models did not find a significant difference between LV and RV IK1.28,29 Finally, some studies have suggested that INa might be smaller in RV than LV.23,35

A: Schematic action potential, its phases and the ionic current contribution to the action potential. CSQ2 = calsequestrin 2; PLB = phospholamban; RyR2 = type-2 ryanodine receptor; SERCA2a = sarcoplasmic reticulum Ca2+ ATPase type-2a; INa = Na+ current; Ito = transient outward K+ current; ICa,L = L-type Ca2+ current; INCX = Na+-Ca2+ exchange current; IK,ATP = ATP-sensitive K+ current; IKr = rapid component of delayed-rectifier K+ current (IK); IKs = slow component of IK; IK1 = inward-rectifier K+ current. B: Representation of ion currents and Ca2+ handling proteins in ventricular cardiomyocytes.

At the cellular level, APs showed deeper notches, shorter APDs at 50 % and 95 % of repolarisation and less APD prolongation on slowing of the pacing rate in RV than LV,27,24,29 consistent with the larger Ito and IKs. Similarly, duration of monophasic APs in vivo was shorter in RV than in LV.25 Resting membrane potential and AP upstroke velocity did not differ between LV and RV in these studies.27,29

Although these results clearly suggest different electrophysiological phenotypes of the RV and LV, there is significant disagreement between the different species and experimental settings, as well as between expression data and functional studies. Ito is a notable exception being consistently larger in RV than LV (see Table 1). Furthermore, the role of individual electrophysiological differences in chamber-specific

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INCX

Intracellular Na+ RyR2

K+ CSQ2

Ca2+

ICa,L

Ca2+

PLB

SERCA2a

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Arrhythmia Mechanisms Figure 3: Representative Right and Left Ventricular Action Potential Waveforms, Chamber-specific Ion Channel Regulation and Statistically Significant Gene Expression Differences

RV versus LV current

RV versus LV expression

INa23

Nav1.523

Cav1.243

INCX

NCX-mRNA33

42–43 Ca,L

Ito,f 27,29,60

Kv4.2, Kv4.323

Ito,s

Kv1.4

IKs26,29,60

KvLQT1, KCNQ1, KCNE126

HERG62

IK129,36–37

Kir2.1–334–35

60 Kr

31 KATP/ K,ACh

Kir6.231

Ionic currents involved in the initiation and maintenance of an action potential (AP) and their chamber-specific differences. Green means up-regulation and red down-regulation in RV versus LV and black indicates no change between chambers. LV = left ventricle; RV = right ventricle. Underlying experimental data are summarised in Table 1.

proarrhythmia is largely unknown. Similarly, only a limited number of studies have investigated whether chamber-specific electrical and structural remodeling processes regulate these differences between both ventricles. Volders et al.30 reported an RV-specific downregulation of IKr and a disappearance of the LV/RV differences in IKs in a dog model with chronic complete atrioventricular block. These findings were confirmed at the transcriptional level by downregulation of KCNH2 and KCNQ1 expression (underlying IKr and IKs, respectively) in subsequent studies.24,25 Reduction of repolarisation reserve due to K+-channel downregulation is linked to an increased risk of ventricular arrhythmias and sudden cardiac death in this experimental model. Differences in Ito between LV and RV, on the other hand, remained intact in this model, highlighting the complexity of chamber-selective and channel-specific remodeling.

Differences in Ca 2+ Handling and Contractility Interventricular differences in Ca2+ handling and contractility have been predominantly investigated in rodents (see Table 1). No intrinsic RV/LV differences were found in gene expression of SERCA2a, its inhibitory regulator phospholamban (PLB), RyR2, NCX1 or the pore-forming α subunit of the L-type Ca2+ channel.28 Similarly, SR Ca2+ uptake was not different between both ventricles. Nonetheless, systolic [Ca2+] and cell shortening were larger in LV than RV. AP clamp experiments showed that the observed interventricular differences in Ca2+ handling were due to differences in AP morphology, with shorter APD in the RV compared with the LV, affecting ICa,L-mediated Ca2+ influx.28 SERCA2a and PLB mRNA levels were also similar in both ventricles in rats,33 whereas protein expression of both was lower in RV.26 In accordance, SR Ca2+ sequestration was slower in RV compared with LV in normal rat myocardium,38,26 and Ca2+-transient decay was slower in RV.26 There were no interventricular differences in diastolic or systolic [Ca2+] but cell shortening was smaller in rat RV cardiomyocytes. Furthermore, both ventricles showed opposite changes in SR Ca2+ sequestration upon induced myocardial infarction. While in the LV Ca2+ uptake decreased, it increased in RV, affecting the rate of relaxation and contraction. This suggests that failure of the LV promotes differential RV remodeling and potentially proarrhythmic chamber dyssynchrony.38 There are important differences in electrophysiology and Ca2+ handling between rodents and larger mammals (including humans). Rodents

AER 5.1_Dobrev_FINAL.indd 16

rely heavily on SR Ca2+ cycling, with >90 % of the total Ca2+ flux during a single beat resulting from SR Ca2+ release and subsequent SR Ca2+ reuptake. By contrast, in larger mammals there is a much larger role for Ca2+ entry via ICa,L and NCX1-mediated Ca2+ extrusion, which account for ~30 % of the total Ca2+ flux.39,40 Thus, extrapolation of the data on LV/RV differences in Ca2+ handling from rodents to humans is difficult. There are few data available about chamber-specific Ca2+-handling properties in large mammals. RyR2 mRNA and protein expression were lower in RV compared with LV in myocardium of control dogs.41 By contrast, RyR2 gene expression was larger in RV in ventricular samples from cardiomyopathy patients.34 At the functional level, no differences in basal Ca2+-transient amplitude or sarcomere shortening could be detected between RV and LV in canine cardiomyocytes.42 Cardiomyocyte shortening and relaxation rate in RV and LV were also similar in cats.43 Interestingly, interventricular differences in RyR2 expression were eliminated, and total RyR2 expression decreased in dogs with arrhythmogenic right ventricular cardiomyopathy. 41 Similarly, Gupta et al.44 found reduced SERCA2a activity and protein levels in LV, but not RV, in dogs with chronic heart failure, eliminating interventricular differences. These data suggest that interventricular differences in Ca2+ handling are species dependent and can be further regulated by chamber-specific disease-related remodeling.

Interventricular Differences in the Regulation of Cardiomyocyte Electrophysiology and Ca 2+ Handling Numerous studies have highlighted the importance of posttranslational regulation of ion channels and Ca2+-handling proteins to control cardiac electrophysiology and contractility in response to various neurohumoral conditions.15,45–47 Activation of β-adrenoceptors with isoprenaline similarly regulates ICa,L and IKs in canine LV and RV cardiomyocytes, whereas it increased sarcomere shortening 10-fold versus 25-fold and Ca2+-transient amplitude two-fold versus threefold in LV versus RV cardiomyocytes, respectively, highlighting clear interventricular differences in the regulation of cardiomyocyte Ca2+ handling.42 These differences were found to be due to a selective isoprenaline-induced increase in cytoplasmic cAMP in RV, resulting from distinct rates of cAMP degradation by type-3 and type-4 phosphodiesterases.42 By contrast, Ca2+/calmodulin-dependent kinase type-II (CaMKII)-dependent phosphorylation of RyR2, SERCA2a and PLB following application of exogeneous calmodulin/Ca2+ was reduced in RV versus LV myocardium of rats,26 thus suggesting potential interventricular differences in CaMKII signaling. The RV and LV also showed opposite inotropic responses to α1-adrenergic stimulation,48 which was at least in part due to heterogeneous effects on LV/RV intracellular Ca2+ handling.49 Finally, β2-adrenoceptors were found highly upregulated in LV, but not RV, in rats with chronic mild stress.50 Thus, although relatively little is known about interventricular differences in ion channel regulation, presently available data suggest a complex system with chamber-specific remodeling of pre-existing interventricular differences in regulatory signaling pathways, which act upon differences in basal LV versus RV electrophysiology and Ca2+ handling.

Mechanisms Underlying Left Ventricle versus Right Ventricle Differences The electrophysiological differences between the LV and RV can at least partially be attributed to the distinct embryological origin

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Left Versus Right Ventricular Electrophysiological Differences

Table 1: Differences in mRNA and Protein Expression and Channel Function Between Left and Right Ventricle for the Major Ion Currents and Ca 2+ Handling Proteins Reported in the Literature

Level

ICa,L

RV vs LV Species/Model

Reference

mRNA (CACNA1C) ↔

WT mouse

mRNA (CACNB2)

+66 %

Human myopathic hearts

Current

↔

Feline myocardium

↔

WT mouse

↔

Canine midmyocardium

-10 %

Guinea pig

Current

↔

Canine midmyocardium Midmyocard. CAVB dogs

↔

WT mouse

↔

IKATP IKr

mRNA (KCNJ8)

↔

SCN5A

mouse

mRNA (KCNA4)

↔

WT and SCN5A

+400 %

Canine septum

+175 %

Canine myocardium

29, 30

↔

WT mouse

+50 %

WT mouse

+/-

mouse

+10 %

SCN5A

mouse

+85 %

WT and SCN5A+/- mouse

23 23

+/-

Guinea pig

-30 %

Guinea pig

Protein (Kv4.3)

+50 %

WT and SCN5A+/- mouse

-33 %

Guinea pig

Protein (Kv1.4)

↔

WT mouse

↔

SCN5A+/- mouse

+25 %

WT mouse

+50 %

SCN5A

+25 %

Canine epicardium

Human samples

Midmyocard. CAVB dogs

Protein (KChIP2)

24 Current

+/-

mouse

↔

Canine midmyocardium

+50 %#

Canine midmyocardium

+70 %

Canine midmyocardium

↔

Midmyocard. CAVB dogs

+60 %

Canine midmyocardium

Midmyocard. CAVB dogs

+100 %

Human samples

+60 %

+250 %

Canine midmyocardium

+55 %

WT mouse

+40 %

WT and SCN5A+/- mouse

↔

Control rat myocardium

+80 %

Canine septum

+90 %

Canine myocardium

Midmyocard. CAVB dogs

24, 25

JSERCA

mRNA (SERCA2a)

mRNA (PLN)

↔

WT mouse

↔

Control rat myocardium

↔

WT mouse

28 26

Canine midmyocardium

↔

Midmyocard. CAVB dogs

24, 25

+20 %

Canine midmyocardium

Protein (SERCA2a)

-14 %

Control rat myocardium

Protein (PLB)

-17 %

Control rat myocardium

Activity

-80 %

Control rat myocardium

+20 %

↔

Midmyocard. CAVB dogs

+69 %

Canine midmyocardium

+50 %

Canine midmyocardium

-75 %

Control rat myocardium

-35 %

Rat 4/8w following MI

↔

INa

+/-

-40 %

↔

IKur

mRNA (KCND3)

mouse

mRNA (KChIP2)

Guinea pig

Current

mRNA (KCND2)

+150 %

Protein (KCNE1)

Ito

-33 %

mRNA (KCNE1)

SCN5A+/-

mRNA (KCNH2)

mRNA (KCNQ1)

WT mouse

Protein (Kv4.2)

+75 %

IKs

↔

WT mouse

mRNA (KCNJ11)

Current

Canine septum

WT mouse

WT and SCN5A+/- mouse

mouse

Control rat myocardium

+50 %

+20 %

↔

WT and SCN5A

-50 %

↔

mRNA (KCNJ2)

↔

mRNA (SLC8A1)

23, 65

IK1

Protein (Kir2.1)

INCX

+/-

Human myopathic hearts

Guinea pig

Human myopathic hearts

Canine septum

-68 %

-30 %

+15 %

↔

mRNA (HCN2)

Human myopathic hearts

mRNA (ATP1A3)

WT and

-33 %

INaK

WT mouse

Human myopathic hearts

mRNA (KCNJ4)

Reference

+50 %

mRNA (CACNA1G) +110 %

Guinea pig

RV vs LV Species/Model

+70 %

ICa,T

-50 %

Level

Midmyocard. CAVB dogs

+37 %

Canine midmyocardium

-27 %

Canine myocardium

↔

WT and SCN5A+/- mouse

↔

Canine HF model

Protein (Kv1.5)

↔

WT and

SCN5A+/-

+22 %

Human myopathic hearts

mRNA (SCN5A)

+50 %

WT mouse

-32 %

Canine myocardium

↔

SCN5A

↔

Canine ARVC model

↔

WT mouse

-55 %

Canine myocardium

↔

Canine ARVC model

mRNA (KCNA5)

Protein (Nav1.5)

Current

+/-

mouse

↔

Canine midmyocardium

↔

WT mouse

-25 %

SCN5A+/- mouse

-18 %

Guinea pig

↔

WT mouse

-35 %

SCN5A+/- mouse

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

AER 5.1_Dobrev_FINAL.indd 17

mouse

JRyR

mRNA (RyR2)

Protein (RyR2)

# = nonsignificant difference. CAVB = complete atrioventricular block; LV = left ventricle; RV = right ventricle; WT= wild-type. See text and Figure 2 for abbreviation of ion currents. Orange = genes (mRNA); Green = protein; Blue = function (current or activity).

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Arrhythmia Mechanisms of the LV, arising from the first heart field, and the RV, arising from the second heart field.5,51 Furthermore, within the RV there are embryological differences between the RV free wall and the outflow tract, with the latter forming at a later stage during development.52 Each developmental origin is associated with expression of different transcription factors.5 For example, Hand1 is predominantly found in the first heart field, and Hand2 in the second heart field. Similarly Tbx2 is specifically found in the outflow tract of the embryonic heart.52 Although the exact factors regulating mRNA expression of each ion channel remain largely unknown, the distinct expression profiles of ion channels and Ca2+ handling proteins in the LV and RV (see Table 1) strongly suggest a role for chamber-specific transcriptional regulation. Quantitative differences between mRNA, protein and current levels in LV versus RV suggest other potential forms of regulation, which may include transcriptional regulation of regulatory subunits or other components of the macromolecular ion-channel complex; microRNAdependent regulation of protein levels; differences in trafficking, membrane insertion or degradation; distinct subcellular localisation or post-translational modification.53,1,45,54

Recent work in post-mortem hearts with familial BrS indeed found evidence for increased local levels of fibrosis and reduced levels of gap-junction proteins (notably connexin-43) in the RV outflow tract,61 supporting a role for region-specific structural abnormalities and conduction disturbances in BrS. A mouse model with heterozygous knock-out of SCN5A has also suggested that the RV might be particularly sensitive to loss of functional Na+ channels, with a larger reduction in INa in RV compared with LV.23 Similarly, Veeraraghavan and Poelzing35 showed that heterogeneity in Nav1.5 expression in guinea pig may become a significant determinant of conduction heterogeneities under conditions where INa is functionally reduced. However, this study also highlights that conduction heterogeneities can be further modulated by interventricular differences in other ion channels, including IK1.35 Indeed, recent non-invasive eletrocardiographic imaging of BrS patients revealed both slow, discontinuous conduction and steep repolarisation gradients in the RV outflow tract, suggesting interactions between both mechanisms.14 Thus, regardless of the exact mechanism (depolarisation versus repolarisation), RV-specific electrophysiological and structural properties play a critical role in the phenotypic presentation of BrS patients.

Clinical implications Due to its unique geometry and cell biology the RV behaves differently from the LV in a variety of pathophysiological conditions and deterioration of right ventricular function strongly predicts clinical outcomes in a variety of circumstances.13,55 In addition to these structural aspects, Brugada syndrome (BrS) provides an example of the relevance of interventricular electrophysiological differences for arrhythmogenesis. BrS is characterised by right-precordial ST-segment elevation on the body-surface electrocardiogram (ECG) and is associated with an increased risk for sudden cardiac death due to malignant ventricular tachyarrhythmias.56,57 It was traditionally considered a congenital channelopathy in the absence of overt structural heart disease, linked predominantly to loss-of-function mutations in the SCN5A gene (locus 3p21) encoding the pore-forming α subunit of the Na+ channel. However, recent work has demonstrated the greater complexity of the disease, with at least 18 other genes as well as acquired functional and structural abnormalities also implicated.58,57 Two arrhythmogenic mechanisms have generally been proposed for BrS.57,59 In the repolarisation disorder hypothesis, the loss of INa in combination with a large Ito in the RV epicardium, particularly near the RV outflow tract, results in a local loss of AP spike-and-dome morphology and pronounced regional APD shortening, producing ST-segment elevation in the right-precordial leads. The resulting repolarisation gradient could predispose to ventricular arrhythmogenesis via phase-2 reentry.60 The depolarisation hypothesis, on the other hand, is based on delayed activation of the RV outflow tract, resulting in large potential gradients that produce the ST-segment elevation.

Bartos DC, Grandi E, Ripplinger CM. Ion channels in the heart. Compr Physiol 2015;5:1423–64. DOI: 10.1002/cphy.c140069; PMID: 26140724; PMCID: PMC4516287 Schram G, Pourrier M, Melnyk P, et al. Differential distribution of cardiac ion channel expression as a basis for regional specialization in electrical function. Circ Res 2002;90:939–50. PMID: 12016259 Bootman MD, Higazi DR, Coombes S, et al. Calcium signalling during excitation-contraction coupling in mammalian atrial myocytes. J Cell Sci 2006;119:3915–25. PMID: 16988026 Dobrev D, Teos LY, Lederer WJ. Unique atrial myocyte Ca2+ signaling. J Mol Cell Cardiol 2009;46:448–51. DOI: 10.1016/j. yjmcc.2008.12.004; PMID: 19150353; PMCID: PMC2836229 Boukens BJ, Christoffels VM, Coronel R, et al. Developmental basis for electrophysiological heterogeneity in the ventricular and outflow tract myocardium as a substrate for life-

AER 5.1_Dobrev_FINAL.indd 18

Besides BrS, interventricular electrophysiological differences may play a role in ventricular arrhythmogenesis in a variety of conditions. In general, steep repolarisation gradients have been considered proarrhythmic, and interventricular differences in ion-channel expression, regulation or disease-related remodeling may contribute to such gradients.5 For example, interventricular differences in IKATP could be an important determinant of LV/RV APD gradients during global ischaemia,32 and heterogeneous ventricular chamber responses to hypokalaemia and IK1 blockade contributed to bifurcated T-wave patterns in guinea pig.62 Similarly, differential downregulation of RV and LV delayed rectifier K+ currents could contribute to repolarisation abnormalities and arrhythmogenesis in patients with cardiac hypertrophy or failure.30

Conclusion Chamber-specific heterogeneity in cardiac electrophysiology is a physiological phenomenon, which contributes to fine-tuning of cardiac function. During the last two decades some studies have started to identify differences in ion channel expression and function between RV and LV. However, only limited information is available about the distinct remodeling of each ventricle and the subsequent impact on cardiac arrhythmogenesis. This holds particularly true for post-translational modifications affecting channel function and cardiomyocyte Ca2+ handling. Further extensive work, ideally in human samples or large animal models, is needed to define the precise role of interventricular electrophysiological differences in ventricular remodeling, cardiac dysfunction and arrhythmogenesis. n

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10. Voigt N, Trausch A, Knaut M, et al. Left-to-right atrial inward rectifier potassium current gradients in patients with paroxysmal versus chronic atrial fibrillation. Circ Arrhythm Electrophysiol 2010;3:472–80. DOI: 10.1161/CIRCEP.110.954636; PMID: 20657029 11. Ellinghaus P, Scheubel RJ, Dobrev D, et al. Comparing the global MRNA expression profile of human atrial and ventricular myocardium with high-density oligonucleotide arrays. J Thorac Cardiovasc Surg 2005;129:1383–90. PMID: 15942582 12. Rodriguez B, Li L, Eason JC, et al. Differences between left and right ventricular chamber geometry affect cardiac vulnerability to electric shocks. Circ Res 2005;97:168–75. PMID: 15976315; PMCID: PMC2925187 13. Walker LA, Buttrick PM. The right ventricle: Biologic insights and response to disease: Updated. Curr Cardiol Rev 2013;9:73– 81. PMID: 23092273; PMCID: PMC3584309

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Left Versus Right Ventricular Electrophysiological Differences

14. Zhang J, Sacher F, Hoffmayer K, et al. Cardiac electrophysiological substrate underlying the ECG phenotype and electrogram abnormalities in Brugada syndrome patients. Circulation 2015;131:1950–9. DOI: 10.1161/ CIRCULATIONAHA.114.013698; PMID: 25810336; PMCID: PMC4452400 15. Bers DM. Calcium cycling and signaling in cardiac myocytes. Annu Rev Physiol 2008;70:23–49. PMID: 17988210 16. Qu Z, Weiss JN. Mechanisms of ventricular arrhythmias: From molecular fluctuations to electrical turbulence. Annu Rev Physiol 2015;77:29–55. DOI: 10.1146/annurevphysiol-021014-071622; PMID: 25340965; PMCID: PMC4342983 17. Michael G, Xiao L, Qi XY, et al. Remodelling of cardiac repolarization: How homeostatic responses can lead to arrhythmogenesis. Cardiovasc Res 2009;81:491–9. DOI: 10.1093/cvr/cvn266; PMID: 18826964 18. Heijman J, Voigt N, Nattel S, et al. Cellular and molecular electrophysiology of atrial fibrillation initiation, maintenance, and progression. Circ Res 2014;114:1483–99. DOI: 10.1161/ CIRCRESAHA.114.302226; PMID: 24763466 19. Llach A, Molina CE, Fernandes J, et al. Sarcoplasmic reticulum and l-type Ca2+ channel activity regulate the beat-to-beat stability of calcium handling in human atrial myocytes. J Physiol 2011;589:3247–62. DOI: 10.1113/ jphysiol.2010.197715; PMID: 21521767; PMCID: PMC3145937 20. Molina CE, Llach A, Herraiz-Martinez A, et al. Prevention of adenosine A2A receptor activation diminishes beat-tobeat alternation in human atrial myocytes. Basic Res Cardiol 2016;111:5. DOI: 10.1007/s00395-015-0525-2; PMID: 26611209 21. Comtois P, Kneller J, Nattel S. Of circles and spirals: Bridging the gap between the leading circle and spiral wave concepts of cardiac reentry. Europace 2005;7 Suppl 2:10–20. PMID: 16102499 22. Pandit SV, Jalife J. Rotors and the dynamics of cardiac fibrillation. Circ Res 2013;112:849–62. DOI: 10.1161/ CIRCRESAHA.111.300158; PMID: 23449547; PMCID: PMC3650644 23. Martin CA, Siedlecka U, Kemmerich K, et al. Reduced Na+ and higher K+ channel expression and function contribute to right ventricular origin of arrhythmias in SCN5A +/- mice. Open Biol 2012;2:120072. DOI: 10.1098/rsob.120072; PMID: 22773948; PMCID: PMC3390792 24. Ramakers C, Stengl M, Spatjens RL, et al. Molecular and electrical characterization of the canine cardiac ventricular septum. J Mol Cell Cardiol 2005;38:153–61. PMID: 15623432 25. Ramakers C, Vos MA, Doevendans PA, et al. Coordinated down-regulation of KCNQ1 and KCNE1 expression contributes to reduction of IKs in canine hypertrophied hearts. Cardiovasc Res 2003;57:486–96. PMID: 12566121 26. Sathish V, Xu A, Karmazyn M, et al. Mechanistic basis of differences in Ca2+-handling properties of sarcoplasmic reticulum in right and left ventricles of normal rat myocardium. Am J Physiol Heart Circ Physiol 2006;291:H88–96. PMID: 16461368 27. Di Diego JM, Sun ZQ, Antzelevitch C. Ito and action potential notch are smaller in left vs. right canine ventricular epicardium. Am J Physiol 1996;271:H548–61. PMID: 8770096 28. Kondo RP, Dederko DA, Teutsch C, et al. Comparison of contraction and calcium handling between right and left ventricular myocytes from adult mouse heart: A role for repolarization waveform. J Physiol 2006;571:131–46. PMID: 16357014; PMCID: PMC1805641 29. 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. PMID: 9892584 30. Volders PG, Sipido KR, Vos MA, et al. Downregulation of delayed rectifier K+ currents in dogs with chronic complete atrioventricular block and acquired torsades de pointes.

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Circulation 1999;100:2455–61. PMID: 10595960 31. Choi SW, Ahn JS, Kim HK, et al. Increased expression of atp-sensitive k channels improves the right ventricular tolerance to hypoxia in rabbit hearts. Korean J Physiol Pharmacol 2011;15:189–94. DOi: 10.4196/kjpp.2011.15.4.189; PMID: 21994476; PMCID: PMC3186919 32. Pandit SV, Kaur K, Zlochiver S, et al. Left-to-right ventricular differences in IKATP underlie epicardial repolarization gradient during global ischemia. Heart Rhythm 2011;8:1732–9. DOI: 10.1016/j.hrthm.2011.06.028; PMID: 21723845; PMCID: PMC3244837 33. Correia Pinto J, Henriques-Coelho T, Roncon-Albuquerque R, Jr., et al. Differential right and left ventricular diastolic tolerance to acute afterload and NCX gene expression in Wistar rats. Physiol Res 2006;55:513–26. PMID: 16343035 34. Sivagangabalan G, Nazzari H, Bignolais O, et al. Regional ion channel gene expression heterogeneity and ventricular fibrillation dynamics in human hearts. PLoS One 2014;9:e82179. DOI: 10.1371/journal.pone.0082179; PMID: 24427266; PMCID: PMC3888386 35. Veeraraghavan R, Poelzing S. Mechanisms underlying increased right ventricular conduction sensitivity to flecainide challenge. Cardiovasc Res 2008;77:749–56. PMID: 18056761 36. Samie FH, Berenfeld O, Anumonwo J, et al. Rectification of the background potassium current: A determinant of rotor dynamics in ventricular fibrillation. Circ Res 2001;89:1216–23. PMID: 11739288 37. Warren M, Guha PK, Berenfeld O, et al. Blockade of the inward rectifying potassium current terminates ventricular fibrillation in the guinea pig heart. J Cardiovasc Electrophysiol 2003;14:621–31. PMID: 12875424 38. Afzal N, Dhalla NS. Differential changes in left and right ventricular sr calcium transport in congestive heart failure. Am J Physiol 1992;262:H868–74. PMID: 1313649 39. Luss I, Boknik P, Jones LR, et al. Expression of cardiac calcium regulatory proteins in atrium v ventricle in different species. J Mol Cell Cardiol 1999;31:1299–314. PMID: 10371704 40. O'Rourke B. The ins and outs of calcium in heart failure. Circ Res 2008;102:1301–3. DOI: 10.1161/CIRCRESAHA.108.178095; PMID: 18535266; PMCID: PMC2713010 41. Meurs KM, Lacombe VA, Dryburgh K, et al. Differential expression of the cardiac ryanodine receptor in normal and arrhythmogenic right ventricular cardiomyopathy canine hearts. Hum Genet 2006;120:111–8. PMID: 16733711 42. Molina CE, Johnson DM, Mehel H, et al. Interventricular differences in beta-adrenergic responses in the canine heart: Role of phosphodiesterases. J Am Heart Assoc 2014;3:e000858. DOI: 10.1161/JAHA.114.000858; PMID: 24904016; PMCID: PMC4309082 43. Kleiman RB, Houser SR. Electrophysiologic and mechanical properties of single feline RV and LV myocytes. J Mol Cell Cardiol 1988;20:973–82. PMID: 3236385 44. Gupta RC, Shimoyama H, Tanimura M, et al. Sr Ca2+-ATPase activity and expression in ventricular myocardium of dogs with heart failure. Am J Physiol 1997;273:H12–8. PMID: 9249469 45. Heijman J, Dewenter M, El-Armouche A, et al. Function and regulation of serine/threonine phosphatases in the healthy and diseased heart. J Mol Cell Cardiol 2013;64:90–8. DOI: 10.1016/j.yjmcc.2013.09.006; PMID: 24051368 46. Lymperopoulos A, Rengo G, Koch WJ. Adrenergic nervous system in heart failure: Pathophysiology and therapy. Circ Res 2013;113:739–53. DOI: 10.1161/CIRCRESAHA.113.300308; PMID: 23989716; PMCID: PMC3843360 47. Rapundalo ST. Cardiac protein phosphorylation: functional and pathophysiological correlates. Cardiovasc Res 1998;38:559–88. PMID: 9747427 48. Wang GY, McCloskey DT, Turcato S, et al. Contrasting inotropic responses to a1-adrenergic receptor stimulation in left versus right ventricular myocardium. Am J Physiol Heart Circ Physiol 2006;291:H2013–7. PMID: 16731650

49. Chu C, Thai K, Park KW, et al. Intraventricular and interventricular cellular heterogeneity of inotropic responses to a1-adrenergic stimulation. Am J Physiol Heart Circ Physiol 2013;304:H946–53. DOI: 10.1152/ajpheart.00822.2012; PMID: 23355341; PMCID: PMC3625891 50. Spasojevic N, Gavrilovic L, Dronjak S. Regulation of catecholamine-synthesising enzymes and betaadrenoceptors gene expression in ventricles of stressed rats. Physiol Res 2011;60 Suppl 1:S171–6. PMID: 21777029 51. Buckingham M, Meilhac S, Zaffran S. Building the mammalian heart from two sources of myocardial cells. Nat Rev Genet 2005;6:826–35. PMID: 16304598 52. Boukens BJ, Coronel R, Christoffels VM. Embryonic development of the right ventricular outflow tract and arrhythmias. Heart Rhythm 2016;13:616–22. DOI: 10.1016/j. hrthm.2015.11.014; PMID: 26586454 53. Balijepalli RC, Kamp TJ. Caveolae, ion channels and cardiac arrhythmias. Prog Biophys Mol Biol 2008;98:149–60. DOI: 10.1016/j.pbiomolbio.2009.01.012; PMID: 19351512; PMCID: PMC2836876 54. Meadows LS, Isom LL. Sodium channels as macromolecular complexes: Implications for inherited arrhythmia syndromes. Cardiovasc Res 2005;67:448–58. PMID: 15919069 55. Leite-Moreira AF, Lourenco AP, Balligand JL, et al. ESC working group on myocardial function position paper: How to study the right ventricle in experimental models. Eur J Heart Fail 2014;16:509–18. DOI: 10.1002/ejhf.66; PMID: 24574252 56. Brugada P, Brugada J. Right bundle branch block, persistent ST segment elevation and sudden cardiac death: A distinct clinical and electrocardiographic syndrome. A multicenter report. J Am Coll Cardiol 1992;20:1391–6. PMID: 1309182 57. Hoogendijk MG, Opthof T, Postema PG, et al. The Brugada ECG pattern: A marker of channelopathy, structural heart disease, or neither? Toward a unifying mechanism of the brugada syndrome. Circ Arrhythm Electrophysiol 2010;3:283–90. DOI: 10.1161/CIRCEP.110.937029; PMID: 20551422 58. Antzelevitch C, Patocskai B. Brugada syndrome: Clinical, genetic, molecular, cellular, and ionic aspects. Curr Probl Cardiol 2016;41:7–57. DOI: 10.1016/j.cpcardiol.2015.06.002; PMID: 26671757; PMCID: PMC4737702 59. Meregalli PG, Wilde AA, Tan HL. Pathophysiological mechanisms of Brugada syndrome: Depolarization disorder, repolarization disorder, or more? Cardiovasc Res 2005;67:367–78. PMID: 15913579 60. Antzelevitch C. The Brugada syndrome: Ionic basis and arrhythmia mechanisms. J Cardiovasc Electrophysiol 2001;12:268–72. PMID: 11232628 61. Nademanee K, Raju H, de Noronha SV, et al. Fibrosis, connexin-43, and conduction abnormalities in the Brugada syndrome. J Am Coll Cardiol 2015;66:1976–86. DOI: 10.1016/j. jacc.2015.08.862; PMID: 26516000; PMCID: PMC4631798 62. Poelzing S, Veeraraghavan R. Heterogeneous ventricular chamber response to hypokalemia and inward rectifier potassium channel blockade underlies bifurcated t wave in guinea pig. Am J Physiol Heart Circ Physiol 2007;292:H3043–51. PMID: 17307991 63. Nerbonne JM, Kass RS. Molecular physiology of cardiac repolarization. Physiol Rev 2005;85:1205–53. PMID: 16183911 64. Volders PG, Sipido KR, Vos MA, et al. Cellular basis of biventricular hypertrophy and arrhythmogenesis in dogs with chronic complete atrioventricular block and acquired torsade de pointes. Circulation 1998;98:1136–47. PMID: 9736601 65. Teutsch C, Kondo RP, Dederko DA, et al. Spatial distributions of Kv4 channels and KChip2 isoforms in the murine heart based on laser capture microdissection. Cardiovasc Res 2007;73:739–49. PMID: 17289005 66. Luo X, Xiao J, Lin H, et al. Genomic structure, transcriptional control, and tissue distribution of HERG1 and KCNQ1 genes. Am J Physiol Heart Circ Physiol 2008;294:H1371–80. DOI: 10.1152/ ajpheart.01026.2007; PMID: 18192214

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Arrhythmia Mechanisms

LE ATION.

e. lare.

Post-extrasystolic Potentiation: Link between Ca 2+ Homeostasis and Heart Failure? David J Sprenkeler and Marc A Vos University Medical Center Utrecht, Utrecht, The Netherlands

Abstract Post-extrasystolic potentiation (PESP) describes the phenomenon of increased contractility of the beat following an extrasystole and has been attributed to changes in Ca2+ homeostasis. While this effect has long been regarded to be a normal physiological phenomenon, a number of reports describe an enhanced potentiation of the post-extrasystolic beat in heart failure patients. The exact mechanism of this increased PESP is unknown, but disruption of normal Ca2+ handling in heart failure may be the underlying cause. The use of PESP as a prognostic marker or therapeutic intervention have recently regained new attention, however, the value of the application of PESP in the clinic is still under debate. In this review, the mechanism of PESP with regard to Ca2+ in the normal and failing heart will be discussed and the possible diagnostic and therapeutic role of this phenomenon will be explored.

Keywords Post-extrasystolic potentiation, Ca2+ handling, force-frequency, heart failure, coupled-pacing Disclosure: The authors have no conflicts of interest to declare. Acknowledgement: Comparative Effectiveness Research to Assess the Use of Primary ProphylacTic Implantable Cardioverter Defibrillators in Europe (EU-CERT-ICD) is a collaboration project funded by the European Union under the 7th Framework Programme under grant agreement number 602299. Received: 15 December 2015 Accepted: 23 February 2016 Citation: Arrhythmia & Electrophysiology Review, 2016;5(1):20–6 Access at: www.AERjournal.com DOI: 10.15420/AER.2015.29.2 Correspondence: Marc A Vos, Department of Medical Physiology, University Medical Center Utrecht, Yalelaan 50, 3584 CM Utrecht, The Netherlands. E: m.a.vos@umcutrecht.nl

The concept of post-extrasystolic potentiation (PESP), which describes the phenomenon of increased contractility of the beat following an extrasystole, has intrigued physiologists and clinicians for more than 120 years. Since its first description in 1885 by Oskar Langendorff,1 PESP has become a widely debated concept, not only for its fundamental basis but also because of the potential diagnostic and therapeutic properties. Existence of PESP has been demonstrated in isolated papillary muscles,2 perfused isolated hearts3,4 and in vivo models, including humans.5 PESP has formerly been attributed to alterations in preload and/or afterload during the compensatory pause following an extrasystolic beat. However, numerous studies in which preload and/or afterload were controlled,6–9 have demonstrated that PESP is independent of these loading conditions and that its mechanism is the consequence of changes in intracellular calcium handling. A number of reports describe differences of PESP magnitude in patients with heart failure and state that PESP could be used as a marker of myocardial dysfunction.10–13 In addition, recent studies by Sinnecker et al. have shown that the presence of PESP of blood pressure could predict mortality in post-MI patients with sinus rhythm or atrial fibrillation.14,15 These results have revived the possible diagnostic or prognostic role of PESP. In this review, the mechanism of PESP with regard to Ca2+ homeostasis will be discussed in normal and in heart failure individuals and the diagnostic and therapeutic consequences will be explored.

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Normal Ca 2+ Homeostasis Excitation–contraction coupling (ECC) is the process by which electrical stimulation results in contraction of cardiac myofilaments, which involves sarcolemmal ion currents and various intracellular pathways.16 Ca2+ has been known to be a major element in both electrical and contractile function of cardiomyocytes. In their resting state, cardiomyocytes have a low cytosolic concentration of Ca2+ ([Ca2+]i) of less than 200 nmol/l.17 When a cardiac cell is depolarised, voltagedependent L-type Ca2+ channels (LTCC) at the sarcolemma open, causing an influx of Ca2+ along its electrochemical gradient into the dyadic cleft. This small inflow of Ca2+ results in release of Ca2+ from the adjacent sarcoplasmic reticulum (SR) through the SR Ca2+ release channels, also known as type 2 ryanodine receptors (RyR2), a process called Ca2+-induced Ca2+-release (CICR). Synchronised opening of RyR2 will generate a global Ca2+ transient,18,19 which increases [Ca2+]i tenfold. Free Ca2+ binds to troponin C, causing a conformational change, which allows the myosin head to bind to actin and move along the actin filament, shortening the cardiomyocyte. For relaxation to occur, Ca2+ needs to be dissociated from troponin C and be removed from the cytosol. In human cardiac cells, approximately 70 % of cytosolic Ca2+ is sequestered back into the SR by SR-Ca2+ ATPase 2a (SERCA2a) and 30 % is extruded out of the cell by the sarcolemmal Na+-Ca2+ exchanger (NCX), which expels one Ca2+ in exchange for three Na+ ions, creating an inward current.20

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Figure 1: Mechanical Restitution and Post-extrasystolic Potentiation

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A. Contractile force normalised to the last steady state (SS) beat. When the extrasystolic interval (ESI) is shortened, the contractile force of the extrasystolic beat decreases but the contractility of the post-extrasystolic beat increases. B. Mechanical restitution (left) and post-extrasystolic potentiation (PESP) (right) curves are mono-exponential curves with similar time constants. When the ESI is sufficiently lengthened, the contractile force of both the extrasystolic and post-extrasystolic beats approaches the contractile force of the SS beat. PESI = postextrasystolic interval.

Calcium Handling in Heart Failure Disruption of Ca 2+ homeostasis is an important contributor to depressed ventricular function in heart failure. Alterations of Ca2+ uptake, storage and release will result in a reduced Ca2+ transient and consequently a diminished contraction. 21–23 Multiple studies suggest that Ca2+ uptake in the SR is diminished due to downregulation or decreased activity of SERCA2a. 24–27 A reduced reuptake results not only in decreased SR Ca2+ content but also in higher cytosolic Ca2+ concentration, which inhibits normal relaxation. Therefore, decreased SERCA2a expression contributes to both systolic and diastolic ventricular dysfunction. On the other hand, expression of NCX appears to be increased in patients with heart failure.28 When functioning in forward mode (Ca2+ efflux and Na+ influx), upregulation of NCX results in increased extrusion of Ca2+ and a decrease of [Ca2+]i. While this may counter the diastolic dysfunction caused by decreased Ca2+ reuptake, there is further reduction in systolic function, due to a decrease in intracellular Ca2+ available for ECC.29

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Next, hyperphosphorylation of RyR2 by proteinkinases, such as CaMKII or PKA, is suggested to cause diastolic Ca2+ leakage from the SR.30,31 This Ca2+ leak results in partial depletion of SR Ca2+ stores and contributes further to high diastolic [Ca2+]i. In addition, a diastolic Ca2+ leak may induce Ca2+ release by activating other RyR2, resulting in Ca2+ waves. When Ca2+ is exchanged for three Na+ by the upregulated NCX, a transient inward current (Iti) is generated. This may result in delayed afterdepolarisations (DAD), which could trigger lethal ventricular arrhythmias. Sensitivity of RyR2 for luminal Ca2+ appears to be enhanced; the set point for Ca2+ release is decreased; therefore, RyR2 are activated at lower SR Ca2+ levels in heart failure compared with normal hearts.32 This sensitisation of RyR2 might be an adaption to the decreased Ca2+ concentration in order to maintain normal Ca2+ transients.33 All of these alterations of Ca2+ homeostasis influence both long-term force–frequency relationship (FFR) and short-term force–interval relationship (FIR).

Force–Frequency and Force–Interval Relationship FFR and FIR describe contractility changes when the stimulation rate is varied. While the FFR describes an altered force of contraction,

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Arrhythmia Mechanisms Figure 2: Mechanism of Post-extrasystolic Potentiation A. Normal beat

3 Na+ = Ca2+

Sarcolemma

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LTCC SERCA2a

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B. Extrasystolic beat

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In most mammalian species, including humans, a positive FFR exists in which contractility is enhanced when stimulation frequency is increased.34 This positive staircase phenomenon or ‘treppe’ was first described by Bowditch in 187135 and is an important mechanism for increased inotropy during exercise.36,37 The rise of contractile force appears to be related to an increased amplitude of the Ca2+ transient at higher frequencies.38,39 This increase in Ca2+ transient is the product of different mechanisms. First, an increased number of depolarisations leads to more Ca2+ influx per unit of time, which results in increased calcium release and uptake in the SR. Next, when increasing the frequency of stimulation, the influx of Na+ during depolarisation is increased. To maintain a low cytosolic concentration of Na+, NCX will switch to its reverse mode to extrude Na+ in exchange for Ca2+.40 This influx of Ca2+ will further increase SR Ca2+ content. Finally, reuptake of Ca2+ by SERCA2a relative to extrusion of Ca2+ by NCX is increased.41 This increased SERCA2a activity might be caused by phosphorylation of phospholambam, the main regulatory protein of SERCA2a. In a dephosphorylated state, phospholambam decreases SERCA2a-affinity for Ca2+. When phospholambam is phosphorylated, this inhibitory effect is removed and reuptake of Ca2+ is enhanced. In failing myocardium, FFR is blunted or even inversed, resulting in a decrease of contractile force with increasing frequency of stimulation.34,42–44 This negative FFR is attributed to decreased Ca2+ reuptake due to downregulation of SERCA2a and upregulation of NCX in failing hearts.45,46 When the stimulation rate increases, time per cycle for Ca2+ reuptake is reduced, which, in the case of fewer Ca2+ pumps, results in insufficient Ca2+ reuptake.

LTCC

Force–Frequency Relationship

NCX

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Change in contractile force, when stimulation frequency is interrupted with a premature beat, is described in the short-term FIR. FIR is divided into two concepts: mechanical restitution (MR) and PESP.2 These phenomena are both related to the coupling interval between the regular beat and the premature beat, the extrasystolic interval (ESI), and the interval between the extrasystolic beat and the following postextrasystolic beat, the post-extrasystolic interval (PESI). MR accounts for recovery of contractile strength of the extrasystolic beat when ESI is lengthened. PESP displays the opposite behaviour: with decreasing ESI, there is an increase in contractility of the post-extrasystolic beat. In other words, the earlier the extrasystolic beat occurs, the weaker the extrasystolic beat and the stronger the post-extrasystolic beat (see Figure 1A).

LTCC SERCA2a

Contractile apparatus

A. Excitation-contraction coupling (ECC) during normal beat. Ca2+ influx through L-type Ca2+ channel (LTCC) activates RyR2 to release Ca2+ from sarcoplasmatic reticulum (SR), which inhibits further sarcolemmal Ca2+ influx. After contraction, Ca2+ is resequestered back in SR by SR-Ca2+-ATPase (SERCA2a) or is extruded out of the cell by Na+-Ca2+-exchanger (NCX) in exchange for three Na+. B. ECC during extrasystolic beat. Some ryanodine receptors (RyR2s) are refractory (dark green), thus less Ca2+ is released from SR. This smaller Ca2+ transient opposes less negative feedback to sarcolemmal Ca2+ influx. This increased cytosolic Ca2+ is taken up by SERCA2a, further loading the SR. C. ECC during post-extrasystolic beat. SR contains more Ca2+ because less Ca2+ was released during extraystole and uptake of Ca2+ was enhanced. After a compensatory pause all RyR2 are recovered from inactivation and Ca2+ sequestered during the two previous beats is released.

when heart rate increases or decreases, FIR accounts for change in contractile force by abrupt variations in stimulation pattern, i.e. by introducing extrasystolic beats.

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Wier and Yue performed pacing experiments with isolated papillary muscles from ferret hearts to demonstrate the concepts of MR and PESP and the relationship with the ESI.2 After a steady-state pacing series, an extrasystolic stimulus was introduced with varying ESI. The PESI was held constant. As expected, contractility of the extrasystolic beat increased and contractility of the post-extrasystolic beat decreased, when ESI was prolonged. When the contractile strength of the extrasystolic beat and the post-extrasystolic beat was plotted as a function of ESI, monoexponential functions were found with similar time constants (see Figure 1B), which indicates a common underlying mechanism for both phenomena. Nowadays the mechanism of these effects is attributed to changes in Ca2+ handling.

Mechanism of Mechanical Restitution and Post-extrasystolic Potentiation A fundamental concept for the mechanism of MR and PESP is a time-consuming recovery period of Ca2+ release. The mechanism was

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Post-extrasystolic Potentiation: Ca2+ Homeostasis and Heart Failure Mechanical restitution

Figure 3: Influence of Slower Mechanical Restitution on Post-extrasystolic Potentiation Normalised contractile force Normalised contractile force

100 % 80 %

Mechanical restitution Normal heart

100 % 80 %

Failing heart Normal heart

Failing heart 500 ms

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Failing heart 140 %

Normalised contractile force Normalised contractile force

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140 %

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500 ms

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A. Mechanical restitution (MR) is slowed in failing hearts. At a certain cycle length (i.e. 500 ms) the failing heart operates at a lower level of contractile performance due to incomplete MR. B. Pacing at a steady state cycle length of 500 ms with an extrasystolic interval (ESI) of 200 ms and a post-extrasystolic interval of 800 ms. When post-extrasystolic potentiation (PESP) is normalised to the incomplete restituted steady state beats, an increased relative PESP is seen.

formerly explained by a model of different Ca2+ compartments within 500 ms 500 ms 200 ms 800 ms the SR, in which diffusion of Ca2+ from uptake compartment to release compartment was time dependent.2,3 However, this model lacks experimental evidence, since no anatomical compartment structures have been found in the SR, and transfer by diffusion of Ca2+ within the SR would occur rapidly.47,48 Refractoriness of Ca2+-release channels has been postulated as an alternative explanation for the process of MR and PESP (see Figure 2). In a study by Fabiato,49 recovery from inactivation of ryanodine receptors had a time constant, which was similar to the kinetics of MR and PESP curves by Wier and Yue. According to this model, when a premature beat occurs, most of the ryanodine receptors are refractory to activation, causing a diminished Ca2+ transient and thus a less forceful contraction. After the premature beat, SR Ca2+ load is increased in a number of ways. First, while less Ca2+ is released, Ca2+ loading of the SR continues. Next, low Ca2+ transient during the premature beat opposes less negative feedback to sarcolemmal Ca2+ influx and this extra Ca2+ further increases SR Ca2+ content. During the compensatory pause there is full MR, thus all release channels have recovered from inactivation. At the post-extrasystolic

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beat, all the Ca2+ sequestered during the previous two beats will be 500 ms 500 ms 200 ms 800 ms released, resulting in increased force of the post-extrasystolic beat.

Post-extrasystolic Potentiation in Heart Failure A number of studies have found differences in PESP of the first derivative of left ventricular pressure (LV dP/dtmax) between heart failure patients and controls. In 1971, Beck et al. observed that patients with obstructed or failing ventricles had an increased potentiation of the post-extrasystolic contraction compared with controls.10 This paradoxical observation was confirmed in other studies.11–13 However, only the study by Seed et al. controlled all coupling intervals (ESI, PESI), which, as we have seen, influence the extent of potentiation.13 Despite the methodological flaws of these clinical studies, a small number of experimental and modelling studies are supportive of this observation. The increase in PESP is attributed to abnormal Ca2+ homeostasis in heart failure. First, abnormal Ca2+ sequestration could result in a higher PESP. In the study of Seed et al. an inverse linear relationship was seen between PESP and the so-called ‘recirculation fraction’, the ratio of contractility of the second post-extrasystolic beat compared with the first post-extrasystolic beat. The recirculation fraction has been suggested to account for the fraction of released Ca2+

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Arrhythmia Mechanisms sequestered back into the SR. Patients with heart failure appeared to have a lower recirculation fraction, which might be related to decreased Ca2+ reuptake seen in these patients.

procedures.54–56 However, this diagnostic approach has not demonstrated consistent results and has largely been replaced by more accurate techniques, such as nuclear imaging or MRI.

Studies by Hoit et al.50,51 confirmed these results. They evaluated MR and PESP in mice with overexpression of phospholambam, in which Ca2+ reuptake was diminished and recirculation fraction was decreased. They found slower MR and increased PESP in these mice compared with isogenic controls, which indicates a role for SR Ca2+ reuptake in these FIRs. The authors hypothesised that lower SR Ca2+ content slows down recovery of RyR2. When more ryanodine receptors are refractory during the premature beat, even more Ca2+ remains in the SR. During the post-extrasystolic beat the build-up of Ca2+ is released, which results in a higher PESP.

Recently, PESP has gained new attention as a possible prognostic marker in MI patients.14 Sinnecker et al. measured PESP of arterial blood pressure using a non-invasive photoplethysmographic device in 941 patients who survived the acute phase of MI and correlated the presence of PESP to all-cause 5-year mortality. PESP was defined as an increase in post-extrasystolic pulse pressure of 3 % or more compared with the mean of the subsequent beats. The authors found a significant higher mortality risk in patients, in whom PESP was present compared with patients, in whom PESP was absent. PESP remained a significant risk predictor after adjusting for left ventricular ejection fraction (LVEF), the amount of ventricular premature beats and GRACE (Global Registry of Acute Coronary Events) score. Addition of PESP to LVEF as risk predictor increased the area under the ROC curve from 0.61 to 0.75 (P<0.001), indicating that the combination of PESP and LVEF could better stratify patients with high- or lowmortality risk.

Another explanation for the augmented potentiation in heart failure might be found in an increased sensitivity of RyR2 for Ca2+. In case of more sensitive ryanodine receptors, a larger fraction of the SR content will be released during the post-extrasystolic beat, resulting in an even higher relative PESP in the failing heart. Both of these hypotheses are supported by a study of Rice et al., in which the experiments of Wier and Yue were simulated using a computational model to address different aspects of the short-term FIR.52 The model computed the effects on MR and PESP when certain parameters of ECC were changed. In this model, PESP increased, when the releasable fraction (i.e. the fraction of total Ca2+ in the SR that is released) was increased. This is in accordance with increased sensitivity of RyR2 as an explanation for higher PESP. Furthermore, a decrease in recirculation fraction (the fraction of Ca2+ sequestered back in SR) was also associated with a higher PESP. While this may sound counterintuitive, a lower recirculation fraction results in higher beat-to-beat variability of SR Ca2+ load, which is essential for MR and PESP. In contrast, a theoretical maximal recirculation fraction (all released Ca2+ is recirculated back in the SR) will cause the same SR load of every beat and which makes potentiation impossible to occur. Finally, overall slower recovery of RyR2 may attribute to the increase in PESP. Prabhu et al. investigated alterations of both MR and PESP in dogs with tachycardia-induced heart failure.48,53 They found slower MR kinetics, which they attributed to slower recovery of RyR2. Thus, at faster heart rates, the failing heart does not operate at optimal performance, because most of the ryanodine receptors are refractory, resulting in incomplete MR. When the cycle length is increased, there is full restitution and contractility will return to normal. This observation is consistent with the negative FFR seen in heart failure. These altered MR kinetics will consequently have implications on PESP. When the failing heart is stimulated at a steady state cycle length below that at which full restitution is achieved, the contractile response of these steady state beats will be suboptimal. During the compensatory pause, the heart is fully restituted and a normal PESP is seen. However, if the magnitude of the post-extrasystolic beat is normalised to the (suboptimal) steady state beats, a higher relative PESP will be found in the failing heart compared with controls (see Figure 3).

Post-extrasystolic Potentiation as a Diagnostic Instrument or Therapeutic Intervention Diagnostics PESP has been studied formerly as a diagnostic instrument to differentiate viable from non-viable myocardium during revascularisation

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The mechanism on how PESP is correlated to a worse prognosis was not made clear. The endpoint all-cause mortality was not further stratified in death of mechanical or arrhythmic origin. As one could assume, changes in PESP displays alterations in Ca2+ handling, which could, in addition to myocardial dysfunction, also lead to early depolarisations and DAD. Thus, altered PESP might indicate an early stage of heart failure, but may also be a marker for increased risk of lethal ventricular arrhythmias. However, some methodological remarks have to be made. First, the rise in blood pressure of the post-extrasystolic beat was compared with the subsequent beats. However, PESP usually decays in a number of beats, therefore, for correct analysis of the percentage of PESP, using the beats preceding the premature ventricular contractions (PVCs) would have been more accurate. Second, in this study PESP was defined as difference in blood pressure, measured with a non-invasive device at the finger, while most studies used invasive measurements of contractility, such as the first derivative of LV pressure (dP/dt). When measuring PESP more distally, vascular influences might alter the blood pressure measurements of PESP. In other words, the phenomenon measured in this study might not be comparable to PESP seen during earlier invasive experiments. More importantly, as seen in other studies of PESP in heart failure, the intervals were not held constant. Therefore, when basic rhythm, extrasystolic intervals or PESI differ, the magnitude of potentiation will change.57,58 Therefore, from a physiological point of view, no strong conclusions can be made on the relationship between high PESP and heart failure, when the intervals are not controlled. Nonetheless, since PESP appears to be a strong predictor of mortality, it could still have prognostic value, even if the underlying mechanism is not completely understood. Further validation of the use of PESP as a prognostic marker will be needed before it could be implemented as a clinical tool.

Therapeutics The therapeutic use of PESP has been extensively investigated in the 1960s and 1970s, but has long been abandoned due to conflicting evidence of its effectiveness.59–62 Inducing PESP, and therefore increasing the force of contraction, might be beneficial in heart failure

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patients. By using coupled or paired pacing, in which a premature beat is introduced after every other intrinsic or paced beat, respectively, the effect of PESP is extended, which improves contractility and cardiac output. This technique has been studied in patients with cardiogenic shock, in which cardiac function significantly improved. However, reports of increased myocardial oxygen consumption and risk of arrhythmias have reduced the interest in this mode of pacing.63 More recently, a number of studies have reevaluated the safety and efficacy of coupled pacing. In 2008, a study by Lieberman et al.64 studied dual chamber coupled pacing (DCCP) in 16 heart failure patients. DCCP increased LV dP/dtmax and arterial pulse pressure; however, other haemodynamic parameters, such as mean arterial pressure, cardiac output and mixed venous O2 saturation did not differ. In the same year, Freudenberg investigated the use of atrioventricular coupled pacing in 10 heart failure patients and concluded that this mode of pacing is safe and well tolerated.65 In this study, coupled pacing was applied over 15–20 minutes. A significant increase in EF and stroke volume and a reduced end systolic volume were seen, accompanied by a decrease in cardiac output due to a decreased pulse rate. Two studies evaluated the use of coupled pacing in addition to cardiac resynchronisation therapy in heart failure patients with mechanical dyssynchrony.66,67 A further increase in contractility and EF was seen along with a decrease in pulse rate without disrupting the synchronisation properties of CRT. While Stegeman et al. concluded that this drop in pulse rate reduced the haemodynamic benefit of paired pacing, Brémont et al. suggested that the heart rate reduction could have an additional beneficial effect because of increased time for ventricular filling and reduced myocardial work.66,67 These recent trials indicate that there still might be a role for coupled pacing in heart failure patients; however, the long-term effects remain unknown. Furthermore, because of introduction of stimuli during the vulnerable period of repolarisation, the risk of inducing ventricular arrhythmias remains present. Another device-based therapy, cardiac contractility modulation (CCM), is increasingly being investigated and has already shown to be a safe and effective alternative to coupled pacing. CCM uses high-intensity, non-excitatory electrical signals applied during the absolute refractory period, which, in contrast to PESP, do not result in an action potential nor contraction.68–70 Studies in isolated papillary muscles,71 isolated hearts,72 in vivo animal models73

Langendorff O. Uentersuchungen am Uberlebenden Saugethierherzen. III. Abhandlung, Vorubergehende Unregelmassigkeiten des Herzschlages und ihre Ausgleichung. Pfluger Arch Physiol 1898;70:473–86. Wier WG, Yue DT. Intracellular calcium transients underlying the short-term force-interval relationship in ferret ventricular myocardium. J Physiol 1986;376:507–30. PMID: 2432238; PMCID: PMC1182812 Yue DT, Burkhoff D, Franz MR, et al. Postextrasystolic potentiation of the isolated canine left ventricle. Relationship to mechanical restitution. Circ Res 1985;56:340–50. PMID: 2578901 Burkhoff D, Yue DT, Franz MR, et al. Mechanical restitution of isolated perfused canine left ventricles. Am J Physiol 1984;246(1 Pt 2):H8–16. PMID: 6696092 Anderson PA, Manring A, Serwer GA, et al. The force-interval relationship of the left ventricle. Circulation 1979;60:334–48. PMID: 87282 Kuijer PJ, van der Werf T, Meijler FL. Post-extrasystolic potentiation without a compensatory pause in normal and diseased hearts. Br Heart J 1990;63:284–6. PMID: 1703773 Wisenbaugh T, Nissen S, DeMaria A. Mechanics of postextrasystolic potentiation in normal subjects and patients with valvular heart disease. Circulation 1986;74:10–20. PMID: 2423268

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10.

11.

12.

13.

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and patients74 have shown a positive effect on cardiac contractility. This treatment might be a good option for patients with advancing heart failure despite optimal medical treatment who are not a candidate for CRT. The exact mechanism of action is unknown, but the effect has been attributed to an increase in Ca2+ transient by a number of possible mechanisms, including an increase in phosphorylation of phospholambam, increased SERCA2a expression75 and normalisation of NCX activity,76 but also an increased influx of Ca2+ through the L-type calcium channels.69 A number of randomised clinical trials77–79 have been executed to investigate the safety and efficacy of CCM in heart failure patients and showed an improved exercise tolerance and quality of life, without increased myocardial oxygen consumption or arrhythmia risk. However, no difference in mortality nor morbidity have yet been found, thus long-term consequences need to be further elucidated before these techniques can be implemented in clinical practice.

Conclusion Since it was last reviewed extensively in 1993 by Cooper, much has been discovered about the phenomenon of PESP.80 The fundamental physiology of an altered calcium homeostasis has been further elucidated; the SR compartment model of Wier and Yue has been replaced by the central role of the ryanodine receptor and its refractory period in the mechanism of PESP. The diagnostic and therapeutic properties of PESP have recently been rediscovered. However, the relationship of PESP and heart failure remains a complex interplay of both FIR and FFR. Therefore, experimental studies of control versus failing hearts, in which all intervals are controlled, will be needed to confirm the assumption of an augmented PESP in failing hearts. In addition, the prognostic value of PESP of blood pressure needs to be further evaluated and validated, since this non-invasive test might be of great value for selecting therapeutic interventions, e.g. ICD therapy, in certain patient groups. The Comparative Effectiveness Research to Assess the Use of Primary Prophylactic Implantable Cardioverter Defibrillators in Europe (EU-CERT-ICD) trial, which investigates new parameters for identification of high arrhythmia risk in ICD patients, is currently ongoing and will incorporate the use of PESP for stratification of mortality and ICD shock risk. Finally, the results of trials on the therapeutic use of coupled pacing in conjunction with CRT therapy have again attracted attention. However, CCM might take its place as a new device-based therapy for heart failure, because of a better safety profile. Further evaluation of the long-term effects of this new therapeutic option will be needed to confirm these promising results. n

Sung CS, Mathur VS, Garcia E, et al. Is postextrasystolic potentiation dependent on Starling’s law? Biplane angiographic studies in normal subjects. Circulation 1980;62:1032–5. PMID: 7418153 Yellin EL, Kennish A, Yoran C, et al. The influence of left ventricular filling on postextrasystolic potentiation in the dog heart. Circ Res 1979;44:712–22. Beck W, Chesler E, Schrire V. Postextrasystolic ventricular pressure responses. Circulation 1971;44:523–33. PMID: 4106154 Kvasnicka J, Liander B, Broman H, et al. Quantitative evaluation of postectopic beats in the normal and failing human heart using indices derived from catheter-tip manometer readings. Cardiovasc Res 1975;9:336–41. PMID: 1175180 Merillon JP, Motte G, Aumont MC, et al. Post-extrasystolic left ventricular peak pressure with and without left ventricular failure. Cardiovasc Res 1979;13:338–44. PMID: 89910 Seed WA, Noble MI, Walker JM, et al. Relationships between beat-to-beat interval and the strength of contraction in the healthy and diseased human heart. Circulation 1984;70:799– 805. PMID: 6488494 Sinnecker D, Dirschinger RJ, Barthel P, et al. Postextrasystolic blood pressure potentiation predicts poor outcome of cardiac

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patients. J Am Hear Assoc 2014;3:e000857. DOI: 10.1161/ JAHA.114.000857; PMID: 24895163 Sinnecker D, Barthel P, Huster KM, et al. Force-interval relationship predicts mortality in survivors of myocardial infarction with atrial fibrillation. Int J Cardiol 2015;182:315–20. DOI: 10.1016/j.ijcard.2015.01.018; PMID: 25585377 Bers DM. Cardiac excitation-contraction coupling. Nature 2002;415:198–205. PMID: 11805843 Barry WH, Bridge JH. Intracellular calcium homeostasis in cardiac myocytes. Circulation 1993;87:1806–15. PMID: 8389258 Mattiazzi A, Bassani RA, Escobar AL, et al. Chasing cardiac physiology and pathology down the CaMKII cascade. Am J Physiol Heart Circ Physiol 2015;308:H1177–91. DOI: 10.1152/ ajpheart.00007.2015; PMID: 25747749 Wang SQ, Song LS, Lakatta EG, et al. Ca2+ signalling between single L-type Ca2+ channels and ryanodine receptors in heart cells. Nature 2001;410:592–6. PMID: 11279498 Bers DM. Altered cardiac myocyte Ca regulation in heart failure. Physiology (Bethesda) 2006;21:380–7. PMID: 17119150 Hasenfuss G, Pieske B. Calcium cycling in congestive heart failure. J Mol Cell Cardiol 2002;34:951–69. PMID: 12234765 Zima A V., Bovo E, Mazurek SR, et al. Ca handling during excitation–contraction coupling in heart failure. Pflügers Arch - Eur J Physiol 2014;466:1129–37. DOI: 10.1007/s00424-014-

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Arrhythmia Mechanisms 1469–3; PMID: 24515294 23. Lompre A-M, Hajjar RJ, Harding SE, et al. Ca2+ cycling and new therapeutic approaches for heart failure. Circulation 2010;121:822–30. DOI: 10.1161/ CIRCULATIONAHA.109.890954; PMID: 20124124 24. Hasenfuss G, Reinecke H, Studer R, et al. Relation between myocardial function and expression of sarcoplasmic reticulum Ca(2+)-ATPase in failing and nonfailing human myocardium. Circ Res 1994;75:434–42. PMID: 8062417 25. Armoundas AA, Rose J, Aggarwal R, et al. Cellular and molecular determinants of altered Ca2+ handling in the failing rabbit heart: primary defects in SR Ca2+ uptake and release mechanisms. AJP Hear Circ Physiol 2006;292:H1607–18. PMID: 17122195; PMCID: PMC2711877 26. Jiang MT, Lokuta AJ, Farrell EF, et al. Abnormal Ca2+ release, but normal ryanodine receptors, in canine and human heart failure. Circ Res 2002;91:1015–22. PMID: 12456487 27. Currie S, Smith GL. Enhanced phosphorylation of phospholamban and downregulation of sarco/endoplasmic reticulum Ca2+ ATPase type 2 (SERCA 2) in cardiac sarcoplasmic reticulum from rabbits with heart failure. Cardiovasc Res 1999;41:135–46. PMID: 10325961 28. Studer R, Reinecke H, Bilger J, et al. Gene expression of the cardiac Na(+)-Ca2+ exchanger in end-stage human heart failure. Circ Res 1994;75:443–53. PMID: 8062418 29. Pogwizd SM, Schlotthauer K, Li L, et al. Arrhythmogenesis and contractile dysfunction in heart failure: Roles of sodiumcalcium exchange, inward rectifier potassium current, and residual beta-adrenergic responsiveness. Circ Res 2001;88:1159–67. PMID: 11397782 30. Lehnart SE, Wehrens XHT, Kushnir A, et al. Cardiac ryanodine receptor function and regulation in heart disease. Ann N Y Acad Sci 2004;1015:144–59. PMID: 15201156 31. Györke S, Terentyev D. Modulation of ryanodine receptor by luminal calcium and accessory proteins in health and cardiac disease. Cardiovasc Res 2008;77:245–55. PMID: 18006456 32. Zhou P, Zhao Y-T, Guo Y-B, et al. Adrenergic signaling accelerates and synchronizes cardiac ryanodine receptor response to a single L-type Ca2+ channel. Proc Natl Acad Sci 2009;106:18028–33. DOI: 10.1073/pnas.0906560106. 33. Kubalova Z, Terentyev D, Viatchenko-Karpinski S, et al. Abnormal intrastore calcium signaling in chronic heart failure. Proc Natl Acad Sci 2005;102:14104–9. PMID: 16172392; PMCID: PMC1236548 34. Schwinger RH, Böhm M, Koch A, et al. Force-frequencyrelation in human atrial and ventricular myocardium. Mol Cell Biochem 1993;119:73–8. PMID: 8455589 35. Bowditch HP. Über die Eigentümlichkeiten der Reizbarkeit welche die Muskelfasern des Herzens zeigen. Ber Verh Saechs Akad Wiss 1871;23:652–89. 36. Freeman GL, Little WC, O’Rourke RA. Influence of heart rate on left ventricular performance in conscious dogs. Circ Res 1987;61:455–64. PMID: 3621503 37. Miura T, Miyazaki S, Guth BD, et al. Influence of the forcefrequency relation on left ventricular function during exercise in conscious dogs. Circulation 1992;86:563–71. PMID: 1638722 38. Palomeque J, Vila Petroff MG, Mattiazzi A. Pacing staircase phenomenon in the heart: From Bodwitch to the XXI century. Hear Lung Circ 2004;13:410–20. PMID: 16352227 39. Endoh M. Force–frequency relationship in intact mammalian ventricular myocardium: physiological and pathophysiological relevance. Eur J Pharmacol 2004;500:73–86. PMID: 15464022 40. Müller-Ehmsen J, Brixius K, Schulze C, et al. Na+ channel modulation and force-frequency relationship in human myocardium. Naunyn Schmiedebergs Arch Pharmacol 1997;355:727–32. PMID: 9205957 41. Pieske B, Maier LS, Bers DM, et al. Ca2+ handling and sarcoplasmic reticulum Ca2+ content in isolated failing and nonfailing human myocardium. Circ Res 1999;85:38–46. PMID: 10400909 42. Ahlberg SE, Hamlen RC, Ewert DL, et al. Novel means to monitor cardiac performance: the impact of the forcefrequency and force-interval relationships on recirculation fraction and potentiation ratio. Cardiovasc Eng 2007;7:32–8.

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PMID: 17318431 43. Mulieri LA, Hasenfuss G, Leavitt B, et al. Altered myocardial force-frequency relation in human heart failure. Circulation 1992;85:1743–50. PMID: 1572031 44. Hasenfuss G, Holubarsch C, Hermann HP, et al. Influence of the force-frequency relationship on haemodynamics and left ventricular function in patients with non-failing hearts and in patients with dilated cardiomyopathy. Eur Heart J 1994;15:164–70. PMID: 8005115 45. Crozatier B. Force-frequency relations in nonfailing and failing animal myocardium. Basic Res Cardiol 1998;93 Suppl.1:46–50. PMID: 9833130 46. Pieske B, Kretschmann B, Meyer M, et al. Alterations in intracellular calcium handling associated with the inverse force-frequency relation in human dilated cardiomyopathy. Circulation 1995;92:1169–78. PMID: 7648662 47. Bers DM. Excitation-Contraction Coupling and Cardiac Contractile Force. Kluwer Academic Publishers; 2001. 48. Prabhu SD, Freeman GL. Effect of tachycardia heart failure on the restitution of left ventricular function in closed-chest dogs. Circulation 1995;91:176–85. PMID: 7805200 49. Fabiato A. Time and calcium dependence of activation and inactivation of calcium-induced release of calcium from the sarcoplasmic reticulum of a skinned canine cardiac Purkinje cell. J Gen Physiol 1985;85:247–89. PMID: 2580043; PMCID: PMC2215800 50. Hoit BD, Tramuta DA, Kadambi VJ, et al. Influence of transgenic overexpression of phospholamban on postextrasystolic potentiation. J Mol Cell Cardiol 1999;31:2007– 15. PMID: 10591027 51. Hoit BD, Kadambi VJ, Tramuta DA, et al. Influence of sarcoplasmic reticulum calcium loading on mechanical and relaxation restitution. Am J Physiol Heart Circ Physiol 2000;278:H958–63. PMID: 10710365 52. Rice JJ, Jafri MS, Winslow RL. Modeling short-term intervalforce relations in cardiac muscle. Am J Physiol Heart Circ Physiol 2000;278:H913–31. PMID: 10710361 53. Prabhu SD, Freeman GL. Postextrasystolic mechanical restitution in closed-chest dogs: effect of heart failure. Circulation 1995;92:2652–9. PMID: 7586369 54. Scognamiglio R, Negut C, Palisi M. Spontaneous recovery of myocardial asynergic segments following acute myocardial infarction. The role of post-extrasystolic potentiation echocardiography in the predischarge evaluation. Eur J Echocardiogr 2003;4:135–40. PMID: 12749875 55. Hodgson JM, O’Neill WW, Laufer N, et al. Assessment of potentially salvageable myocardium during acute myocardial infarction: use of postextrasystolic potentiation. Am J Cardiol 1984;54:1237–44. PMID: 6507294 56. Diamond GA, Forrester JS, deLuz PL, et al. Post-extrasystolic potentiation of ischemic myocardium by atrial stimulation. Am Heart J 1978;95:204–9. PMID: 622954 57. Cooper MW, Lutherer LO, Lust RM. Postextrasystolic potentiation and echocardiography: the effect of varying basic heart rate, extrasystolic coupling interval and postextrasystolic interval. Circulation 1982;66:771–6. PMID: 6180844 58. Lust RM, Lutherer LO, Gardner ME, et al. Postextrasystolic potentiation and contractile reserve: requirements and restrictions. Am J Physiol 1982;243:H990–7. PMID: 7149051 59. Braunwald E, Ross Jr. J, Frommer PL, et al. Clinical observations on paired electrical stimulation of the heart: Effects on ventricular performance and heart rate. Am J Med 1964;37:700–11. PMID: 14237426 60. Frommer P. Studies on coupled pacing techniques and some comments on paired electrical stimulation. Bull N Y Acad Med 1965;41:670–80. PMID: 14323011 61. Frommer PL, Robinson BF, Braunwald E. Paired electrical stimulation. A comparison of the effects on performance of the failing and nonfailing heart. Am J Cardiol 1966;18:738–44. PMID: 5921399 62. Chevalier-Cholat AM, Torresani J, Saadjian A, et al. Post extra-systolic potentiation during coupled stimulation of the heart. J Electrocardiol 1971;4:341–6. PMID: 4110268 63. Hoffman B, Bartelstone H, Scherlag B, et al. Effects of postextrasystolic potentiation on normal and failing hearts. E. Bull N Y Acad Med 1965;41:498–534. PMID: 14286155

64. Lieberman RA, Yee R, Shorofsky S, et al. Acute hemodynamic response to dual chamber coupled pacing in heart failure Patients – Impact of LV vs RV Stimulation. J Card Fail 2008;14:S58. 65. Freudenberger R, Aaron M, Krueger S, et al. Acute electromechanical effects of atrioventricular coupled pacing in patients with heart failure. J Card Fail 2008;14:35–40. DOI: 10.1016/j.cardfail.2007.09.003; PMID: 1822677 66. Stegemann B, Mihalcz A, Földesi C, et al. Extrasystolic stimulation with bi-ventricular pacing: an acute haemodynamic evaluation. Europace 2011;13:1591–6. DOI: 10.1093/europace/eur183. Epub 2011 Jun 28; PMID: 21712265 67. Brémont C, Lim P, Elbaz N, et al. Cardiac resynchronization therapy plus coupled pacing improves acutely myocardial function in heart failure patients. Pacing Clin Electrophysiol 2014;37:803–9. DOI: 10.1111/pace.12348. Epub 2014 Jan 27; PMID: 24467552 68. Lyon AR, Samara MA, Feldman DS. Cardiac contractility modulation therapy in advanced systolic heart failure. Nat Rev Cardiol 2013;10:584–98. DOI: 10.1038/ nrcardio.2013.114; PMID: 23939481 69. Winter J, Brack KE, Ng GA. Cardiac contractility modulation in the treatment of heart failure: initial results and unanswered questions. Eur J Heart Fail 2011;13:700–10. DOI: 10.1093/ eurjhf/hfr042; PMID: 21511811 70. Kuck K-H, Bordachar P, Borggrefe M, et al. New devices in heart failure: an European Heart Rhythm Association report: developed by the European Heart Rhythm Association; endorsed by the Heart Failure Association. Europace 2014;16:109–28. DOI: 10.1093/europace/eut311; PMID: 24265466 71. Brunckhorst CB, Shemer I, Mika Y, et al. Cardiac contractility modulation by non-excitatory currents: studies in isolated cardiac muscle. Eur J Heart Fail 2006;8:7–15. PMID: 16202650 72. Mohri S, He K-L, Dickstein M, et al. Cardiac contractility modulation by electric currents applied during the refractory period. Am J Physiol Heart Circ Physiol 2002;282:H1642–7. PMID: 11959626 73. Sabbah HN, Haddad W, Mika Y, et al. Cardiac contractility modulation with the impulse dynamics signal: studies in dogs with chronic heart failure. Heart Fail Rev 2001;6:45–53. PMID: 11248767 74. Pappone C, Rosanio S, Burkhoff D, et al. Cardiac contractility modulation by electric currents applied during the refractory period in patients with heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 2002;90:1307–13. PMID: 12480039 75. Imai M, Rastogi S, Gupta RC, et al. Therapy with cardiac contractility modulation electrical signals improves left ventricular function and remodeling in dogs with chronic heart failure. J Am Coll Cardiol 2007;49:2120–8. PMID: 17531662 76. Gupta RC, Mishra S, Wang M, et al. Cardiac contractility modulation electrical signals normalize activity, expression, and phosphorylation of the Na+-Ca2+ exchanger in heart failure. J Card Fail 2009;15:48–56. DOI: 10.1016/j. cardfail.2008.08.011; PMID: 19181294 77. Borggrefe MM, Lawo T, Butter C, et al. Randomized, double blind study of non-excitatory, cardiac contractility modulation electrical impulses for symptomatic heart failure. Eur Heart J 2008;29:1019–28. DOI: 10.1093/eurheartj/ehn020; PMID: 18270213 78. Kadish A, Nademanee K, Volosin K, et al. A randomized controlled trial evaluating the safety and efficacy of cardiac contractility modulation in advanced heart failure. Am Heart J 2011;161:329–37.e1–2. DOI: 10.1016/j.ahj.2010.10.025; PMID: 21315216 79. Abraham WT, Burkhoff D, Nademanee K, et al. A randomized controlled trial to evaluate the safety and efficacy of cardiac contractility modulation in patients with systolic heart failure: rationale, design, and baseline patient characteristics. Am Heart J 2008;156:641–8.e1. DOI: 10.1016/j.cardfail.2011.05.006; PMID: 21872139 80. Cooper MW. Postextrasystolic potentiation. Do we really know what it means and how to use it? Circulation 1993;88:2962–71. PMID: 7504591

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Arrhythmia Mechanisms

Post-extrasystolic Blood Pressure Potentiation as a Risk Predictor in Cardiac Patients Alexander Steger, Daniel Sinnecker, Petra Barthel, Alexander Müller, Josef Gebhardt and Georg Schmidt 1st Medical Clinic and Policlinic, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany

Abstract For more than 100 years physicians have observed that heartbeats following extrasystolic beats are characterised by augmented myocardial contractility. This phenomenon was termed post-extrasystolic potentiation (PESP). In the 1970s it was first noted that PESP measured at the blood pressure level is typically pronounced in heart failure patients. Only recently, it was shown that PESP measured non-invasively as post-extrasystolic blood pressure potentiation was a strong and independent predictor of death in survivors of myocardial infarction and in patients with chronic heart failure. A similar parameter (PESPAfib) can be also assessed in patients with atrial fibrillation. PESP and PESPAfib can be understood as non-invasive parameters that indicate myocardial dysfunction. They have the potential to improve risk stratification strategies for cardiac patients.

Keywords Post-extrasystolic potentiation, risk prediction, myocardial infarction Disclosure: The authors have no conflicts of interest to declare. Received: 28 December 2015 Accepted: 18 April 2016 Citation: Arrhythmia & Electrophysiology Review 2016;5(1):27–30 Access at: www.AERjournal.com; DOI: 10.15420/AER.2016.14.2 Correspondence: Georg Schmidt, Medical Clinic and Polyclinic, The ISAR Hospital, Technical University of Munich, Ismaninger Str. 22, 81675 Munich, Germany. E: gschmidt@tum.de

In 1885, Oscar Langendorff was the first person to describe the increase in contractility (‘Pulsverstärkung‘) that follows an extrasystole.1 Langendorff experimented with spontaneously beating isolated frog hearts. He recorded the heartbeats by using a lever that transferred the contractile movements of the heart to a rotating drum. Electrical stimulation resulted in premature contractions that were followed by compensatory pauses. In these experiments, he noticed that myocardial contractility during the first post-ectopic beats was typically stronger compared with the normal beats (see Figure 1A). Decades later, this phenomenon was termed postextrasystolic potentiation (PESP).2 PESP is present at the level of the myocardium, independently of pre- or afterload conditions.3 The driving force behind the augmented post-extrasystolic contractility is augmented calcium release from the intracellular stores during the post-extrasystolic action potential.4,5 Historically, PESP has been studied intensively with regard to two possible clinical applications (reviewed in Cooper3): • PESP was induced during contrast ventriculography with the aim of identifying ischaemic but viable myocardial regions that might benefit from revascularisation. • PESP was elicited by paired pacing with the aim of augmenting myocardial contractility in heart failure patients. Besides these now widely abandoned applications, several studies have documented an interesting relationship between PESP and myocardial dysfunction.

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Post-extrasystolic Potentiation and Heart Disease: A Forgotten Association? PESP can be measured as post-extrasystolic augmentation of the maximum left-ventricular pressure rise (LV dP/dt) or as systolic blood pressure potentiation. The parameter that is most closely related to myocardial contractility is LV dP/dt. At the level of LV dP/dt, PESP was observed both in healthy people and in heart failure patients.6 However, potentiation of LV dP/dt was typically more pronounced in failing than in healthy hearts.7–10 At the level of blood pressure, it has to be taken into account that systolic blood pressure is not only determined by cardiac output, but also by vascular factors, such as peripheral vascular resistance. When PESP was measured at the level of maximum systolic blood pressure (or maximum LV pressure, which are roughly equivalent in the absence of aortic stenosis), the typical finding in healthy probands was that the first post-ectopic heartbeat elicited a lower pulse wave than the regular ones. By contrast, in heart failure patients, PESP of systolic blood pressure could generally be observed.6–10 In a series of 100 consecutive patients with coronary artery disease, the pattern of post-extrasystolic blood pressure potentiation was associated with an increased prevalence of congestive heart failure and cardiomegaly as well as with higher left-ventricular end-diastolic pressure, lower cardiac output and lower left-ventricular ejection fraction (LVEF).11 At the cellular level, PESP of contractility is caused by an increased magnitude of the post-extrasystolic systolic calcium transient.4,5 During the premature heartbeat, calcium release from the intracellular stores is reduced due to refractoriness of the calcium release channels (ryanodine receptors) located in the membrane of the intracellular

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Arrhythmia Mechanisms Figure 1: Post-extrasystolic Potentiation

Post-extrasystolic Potentiation as a Risk Predictor in Cardiac Patients To investigate whether PESP at the blood pressure level is associated with adverse outcome in cardiac patients, we prospectively analysed its correlation with mortality in a cohort of 941 survivors of acute myocardial infarction (MI).14 To establish a new, simply applicable, non-invasive risk predictor, we decided to investigate PESP at the blood pressure level using non-invasive measurements. On days 5–9 after MI, patients underwent a 30-minute recording of ECG and blood pressure. Blood pressure was continuously recorded using a photoplethysmographic finger cuff device. PESP was assessed after spontaneously occurring ventricular premature contractions (VPCs). Of the 941 patients, 220 (23.4 %) exhibited at least one VPC suitable for PESP quantification during the 30-minute recording period. In these patients, we calculated the ratio of the systolic blood pressure of the first post-ectopic beat (P1) divided by the average blood pressure of the nine following beats (P2–10; see Figure 1B). We considered PESP present if the ratio was >1.03 (i.e. if the post-VPC pulse wave exceeded the mean of the nine subsequent pulse waves by more than 3 %). According to this definition, PESP was present in 62 (28.2 %) and absent in 158 (71.8 %) of the 220 patients in whom PESP could be quantified.

A: The first description of post-extrasystolic potentiation in the scientific literature (Source: Langedorff, 1885). The contractions of an isolated, spontaneously beating frog heart (Rana temporaria) were recorded on a rotating drum by using a lever lying on the heart. Premature ventricular contractions were elicited by electrical stimulation (arrows). The contractions following the premature beats (arrowheads) were stronger than the regular contractions. B: Determination of post-extrasystolic blood pressure potentiation. Typical ECG and blood pressure recordings from a patient who died during follow-up (upper panel) and a long-term survivor (lower panel). Sequences elicited by a ventricular ectopic beat (asterisk) are shown. The systolic blood pressure of the first post-ectopic heart beat (P1 ) and the mean systolic blood pressure of the nine subsequent heartbeats (P2–10 ) are shown. Post-extrasystolic potentiation (PESP) was considered to be present if the ratio P1 /P2–10 exceeded 1.03. Based on data published in Iribe et al., 2006.

calcium stores. Accordingly, more calcium remains in the intracellular stores. In the post-extrasystolic pause, the calcium content of the intracellular stores is further increased due to activity of the sarcoendoplasmic reticulum calcium ATPase (SERCA). Since the amplitude of the systolic calcium transient largely depends on the filling state of the intracellular stores, it is augmented in the first post-ectopic heartbeat. Both animal experiments12 and simulation studies13 indicate that increased PESP might result from heart failure-induced alterations of intracellular calcium cycling. In failing myocardium, the steady-state calcium content of the intracellular stores is reduced due to increased diastolic calcium leak via the ryanodine receptors. Starting from this lower steady state, the relative augmentation after an ectopic beat may be increased as compared with non-failing myocardium. Already in 1971, Beck et al.6 reported that the potentiation of the first post-extrasystolic blood pressure wave is typically seen in failing ventricles but rarely in healthy hearts. The authors concluded that PESP measured on the level of blood pressure could be used to detect ’abnormal‘ left ventricles. However, the use of PESP as a diagnostic tool for myocardial dysfunction has not been pursued further for many years.

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The presence of PESP was associated with a marked increase of 5-year all-cause mortality (see Figure 2A), which amounted to 29.4 % in patients with PESP present and 5.8 % in patients with PESP absent. Patients in whom PESP could not be measured due to lack of suitable VPCs had a low mortality rate of 6.3 %, almost indistinguishable from that of patients with PESP absent (see Figure 2A). Therefore, we merged the patient categories PESP absent and PESP not detectable, which allowed us to base the analyses on the whole dataset of 941 patients. In multivariable analysis considering LVEF, VPC count and GRACE (Global Registry of Acute Coronary Events) score as independent variables, PESP remained a strong independent predictor of mortality with a hazard ratio of 3.2 (95 % confidence interval 1.8–5.7; see Figure 2B). If applied together for post-MI risk stratification, PESP and LVEF provided complementary information (see Figure 2C). Patients in whom both parameters were normal were at a low 5-year mortality risk of 5.1 %. Patients, in whom one of the parameters was abnormal, had a substantially higher risk of 18.2 % (LVEF abnormal) or 23.8 % (PESP abnormal). The small group of patients in whom both parameters were abnormal had an excess 5-year mortality risk of 46.7 % (see Figure 2C). There was no evidence for relevant confounding by baseline variables such as age, sex, diabetes mellitus or baseline medical therapy (use of b-blockers, ACE inhibitors, statins, diuretics, acetylsalicylic acid or clopidogrel). If any of these variables was additionally included in a Cox regression model consisting of PESP, LVEF, VPC count and GRACE score, the association of PESP and mortality remained highly significant.14 To validate these findings in a different patient population, we analysed data from a previously reported cohort of 146 patients with chronic heart failure,15 who were followed up for 2.7 years. At inclusion, all patients also underwent a continuous blood pressure measurement allowing PESP assessment. The mortality rate during follow-up was 28.8 %. Also in this cohort of heart failure patients, presence of PESP was a strong and independent risk predictor, with mortality amounting to 42 % and 20 % in patients with PESP present and absent/not calculable, respectively.14

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Post-extrasystolic Blood Pressure Potentiation in Cardiac Risk Prediction

PESPAfib values were significantly higher in non-survivors than in survivors. When dichotomised at its median, PESPAfib distinguished between patient groups with 5-year mortality rates of 63 % and 19 %, respectively. The association of PESPAfib with mortality was independent from established risk factors such as LVEF, diabetes mellitus, age or the mean heart rate.

Figure 2: Post-extrasystolic Potentiation Predicts Mortality after Myocardial Infarction A

50 Probability of death (%)

PESP as described above can only be assessed in patients with sinus rhythm. However, in atrial fibrillation, the myocardial force-interval relationship translates the random variability of beat-to-beat intervals into a corresponding pulse pressure variability.16,17 We hypothesised that a parameter analogous to PESP could also be determined in atrial fibrillation. Therefore, we developed a PESP-analogous parameter (PESPAfib) and evaluated its association with mortality in a small cohort of 32 MI survivors with atrial fibrillation.18 The ECGs were screened for short–long sequences, in which a heartbeat interval shorter than 80 % of the local average (Pi) was followed by an interval longer than 140 % of the local average (Pi+1). Based on the systolic blood pressure values elicited by Pi and Pi+1 and the corresponding RR intervals (RRi and RRi+1), we calculated PESPAfib as (Pi+1-Pi) / (RRi+1-RRi), i.e. by relating the systolic pressure change to the RR interval change.18

χ2=49.71 p<0.0001

40 PESP present

30 20 10

PESP not calculable PESP absent

No. of patients at risk:

62 721 158

57 703 157

2 3 Follow-up (years) 50 697 155

46 687 153

44 671 151

40 633 139

p<0.0001

PESP present

p=0.001

LVEF≤35 %

p=0.42

VPC≥10 per hour

Taken together, these results indicate that PESP (and PESPAfib in atrial fibrillation) is a promising new risk predictor for cardiac patients.

p<0.0001

GRACE score ≥120 points

6 2 4 Hazard ratio (95 % confidence interval)

Future Directions

If changes in the clinical status of a patient translate into changes of PESP, PESP might become a tool to monitor the therapy of heart failure patients. This would be especially interesting since, in theory, sensors and algorithms necessary to quantify PESP might be incorporated into implantable cardiac devices such as pacemakers, ICDs or event recorders.

50 Probability of death (%)

One explanation for the close association of PESP and mortality in cardiac patients is that PESP is a surrogate parameter for myocardial dysfunction. It remains to be investigated whether PESP will be useful for clinical applications beyond risk stratification.

χ2=81.06 p<0.0001

LVEF≤35 % and PESP present

40 30 LVEF>35 % and PESP present

20 LVEF≤35 % and PESP absent

10 0

LVEF >35 % and PESP absent

2 3 Follow-up (years)

8 36 60 762

8 32 53 718

To test the hypothesis that PESP could be used to monitor the clinical status of heart failure patients, we initiated a study in which patients with acutely decompensated heart failure undergo PESP assessments at admission, before discharge and after 4 weeks. In addition, NT-proBNP (N-terminal of the prohormone brain natriuretic peptide) plasma levels are determined. Preliminary data from two patients are shown in Figure 3. Numerical PESP ratios (i.e. P1/P2–10) at admission were >1.03 in both patients, meaning that both patients would be classified as ’PESP present‘ according to the definition used in the post-MI study described above.14 In one of the patients (Patient 1), PESP numerical ratio at discharge decreased to 0.98, re-classifying the patient as ’PESP absent‘ at this time point. Concomitantly, the NT-proBNP plasma level was also lower at discharge than at admission. In the other patient (Patient 2), both PESP numerical ratio and plasma NT-proBNP level increased from admission to discharge. While the correlation of PESP with natriuretic peptide levels in these examples is encouraging, it is necessary to include additional patients before any solid conclusions can be drawn.

the ongoing INVADE (Prevention of Stroke and Dementia in Primary Care) study,19 in which PESP was determined in a general population sample of 1,900 patients aged ≥65 years, who are now followed up for cardiovascular events. Follow-up of this study will be completed in late 2016.

It is also possible that PESP could be used in the general population to predict cardiac events or to identify patients with unrecognised cardiac conditions. This hypothesis is currently being addressed in

Another open question is whether PESP might improve patient selection for primary prophylactic ICD therapy. The limitations of LVEF in this regard are well known20 and the complementary nature of the prediction

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No. of patients 15 at risk: 47 72 807

12 45 63 797

11 39 62 790

9 37 60 780

A: Incidence of death during a follow-up period of 5 years in patients stratified according to the presence or absence of post-extrasystolic potentiation (PESP) (red and green curve, respectively). The mortality of those patients, who did not have suitable VPCs for PESP assessment is also shown (grey curve). B: Hazard ratios with 95 % confidence intervals obtained by multivariable Cox regression analysis for 5-year all-cause mortality are shown. All shown variables were included in the model. The grey line indicates a hazard ratio of 1.0. C: Mortality in patients stratified by the combination of PESP (absent or present) and LVEF (≤35 % or >35 %). In panels (A) and (C), the number of patients at risk at 0, 1, 2, 3, 4, 5 years are shown below the graphs in the same colour coding and P values for the overall comparison at 5 years are indicated. Based on data published in Iribe et al., 2006. GRACE = Global Registry of Acute Coronary Events; LVEF = left-ventricular ejection fraction; PESP = post-extrasystolic potentiation; VPC = ventricular premature contraction.

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Arrhythmia Mechanisms Figure 3: Monitoring Decompensated Heart Failure with Post-extrasystolic Potentiation 1,00,000

140

1.1

10,000

120

1.05

1,000

1.15

that typically dies from a cause (e.g. progressive heart failure) that cannot be prevented by ICD therapy. Accordingly, larger studies are necessary to investigate the utility of PESP to identify ICD candidates.

100

Patient 1

0.95

100 Patient 2

80 60

Conclusion Body weight (kg)

NT-proBNP (pg/ml)

PESP numerical ratio

Patient 2

Patient 1 0.9

1 Admission

Discharge

40 Admission

Discharge

Post-extrasystolic potentiation numerical ratios (left panel, blue symbols), NT-proBNP plasma levels (left panel, red symbols) and body weight (right panel) measured at admission and at discharge in two patients presenting with acute decompensated heart failure. NT-proBNP = N-terminal of the prohormone brain natriuretic peptide.

of post-MI mortality by LVEF and PESP (see Figure 2C) suggests that this might be the case. However, it should be noted that, in this study, the primary endpoint was all-cause mortality. While PESP was also significantly associated with cardiac death and with sudden cardiac death (with p values of 5.9 × 10-5 and 1.9 × 10-4, respectively), the numbers of events (38 and 14, respectively) were too small to investigate whether the association of PESP with these more specific endpoints was independent from established risk predictors or whether PESP is differentially associated with sudden and non-sudden cardiac death. It is, therefore, possible that presence of PESP identifies a patient group

1. 2.

6. 7.

Langendorff O. Ueber elektrische Reizung des Herzens. Du-Bois-Reymond’s Archiv f. Physiologie 1885;8:284–7. Hoffman BF, Bindler E, Suckling EE. Postextrasystolic potentiation of contraction in cardiac muscle. Am J Physiol 1956;185:95–102. PMID: 13313754 Cooper MW. Postextrasystolic potentiation: Do we really know what it means and how to use it? Circulation 1993;88:2962–71. PMID: 7504591 Wier WG, Yue DT. Intracellular calcium transients underlying the short-term force-interval relationship in ferret ventricular myocardium. J Physiol 1986;367:507–30. PMID: 2432238; PMCID: PMC1182812 Rice JJ, Jafri MS, Winslow RL. Modeling short-term intervalforce relations in cardiac muscle. Am J Physiol Heart Circ Physiol 2000;278:H989–31. PMID: 10710361 Beck W, Chesler E, Schrire V. Postextrasystolic ventricular pressure responses. Circulation 1971;44:523–33. PMID: 4106154 Kvasnicka J, Liander B, Broman H, Varnauskas E. Quantitative evaluation of postectopic beats in the normal and failing human heart using indices derived from catheter-tip manometer readings. Cardiovasc Res 1975;9:336–41. PMID: 1175180 Merillon JP, Motte G, Aumont MC, et al. Post-extrasystolic left ventricular peak pressure with and without left ventricular failure. Cardiovasc Res 1979;13:338–44. PMID: 89910 Seed WA, Noble MIM, Walker JM, et al. Relationships between

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10.

11.

12.

13.

14.

15.

Post-extrasystolic blood pressure potentiation is a strong and independent risk predictor in survivors of MI and in heart failure patients. An analogous parameter (PESPAfib) can be determined in patients with atrial fibrillation. Open questions are whether PESP is suitable as a parameter for therapy monitoring and whether it may aid patient selection for prophylactic ICD therapy. ■

Clinical Perspective • Post-extrasystolic potentiation (PESP) is the increase of myocardial contractility in the heartbeat that follows a premature beat. PESP can also be measured at the blood pressure level as post-extrasystolic blood pressure potentiation. • At the blood pressure level, PESP is typically pronounced in heart failure patients. • In survivors of myocardial infarction and in patients with chronic heart failure, PESP at the blood pressure level is an independent predictor of mortality. • The suitability of PESP as a parameter to monitor heart failure treatment and as a predictor of efficacy of ICD implantation remains to be investigated.

beat-to-beat interval and the strength of contraction in the healthy and diseased human heart. Circulation 1984;70: 799–805. PMID: 6488494 Voss A, Baier V, Schumann A, et al. Postextrasystolic regulation patterns of blood pressure and heart rate in patients with idiopathic dilated cardiomyopathy. J Physiol 2002;538:271–8. PMID: 11773334; PMCID: PMC2290033 Hamby RI, Aintablian A, Roberts G, Kramer RJ. Postextrasystolic aortic pressure pulse response in coronary artery disease. Am Heart J 1978;96:195–202. DOI: 10.1016/0002-8703(78)90086-8; PMID: 79308 Hoit BD, Tramuta DA, Kadambi R, et al. Influence of transgenic overexpression of phospholamban on postextrasystolic potentiation. J Mol Cell Cardiol 1999;31:2007–15. PMID: 10591027 Iribe G, Kohl P, Noble D. Modulatory effect of calmodulindependent kinase II (cAMKII) on sarcoplasmatic reticulum Ca2+ handling and interval-force relations: a modelling study. Philos Trans A Math Phys Eng Sci 2006;364:1107–33. PMID: 16608699 Sinnecker D, Dirschinger R, Barthel P, et al. Postextrasystolic blood pressure potentiation predicts poor outcome of cardiac patients. J Am Heart Assoc 2014;3:e000857. DOI: 10.1161/ JAHA.114.000857. PMID: 24895163; PMCID: PMC4309081 Bauer A, Morley-Davies A, Barthel P, et al. Bivariate phase-

16.

17.

18.

19.

20.

rectified signal averaging for assessment of spontaneous baroreflex sensitivity: pilot study of the technology. J Electrocardiol 2010;43:649–53. DOI: 10.1016/j. jelectrocard.2010.05.012; PMID: 20638668 Hardman SMC, Noble MIM, Seed WA. Postextrasystolic potentiation and its contribution to the beat-to-beat variation of the pulse during atrial fibrillation. Circulation 1992;86:1223–32. PMID: 1382889 Endoh M. Force-frequency relationship in intact mammalian ventricular myocardium: physiological and pathophysiological relevance. Eur J Pharmacol 2004;500:73–86. PMID: 15464022 Sinnecker D, Barthel P, Huster KM, et al. Force-interval relationship predicts mortality in survivors of myocardial infarction with atrial fibrillation. Int J Cardiol 2015;182: 315–20. DOI: 10.1016/j.ijcard.2015.01.018; PMID: 25585377 Bickel H, Ander KH, Brönner M, et al. Reduction of long-term care dependence after an 8-year primary care prevention program for stroke and dementia: the INVADE trial. J Am Heart Assoc 2012;1:e000786. DOI: 10.1161/JAHA.112.000786; PMID: 23130154; PMCID: PMC3487359 Dagres N, Hindricks G. Risk stratification after myocardial infarction: is left ventricular ejection fraction enough to prevent sudden cardiac death? Eur Heart J 2013;34: 1964–71. DOI: 10.1093/eurheartj/eht10; PMID: 23644180

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Periodic Repolarisation Dynamics: A Natural Probe of the Ventricular Response to Sympathetic Activation Konstantinos D Rizas, 1,2 Wolfgang Hamm, 1,2 Stefan Kääb, 1,2 Georg Schmidt 2,3 and Axel Bauer 1,2 1. Munich University Clinic, Munich, Germany; 2. Deutsches Zentrum für Herzkreislaufforschung (DZHK), Munich, Germany; 3. Technical University of Munich, Munich, Germany

Abstract Periodic repolarisation dynamics (PRD) refers to low-frequency (≤0.1Hz) modulations of cardiac repolarisation instability. Spontaneous PRD can be assessed non-invasively from 3D high-resolution resting ECGs. Physiological and experimental studies have indicated that PRD correlates with efferent sympathetic nerve activity, which clusters in low-frequency bursts. PRD is increased by physiological provocations that lead to an enhancement of sympathetic activity, whereas it is suppressed by pharmacological b-blockade. Electrophysiological studies revealed that PRD occurs independently from heart rate variability. Increased PRD under resting conditions is a strong predictor of mortality in post-myocardial infarction (post-MI) patients, yielding independent prognostic value from left-ventricular ejection fraction (LVEF), heart rate variability, the Global Registry of Acute Coronary Events score and other established risk markers. The predictive value of PRD is particularly strong in post-MI patients with preserved LVEF (>35 %) in whom it identifies a new high-risk group of patients. The upcoming Implantable Cardiac Monitors in High-Risk Post-Infarction Patients with Cardiac Autonomic Dysfunction and Moderately Reduced Left Ventricular Ejection Fraction (SMART-MI) trial will test prophylactic strategies in high-risk post-MI patients with LVEF 36–50 % identified by PRD and deceleration capacity of heart rate (NCT02594488).

Keywords myocardial infarction, periodic repolarisation dynamics, risk stratification, spatial dispersion of repolarisation, sudden death, sympathetic nervous system Disclosure: The authors have no conflicts of interest to declare. Received: 18 December 2015 Accepted: 18 April 2016 Citation: Arrhythmia & Electrophysiology Review 2016;5(1):31–6 Access at: www.AERjournal.com DOI: 10.15420/AER.2015:30:2 Correspondence: Prof. Dr. med. Axel Bauer, Medizinische Klinik und Poliklinik I, Munich University Clinic, Marchioninistr. 15,81377 München. E: axel.bauer@med.uni-muenchen.de

Experimental and clinical studies have demonstrated that enhanced sympathetic autonomic nervous system (SANS) activity can destabilise myocardial repolarisation,1–4 increasing vulnerability to developing fatal cardiac arrhythmias.5–8 Accordingly, assessment of SANS activity has always been a major goal for cardiac risk stratification methods. Various non-invasive methods including assessment of heart rate variability (HRV) and baroreflex sensitivity have been employed to study the activity of the SANS under routine clinical conditions.9 These methods are based on two principles. First, activation of the SANS evokes physiological effects on the cardiovascular system, such as acceleration of heart rate, increased vasomotor tone or systolic contractility.4 Second, as SANS activity is clustered in low-frequency bursts, SANS-induced physiological responses are likely to exhibit low-frequency dynamics.10–14 Previous studies have shown that SANS assessment based on HRV and baroreflex sensitivity is a marker of increased vulnerability to fatal cardiac arrhythmias.15,16 However, both methods are limited by the fact that they only provide an indirect probe of the sympathetic effect on cardiac repolarisation, as they reflect influences on the sinoatrial node and blood vessels and not on the ventricular myocardium. In addition, both HRV and baroreflex sensitivity are confounded by the concomitant action of other systems exhibiting periodic dynamics, such

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as the parasympathetic nervous system and the renin–angiotensin– aldosterone system, respectively. We proposed a novel approach to SANS assessment that substantially differs from previous methods.17 So-called periodic repolarisation dynamics (PRD) evaluates sympathetic activity-associated lowfrequency periodic changes of cardiac repolarisation instability and opens new perspectives for identifying high-risk patients, who would potentially benefit from prophylactic interventions. The first section of this review briefly depicts the methodology of PRD assessments. The second section focuses on potential mechanisms of PRD. In the third section, the clinical application of PRD as risk predictor after myocardial infarction (MI) is presented. In the fourth section, we present an alternative method for PRD assessment, which provides some technical advantages over the standard method. The final sections are dedicated to ongoing and future projects aimed at developing individualised treatment strategies.

Methodology of Periodic Repolarisation Dynamics Assessment PRD is typically assessed using a high-resolution ECG recorded in or converted to the three orthogonal axes X, Y and Z (‘Frank lead configuration’). As low-frequency patterns are of interest, the recording

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Arrhythmia Mechanisms Figure 1. Calculation of Periodic Repolarisation Dynamics A

-Y X Z

-Y

16 Power (deg2)

dTº (deg rad)

100

200 T-wave number (#)

n-50

12 8

PRD

4 0

0.1

0.2 0.3 0.4 (Pseudo-) frequency (Hz)

0.5

A: Assessment of PRD using a surface ECG recorded in the Frank leads configuration. B: Each T-wave is condensed into a weight-averaged vector of repolarisation (T°). B and C: The angle dT° between two successive repolarisation vectors T° is illustrated in the virtual spheres (B) and is calculated for the entire ECG (C). D: The emerging signal features periodic modulations in the low-frequency range (red line). PRD was quantified by means of wavelet analysis. PRD = periodic repolarisation dynamic.

time should be >10 minutes, although PRD has also been assessed in shorter time periods.17 Ideally, the ECG is performed under strict standardised conditions in the supine position. The technique used to calculate PRD is briefly illustrated in Figure 1.17 In a first step, the ECG is converted to a set of polar coordinates defined by two angles (azimuth and elevation) and the ‘resultantforce’ amplitude (Amp). The beginning and ending of each T-wave are identified using previously published algorithms.18,19 In a second step, the spatiotemporal characteristics of each T-wave are mathematically integrated into a single vector T° (see Figure 2), defined by the so-called weight-averaged azimuth (WAA) and weight-averaged elevation (WAE). The computation of WAA and WAE are given by Equations 1 and 2, respectively:

In a third step, the instantaneous degree of repolarisation instability is estimated by the angle dT° between successive repolarisation vectors. dT° can be calculated as the scalar product of two successive repolarisation vectors T°, which by two vectors of the same length r can be simplified by Equation 3 (see Figure 2):

dT º = a cos [sin(WAE1)*cos(WAA1)*sin(WAE2)*cos(WAA2) + cos(WAE1)*cos(WAE2) + sin(WAE1)*sin(WAA1)*sin(WAE2)*sin(WAA2)] (Equation 3) In a final step, low-frequency (≤0.1 Hz) oscillations are quantified within the dT° signal by means of a continuous wavelet transformation (PRDwavelet; see Figure 1D).17

Potential Mechanisms of Periodic Repolarisation Dynamics The exact mechanisms underlying PRD are still unknown. However, it is most likely that PRD represents the effect of the sympathetic nervous system on the myocardium.

Of note, WAE and WAA are weighted by Amp. This means that each point of the T-wave contributes proportionately to its absolute amplitude to the final direction of vector T°. Accordingly, the boundaries of the T-wave are less crucial than the T-wave peak.

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First, PRD mimics the characteristic low-frequency pattern of efferent sympathetic activity. 11,12,14 Low-frequency patterns can also be found in other biological time series such as heart rate or arterial blood pressure, where they have been shown to correlate with low-frequency sympathetic bursts (muscle sympathetic nervous activity).10 Moreover, the amplitude of these oscillations has been shown to be related to the level of sympathetic stimulation. For instance, Pagani et al. showed that sympathetic activation provoked by infusion of nitroprusside in healthy human subjects increased low-frequency oscillations of heart rate and systolic arterial blood pressure.10

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Figure 2: Calculation of the Angle dT° Between Two Successive Repolarisation Vectors T1 and T2

Figure 3: Periodic Repolarisation Dynamics in post-MI Patients A

120 Original signal

y Tx = r * sin(WAE) * cos(WAA) Ty = r * cos(WAE) Tz = r * sin(WAE) * sin(WAA)

T= r

80 dTº (deg rad)

Ty WAE

Tz z

WAA

Low-pass filtered signal

100

Txz 20

dTº = acos [sin(WAE1) * cos(WAA1) * sin(WAE2) * cos(WAA2) + cos(WAE1) * cos(WAE2) + sin(WAE1) * sin(WAA1) * T2 sin(WAE2) * sin(WAA2)]

120

100

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200 250 Beat number

300

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Original signal Low-pass filtered signal

100

dTº (deg rad)

Second, indirect evidence comes from physiological and pharmacological studies. Provocations such a tilt test or exercise led to increased PRD in healthy individuals, while pharmacological blockade of the sympathetic nervous system by b-blockers suppressed PRD.17 PRD remained intact after elimination of HRV and respiratory variability using fixed atrial pacing in patients during an electrophysiological study and fixed-rate, volume-controlled ventilation in a swine model, respectively.17 Third, a potential electrophysiological correlate of PRD was identified by Hanson et al.20 The authors assessed action potential durations (APDs) from unipolar electrograms in patients with heart failure invasively recorded during an electrophysiology study and demonstrated a low-frequency pattern of APD. Although the correlation of oscillations of APD with PRD was not tested in that study, it is likely that both oscillations are driven by the same mechanism. The mechanistic link of low-frequency sympathetic activity to periodic changes in cardiac repolarisation requires further investigation. A possible mechanism could involve non-uniform response of ventricular myocardial cells to sympathetic activation. Generally, sympathetic activation results in a shortening of APD. Studies conducted over the past few decades demonstrated that the ventricular myocardium is not homogenous, but is comprised of at least three different cell types (epicardial cells, M cells and endocardial cells) with distinct electrophysiological characteristics and pharmacological properties.21 The electrical heterogeneity between the three cell types of ventricular myocardium creates transmural and apico-basal voltage gradients during the repolarisation phase, causing inscription of the T-wave on the surface ECG.22 It has been shown that the myocardial cells of

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0 C

100

150

200 250 Beat number

PRDwavelet≥5.75deg2 PRDwavelet<5.75deg2

Mortality (%)

Projection of a vector T on the three orthogonal axes X, Y and Z (upper panel). Two repolarisation vectors T1 and T2 with length r are projected on a virtual sphere (lower panel). The dot product of the two vectors is used to calculate the angle dT° between T1 and T2. WAA = weight-averaged azimuth; WAE = weight-averaged elevation.

Log-rank=49.1, P<0.001

3 2 Years elapsed

227

214

205

681

672

666

196

189

175

659

647

608

Typical dT° signals obtained from post-MI patients who survived (A, green line) and did not survive (B, red line) the 5-year follow-up period. Both signals show characteristic low-frequency oscillations (black line). However, the amplitude of those oscillations is substantially enhanced in the non-survivor. Cumulative mortality rates of patients stratified by PRD ≥5.75 deg2 (C). PRD = periodic repolarisation dynamic.

the various cell layers respond differently to sympathetic activation. Therefore, theoretically sympathetic activation should lead to changes in the spatio-temporal properties of the T-wave in the surface ECG, which are captured by PRD. The heterogeneity of sympathetically induced APD changes can be augmented in various diseases, including MI,4 diabetes mellitus23 and inherited channelopathies.2,24

Periodic Repolarisation Dynamics as a Risk Predictor After Myocardial Infarction The prognostic significance of PRD has been tested in a cohort of 908 survivors of acute MI of the Autonomic Regulation Trial.17 The primary endpoint was all-cause mortality. In the first 5 years of follow-up, 69 patients died. Figure 3 shows typical dT° signals in surviving and nonsurviving patients. In both signals, low-frequency oscillations of dT°

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Arrhythmia Mechanisms Figure 4: PRD PRSA as Predictor of Mortality after Myocardial Infarction A

Mortality (%)

PRDPRSA

Relative dTº (deg rad)

-5

anchor points -40

-20 0 20 PRSA beat number

Non-survivor Survivor 40

60 D

1.0

0.1

242 666

228 658

216 655

206 649

198 638

184 599

PRDPRSA≥4.16º and DM

0.3 Mortality (%)

0.6

3 Years elapsed

0.4

0.8

Sensitivity

0.2

0.0

-10

PRDPRSA<4.16º

Log-rank=64.3, P<0.0001

0.3

-60

PRDPRSA≥4.16º

0.4

PRDPRSA≥4.16º and no DM PRDPRSA<4.16º and DM

PRDPRSA<4.16º and no DM

0.2

Log-rank=126, P<0.001, 3 df 0.1

0.4 0.0 0.2 0.0 1.0

0.8

0.6 0.4 Specificity

0.2

0.0

49 193 130 536

42 186 128 530

2 3 Years elapsed 36 31 180 175 127 124 528 525

29 169 123 515

28 156 117 482

A: PRSA transformation of the signals in Figures 3A and 3B. The emerging PRSA signals highlight the periodic components of the dT° signals into a condensed signal consisting of a total of 120 beats around a the central convergence of all anchor points (point 0). The magnitude of the oscillations is quantified by means of PRDPRSA, which is a measure of the amplitude of central part of the PRSA curves. B: Cumulative mortality rates of patients stratified by PRDPRSA ≥4.16 deg2. C: Receiver-operator characteristic curve of PRDPRSA for prediction of 5-year total mortality in the subgroup of patients with DM (n=179). The AUC for this curve was computed to 83.58 %. D: Cumulative mortality rates of patients stratified by PRDPRSA ≥4.16 deg2 and presence of DM. AUC = area under the curve; DM = diabetes mellitus; PRD = periodic repolarisation dynamic; PRSA = phase-rectified signal averaging.

were present, but in the non-surviving patient the amplitude of these oscillation was much more pronounced. For survival analyses, PRDwavelet was dichotomised at the upper quartile of the study population.17 The 5-year mortality rate in the group of the 227 patients with PRDwavelet ≥5.75 deg2 was 18.2 % compared with 4.1 % in the 681 patients with PRDwavelet <5.75 deg2 (P<0.001; see Figure 3B). In multivariable analyses PRDwavelet was revealed to be a strong predictor of mortality after MI and its predictive ability was independent from established risk predictors, such as left-ventricular ejection fraction (LVEF), the Global Registry of Acute Coronary Events (GRACE) score, presence of diabetes mellitus, reduced HRV and increased QT-variability index.

Alternative Quantification of Periodic Repolarisation Dynamics by Means of Phase-rectified Signal Averaging The original assessment of PRD from the dT° signal includes continuous wavelet transformation, which requires some computational resources and which might not be available in all software packages. In this section, we therefore describe an alternative method to quantify PRD from the dT° signal using the technique of phase-rectified signal averaging (PRSA). PRSA is a mathematical procedure that allows the extraction of periodicities from complex time series that might include non-stationarities, noise and artefacts.25 PRSA has been originally used to detect deceleration-related (deceleration capacity; DC) and acceleration-related (acceleration capacity; AC) modulations of heart rate. DC has been shown to yield strong and independent prognostic information in survivors of acute MI.26 The PRSA technique consists of a three-step procedure and allows for several adjustments, which can optimise the method to the particular signal analysed and the

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frequency range of the detected oscillations. In the first step, anchor points are selected according to certain properties of the signal. In the case of the dT° signal we defined absolute angle increases greater than 1.25° (deg rad) as anchor points. To amplify the low-frequency periodicities, a low-pass filter of T=9 (average of nine successive beats) is intentionally set up for the selection of anchor points. Although the PRSA technique is able to detect oscillations in a wide frequency range, it has been shown mathematically to be more sensitive for strictly periodic oscillations with frequency {f=1/[2.7*T]}. This means that for frequencies between 0.025 and 0.1 Hz the optimal T ranges between 4 and 15. To maximise the sensitivity at the centre of our spectrum while maintaining a good sensitivity at the boundaries of the frequency range, we used the mean value of T=9. In the second step of the PRSA method, windows (L) around each anchor points are defined to both the left and right of the anchor point (in this case L=60 beats). Finally, in the third step, a new PRSA signal is obtained by averaging over all windows. The central part of the PRSA signal (see Figure 4A) is then quantified by Haar wavelet analysis and is defined as PRDPRSA. Table 1 depicts the Spearman’s correlation coefficients between different repolarisation parameters in the 908 patients of the Autonomic Regulation Trial. The correlation coefficient between PRDPRSA and PRDwavelet was 0.854 (95 % CI [0.835–0.871]; P<0.001; see Table 1). Of interest, the correlation of PRDPRSA and PRDwavelet with other ECGbased measures of repolarisation was weak (see Table 1). Figure 4A illustrates the corresponding PRSA transformations of the dT° signals illustrated in Figure 3. PRDPRSA was significantly associated with mortality (4.99° [interquartile range (IQR) 3.19] in non-survivors versus 2.58° [IQR 2.29] in survivors; P<0.001). To identify the optimal cut-off value for

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Table 1: Spearman’s Correlation Coefficient Between Different Repolarisation Parameters r [95 % CI]

PRD wavelet

PRDPRSA

Tduration

Tpeak-end

TAUC

PRDwavelet

0.85 [0.83 - 0.87]

0.21 [0.14 - 0.27]

0.27 [0.21 - 0.33]

-0.33 [-0.28 - -0.39]

PRDPRSA

0.85 [0.83 - 0.87]

0.20 [0.13 - 0.26]

0.24 [0.18 - 0.30]

-0.16 [-0.10 - -0.22]

Tduration

0.21 [0.14 - 0.27]

0.20 [0.13 - 0.26]

0.91 [0.89 - 0.92]

0.16 [0.10 - 0.22]

Tpeak-end

0.27 [0.21 - 0.33]

0.24 [0.18 - 0.30]

0.91 [0.89 - 0.92]

0.08 [0.01 - 0.14]

TAUC

–0.33 [-0.28 - -0.39]

–0.16 [-0.10 - -0.22]

0.16 [0.10 - 0.22]

0.08 [0.01 - 0.14]

AUC = area under the curve; PRD = periodic repolarisation dynamic; PRSA = phase-rectified signal averaging.

PRDPRSA we used log-rank statistics for all possible cut-off values. The maximum log-rank value was achieved with a cut-off value of 4.16. Figure 4B shows 5-year cumulative mortality rates stratified according to patients with PRDPRSA ≥4.16° and <4.16°. The 242 patients classified to the high-risk group (PRDPRSA ≥4.16°) had a 5-year mortality rate of 19.1 %, compared with 3.5 % for the 666 patients belonging to the low-risk group (PRDPRSA <4.16°). Multivariable analyses revealed that PRDPRSA was a strong predictor of mortality that was independent from LVEF ≤35 %, the GRACE score, HRV and other established risk markers. Sympathetic-associated modulations of repolarisation might be of great prognostic value in patients with inhomogeneous innervation of the ventricular myocardium. We therefore tested the predictive power of PRDPRSA in a subgroup of 179 patients suffering from diabetes mellitus. PRDPRSA was significantly associated with all-cause mortality in this subgroup. Receiver operating characteristics analysis revealed an area under the curve (AUC) of 83.58 % (see Figure 4C; 95 % CI [73.10–91.00]) for prediction of 5-year mortality. Figure 4D depicts risk stratification by PRDPRSA in patients with diabetes (red and blue curves) and those without diabetes (green and black curves). The 49 patients with diabetes with abnormal PRDPRSA values have the worst prognosis with a cumulative 5-year mortality rate of 40.80 %.

New Perspectives in Risk Stratification and Risk Reduction Strategies Periodic Repolarisation Dynamics in Patients With Inherited Channelopathies Increased sympathetic activity is associated with unfavourable outcomes not only in post-MI patients, but also in patients with inherited channelopathies such as the long-QT syndrome.2 Assessment of PRD in this group of patients would be of great clinical interest and might open a new era in the identification of high-risk individuals.

The SMART-MI Study Future interventional studies are needed to test whether high-risk patients identified by PRD or other markers benefit from prophylactic strategies. Considering the fact that prevention of malignant arrhythmias is one of the main goals, prophylactic implantable

1. 2.

4. 5. 6.

Lown B, Verrier RL. Neural activity and ventricular fibrillation. N Engl J Med 1976;294:1165–70. PMID: 57572. Verrier RL, Antzelevitch C. Autonomic aspects of arrhythmogenesis: the enduring and the new. Curr Opin Cardiol 2004;19:2–11. PMID: 14688627. Cao JM, Fishbein MC, Han JB, et al. Relationship between regional cardiac hyperinnervation and ventricular arrhythmia. Circulation 2000;101:1960–9. PMID: 10779463. Rubart M, Zipes DP. Mechanisms of sudden cardiac death. J Clin Invest 2005;115:2305–15. PMID: 16138184. Han J, Garcia de Jalon P, Moe GK. Adrenergic effects on ventricular vulnerability. Circ Res 1964;14:516–24. PMID: 14169970. Maling HM, Moran NC. Ventricular arrhythmias induced by sympathomimetic amines in unanesthetized dogs following coronary artery occlusion. Circ Res 1957;5:409–13.

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cardioverter defibrillator implantation might appear to be the most logical approach. However, it might not be the only one. In the Cardiac Arrhythmias and Risk Stratification After Acute Myocardial Infarction (CARISMA) trial, implantable cardiac monitors (ICMs) were used to ultimately detect arrhythmias in high-risk post-MI patients characterised by LVEF ≤40 %.27 Predefined arrhythmias including AF as well as relevant brady- and tachyarrhythmias could be recorded with a high prevalence (46 % of the patients). Importantly, most of the detected arrhythmias (86 %) were initially asymptomatic, but predicted increased mortality risk, suggesting a potential window of opportunity for pre-emptive interventions. The upcoming Implantable Cardiac Monitors in High-Risk PostInfarction Patients With Cardiac Autonomic Dysfunction and Moderately Reduced Left Ventricular Ejection Fraction (SMART-MI) study will test such an approach (Clinicaltrials.gov ID NCT02594488). Survivors of acute MI and LVEF 36–50 % will undergo autonomic testing for the presence of abnormal PRD17or DC.26 Patients with autonomic abnormalities will be randomised to ICM-based or conventional follow-up. Treatment paths have been developed for different kinds of arrhythmias including diagnostic work-up as well as medical or interventional treatments. The primary endpoint will be the time to detection of predefined relevant brady- and tachyarrhythmic events. The effect on clinical endpoints will be tested secondarily.

Conclusion Spontaneous cardiac repolarisation instability is subject to rhythmic modulations in the low-frequency range (≤0.1Hz), which can be noninvasively assessed using 3D high-resolution ECGs. PRD most likely reflects the response of the ventricular myocardium to sympathetic activation. Factors that predispose to an inhomogeneous sympathetic innervation such as history of MI or diabetes mellitus are associated with increased PRD. In post-MI patients, increased PRD is a strong and independent predictor of mortality. PRSA-based assessment of PRD is a valuable alternative to the more complex conventional waveletbased PRD assessment. Future interventional studies are needed to test whether PRD-based risk prediction can be translated into risk reduction. n

PMID: 13447186. Kliks BR, Burgess MJ, Abildskov JA. Influence of sympathetic tone on ventricular fibrillation threshold during experimental coronary occlusion. Am J Cardiol 1975;36:45–9. PMID: 1146697. 8. Butrous GS, Gough WB, Restivo M, et al. Adrenergic effects on reentrant ventricular rhythms in subacute myocardial infarction. Circulation 1992;86:247–54. PMID: 1617776. 9. Verrier RL, Kumar K, Nearing BD. Basis for sudden cardiac death prediction by T-wave alternans from an integrative physiology perspective. Heart Rhythm 2009;6:416–22. DOI: 10.1016/j.hrthm.2008.11.019; PMID: 19251221. 10. Pagani M, Montano N, Porta A, et al. Relationship between spectral components of cardiovascular variabilities and direct measures of muscle sympathetic nerve activity in humans. Circulation 1997;95:1441–8. PMID: 9118511.

11. Malliani A, Pagani M, Lombardi F, Cerutti S. Cardiovascular neural regulation explored in the frequency domain. Circulation 1991;84:482–92. PMID: 1860193. 12. Pagani M, Lombardi F, Guzzetti S, et al. Power spectral analysis of heart rate and arterial pressure variabilities as a marker of sympatho-vagal interaction in man and conscious dog. Circ Res 1986;59:178–93. PMID: 2874900. 13. Montano N, Lombardi F, Gnecchi Ruscone T, et al. Spectral analysis of sympathetic discharge, R-R interval and systolic arterial pressure in decerebrate cats. J Auton Nerv Syst 1992;40:21–31. PMID: 1401724. 14. Furlan R, Porta A, Costa F, et al. Oscillatory patterns in sympathetic neural discharge and cardiovascular variables during orthostatic stimulus. Circulation 2000;101:886–92. PMID: 10694528.

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Arrhythmia Mechanisms 15. Billman GE, Schwartz PJ, Stone HL. Baroreceptor reflex control of heart rate: a predictor of sudden cardiac death. Circulation 1982;66:874–80. PMID: 7116603. 16. Schmidt G, Malik M, Barthel P, et al. Heart-rate turbulence after ventricular premature beats as a predictor of mortality after acute myocardial infarction. Lancet 1999;353:1390–6. PMID: 10227219. 17. Rizas KD, Nieminen T, Barthel P, et al. Sympathetic activityassociated periodic repolarization dynamics predict mortality following myocardial infarction. J Clin Invest 2014;124:1770–80. DOI: 10.1172/JCI70085; PMID: 24642467. 18. Laguna P, Jané R, Caminal P. Automatic detection of wave boundaries in multilead ECG signals: validation with the CSE database. Comput Biomed Res 1994;27:45–60. PMID: 8004942. 19. Pan J, Tompkins WJ. A real-time QRS detection algorithm. IEEE Trans Biomed Eng 1985;32:230–6. PMID: 3997178.

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20. Hanson B, Child N, Van Duijvenboden S, et al. Oscillatory behavior of ventricular action potential duration in heart failure patients at respiratory rate and low frequency. Front Physiol 2014;5:414. DOI: 10.3389/fphys.2014.00414; PMID: 25389408. 21. Antzelevitch C. Transmural dispersion of repolarization and the T wave. Cardiovasc Res 2001;50:426–31. PMID: 11376617. 22. Antzelevitch C. Cellular basis for the repolarization waves of the ECG. Ann N Y Acad Sci 2006;1080:268–81. PMID: 17132789. 23. Wei K, Dorian P, Newman D, Langer A. Association between QT dispersion and autonomic dysfunction in patients with diabetes mellitus. J Am Coll Cardiol 1995;26:859–63. PMID: 7560609. 24. Antzelevitch C. Role of spatial dispersion of repolarization in inherited and acquired sudden cardiac death syndromes.

Am J Physiol Heart Circ Physiol 2007;293:H2024–38. PMID: 17586620. 25. Bauer A, Kantelhardt J, Bunde A, et al. Phase-rectified signal averaging detects quasi-periodicities in non-stationary data. Physica A 2006;364:423–34. DOI:10.1016/j.physa.2005.08.080. 26. Bauer A, Kantelhardt JW, Barthel P, et al. Deceleration capacity of heart rate as a predictor of mortality after myocardial infarction: cohort study. Lancet 2006;367:1674–81. PMID: 16714188. 27. Bloch-Thomsen P-E, Jons C, Raatikainen MJ, et al. Longterm recording of cardiac arrhythmias with an implantable cardiac monitor in patients with reduced ejection fraction after acute myocardial infarction: the Cardiac Arrhythmias and Risk Stratification After Acute Myocardial Infarction (CARISMA) study. Circulation 2010;122:1258–64. DOI: 10.1161/ CIRCULATIONAHA.109.902148; PMID: 20837897.

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Arrhythmia Mechanisms

Microvolt T-wave Alternans: Where Are We Now? Aa po L A r o, 1 Tu o m a s V Ke n t t ä , 2 H e i k k i V H u i k u r i 2 1. Helsinki University Hospital, Helsinki, Finland; 2. University Hospital of Oulu and University of Oulu, Oulu, Finland

Abstract Microvolt T-wave alternans (TWA), characterised as beat-to-beat fluctuation of T-wave amplitude and morphology, is an electrophysiological phenomenon associated clinically with impending ventricular arrhythmias and is an important marker of arrhythmia risk. Currently, two main methods for the detection of TWA exist, namely, the spectral method and the time-domain modified moving average method; both are discussed in this review. Microvolt TWA has been associated with cardiovascular mortality and sudden cardiac death in several clinical studies involving >14,000 subjects with reduced as well as preserved left ventricular function. Although TWA appears to be a useful marker of susceptibility for lethal ventricular arrhythmias and cardiovascular death, so far there is no sufficient evidence from randomised clinical trials to support its use in guiding therapy. However, several ongoing trials are expected to provide more information about the clinical use of TWA testing.

Keywords Alternans, electrocardiogram, lethal arrhythmias, repolarisation, risk stratification, sudden death Disclosure: The authors have no conflicts of interest to declare. Acknowledgements: Heikki Huikuri was supported in part by Medtronic Bakken Research Center and by EU-CERT-ICD Collaboration Project funded by the European Union under the 7th Framework Programme under grant agreement no. 602299. Received: 16 December 2015 Accepted: 21 March 2016 Citation: Arrhythmia & Electrophysiology Review 2015;5(1):37–40 Access at: www.AERjournal.com DOI: 10.15420/AER.2015.28.1 Correspondence: Heikki Huikuri, Medical Research Center, Research Unit of Internal Medicine, University Hospital of Oulu and University of Oulu, P.O. Box 5000, 90014 Oulu, Finland. E: heikki.huikuri@oulu.fi

Sudden cardiac death (SCD) is a major public health concern worldwide, accounting for 50 % of cardiovascular mortality.1 Reduced left ventricular ejection fraction (LVEF) is presently used to identify patients at high risk for primary prevention using implantable cardioverter defibrillator (ICD) therapy, but currently only a minority of patients meeting the criteria for prophylactic ICD receive lifesaving therapies from the device.2 On the other hand, in absolute numbers, the majority of SCDs occur among individuals considered to be at low risk based on LVEF, which has promoted vast interest in developing additional risk markers in order to identify these patients before the fatal event. As the immediate mechanisms of SCD are primarily electrical, much of the research has focused on different electrocardiographic risk markers.3

Physiological Bases of T-wave Alternans Microvolt T-wave alternans (TWA), a subtle beat-to-beat fluctuation in the morphology and amplitude of the ST-segment and T-wave, has emerged as a promising tool to estimate risk of mortality and SCD in patients with cardiac disease. It reflects spatiotemporal heterogeneity of repolarisation that stems from beat-to-beat alterations in intracellular calcium handling, which is reflected in the shape and duration of the action potential at the level of cardiac myocytes (see Figure 1). These local differences in the repolarisation of the neighbouring myocardial regions can ultimately predispose the individual to lethal arrhythmias such as ventricular tachycardia or ventricular fibrillation.4 Several physiological as well as pathological conditions can alter the levels of TWA, and the magnitude of TWA and risk of arrhythmias often

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concur. Conditions that are associated with increased risk of ventricular arrhythmias (e.g. increased heart rate, ventricular premature beats, coronary ischaemia and adrenergic stimulation) also amplify TWA, and conversely, interventions such as b-blockers, sympathetic denervation and vagus nerve stimulation that reduce susceptibility to ventricular arrhythmias also cause TWA to diminish.5

T-wave Alternans Analysis Techniques To analyse the microvolt level alternations in the ST-segment and T-wave, special equipment and/or software are needed. Several analysis methods have been proposed over the past three decades,6,7 but two of the most widely used TWA analysis techniques in clinical studies are the spectral method8 and the modified moving average (MMA) method.9 Both of these methods perform similarly in terms of risk prediction,5,10 but there are significant differences in their implementation and interpretation. The spectral method was first described nearly three decades ago.11 It requires the patient to achieve a target heart rate of 105–110 beats per minute for a period of time using a specialised exercise protocol, pharmacological agents or atrial pacing. As opposed to the time-domain MMA method, the spectral method also requires the use of proprietary high-resolution electrodes. In the spectral method, a composite power spectrum of the ST–T segment amplitude fluctuations is formed by applying fast Fourier transform technique to the beat-to-beat series of amplitude measurements along the JT-interval in 128 consecutive QRS-aligned ECG complexes (see Figure 2). The alternans voltage is defined as the square root of the spectral power occurring at the alternans frequency (0.5 cycles/beat) after noise reduction, which corresponds to the

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Arrhythmia Mechanisms Figure 1. Electrocardiographic Tracing Acquired During Coronary Occlusion in a Porcine Model Showing a Visible T-Wave Alternans Pattern at the Level of 162 µV

Figure 2. T-wave Alternans Assessment with the Spectral Method ECG (128 beats)

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difference in voltage between the overall average beat and either the averaged even or odd-numbered beat (i.e. half of the difference between the averaged even and odd beats). A TWA level ≥1.9 µV with sufficient signal-to-noise ratio for >2 min is defined as a positive test result, while a TWA level <1.9 µV is considered negative. However, as the spectral method requires a stable target heart rate to be achieved, a relatively large proportion (approximately 20–40 %) of tests are classified as ‘indeterminate’, either due to patient-related factors such as failure to achieve the target heart rate, excessive ventricular ectopy, atrial fibrillation or unsustained TWA, or technical problems such as noise in the recording.5 The MMA method is time-domain based, and employs recursive averaging (see Figure 3). The algorithm continuously streams odd and even beats into separate bins and creates averaged complexes for both bins. These complexes are then superimposed, and the maximum difference between the odd and even complexes at any point within the JT-segment is averaged for every 10 or 15 seconds and reported as the TWA value. The MMA method allows TWA analysis during routine exercise stress testing and also during 24-hour ambulatory ECG monitoring. No special electrodes are required using this technique, and as no target heart rate is required, indeterminate results are infrequent with the MMA method. Risk stratification is based on the peak TWA value using the MMA, and based on the study population, cut-off levels of ≥47 µV and ≥60 µV have been most commonly used to define abnormal and severely abnormal TWA, respectively.5

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Prognostic Significance of T-wave Alternans Microvolt TWA has been associated with cardiovascular mortality and SCD in numerous studies involving >14,000 individuals with both ischaemic and non-ischaemic cardiomyopathy, and with reduced as well as preserved left ventricular function. These prognostic implications were independent from several demographic and clinical factors associated with coronary artery disease and SCD, including LVEF. The spectral method has demonstrated TWA to be predictive of future cardiovascular events in >8,000 patients mostly with ischaemic heart disease and prior MI, but also in non-ischaemic cardiomyopathy and heart failure.5 In most of these studies, the risk associated with TWA has been at least two- to threefold,5 but much higher hazard ratios have been reported in some patient groups.12,13 Indeterminate test results have been shown to predict mortality at least as well as positive tests,14 thus positive and indeterminate test results are often pooled together as ‘non-negative’ TWA, and compared with negative TWA.15 In some studies, the spectral method has failed to demonstrated significant association between TWA and SCD or mortality. These negative results are at least partly due to discontinuation of b-blocker therapy before the test,16 TWA testing shortly after occurrence of MI during ongoing remodelling17,18 and using ICD discharge as the endpoint.19 The prognostic significance of the MMA method has been demonstrated in >6,000 patients with reduced and preserved LVEF, including those with coronary artery disease and prior MI.5 To date, the largest study on TWA is the Finnish Cardiovascular Study (FINCAVAS) with nearly 3,600 patients with generally preserved left ventricular function referred to routine exercise testing and analysed using the MMA method.20,21 TWA was demonstrated to be associated with increased cardiovascular mortality and SCD rates, with higher TWA values indicating greater risk. In a meta-analysis on TWA in the setting of ambulatory ECG, the group with positive TWA had over a sevenfold risk of SCD compared with those with negative TWA.22

T-wave Alternans-guiding Prophylactic Implantable Cardioverter Defibrillator Therapy As it is well known that only a minority of patients qualifying for prophylactic ICD based on reduced LVEF ≤35 % receive appropriate therapies from the device,2 many TWA studies have tried to distinguish patients who are likely to benefit from ICD therapy from those that are not. In a pooled cohort of patients with EF ≤35 % but no ICD therapy, negative TWA was associated with a low incidence of SCD, compared with substantial SCD risk associated with both positive TWA and indeterminate TWA.23 In another study among patients with ischaemic cardiomyopathy, ICDs were associated with lower all-cause mortality rate in patients with non-negative TWA, but not in patients with negative TWA.24 However, in the Microvolt T Wave Alternans Testing for Risk Stratification of Post MI Patients (MASTER I) study (ClinicalTrials.gov ID NCT00305240), which enrolled MADIT-II (Second Multicenter Automated Defibrillator Implantation Trial) type ICD-patients with LVEF ≤30 %, risk of ventricular arrhythmias did not differ according to TWA classification, despite differences in total mortality rates.25 Similar results have been reported from a SCD-HeFT ICD-study (Sudden Cardiac Death in Heart Failure Trial; NCT00000609), in which TWA could not predict arrhythmic events or mortality.26 These results have been partly attributed to the use of ICD discharge as an endpoint, which may have underestimated the use of TWA.19 The ABCD (Alternans Before Cardioverter Defibrillator;

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Microvolt T-wave Alternans

NCT00187291) trial tested whether TWA can guide ICD therapy in patients with ischaemic cardiomyopathy and non-sustained ventricular tachycardia.27 Event rates were over twofold higher both among patients with positive TWA and positive electrophysiological study at the pre-specified 1-year endpoint. However, TWA did not predict endpoint events at 2 years.

Figure 3: T-wave Alternans Measurement with the Modified Moving Average Method

Modification of T-wave Alterans Pharmacological therapy with b-blockers significantly reduces the level of TWA, and can convert a positive test to negative in approximately in half of the cases.28 It is reasonable to assume, that while b-blockers may alter the development of TWA, they may similarly modulate susceptibility to ventricular arrhythmias. In a meta-analysis among patients with left ventricular dysfunction on continuous b-blocker therapy, abnormal TWA testing was associated with a fivefold risk of ventricular arrhythmic events, whereas only weak association was noted in studies on which b-blocker therapy was withheld prior to screening.16 Consequently, any TWA testing is suggested to be performed under continuous medical therapy. Recent evidence suggests that TWA may also detect influences of non-pharmacological interventions that are known to be associated with reduced mortality rates as well. In patients with stable coronary artery disease, exercise rehabilitation reduced TWA levels both patients with and without diabetes, and during the 2-year follow-up a large proportion of the patients with positive TWA converted to negative TWA.29 Thus, TWA seems to be a method that may capture and quantify influence of mainstream clinical interventions to arrhythmia susceptibility.

Role of T-wave Alternans Testing to Guide Therapy in Clinical Practice A large body of literature has accumulated on the potential of microvolt TWA to assess cardiovascular risk in a broad range of patients with cardiac disease beyond traditional cardiovascular risk markers or left ventricular function. There is also emerging evidence that quantitative TWA assessment might be useful to determine the efficacy of clinical interventions such as pharmacological therapy and cardiac rehabilitation.30 According to the REFINE (Risk Estimation Following Infarction Noninvasive Evaluation; NCT00399503) study, TWA testing should be performed only 10 to 14 weeks after an MI, as TWA testing in the early recovery period did not reliably identify patients at long-term risk of cardiac death.10 It should be performed on permanent medication, as halting b-blocker medication prior to TWA affects the results and does not reflect the long-lasting circumstances.16 Repeated annual testing has been also suggested, as an individual’s vulnerability to ventricular arrhythmias may change over time.19 What are the current recommendations on the use of TWA? An expert consensus statement by the American Heart Association/American College of Cardiology Foundation on risk stratification techniques on SCD in 2008 asserted that TWA may be useful for SCD risk stratification, but further information is needed on how to implement this test in clinical practice.31 Similar recommendations were provided in a consensus document focusing specifically on TWA in 2011.5 The paper concluded that it is reasonable to consider TWA evaluation when there is suspicion of vulnerability to lethal arrhythmias, but also acknowledged that there is not sufficient evidence from interventional trials to suggest that TWA can be used to guide therapy. However, the recent European

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Beat separation

Averaged beat

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Averaged beat

Society of Cardiology guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death made no recommendations for the use of TWA in risk assessment.32 Although abnormal TWA clearly has prognostic implications, and positive or non-negative tests have been associated with substantially increased risk, currently there is not enough evidence to recommend that TWA should be used to guide therapy, such as ICD implantation. However, the EU-CERT-ICD (Comparative Effectiveness Research to Assess the Use of Primary Prophylactic Implantable Cardioverter Defibrillators in Europe; NCT02064192) study should shed more light on this important issue. EU-CERT-ICD study is a large observational study in Europe, in which extensive risk stratification tests, including TWA, are performed in a large number of patients (n=2,600) receiving prophylactic ICD aimed at studying the clinical value of non-invasive testing in predicting the appropriate ICD shocks and mortality. The EU-CERT-ICD study employs the MMA method for TWA analysis. At present, there is not sufficient evidence to recommend TWA to be used to exclude patients with LVEF ≤35 % from prophylactic ICD therapy either, despite some studies suggesting that subjects qualifying for primary prevention ICD based on reduced LVEF but with negative TWA test are at low risk of SCD and may not benefit from ICD implantation.19 However, this approach would need to be prospectively tested before it can be recommended for clinical practice.

Conclusion Over the last decade, TWA has remained a promising tool to assess the vulnerability to lethal arrhythmias among patients with cardiac disease to identify individuals at highest risk who may benefit from further medical interventions, especially in borderline cases. However, at present, there is not enough clinical evidence to support the use of TWA testing in routine clinical practice to guide therapy. Randomised controlled trials are needed to determine whether strategies incorporating TWA analysis alone or in combination with other risk stratification methods would enable better identification of patients at highest and lowest risk for SCD. Unfortunately, a randomised controlled REFINE-ICD trial (NCT00673842) was recently suspended because of a low recruitment rate. Therefore, it is evident that definite answer about the clinical use of TWA testing will not be obtained in the near future. n

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Arrhythmia Mechanisms

Clinical Perspective • T-wave alternans (TWA) refers to beat-to-beat fluctuations of congestive heart failure, low ejection fraction or a recent MI is T-wave amplitude and morphology, and is associated clinically with associated with a low risk of sudden cardiac death. impending ventricular arrhythmias and increased risk of sudden • Within candidates for implantable cardioverter defibrillator (ICD) cardiac arrest. therapy, a negative TWA test may be useful in identifying low-risk • TWA analysis can be done as part of an exercise stress test or patients who are unlikely to benefit from ICD placement. However, during a long-term (Holter) ECG recording. currently there is not enough evidence to support the use of TWA • Absence of significant TWA in a patient with cardiac disease with in clinical practice to guide therapy.

10.

11.

12.

13.

Huikuri HV, Castellanos A, Myerburg RJ. Sudden death due to cardiac arrhythmias. N Engl J Med 2001;345:1473–82. PMID: 11794197. Sabbag A, Suleiman M, Laish-Farkash A, et al. Contemporary rates of appropriate shock therapy in patients who receive implantable device therapy in a real-world setting: From the Israeli ICD Registry. Heart Rhythm 2015;12:2426–33. DOI: 10.1016/j.hrthm.2015.08.020; PMID: 26277863. Wellens HJ, Schwartz PJ, Lindemans FW, et al. Risk stratification for sudden cardiac death: Current status and challenges for the future. Eur Heart J 2014;35:1642–51. DOI: 10.1093/eurheartj/ehu176; PMID: 24801071. Narayan SM. T-wave alternans and the susceptibility to ventricular arrhythmias. J Am Coll Cardiol 2006;47:269–81. PMID: 16412847. Verrier RL, Klingenheben T, Malik M, et al. Microvolt T-wave alternans physiological basis, methods of measurement, and clinical utility--consensus guideline by International Society for Holter and Noninvasive Electrocardiology. J Am Coll Cardiol 2011;58:1309–24. DOI: 10.1016/j.jacc.2011.06.029; PMID: 21920259. Burattini L, Bini S, Burattini R. Comparative analysis of methods for automatic detection and quantification of microvolt T-wave alternans. Med Eng Phys 2009;31:1290–8. DOI: 10.1016/j.medengphy.2009.08.009; PMID: 19758833. Martinez JP, Olmos S. Methodological principles of T wave alternans analysis: A unified framework. IEEE Trans Biomed Eng 2005;52:599–613. PMID: 15825862. Rosenbaum DS, Jackson LE, Smith JM, et al. Electrical alternans and vulnerability to ventricular arrhythmias. N Engl J Med 1994;330:235–41. PMID: 8272084. Nearing BD, Verrier RL. Modified moving average analysis of T-wave alternans to predict ventricular fibrillation with high accuracy. J Appl Physiol 1985;92:541–9. PMID: 11796662. Exner DV, Kavanagh KM, Slawnych MP, et al. Noninvasive risk assessment early after a myocardial infarction the REFINE study. J Am Coll Cardiol 2007;50:2275–84. PMID: 18068035. Smith JM, Clancy EA, Valeri CR, et al. Electrical alternans and cardiac electrical instability. Circulation 1988;77:110–21. PMID: 3335062. Bloomfield DM, Bigger JT, Steinman RC, et al. Microvolt T-wave alternans and the risk of death or sustained ventricular arrhythmias in patients with left ventricular dysfunction. J Am Coll Cardiol 2006;47:456–63. PMID: 16412877. Ikeda T, Yoshino H, Sugi K, et al. Predictive value of microvolt T-wave alternans for sudden cardiac death in patients with preserved cardiac function after acute myocardial infarction: results of a collaborative cohort study. J Am Coll Cardiol 2006;48:2268–74. PMID: 17161258.

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14. Kaufman ES, Bloomfield DM, Steinman RC, et al. “Indeterminate” microvolt T-wave alternans tests predict high risk of death or sustained ventricular arrhythmias in patients with left ventricular dysfunction. J Am Coll Cardiol 2006;48:1399–404. PMID: 17010802. 15. Chen Z, Shi Y, Hou X, et al. Microvolt T-wave alternans for risk stratification of cardiac events in ischemic cardiomyopathy: a meta-analysis. Int J Cardiol 2013;167:2061–5. DOI: 10.1016/j. ijcard.2012.05.050; PMID: 22683284. 16. Chan PS, Gold MR, Nallamothu BK. Do beta-blockers impact microvolt T-wave alternans testing in patients at risk for ventricular arrhythmias? A meta-analysis. J Cardiovasc Electrophysiol 2010;21:1009–14. DOI: 10.1111/j.15408167.2010.01757.x; PMID: 20384655. 17. Tapanainen JM, Still AM, Airaksinen KE, et al. Prognostic significance of risk stratifiers of mortality, including T wave alternans, after acute myocardial infarction: Results of a prospective follow-up study. J Cardiovasc Electrophysiol 2001;12:645–52. PMID: 11405397. 18. Huikuri HV, Raatikainen MJ, Moerch-Joergensen R, et al. Prediction of fatal or near-fatal cardiac arrhythmia events in patients with depressed left ventricular function after an acute myocardial infarction. Eur Heart J 2009;30:689–98. DOI: 10.1093/eurheartj/ehn537; PMID: 19155249. 19. Hohnloser SH, Ikeda T, Cohen RJ. Evidence regarding clinical use of microvolt T-wave alternans. Heart Rhythm 2009;6:S36–44. DOI: 10.1016/j.hrthm.2008.10.011; PMID: 19168396. 20. Nieminen T, Lehtimaki T, Viik J, et al. T-wave alternans predicts mortality in a population undergoing a clinically indicated exercise test. Eur Heart J 2007;28:2332–7. PMID: 17652105. 21. Leino J, Verrier RL, Minkkinen M, et al. Importance of regional specificity of T-wave alternans in assessing risk for cardiovascular mortality and sudden cardiac death during routine exercise testing. Heart Rhythm 2011;8:385–90. doi: 10.1016/j.hrthm.2010.11.004; PMID: 21056698. 22. Quan XQ, Zhou HL, Ruan L, et al. Ability of ambulatory ECGbased T-wave alternans to modify risk assessment of cardiac events: A systematic review. BMC Cardiovasc Disord 2014;14:198. DOI: 10.1186/1471-2261-14-198; PMID: 25528490. 23. Merchant FM, Ikeda T, Pedretti RF, et al. Clinical utility of microvolt T-wave alternans testing in identifying patients at high or low risk of sudden cardiac death. Heart Rhythm 2012;9:1256–64. DOI: 10.1016/j.hrthm.2012.03.014; PMID: 22406384. 24. Chow T, Kereiakes DJ, Bartone C, et al. Microvolt T-wave alternans identifies patients with ischemic cardiomyopathy who benefit from implantable cardioverter-defibrillator therapy. J Am Coll Cardiol 2007;49:50–8. PMID: 17207722.

25. Chow T, Kereiakes DJ, Onufer J, et al. Does microvolt T-wave alternans testing predict ventricular tachyarrhythmias in patients with ischemic cardiomyopathy and prophylactic defibrillators? The MASTER (Microvolt T Wave Alternans Testing for Risk Stratification of Post-Myocardial Infarction Patients) trial. J Am Coll Cardiol 2008;52:1607–15. DOI: 10.1016/j. jacc.2008.08.018; PMID: 18992649. 26. Gold MR, Ip JH, Costantini O, et al. Role of microvolt T-wave alternans in assessment of arrhythmia vulnerability among patients with heart failure and systolic dysfunction: Primary results from the T-wave alternans sudden cardiac death in heart failure trial substudy. Circulation 2008;118:2022–8. DOI: 10.1161/CIRCULATIONAHA.107.748962; PMID: 18955671. 27. Costantini O, Hohnloser SH, Kirk MM, et al. The ABCD (alternans before cardioverter defibrillator) trial: Strategies using T-wave alternans to improve efficiency of sudden cardiac death prevention. J Am Coll Cardiol 2009;53:471–9. DOI: 10.1016/j.jacc.2008.08.077; PMID: 19195603. 28. Rashba EJ, Cooklin M, MacMurdy K, et al. Effects of selective autonomic blockade on T-wave alternans in humans. Circulation 2002;105:837–42. PMID: 11854124. 29. Kentta T, Tulppo MP, Nearing BD, et al. Effects of exercise rehabilitation on cardiac electrical instability assessed by T-wave alternans during ambulatory electrocardiogram monitoring in coronary artery disease patients without and with diabetes mellitus. Am J Cardiol 2014;114:832–7. DOI: 10.1016/j.amjcard.2014.06.014; PMID: 25107578. 30. Verrier RL, Malik M. Quantitative T-wave alternans analysis for guiding medical therapy: an underexploited opportunity. Trends Cardiovasc Med 2015;25:201–13. DOI: 10.1016/j. tcm.2014.10.006; PMID: 25541329. 31. Goldberger JJ, Cain ME, Hohnloser SH, et al. American Heart Association/American College of Cardiology Foundation/ Heart Rhythm Society scientific statement on noninvasive risk stratification techniques for identifying patients at risk for sudden cardiac death: A scientific statement from the American Heart Association Council on Clinical Cardiology Committee on Electrocardiography and Arrhythmias and Council on Epidemiology and Prevention. Circulation 2008;118:1497–518. PMID: 18833586. 32. 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: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC) endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). Eur Heart J 2015;36:2793–867. DOI: 10.1093/eurheartj/ehv316; PMID: 26320108.

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Clinical Arrhythmias

Pharmacological Therapy of Tachyarrhythmias During Pregnancy Ameeta Yaksh, Lisette JME van der Does, Eva AH Lanters and Natasja MS de Groot Erasmus Medical Center, Rotterdam, The Netherlands

Abstract Tachyarrhythmias are the most frequently observed cardiac complications during pregnancy. The majority of these maternal and foetal arrhythmias are supraventricular tachyarrhythmias; ventricular tachyarrhythmias are rare. The use of anti-arrhythmic drugs (AADs) during pregnancy is challenging due to potential foetal teratogenic effects. Maintaining stable and effective therapeutic maternal drug levels is difficult due to haemodynamic and metabolic alterations. Pharmacological treatment of tachyarrhythmias is indicated in case of maternal haemodynamic instability or hydrops fetalis. Evidenc e regarding the efficacy and safety of AAD therapy during pregnancy is scarce and the choice of AAD should be based on individual risk assessments for both mother and foetus. This review outlines the current knowledge on the development of tachyarrhythmias during pregnancy, the indications for and considerations of pharmacological treatment and its potential side-effects.

Keywords Pregnancy, tachyarrhythmia, anti-arrhythmic drugs, teratogenicity, foetus Disclosure: The authors have no conflicts of interest to declare. Received: 5 January 2016 Accepted: 15 March 2016 Citation: Arrhythmia & Electrophysiology Review 2016;5(1):41–4 Access at: www.AERjournal.com DOI: 10.15420/AER.2016.1.2 Correspondence: NMS de Groot, Erasmus Medical Center, Department of Cardiology, Thorax Center, Room Ba579’s Gravendijkwal 230 3015CE Rotterdam, The Netherlands. E: nmsdegroot@yahoo.com

Cardiac arrhythmias during pregnancy pose a serious threat to the health of both mother and foetus. Women with established tachyarrhythmias, congenital heart defects or channelopathies have the highest risk for development of arrhythmias.1,2 They also develop de novo or occur in women without apparent heart diseases. Tachyarrhythmias, including both supraventricular and ventricular tachycardias, are the most common cardiac complications observed during pregnancy. Not only the mother, but also the foetus may develop tachyarrhythmias.3 The exact mechanisms underlying the development of cardiac arrhythmias during pregnancy are unknown, and selection of the appropriate treatment modality is hampered by the lack of randomised studies in pregnant women.1,4,5 This review outlines the current knowledge on the development of tachyarrhythmias during pregnancy, the indications for and considerations of pharmacological treatment and its potential side-effects.

Incidences of Cardiac Arrhythmia During Pregnancy Maternal Arrhythmias (Supra)ventricular premature beats are the most frequently observed arrhythmias during pregnancy followed by paroxysmal supraventricular tachycardias (SVT); incidences are 33 and 24 per 100,000 pregnancies respectively.6 Atrioventricular nodal reentrant tachycardia (AVNRT) and atrioventricular reentry tachycardia (AVRT) are the most common supraventricular tachycardias both in pregnant and non-pregnant women with structurally normal hearts and usually do not cause haemodynamic deterioration.7,8 Studies investigating the risk of first onset paroxysmal SVT have shown inconsistent results. 7,9–12 Tawam et al. 9 described development of de novo paroxysmal SVTs during pregnancy in 13 out of 38 women (34 %).

de Groot_FINAL.indd 41

This is in contrast to a study by Lee et al. 7 who reported development of de novo paroxysmal SVT in only 3.9 % of the pregnancies. Recurrences were observed in 55 out of 65 (85 %) pregnant women with a history of paroxysmal SVT.7 In women with congenital heart disease (CHD) arrhythmias, mainly SVT, occurred in 4.5 % and were associated with multiple factors, including the presence of cyanotic heart disease (corrected/uncorrected) and usage of cardiac medication prior to gestation.1,13 Focal atrial tachycardia (FAT) occurs rarely during pregnancy and has mainly been described in case reports.14–19 Atrial fibrillation (AF) or atrial flutter (AFL) develop infrequently during pregnancy; a combined incidence of 2 per 100,000 pregnancies has been reported.6 In patients with known AF/AFL, a recurrence rate of 52 % has been described.20 The overall incidence of ventricular tachyarrhythmias (VT) or fibrillation (VF) in pregnant women is also very low (2 per 100,000 pregnancies).6 In women with structurally normal hearts monomorphic VT may develop during pregnancy, for example as a result of coronary artery disease or left ventricular dysfunction.21,22 VTs occur more often in patients with underlying acquired (coronary artery disease, valvular heart disease, peripartum cardiomyopathy) or inherited (CHD or channelopathies) heart disease. VT recurrences have been described in 27 % of women with heart disease and VT episodes prior to pregnancy.20

Foetal Arrhythmias Foetal tachyarrhythmias occur in approximately 2 % of pregnancies. Most arrhythmias are paroxysmal SVT (73 %) or AFL (26 %).23,24 VTs have been described in a review by Krapp et al.23 in 3 out of 485 cases (0.6 %) and may be associated with myocarditis, total atrioventricular block or congenital long QT syndrome.25

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Clinical Arrhythmias Table 1: Safety of Anti-arrhythmic Drugs During Pregnancy and Breastfeeding

Use During Pregnancy FDA Reported Negative Foetal Effects

Use During Breastfeeding Compatibility Reported Negative Neonatal Effects

Class 1 Procainamide C

–

compatible

none

Quinidine

neonatal thrombocytopenia, premature birth,

compatible

none

vestibulocochlear nerve toxicity

Lidocaine

bradycardia, acidosis, central nervous system toxicity

compatible

none

Flecainide

–

compatible

not described

Class 2 Metoprolol

bradycardia, hypoglycaemia

compatible

none

Bisoprolol

bradycardia, hypoglycaemia

–

Atenolol

growth retardation, bradycardia, hypoglycaemia

with caution

cyanosis, bradycardia

Propranolol

bradycardia, hypoglycaemia, growth retardation

compatible

none

Class 3 Amiodarone

hypothyroidism, goiter, growth retardation, bradycardia,

premature birth, prolonged QT interval

Sotalol

bradycardia, hypoglycaemia

unknown

possible hypothyroidism

compatible

not described

Class 4 Verapamil

Diltiazem C

bradycardia, heart block

compatible

–

compatible none

none

Other Digoxin C

–

compatible none

Adenosine C

–

Magnesium

neuromuscular and/or respiratory depression in newborn*,

compatible

none

sulphate

skeletal abnormalities§

Data derived from ESC guidelines (2011)4 and American Academy of Pediatrics Committee on Drugs (2001).45 * = if administered in the hours before partus54; § = if administered continuously for >7 days55; – = insufficient data; FDA = US Food and Drug Administration.

Haemodynamic Alterations During Pregnancy During pregnancy, the cardiovascular system is faced with significant changes which can precipitate the occurrence of arrhythmias. First, the blood volume increases by 35–40 % and is accompanied by an increase in heart rate and simultaneous decrease in vascular resistance. This leads to an increase in cardiac output of 30–50 %, already starting within the first weeks of pregnancy and with the largest increase occuring in the first 16 weeks.26–30 The increased blood volume has a physiological structural impact on the heart. The ventricles and atria dilate and the left ventricular mass increases during pregnancy.27,31 These effects are even greater in twin/multiple pregnancies.27,32 Mechanical stretch can facilitate arrhythmias by depolarisation of the membrane potential, premature depolarisations and dispersion in refractoriness.33,34 Furthermore, the increase in heart rate during pregnancy may act as a trigger in susceptible patients.35 There are also indications that oestrogen and progesterone may contribute to altered cardiac repolarisation facilitating arrhythmias.36 Besides the hyperdynamic state and altered hormonal status possibly predisposing pregnant women to arrhythmias, the high incidence of arrhythmias in patients with pre-existent heart disease or previous arrhythmic episodes indicates that this is probably the most important risk factor for arrhythmias in pregnancy.20

Indications and Considerations for Anti-arrhythmic Drug Therapy during Pregnancy The goal of anti-arrhythmic drug (AAD) therapy in general is to reduce ectopic activity or to modify critically impaired conduction. The ideal AAD has a greater effect on the arrhythmogenic substrate than on normal depolarising tissues, decreases mortality and has no sideeffects. However, many of the currently available AADs have proarrhythmogenic effects and could even increase mortality.4

de Groot_FINAL.indd 42

Pharmacological therapy of a pregnant woman is imperative in case of haemodynamic instability and/or diminished placentouterine blood flow. The main issue of pharmacological treatment of tachyarrhythmias during gestation is the potential teratogenic effect on the foetus as most AADs cross the placental barrier. Maintenance of adequate therapeutic drug levels in pregnant women is challenged by an increased intravascular volume, reduction of plasma proteins concentrations, increased renal blood flow and hepatic metabolism. Gastrointestinal absorption is also altered by changes in gastric secretion and intestinal motility.37,38 Foetal tachyarrhythmias should be treated when there is a risk of developing foetal heart failure. Subsequently, hydrops fetalis may develop and premature delivery or foetal death may occur.39,40

Effects and Safety of Anti-arrhythmic Drugs There are very limited data available for the effects and safety of AAD therapy in pregnancy. The US Food and Drug Administration (FDA) has classified drugs into five categories (A–D and X) to indicate the supposed effects and level of evidence. In categories A and B studies did not show any foetal toxic effects, where in category B the evidence is only from animal studies. In category C there have been adverse foetal effects demonstrated in animal studies, and in category D adverse foetal effects have been reported in human studies. However, for all these categories potential benefits may outweigh the risks and the drug may therefore be administrated if the situation requires it. Only in category X is the drug clearly contraindicated due to substantial evidence for adverse foetal effects. Here the risks do not outweigh the possible benefits. However, it is important to keep in mind that this system is a simplified classification and detailed drug information should be used when determining the potential safety in individual patients. Table 1 demonstrates that for most AADs some negative foetal effects have been reported in animal studies (category C), the most safe AADs appear to be lidocaine and sotalol

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Pharmacotherapy of Tachyarrhythmias During Pregnancy

and most adverse foetal effects during pregnancy have been reported with amiodarone and atenolol. The negative foetal effects of AADs that have been reported are also summarised in Table 1.4,41–44 The American Academy of Pediatrics (AAP) has classified most AADs as compatible with breastfeeding; only atenolol and amiodarone are possibly less favourable to use during the lactation period.45 AADs during pregnancy have been more extensively investigated for the treatment of foetal arrhythmias. The AADs recommended for foetal arrhythmias include sotalol and digoxin.46

Drug Therapy

Ventricular Tachycardia Acute treatment of ventricular tachycardia (VT) is indicated in all patients and can be achieved by electrical (first choice) or pharmacological cardioversion.4 Amiodarone IV should only be used if VT persists, or when the VT is refractory to electrical cardioversion, drug resistant and haemodynamically comprising. Patients with structurally normal hearts or congenital long QT syndrome should be treated with b-blockers as a prophylaxis for development of VT recurrences. Verapamil could also be considered in patients without structural heart disease.3,4

Supraventricular Tachycardia If immediate conversion of AVNRT or AVRT is required and the vagal manoeuvre is unsuccessful, administration of adenosine IV is recommended.3,4 This terminates approximately 90 % of the AV(N) RTs;47 an alternative is IV metoprolol.3 If long-term treatment for AVNRT is required, digitalis or metoprolol are the first-line drugs.3 Electrical or pharmacological cardioversion for FAT, although often successful, is discouraged due to the relatively high risk of recurrences and is only indicated in case of haemodynamic instability. Administration of adenosine may successfully terminate FAT in 30 %.4 Rate control in FAT is indicated for the prevention of tachycardiomyopathy and can be achieved with the use of digitalis or metoprolol.3,4 Flecainide or propafenone could be considered for rhythm control therapy. Use of the lowest effective dose of amiodarone should only be considered when the FAT results in haemodynamic instability, it is refractory to all other AADs and conversion to sinus rhythm is required.4 In case of AF or AFL requiring conversion to sinus rhythm, the use of ibutilide or flecainide is effective and recommended for non-pregnant patients,48,49 however experience of these drugs during pregnancy is limited.3,4 In pregnant women with an AF or AFL episode with a duration longer than 48 hours that requires direct current cardioversion, the use of oral anticoagulants at least three weeks before cardioversion is necessary.4 Atrial stunning after cardioversion increases the risk of thromboembolic events, and it is therefore recommended that oral anticoagulants are continued for at least four weeks.4 Oral anticoagulants should be replaced by low molecular weight heparin in the first and third trimester of pregnancy because of the potential negative effects on the foetus. Metoprolol is the drug of first choice to control ventricular heart rate. Verapamil is the drug of second choice since the blood levels of digoxin during pregnancy are unreliable. Propafenone or flecainide in conjunction with AV nodal blocking agents or sotalol can be used when other rate control strategies fail.3,4,48,49

Drenthen W, Pieper PG, Roos-Hesselink JW, et al. Outcome of pregnancy in women with congenital heart disease: a literature review. J Am Coll Cardiol 2007;49:2303–11. PMID: 17572244 Siu SC, Sermer M, Colman JM, et al. Prospective multicenter study of pregnancy outcomes in women with heart disease. Circulation 2001;104:515–21. PMID: 11479246 Blomstrom-Lundqvist C, Scheinman MM, Aliot EM, et al. ACC/AHA/ESC guidelines for the management of patients with supraventricular arrhythmias--executive summary. a report of the American college of cardiology/American heart association task force on practice guidelines and the European society of cardiology committee for practice guidelines (writing committee to develop guidelines for the management of patients with supraventricular arrhythmias) developed in collaboration with NASPE-Heart Rhythm Society. J Am Coll Cardiol 2003;42:1493–1531. PMID: 14563598 European Society of G, Association for European Paediatric C, German Society for Gender M, et al. ESC Guidelines on the management of cardiovascular diseases during pregnancy: the Task Force on the Management of Cardiovascular Diseases during Pregnancy of the European Society of Cardiology (ESC). Eur Heart J 2011;32:3147–97. DOI: 10.1093/ eurheartj/ehr218; PMID: 21873418 Gowda RM, Khan IA, Mehta NJ, et al. Cardiac arrhythmias in

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de Groot_FINAL.indd 43

Foetal Arrhythmias As mentioned above, persistence of foetal arrhythmias predisposes for development of hydrops fetalis, ventricular dysfunction or eventually death.4 Hence, treatment of persistent foetal arrhythmias is indicated. Pharmacological treatment of primary foetal arrhythmias includes digoxin as the first choice.46 If unsuccessful, sotalol and verapamil, procainamide or quinidine can be administered. Sodium and potassium channel blockers have been safely applied during foetal ventricular arrhythmias.50,51 If maternal, transplacental treatment is not successful, umbilical or intraperitoneal52 drug administration or direct foetal intramuscular injection53 of anti-arrhythmic agents have been described. However, this approach has not (yet) been incorporated in the European or American Guidelines.

Conclusion Prescription of anti-arrhythmic drug therapy in pregnant women is challenging due to the potential severe side-effects in both the mother and foetus. In addition, there are no major studies guiding selection of the safest and most effective anti-arrhythmic drug. Hence, initiation of anti-arrhythmic drug therapy requires careful consideration of the potential risks and benefits to the individual patient. n

Clinical Perspective • Initiation of anti-arrhythmic drug therapy requires careful consideration of the potential risks and benefits to the individual patient. • Pharmacological therapy of a pregnant woman is required in cases of haemodynamic instability and/or diminished placento-uterine blood flow. • However, the use of AADs during pregnancy should be avoided whenever possible.

pregnancy: clinical and therapeutic considerations. Int J Cardiol 2003;88:129–33. PMID: 12714190 6. Li JM, Nguyen C, Joglar JA, et al. Frequency and outcome of arrhythmias complicating admission during pregnancy: experience from a high-volume and ethnically-diverse obstetric service. Clin Cardiol 2008;31:538–41. DOI: 10.1002/ clc.20326; PMID: 19006111 7. Lee SH, Chen SA, Wu TJ, et al. Effects of pregnancy on first onset and symptoms of paroxysmal supraventricular tachycardia. Am J Cardiol 1995;76:675–8. PMID: 7572623 8. Leung C, Brodsky M. Cardiac Arrhythmias and Pregnancy. In: Elkayam. U, Gleicher. N, eds. Cardiac Problems in Pregnancy: Diagnosis and Management of Maternal and Fetus. USA: Wiley-Liss, Inc.;1998:158–66. 9. Tawam M, Levine J, Mendelson M, et al. Effect of pregnancy on paroxysmal supraventricular tachycardia. Am J Cardiol 1993;72:838–40. PMID: 8213524 10. Widerhorn J, Widerhorn AL, Rahimtoola SH, et al. WPW syndrome during pregnancy: increased incidence of supraventricular arrhythmias. Am Heart J 1992;123:796–8. PMID: 1539536 11. Kounis NG, Zavras GM, Papadaki PJ, et al. Pregnancy-induced increase of supraventricular arrhythmias in Wolff-ParkinsonWhite syndrome. Clin Cardiol 1995;18:137–40. PMID: 7743683 12. Szekely P, Snaith L. Paroxysmal tachycardia in pregnancy.

Br Heart J 1953;15:195–8. PMID: 13041998; PMCID: PMC479485 13. Drenthen W, Boersma E, Balci A, et al. Predictors of pregnancy complications in women with congenital heart disease. Eur Heart J 2010;31:2124–32. DOI: 10.1093/eurheartj/ ehq200; PMID: 20584777 14. Doig JC, McComb JM, Reid DS. Incessant atrial tachycardia accelerated by pregnancy. Br Heart J 1992;67:266–8. PMID: 1554546; PMCID: PMC1024804 15. Hubbard WN, Jenkins BA, Ward DE. Persistent atrial tachycardia in pregnancy. Br Med J (Clin Res Ed) 1983;287:327. PMID: 6409293; PMCID: PMC1548570 16. Murphy JJ, Hutchon DJ. Incessant atrial tachycardia accelerated by pregnancy. Br Heart J 1992;68:342. PMID: 1389773; PMCID: PMC1025086 17. Robards GJ, Saunders DM, Donnelly GL. Refractory supraventricular tachycardia complicating pregnancy. Med J Aust 1973;2:278–80. PMID: 4744112 18. Schroeder JS, Harrison DC. Repeated cardioversion during pregnancy. Treatment of refractory paroxysmal atrial tachycardia during 3 successive pregnancies. Am J Cardiol 1971;27:445–6. PMID: 5572585 19. Treakle K, Kostic B, Hulkower S. Supraventricular tachycardia resistant to treatment in a pregnant woman. J Fam Pract 1992;35:581–4. PMID: 1431774 20. Silversides CK, Harris L, Haberer K, et al. Recurrence rates

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of arrhythmias during pregnancy in women with previous tachyarrhythmia and impact on fetal and neonatal outcomes. Am J Cardiol 2006;97:1206–12. PMID: 16616027 Brodsky M, Doria R, Allen B, et al. New-onset ventricular tachycardia during pregnancy. Am Heart J 1992;123:933–41. PMID: 1550003 Nakagawa M, Katou S, Ichinose M, et al. Characteristics of new-onset ventricular arrhythmias in pregnancy. J Electrocardiol 2004;37:47–53. PMID: 15132369 Krapp M, Kohl T, Simpson JM, et al. Review of diagnosis, treatment, and outcome of fetal atrial flutter compared with supraventricular tachycardia. Heart 2003;89:913–7. PMID: 12860871; PMCID: PMC1767787 Moodley S, Sanatani S, Potts JE, et al. Postnatal outcome in patients with fetal tachycardia. Pediatr Cardiol 2013;34:81–7. DOI: 10.1007/s00246-012-0392-7; PMID: 22639009 Strasburger JF. Prenatal diagnosis of fetal arrhythmias. Clin Perinatol 2005;32:891–912, viii. PMID: 16325668 Hytten FE, Paintin DB. Increase in plasma volume during normal pregnancy. J Obstet Gynaecol Br Emp 1963;70:402–7. PMID: 13956023 Hunter S, Robson SC. Adaptation of the maternal heart in pregnancy. Br Heart J 1992;68:540–3. PMID: 1467047; PMCID: PMC1025680 Ouzounian JG, Elkayam U. Physiologic changes during normal pregnancy and delivery. Cardiol Clin 2012;30:317–29. DOI: 10.1016/j.ccl.2012.05.004; PMID: 22813360 Boron WF, Boulpaep EL. Medical Physiology. Updated ed. Philadelphia: Elsevier Inc; 2005:1181–2. Robson SC, Hunter S, Boys RJ, et al. Serial study of factors influencing changes in cardiac output during human pregnancy. Am J Physiol 1989;256:H1060–5. PMID: 2705548 Kametas NA, McAuliffe F, Hancock J, et al. Maternal left ventricular mass and diastolic function during pregnancy. Ultrasound Obstet Gynecol 2001;18:460–6. PMID: 11844165 Kametas NA, McAuliffe F, Krampl E, et al. Maternal cardiac function in twin pregnancy. Obstet Gynecol 2003;102:806–15. PMID: 14551012 Kamkin A, Kiseleva I, Isenberg G. Stretch-activated currents

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in ventricular myocytes: amplitude and arrhythmogenic effects increase with hypertrophy. Cardiovasc Res 2000;48:409–20. PMID: 11090836 Zabel M, Portnoy S, Franz MR. Effect of sustained load on dispersion of ventricular repolarization and conduction time in the isolated intact rabbit heart. J Cardiovasc Electrophysiol 1996;7:9–16. PMID: 8718979 Soliman EZ, Elsalam MA, Li Y. The relationship between high resting heart rate and ventricular arrhythmogenesis in patients referred to ambulatory 24 h electrocardiographic recording. Europace 2010;12:261–5. DOI: 10.1093/europace/ eup344; PMID: 19887457 Yang PC, Clancy CE. Effects of sex hormones on cardiac repolarization. J Cardiovasc Pharmacol 2010;56:123–9. DOI: 10.1097/FJC.0b013e3181d6f7dd; PMID: 20164789 Cox JL, Gardner MJ. Treatment of cardiac arrhythmias during pregnancy. Prog Cardiovasc Dis 1993;36:137–78. PMID: 8103603 Page RL. Treatment of arrhythmias during pregnancy. Am Heart J 1995;130:871–6. PMID: 7572599 Naheed ZJ, Strasburger JF, Deal BJ, et al. Fetal tachycardia: mechanisms and predictors of hydrops fetalis. J Am Coll Cardiol 1996;27:1736–40. PMID: 8636562 van Engelen AD, Weijtens O, Brenner JI, et al. Management outcome and follow-up of fetal tachycardia. J Am Coll Cardiol 1994;24:1371–5. PMID: 7930263 Lip GY, Beevers M, Churchill D, et al. Effect of atenolol on birth weight. Am J Cardiol 1997;79:1436–8. PMID: 9165181 Joglar JA, Page RL. Antiarrhythmic drugs in pregnancy. Curr Opin Cardiol 2001;16:40–5. PMID: 11124717 Widerhorn J, Bhandari AK, Bughi S, et al. Fetal and neonatal adverse effects profile of amiodarone treatment during pregnancy. Am Heart J 1991;122:1162–6. PMID: 1927869 Pruyn SC, Phelan JP, Buchanan GC. Long-term propranolol therapy in pregnancy - maternal and fetal outcome. Am J Obstet Gynecol 1979;135:485–9. PMID: 573555 American Academy of Pediatrics Committee on Drugs. Transfer of drugs and other chemicals into human milk. Pediatrics 2001;108:776–9. PMID: 11533352

46. Oudijk MA, Ruskamp JM, Ambachtsheer BE, et al. Drug treatment of fetal tachycardias. Paediatr Drugs 2002;4:49–63. PMID: 11817986 47. Elkayam U, Goodwin TM. Adenosine therapy for supraventricular tachycardia during pregnancy. Am J Cardiol 1995;75:521–3. PMID: 7864004 48. Camm AJ, Lip GY, De Caterina R, et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J 2012;33:2719–47. DOI: 10.1093/eurheartj/ehs253; PMID: 22922413 49. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/ HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014;64:e1–76. DOI: 10.1016/j.jacc.2014.03.022; PMID: 24685669 50. Joglar JA, Page RL. Treatment of cardiac arrhythmias during pregnancy - Safety considerations. Drug Safety 1999;20:85–94. PMID: 9935279 51. Tan HL, Lie KI. Treatment of tachyarrhythmias during pregnancy and lactation. Eur Heart J 2001;22:458–64. PMID: 11237540 52. Hansmann M, Gembruch U, Bald R, et al. Fetal tachyarrhythmias – transplacental and direct treatment of the fetus – a report of 60 cases. Ultrasound Obst Gyn 1991;1:162–70. PMID: 12797066 53. Cuneo BF, Strasburger JF. Management strategy for fetal tachycardia. Obstet Gynecol 2000;96:575–81. PMID: 11004362 54. Riaz M, Porat R, Brodsky NL, et al. The effects of maternal magnesium sulfate treatment on newborns: a prospective controlled study. J Perinatol 1998;18:449–54. PMID: 9848759 55. Holcomb WL, Jr, Shackelford GD, Petrie RH. Magnesium tocolysis and neonatal bone abnormalities: a controlled study. Obstet Gynecol 1991;78:611–4. PMID: 1923163

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LE ATION.

e. lare.

The Role of Flecainide in the Management of Catecholaminergic Polymorphic Ventricular Tachycardia Krystien VV Lieve, 1 Arthur A Wilde, 1,2 Christian van der Werf 1 1. Heart Centre, Academic Medical Centre, Amsterdam, The Netherlands; 2. Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, Jeddah, Kingdom of Saudi Arabia

Abstract Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare but severe genetic cardiac arrhythmia disorder, with symptoms including syncope and sudden cardiac death due to polymorphic VT or ventricular fibrillation typically triggered by exercise or emotions in the absence of structural heart disease. The cornerstone of medical therapy for CPVT is β-blockers. However, recently flecainide has been added to the therapeutic arsenal for CPVT. In this review we summarise current data on the efficacy and role of flecainide in the treatment of CPVT.

Keywords Antiarrhythmic therapy, catecholaminergic ventricular tachycardia, flecainide, genetic, inherited channelopathies, sudden death Disclosure: The authors have no conflicts of interest to declare Acknowledgements: We acknowledge the support from The Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, Dutch Federation of University Medical Centres, the Netherlands Organisation for Health Research and Development and the Royal Netherlands Academy of Sciences (CVON 2010-12 PREDICT). Received: 9 January 2016 Accepted: 7 March 2016 Citation: Arrhythmia & Electrophysiology Review 2016;5(1):45–9 Access at: www.AERjournal.com DOI: 10.15420/AER.2016.3.3 Correspondence: Christian van der Werf, Department of Cardiology, Academic Medical Centre, PO Box 22660, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. E-mail: c.vanderwerf@amc.uva.nl

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare but severe genetic cardiac arrhythmia disorder. Clinically, CPVT most often presents in childhood with symptoms such as syncope or sudden cardiac death due to polymorphic ventricular tachycardia (VT) or ventricular fibrillation typically triggered by exercise or emotions in the absence of structural heart disease.1 Mutations in the RYR2 gene, which encodes the cardiac ryanodine receptor calcium release channel (RyR2), can be identified in the vast majority of the CPVT cases and follow an autosomal dominant inheritance pattern,2 whereas a small percentage of cases are due to homozygous or compound heterozygous mutations in the gene encoding cardiac calsequestrin (CASQ2).3 Both RyR2 and CASQ2 are involved in intracellular calcium homeostasis in the cardiomyocyte. Mutations in these genes mainly cause diastolic calcium leakage from the sarcoplasmatic reticulum through the RyR2 receptor, eventually resulting in delayed afterdepolarisations and triggered activity, which is most pronounced during states of sympathetic activation.4 Other genes that have been discovered and only represent a small percentage of CPVT cases are TRDN (encoding triadin) and CALM1 (encoding calmodulin).5,6 Mutations in the CALM2 gene have been associated with overlapping features of the congenital long-QT syndrome and CPVT.7 A yet-to-be-identified gene on chromosome 7p14–p22 has been linked to a highly malignant autosomal recessive form of CPVT. This phenotype is characterised by exercise-induced ventricular arrhythmia, and patients have a minor QT prolongation.8 Approximately 40 % of the CPVT cases remain mutation negative.9,10

Van Der Werf_FINAL.indd 45

Untreated, CPVT has a high mortality rate of up to 30 % among individuals with the classic phenotype who are aged <40 years.9,11 Since CPVT was first described,12 β-blockers have been acknowledged for their efficacy in its treatment, and they have remained the cornerstone of therapy to date.13 However, a significant percentage of CPVT cases remain symptomatic despite receiving adequate β-blocker therapy or suffer from severe side-effects such as fatigue due to β-blocker therapy.2,9,14 Up until a few years ago, patients who remained symptomatic despite receiving β-blocker therapy could only be additionally protected by an implantable cardioverter defibrillator (ICD). In 2009, flecainide was shown to reduce the rate of ventricular arrhythmias among patients with CPVT.15 This has been considered an important discovery and current guidelines now recommend flecainide in patients with recurrent syncope or PVT while on β-blockers.13 Here, we review the efficacy of flecainide therapy and its role in the treatment of patients with CPVT.

Flecainide Flecainide, a class 1c antiarrhythmic drug, was synthesised in 1972 and approved by the US Food and Drug Administration in 1984 for the suppression of VT. Orally administered flecainide is rapidly absorbed and has a 90 % bioavailability after ingestion. Flecainide is metabolised by cytochrome P450 (CYP)2D6 and CYP1A2 before it is renally excreted. In healthy subjects, peak plasma levels are reached after 2–3 hours and steady-state levels are achieved within 3–5 days. The elimination half-life of flecainide is 12–27 hours.16,17

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Van Der Werf_FINAL.indd 46

32/1/0/0

NR 25 (7–68)

32 31 (94 %)

1 (100 %) 20 months (12–40)

3 months

1 (100 %)

100 mg

12 months

1: appropriate

200 mg

2/10 (20%):

Wangüemert

3/2/2/0

7 (100 %)

3 (100 %)

2.3±1 mg/kg

4.0 years (1.7–19.9)

29 (7–82) months

12 months

3.5–4.0 kg/kg

Retrospective 15/63 (24 %)

cohort study

De Ferrari

et al. 201527†

13 (87 %)

0 (0 %)

150 mg

37.1 months NR

(1.4–75.5) 13/14 (93 %)†

–

No (6/8)

–

1 (12.5 %)

5 (10 %)

ACA = aborted cardiac arrest; ICD = implantable cardioverter defibrillator; NR = not reported; SCD = sudden cardiac death. *Mean ± standard deviation or median (range) † In this study a total of 22 patients received flecainide. However, outcomes are only reported in the subgroup of 14 patients who experienced cardiac events before and/or after left cardiac sympathetic denervation. In 13 of 14 patients (93%) ventricular arrhythmias were not suppressed. However, it is unknown if this is synonymous with experiencing cardiac events.

8/0/0/0

suboptimal dose) (100–200 mg)

1.3 years (0.9–2.7)

cohort study

Retrospective 8

43 (96 %)

Padfield et al.

201526

8 (16 %; 7

cohort study

appropriate

2/7 (29 %):

201514

4 (57 %)

1 (100 %)

100 mg

ICD shock

cohort study

201441

1/0/1/1

1 (100 %)

Retrospective 51/211(24 %)

Retrospective 7/13 (53 %)

Roses-Noguer

8 (33 %)

1/0/0/0

Roston et al.

cohort study

0 (0 %)

1/0/0/0

Retrospective 3/24 (13 %)

Miyake et al.

Case report

201340

et al. 201439

1 (100 %)

et al. 201338

tachycardia)

Case report

Mantziari

0 (0 %)

supraventricular

Yes

appropriate preceded by

15.5 ± 10.4 months

0 (0 %)

(150–300 mg)

ICD shocks (both

10 (100 %)

2/11 (18 %): 1 SCD, 1 ACA

–

6 (18 %)

–

17 ± 2.5

48 ± 94 months

2 years

(2.9 ± 1.3 mg/kg)

165 ± 46 mg

4 mg/kg

–

Side-effects

0/10/0/0

cohort study

4 (40 %)

Retrospective 10

12 (100 %)

1 (100 %)

Khoury et al.

22 ± 11

201324

0/0/12/0

1/0/0/0

cohort study

6 (50 %)

0 (0 %)

Retrospective 12

Watanabe

Case report

et al. 201325

et al. 201237

Jacquemart

0/1/0/0

ICD shock

0 (0 %)

17 months

(0.20 mg/L)

90 mg/day

201236

Case report

Hong et al.

cohort study

Retrospective 5/27 (19 %)

1 (100 %)

Sy et al.

201135

1/0/0/0

0 (0 %)

201134

Case report

ICD shock

appropriate

1/33 (3 %):

–

Pott et al.

1.5–4.5 mg/kg)

150 mg (100–300;

100 mg

Compliant

Cardiac events

Retrospective 33

24 (73 %)

1 (100 %)

cohort study

Van der Werf

Case report

RYR2 mutation/ Age at start Combined Daily Follow- up* CASQ2 mutation/ of flecainide with β-blocker flecainide no mutation (years)* dosage identified/ genetic testing not performed 1/1/0/0 36 and 12 1 (50 %) 3 mg/kg, NR 12 weeks

et al. 201123

et al. 201033

Biernacka

et al. 200915

Study Design Number of Female patients Watanabe Case report 2 1 (50 %)

Table 1: Clinical Studies of Patients With Catecholaminergic Polymorphic Ventricular Tachycardia Treated With Flecainide

Clinical Arrhythmias

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Flecainide in Catecholaminergic Polymorphic Ventricular Tachycardia

Experimental Studies In 2009, the first study on the efficacy of flecainide in patients with CPVT showed that flecainide dramatically reduced rates of calcium sparks in vitro and ventricular arrhythmias in vivo in a CASQ2-knockout mouse model.15 In in vitro studies in isolated cardiomyocytes flecainide reduced the duration of RyR2 channel opening. This effect was most pronounced in the setting of RyR2 activation by high luminal calcium with flecainide. This situation mimics spontaneous calcium release through the sarcoplasmatic reticulum, which triggers ventricular arrhythmias in patients with CPVT. Flecainide reduced spontaneous calcium spark frequency in isolated cardiomyocytes. In vivo flecainide completely suppressed VT in all mice. This discovery led to the successful treatment of two severely affected patients.15 The proposed mechanism of action is that, apart from the known sodium channel-blocking effect, flecainide has an additional direct-blocking effect on the RyR2 channel, through which it inhibits triggered activity.15 However, two other groups have independently opposed this mechanism and proposed an alternative mechanism by an effect that could solely be attributed to the sodium channel-blocking properties of the drug.18–20 It has also been suggested that a potential action of flecainide is by an indirect effect on RyR2 through binding to calmodulin or other modulators of RyR2.21

Figure 1: ECGs at Maximum Heart Rate During Exercise Testing Before and After Drug Treatments in a Female Patient with Catecholaminergic Polymorphic Ventricular Tachycardia A

Propafenone Apart from flecainide, the only other class 1c antiarrhythmic drug available in the US that has been shown to block RyR2 channels is propafenone.22 Propafenone was effective in suppressing calcium waves in vitro and reduced the rate of ventricular arrhythmias in CASQ2-knockout mice.22 Propafenone was also tested in a 22-year-old patient with CPVT carrying the p.L4105F RYR2 mutation who suffered from frequent appropriate ICD discharges and who was refractory to conventional therapy (excluding flecainide). Propafenone was prescribed because flecainide is not available in Turkey. The use of propafenone led to a significant decrease in the frequency of ICD discharges and complete ventricular arrhythmia suppression on exercise testing at 12 months of follow-up.22

Clinical Studies Since 2009, there have been 15 published clinical studies on flecainide treatment in patients with CPVT (see Table 1). The first relatively large cohort included 33 genotype-positive patients (1 CASQ2 and 32 RYR2 mutation carriers) and evaluated the efficacy of flecainide in difficultto-treat patients who were either symptomatic on maximally tolerated therapy or had persistent severe ventricular arrhythmias despite maximally tolerated therapy.23 The vast majority of these patients used flecainide in combination with a β-blocker (94 %), whereas two patients used flecainide as monotherapy due to significant side effects of β-blockers. Partial or complete suppression of the ventricular arrhythmias was achieved in 76 % of patients. During a mean follow-up of 20 months, one patient suffered from an episode of several appropriate ICD shocks due to confirmed non-compliance.23 Subsequently, the efficacy of flecainide was confirmed in a relatively large cohort of homozygous CASQ2 D307H mutation carriers.24 In this study, all patients used flecainide in combination with β-blockers. After the initiation of flecainide, the ventricular arrhythmia burden decreased in all patients and during a mean follow-up of 15.5 ± 10.4 months, and two patients suffered from appropriate ICD shocks, which in both cases were preceded by supraventricular tachyarrhythmias. Flecainide also suppressed ventricular arrhythmias in patients without a proven pathogenic mutation in the RYR2, CASQ2 or KCNJ2 genes.25

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Van Der Werf_FINAL.indd 47

A: At baseline before medication; polymorphic NSVT and VES were observed. B: After bisoprolol (5 mg/day); VES, bigeminy and a couplet. C: With metropolol 50 mg/day and flecainide 150 mg/day ventricular arrhythmias were completely suppressed. CPVT = catecholaminergic polymorphic ventricular tachycardia; NSVT = non-sustained ventricular tachycardia; VES = ventricular extrasystoles.

This study consisted of 12 patients, all of whom showed ventricular arrhythmias despite maximal tolerated therapy. During a mean followup of 48 months, two patients experienced a cardiac event due to non-compliance. To the best of our knowledge, only sporadic cases have been treated with flecainide monotherapy, most often due to the significant side-effects of β-blockers. In a small retrospective cohort consisting of nine patients carrying RYR2 mutations, all intolerant to β-blockers, no patient suffered from treatment failure during a median follow-up of 37.1 months.26 Therefore, flecainide monotherapy may potentially be considered an option for patients that are intolerant to β-blockers. A placebo-controlled, randomised crossover trial of flecainide in patients with CPVT assessing the efficacy of flecainide in reducing cardiac events in CPVT is ongoing (ClinicalTrials.gov ID NCT01117454). One study that focused on left cardiac sympathetic denervation (LCSD) reported a high number of patients without ventricular arrhythmia suppression despite treatment with flecainide and β-blockers and/or LCSD.27 However, it is

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Clinical Arrhythmias unknown whether these patients also experienced cardiac events. In addition, this is a highly symptomatic cohort of whom 19 % experienced cardiac events within 2 years after LCSD. Overall, the studies published so far have reported treatment failure to be most frequently associated with non-compliance or suboptimal flecainide dosing (see Table 1).

Role of Flecainide in Treatment of Patients With Catecholaminergic Polymorphic Ventricular Tachycardia At present, exercise restriction and β-blocker treatment are the cornerstone of therapies in patients with CPVT.13 The current consensus is to treat each patient with a clinical or genetic diagnosis of CPVT with the highest tolerable dose of β-blockers. A robust comparison between different types of β-blockers has not been performed, but there is growing evidence that nadolol, a long-acting drug, is the most effective β-blocker in terms of ventricular arrhythmia suppression and cardiac event rates.9,28 Other nonselective β-blockers such as propanolol might be an alternative in those countries where nadolol is not available.13 Flecainide is the first addition to β-blockers when ventricular arrhythmia suppression seems incomplete. Current expert consensus guidelines have given a class IIa recommendation for the use of flecainide in patients with CPVT.13,29 In addition, flecainide is considered an ‘emerging recommendation’ according to the 2015 European Society of Cardiology VT guideline.29 Figure 1 shows the effect of β-blocker therapy and flecainide added to β-blockers in a CPVT patient. Flecainide should be considered in patients who continue to have ventricular arrhythmias and/or symptoms despite maximum tolerated β-blocker dose in patients with or without an ICD.13 A dose–response effect has been observed in previous studies on flecainide and optimal dosing for ventricular arrhythmia suppression in adults is approximately 150–300 mg/day, while dosages below 100 mg/day have been associated with a lack of therapeutic response.23 In most cases, treatment failure has so far been associated with low flecainide dosing and/or non-compliance. At present, the only measure of efficacy of flecainide is the ventricular arrhythmic burden on the exercise test. It is, however, important to realise that cases in which the ventricular arrhythmia burden on the exercise test was not a reliable predictor of cardiac events (i.e.

Leenhardt A, Lucet V, Denjoy I, et al. Catecholaminergic polymorphic ventricular tachycardia in children. A 7-year follow-up of 21 patients. Circulation 1995;91:1512–9. PMID: 7867192. Priori SG, Napolitano C, Tiso N, et al. Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia. Circulation 2001;103:196– 200. PMID: 11208676. Lahat H, Pras E, Olender T, et al. A missense mutation in a highly conserved region of CASQ2 is associated with autosomal recessive catecholamine-induced polymorphic ventricular tachycardia in Bedouin families from Israel. Am J Hum Genet 2001;69:1378–84. PMID: 11704930. Priori SG, Chen SRW. Inherited dysfunction of sarcoplasmic reticulum Ca2+ handling and arrhythmogenesis. Circ Res 2011;108:871–83. DOI: 10.1161/CIRCRESAHA.110.226845; PMID: 21454795. Roux-Buisson N, Cacheux M, Fourest-Lieuvin A, et al. Absence of triadin, a protein of the calcium release complex, is responsible for cardiac arrhythmia with sudden death in human. Hum Mol Genet 2012;21:2759–67. DOI: 10.1093/hmg/ dds104; PMID: 22422768. Nyegaard M, Overgaard MT, Søndergaard MT, et al. Mutations in calmodulin cause ventriculartachycardia and sudden cardiac death. Am J Hum Genet 2012;91:703–12. DOI: 10.1016/j. ajhg.2012.08.015; PMID: 23040497. Makita N, Yagihara N, Crotti L, et al. Novel calmodulin mutations associated with congenital arrhythmia susceptibility. Circ Cardiovasc Genet 2014;7:466–74. DOI: 10.1161/CIRCGENETICS.113.000459; PMID: 24917665. Bhuiyan ZA, Hamdan MA, Shamsi ETA, et al. A novel early onset lethal form of catecholaminergic polymorphic ventricular tachycardia maps to chromosome 7p14-p22. J Cardiovasc Electrophysiol 2007;18:1060–6. PMID: 17666061.

Van Der Werf_FINAL.indd 48

10.

11.

12.

13.

14.

15.

who experienced a cardiac event while a previous exercise test did not show significant ventricular arrhythmias) have been described.30 Therefore, optimal therapeutic range can be evaluated by comparing the ventricular arrhythmia burden on the exercise test before and after the initiation of flecainide. It is unknown whether the once- or twice-daily administration is beneficial, but a slow-release drug is preferred to avoid non-compliance. Overall, the reported side-effects of flecainide are mild and have led to discontinuation in only a small proportion of patients (see Table 1). LSCD and/or ICD implantation may be considered in patients who remain symptomatic or continue to have persistent arrhythmias despite treatment with β-blockers and flecainide. Although the beneficial effects of flecainide in patients with CPVT patients seem overt, one must exercise caution with regard to the pro-arrhythmic effects of flecainide. The Cardiac Arrhythmia Suppression Trial (CAST) has shown that class I antiarrhythmic drugs are associated with an increased rate of sudden cardiac death in post-infarct patients when compared with placebo.31 Therefore, a contraindication has been issued for patients with a structural heart disease and a history or suspicion of coronary artery disease. It is thought that flecainide can become pro-arrhythmic due to myocardial conduction velocity slowing, which may consequently trigger re-entry and may be particular relevant in the setting of myocardial ischaemia. It is recommended that heart rate-related QRS prolongation is closely monitored on the exercise test; if the QRS interval is prolonged by >25 %, flecainide dosing should be decreased or discontinued. It is, however, reassuring that in the published reports a proarrhythmic effect of flecainide has not been observed in patients with CPVT. Furthermore, data accumulated over the past 27 years indicate that flecainide is safe to use in carefully selected patients without structural heart disease.32 Additionally, long-term (27–29 years) follow-up data have been reported for two patients with CPVT patients on flecainide.23,25

Conclusion Preliminary results with flecainide in patients with CPVT are encouraging. However, a larger study with long-term follow-up is needed to fully elucidate the efficacy of flecainide, in particular its ability to prevent cardiac events in the long term. n

Hayashi M, Denjoy I, Extramiana F, et al. Incidence and risk factors of arrhythmic events in catecholaminergic polymorphic ventricular tachycardia. Circulation 2009;119:2426–34. DOI: 10.1161/ CIRCULATIONAHA.108.829267; PMID: 19398665. Medeiros-Domingo A, Bhuiyan ZA, Tester DJ, et al. The RYR2encoded ryanodine receptor/calcium release channel in patients diagnosed previously with either catecholaminergic polymorphic ventricular tachycardia or genotype negative, exercise-induced long QT syndrome: a comprehensive open reading frame mutation analysis. J Am Coll Cardiol 2009;54:2065–74. DOI: 10.1016/j.jacc.2009.08.022; PMID: 19926015. Priori SG, Napolitano C, Memmi M, et al. Clinical and molecular characterization of patients with catecholaminergic polymorphic ventricular tachycardia. Circulation 2002;106:69–74. PMID: 12093772. Coumel P, Fidelle J, Lucet V, et al. Catecholamine-induced severe ventricular arrhythmias with Adam-Stokes in children: report of four cases. Br Heart J 1978;40:28–37. Priori SG, Wilde AA, Horie M, et al. HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013. Heart Rhythm 2013;10:1932–63. DOI: 10.1016/j.hrthm.2013.05.014; PMID: 24011539. Roston TM, Vinocur JM, Maginot KR, et al. Catecholaminergic polymorphic ventricular tachycardia in children: analysis of therapeutic strategies and outcomes from an international multicenter registry. Circ Arrhythm Electrophysiol 2015;8:633–42. DOI: 10.1161/CIRCEP.114.002217; PMID: 25713214. Watanabe H, Chopra N, Laver D, et al. Flecainide prevents catecholaminergic polymorphic ventricular tachycardia in

16.

17. 18.

19.

20.

21.

22.

23.

mice and humans. Nat Med 2009;15:380–3. DOI: 10.1038/ nm.1942; PMID: 19330009. Holmes B, Heel RC. Flecainide. A preliminary review of its pharmacodynamic properties and therapeutic efficacy. Drugs 1985;29:1–33. PMID: 3882390. Roden DM, Woosley RL. Drug therapy. Flecainide. N Engl J Med 1986;315:36–41. PMID: 3520324. Bannister ML, Thomas NL, Sikkel MB, et al. The mechanism of flecainide action in CPVT does not involve a direct effect on RyR2. Circ Res 2015;116:1324–35. DOI: 10.1161/ CIRCRESAHA.116.305347; PMID: 25648700. Liu N, Denegri M, Ruan Y, et al. Short communication: flecainide exerts an antiarrhythmic effect in a mouse model of catecholaminergic polymorphic ventricular tachycardia by increasing the threshold for triggered activity. Circ Res 2011;109:291–5. DOI: 10.1161/CIRCRESAHA.111.247338; PMID: 21680895. Sikkel MB, Collins TP, Rowlands C, et al. Flecainide reduces Ca(2+) spark and wave frequency via inhibition of the sarcolemmal sodium current. Cardiovasc Res 2013;98:286–96. DOI: 10.1093/cvr/cvt012; PMID: 23334259. Smith GL, MacQuaide N. The direct actions of flecainide on the human cardiac ryanodine receptor: keeping open the debate on the mechanism of action of local anesthetics in CPVT. Circ Res 2015;116:1284–6. DOI: 10.1161/ CIRCRESAHA.115.306298; PMID: 25858058. Hwang HS, Hasdemir C, Laver D, et al. Inhibition of cardiac Ca2+ release channels (RyR2) determines efficacy of class I antiarrhythmic drugs in catecholaminergic polymorphic ventricular tachycardia. Circ Arrhythm Electrophysiol 2011;4:128– 35. DOI: 10.1161/CIRCEP.110.959916; PMID: 21270101. van der Werf C, Kannankeril PJ, Sacher F, et al. Flecainide therapy reduces exercise-induced ventricular arrhythmias

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24.

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26.

27.

28.

29.

in patients with catecholaminergic polymorphic ventricular tachycardia. J Am Coll Cardiol 2011;57:2244–54. DOI: 10.1016/j.jacc.2011.01.026; PMID: 21616285. Khoury A, Marai I, Suleiman M, et al. Flecainide therapy suppresses exercise-induced ventricular arrhythmias in patients with CASQ2-associated catecholaminergic polymorphic ventricular tachycardia. Heart Rhythm 2013;10:1671–5. DOI: 10.1016/j.hrthm.2013.08.011; PMID: 23954267. Watanabe H, van der Werf C, Roses-Noguer F, et al. Effects of flecainide on exercise-induced ventricular arrhythmias and recurrences in genotype-negative patients with catecholaminergic polymorphic ventricular tachycardia. Heart Rhythm 2013;10:542–7. DOI: 10.1016/j. hrthm.2012.12.035; PMID: 23286974. Padfield GJ, AlAhmari L, Lieve KV et al. Flecainide monotherapy is an option for selected patients with catecholaminergic polymorphic ventricular tachycardia intolerant of β-blockade. Heart Rhythm 2016;13:609–13. DOI: 10.1016/j.hrthm.2015.09.027; PMID: 26416620. De Ferrari GM, Dusi V, Spazzolini C, et al. Clinical management of catecholaminergic polymorphic ventricular tachycardia: the role of left cardiac sympathetic denervation. Circulation 2015;131:2185–93. DOI: 10.1161/ CIRCULATIONAHA.115.015731; PMID: 26019152. Leren IS, Saberniak J, Majid E, et al. Nadolol decreases the incidence and severity of ventricular arrhythmias during exercise stress testing compared with β1-selective β-blockers in patients with catecholaminergic polymorphic ventricular tachycardia. Heart Rhythm 2016;13:433–40. DOI: 10.1016/j.hrthm.2015.09.029; PMID: 26432584. Priori SG, Blomström-Lundqvist C, Mazzanti A, et al. 2015

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30.

31.

32.

33.

34.

35.

ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the Europe. Eur Heart J 2015;36:2793–867. DOI: 10.1093/eurheartj/ehv316; PMID: 26320108. Hayashi M, Denjoy I, Extramiana F, et al. The role of stress test for predicting genetic mutations and future cardiac events in asymptomatic relatives of catecholaminergic polymorphic ventricular tachycardia probands. Europace 2012;14:1344–51. DOI: 10.1093/europace/eus031; PMID: 22383456. Echt DS, Liebson PR, Mitchell LB, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med 1991;324:781–8. PMID: 1900101. Aliot E, Capucci A, Crijns HJ, et al. Twenty-five years in the making: flecainide is safe and effective for the management of atrial fibrillation. Europace 2011;13:161–73. DOI: 10.1093/ europace/euq382; PMID: 21138930. Biernacka EK, Hoffman P. Efficacy of flecainide in a patient with catecholaminergic polymorphic ventricular tachycardia. Europace 2011;13:129–30. DOI: 10.1093/europace/euq279; PMID: 20798117. Pott C, Dechering DG, Reinke F, et al. Successful treatment of catecholaminergic polymorphic ventricular tachycardia with flecainide: a case report and review of the current literature. Europace 2011;13:897–901. DOI: 10.1093/europace/euq517; PMID: 21292648. Sy RW, Gollob MH, Klein GJ, et al. Arrhythmia characterization and long-term outcomes in catecholaminergic polymorphic

ventricular tachycardia. Heart Rhythm 2011;8:864–71. DOI: 10.1016/j.hrthm.2011.01.048; PMID: 21315846. 36. Hong RA, Rivera KK, Jittirat A, et al. Flecainide suppresses defibrillator-induced storming in catecholaminergic polymorphic ventricular tachycardia. Pacing Clin Electrophysiol 2012;35:794–7. DOI: 10.1111/j.1540-8159.2012.03421.x; PMID: 22553997. 37. Jacquemart C, Ould Abderrahmane F, Massin MM. Effects of flecainide therapy on inappropriate shocks and arrhythmias in catecholaminergic polymorphic ventricular tachycardia. J Electrocardiol 2012;45:736–8. DOI: 10.1016/j. jelectrocard.2012.05.002; PMID: 22672791. 38. Mantziari L, Vassilikos V, Anastasakis A, et al. A de novo novel cardiac ryanodine mutation (Ser4155Tyr) associated with catecholaminergic polymorphic ventricular tachycardia. Ann Noninvasive Electrocardiol 2013; 18:571–6. DOI: 10.1111/ anec.12089; PMID: 24147812. 39. Wangüemert-Pérez F, Ruiz-Hernández PM, Campuzano O, et al. Flecainide in patient with aggressive catecholaminergic polymorphic ventricular tachycardia due to novel RYR2 mutation. Minerva Cardioangiol 2014;62:363–6. PMID: 25012103. 40. Miyake CY, Webster G, Czosek RJ, et al. Efficacy of implantable cardioverter defibrillators in young patients with catecholaminergic polymorphic ventricular tachycardia: success depends on substrate. Circ Arrhythm Electrophysiol 2013;6:579–87. DOI: 10.1161/CIRCEP.113.000170; PMID: 23667268. 41. Roses-Noguer F, Jarman JW, Clague JR, et al. Outcomes of defibrillator therapy in catecholaminergic polymorphic ventricular tachycardia. Heart Rhythm 2014;11:58–66. DOI: 10.1016/j.hrthm.2013.10.027; PMID: 24120999.

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Diagnostic Electrophysiology & Ablation

Novel Interventional Strategies for the Treatment of Atrial Fibrillation Konstantinos C Siontis and Hakan Oral Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI, US

Abstract The landscape of the invasive management of atrial fibrillation, the most common sustained arrhythmia in humans, has changed dramatically in the last decade owing to numerous advances in arrhythmia mapping and ablation technologies. The current review critically appraises novel interventional strategies for the treatment of atrial fibrillation with a focus on clinical effectiveness and safety.

Keywords Atrial fibrillation, ablation, mapping, outcomes, safety Disclosure: The authors have no conflicts of interest to declare. Received: 10 November 2015 Accepted: 24 March 2016 Citation: Arrhythmia & Electrophysiology Review 2016;5(1):50–6 Access at: www.AERjournal.com DOI: 10.15420/AER.2015.23.3 Correspondence: Dr Oral, Division of Cardiovascular Medicine, Cardiovascular Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109-5853. E-mail: oralh@med.umich.edu

Advanced catheter-based technologies employed for the ablation of symptomatic atrial fibrillation (AF) have revolutionised the management of this common sustained arrhythmia. In the late 1990s, premature depolarisations originating from the myocardial sleeves within the pulmonary veins were recognised to initiate AF. This landmark discovery rendered pulmonary vein isolation (PVI) as the cornerstone of the nonpharmacological management of AF.1 The utilisation of modern 3D electroanatomical mapping and PVI-based ablation approaches in carefully selected patients with AF often offers therapeutic benefit.2 However, PVI alone may be insufficient, especially in patients with long-standing persistent AF. Linear ablation and ablation of complex fractionated atrial electrograms (CFAEs) have been proposed as strategies to improve the efficacy of PVI in patients with persistent AF with variable efficacy.3 The need to improve procedural outcomes while furthering the safety of the procedure has led to continuous efforts for the refinement of mapping and ablation technologies. Herein, we aim to review the current status of selected novel interventional strategies employed for the treatment of AF.

• Intracardiac multielectrode contact mapping using a 64-electrode basket catheter, • Non-invasive body surface potential mapping (BSPM); discussed in detail later in this review.

frequency and phase domain analysis (Hilbert transformation and analysis of Shannon entropy).5 In the first approach, focal impulse and rotor modulation (FIRM) computational maps demonstrating rotors and focal impulses are created with the use of commercially available software (see Figure 1).6 The feasibility of this approach is based on the premise that focal sources are spatially and temporally stable and therefore may be feasible to be targeted for ablation. Interestingly, CFAE sites were shown to be in poor spatial association with AF sources.7 In the context of these observations, the pivotal prospective non-randomised Conventional Ablation for Atrial Fibrillation With or Without Focal Impulse and Rotor Modulation (CONFIRM) study was performed.8 Thirty-six patients (81 % with persistent AF) underwent FIRM-guided ablation and 71 patients (66 % with persistent AF) underwent conventional PVI. Localised AF sources were present in the vast majority of persistent AF cases (97 %) with a mean 2.1 ± 1.0 sources per subject. The number of rotors and focal impulses was higher among patients with persistent AF than those with paroxysmal AF (mean 2.2 ± 1.0 versus 1.7 ± 0.9, p=0.03). FIRM-guided ablation resulted in acute AF termination in 31 of 36 (86 %) patients, whereas conventional ablation was acutely successful in 13 of 65 (20 %) patients with sustained AF. After median 273 days, more patients in the FIRM-guided group were free of AF than in the FIRM-blinded group (82 % versus 45 %, p<0.001). In an extended 3-year followup of the CONFIRM study, FIRM-guided ablation conferred more sustained freedom from AF after 1.2 ± 0.4 procedures (78 % versus 39 % in the FIRM-blinded group, p=0.001) and a single procedure (p<0.001).9 Preliminary results from Precise Rotor Elimination Without Concomitant Pulmonary Vein Isolation For Subsequent Elimination Of PAF (PRECISE) trial performed by the same groups of investigators also demonstrated the superiority of the FIRM-guided over the FIRMblinded approach in paroxysmal AF.

Both approaches utilise proprietary signal processing algorithms based on a number of steps which may include interpolation, filtering,

These clinical trial results are promising; however, important limitations of the approach remain to be addressed. Electrogram

Focal Impulse and Rotor Modulation One of the mechanistic hypotheses of AF suggests that the arrhythmia is initiated by localised triggers (drivers) and propagated in the form of high-frequency reentrant sources (rotors) or focal impulses that degenerate into fibrillatory waves.4 Targeting of such distinct AF drivers could therefore improve ablation outcomes. Two methods have recently been proposed for panoramic/global mapping of AF drivers:

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Novel Interventional Strategies for Atrial Fibrillation

Figure 1: Focal Impulse and Rotor Modulation (FIRM) Ablation

Figure 2: Body Surface Potential Mapping of Driver Sites A

C AF rotor in low left atrium

aVF V1 CS 1 sec

Basket catheters in both atria

Implanted ECG monitor

Left atrial basket

Septal

Lateral tricuspid

Right atrium Superior vena cava

activation along rotor path

Left atrium Superior mitral

C D E F G H A B

0 ms

1st revolution (AF1) C D E F G H A B

200

A6 H7

2.5

H5 H4 H3 200

H2 A2

A3 0 ms

100 ms

While three-dimensional electroanatomic mapping represents standard practice in AF ablation, pre-procedural non-invasive mapping may be useful in localising potential ablation targets. The standard 12-lead electrocardiogram is insufficient to characterise the complex electrical activation in AF. In a recent study, BSPM using 56 torso leads in addition to the standard limb leads was performed and four different patterns of wavefront propagation were described.14 In a subsequent study, the same group performed simultaneous BSPM and intracardiac real-time frequency electroanatomical mapping and observed good correlation between the highest dominant frequency sites in the right and left atria and the corresponding right- and left-sided surface leads (see Figure 2).15 Applying a similar concept of ‘panoramic mapping’, Haïssaguerre et al. integrated unipolar body surface potentials obtained from a 252-electrode vest with biatrial geometry obtained with high-resolution thoracic computed tomography (CT).16 Relative electrode positions were also determined by CT imaging, and activation, dominant frequency and cycle length maps were constructed. AF sources were also classified into focal and reentry (either functional or fixed-anatomical). In early clinical studies, the information obtained from this mapping approach was used to guide ablation. Whether non-invasive AF

quality is often insufficient for accurate mapping with the currently available multielectrode catheter technology, especially in atria with large dimensions.6 Due to insufficient electrogram quality, extensive

Body Surface Potential Mapping

A: Electrocardiogram (ECG) and intracardiac signals in patient with paroxysmal atrial fibrillation (AF); B: 64-pole catheter in each atrium, an implanted continuous electrocardiography 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 processing centre for 3 cycles (AF1– AF3); D: computationally processed and filtered intracardiac signals show sequential activation over the rotor path for cycles AF1–AF3 (arrowed). FIRM ablation at this rotor terminated AF to sinus rhythm in 1 min. Reproduced with permission from Narayan, et al.8

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interpolation may often be necessary which has its own inherent limitations. Additionally, while FIRM analysis generates maps that demonstrate stable rotors for several minutes, analysis of body surface potentials suggests that sites of high dominant frequency may actually be spatially and temporally unstable.10 Also, the mapping capability of the septal left atrium with this catheter is suboptimal while exclusively endocardial mapping may be unable to identify transmural or epicardial sources.11 Reproducibility of FIRM mapping in accurately identifying AF sources and superior clinical outcomes after FIRM-guided ablation will be critically important for widespread adoption of this novel technology.12,13

Frequency difference (Hz)

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A ECG and intracardiac signals

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A and B: differences between maximum intracardiac electrogram (EGM) dominant frequency (DF) and local surface DF represented in a colour scale for two different patients. The red colour domain on the surface (pale blue arrows) represents the region with zero difference between the intracardiac and the surface DFs. A: patient with a left-to-right DF gradient; B: patient with right-to-left DF gradient. C and D: summary maps showing the percent patients with the surface DFs <0.5 Hz different than the maximal left (C) and maximal right (D) intracardiac DFs. Areas outlined by the dashed curves represent the portion of the torso with a best correspondence with left and right EGMs. E: correlation plot showing highest DFs found in left EGMs versus highest DFs found on the left portion of the torso. F: correlation plot showing highest DFs found in right EGMs versus highest DFs found on the right portion of the torso. BSPM = body surface potential mapping. Reproduced with permission from Guillem, et al.15

mapping can effectively guide AF ablation is a matter of ongoing investigation. Evidence is currently limited to a single-centre clinical study in 103 patients with persistent or long-lasting AF. Driverguided ablation resulted in termination of AF (into sinus rhythm or atrial tachycardia) in 75 % and 15 % of persistent and long-lasting AF cases, respectively.17 The preliminary results of another clinical trial, the multicentre Non-Invasive Mapping Before Ablation for Atrial Fibrillation (AFACART) study, showed overall similar success rates with driver ablation only.18 These studies demonstrated that AF drivers were rather unstable and had a mean duration of less than 1 second. However, there was a tendency of these drivers to occur at certain sites in the atria. Therefore, the investigators utilised maps that displayed the hierarchy of sites based on the probability of exhibiting a driver. Furthermore, approximately 80 % of the drivers were microreentrant and 20 % were focal.

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Diagnostic Electrophysiology & Ablation Figure 3: Delayed-enhancement MRI for Quantification of Atrial Fibrosis in Atrial Fibrillation A

Delayed enhancement magnetic resonance imaging analysis Step 1: Aquire axial views of left atrium

Schematic posterior view of left atrium

Step 2: Isolate and identify left atrial wall

Left pulmonary veins

Aorta

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Left atrium Axial view Heart

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Step 4: Render 3D model on left atrium

Left pulmonary veins

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Left atrium

Healthy

Fibrotic tissue

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Fibrotic tissue

High-resolution 3D delayed enhancement magnetic resonance imaging (MRI) scans of the left atrium are acquired (step 1). Epicardial and endocardial borders are contoured in each MRI slice to define the left atrial wall segmented region (step 2).Wall segmentations include the 3D extent of both the left atrial wall and the antral regions of the pulmonary veins, but exclude the mitral valve. Quantification of fibrosis is based on relative intensity of contrast enhancement (step 3). The 3D model of the left atrium is rendered from the endocardial (left atrial cavity) and left atrial wall segmentations, and the maximum enhancement intensities are projected on the surface of the model (step 4). Reproduced with permission from Marrouche, et al.22

Proportion of atrial arrhythmia-free patients

Figure 4: Pulmonary Vein Isolation Combined with Ganglionated Plexi Ablation 1.00

PVI + GP

0.75

PVI GP

0.50

encouraging results in the pre-procedural planning of AF catheter ablation as it allows for direct signal quantification. In a controlled study of 112 patients undergoing radiofrequency ablation, the T1 time was the only predictor of 12-month arrhythmia recurrence in multivariate analysis.23 The real-time use of MRI to guide ablation intraprocedurally has also been investigated.24 Specifically for AF, using a 3-Tesla MRI system, Vergara et al. were the first to combine real-time MRI tracking of catheters with recording of electrograms in order to guide radiofrequency ablation and visualise lesion formation in a swine model.25 The same group used real-time DE-CMR to identify and target gaps in ablation lesions sets,26 even though it has also been argued that DE-CMR may not be accurate enough to reliably assess lesion distribution.27 While real-time MRI is radiation-free and allows for the accurate visualisation of the location and extend of lesion formation, its disadvantages may include the compatibility of catheters and existing ablation technology, cost and incompatibility with implantable cardiac devices or other hardware.

Ganglionated Plexi Ablation Vagal denervation during circumferential PVI may improve the longterm outcome of ablation.28 The ganglionated plexi (GP), are located in the epicardial aspect of the junctions of all four pulmonary veins (PVs) with the left atrium and are responsible for both the sympathetic and parasympathetic innervation of the atrium.29 Since parasympathetic influences can facilitate AF by both increasing triggered activity and shortening the effective refractory period, it has been suggested that ablation of the GP may lead to more successful elimination of the arrhythmia. The approach to identify the exact location of the GP in the electrophysiology laboratory has evolved from the use of high-frequency stimulation (HFS) in order to elicit a vagal response30 to the anatomically-guided ablation of regions known to harbour the GP. The latter approach has been proven feasible and safe31 and in a direct comparison to HFS-driven GP ablation, it was also shown to be more effective.32

0.25 p=0.0036 0.00 0

10 Follow-up (months)

Number at risk GP 82 PVI 78 PVI + GP 82

59 55 65

55 51 63

40 48 61

39 44 60

Comparison was performed using the log-rank test stratified by study site. GP = ganglionated plexi; PVI = pulmonary vein isolation. Reproduced with permission from Katritsis, et al.34

Magnetic Resonance Imaging-guided Ablation Atrial fibrosis, which plays an important role in the genesis and perpetuation of AF, can be detected by invasive electroanatomical mapping,19 but more recently delayed-enhancement cardiac magnetic resonance (DE-CMR) imaging has emerged as a promising noninvasive modality for the quantification and classification of the extent of fibrosis based on the Utah classification (see Figure 3).20,21 In the Delayed-Enhancement MRI Determinant of Successful Radiofrequency Catheter Ablation of Atrial Fibrillation (DECAAF) study, the degree of fibrosis was independently associated with arrhythmia recurrence after catheter ablation.22 Other prospective studies are currently underway where patients are being randomised to fibrosisguided versus conventional radiofrequency ablation. In addition to DE-CMR, T1 mapping is another MRI-based technique that has shown

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In clinical studies, GP ablation has been examined alone and in association with PVI in paroxysmal and persistent AF with variable results. In the first randomised controlled trial on the topic, Katritsis et al. compared GP ablation plus PVI with PVI alone in 67 patients with paroxysmal AF.33 At mean follow-up periods of 11.3 ± 1.9 months for the GP + PV group and 9.7 ± 3.4 months for the PV group, 15 (46 %) patients in the PV group and 25 (74 %) patients in the GP + PV group remained arrhythmia-free after a single procedure (log rank p=0.022). In a subsequent larger trial by the same investigators, 242 patients with paroxysmal AF were randomised to PVI alone (n=78), GP ablation alone (n=82), or PVI plus GP ablation (n=82).34 At 2-year follow-up, a total of 44 (56 %), 39 (48 %), and 61 (74 %) patients in the PVI, GP and PVI + GP ablation groups, respectively, remained in sinus rhythm (see Figure 4). These data support the role of autonomic denervation in the ablative management of AF. It is unclear, however, whether these outcomes are mediated by a truly independent effect of autonomic modulation or whether GP ablation simply results in more durable isolation of the pulmonary veins. Also, additional questions remain in regards to the safety of the approach. In theory, the application of extra radiofrequency lesions required for ablation of the GPs may increase the risks of tamponade and oesophageal injury, whereas excess atrial scar tissue formation could be pro-arrhythmic. Notably, however, in the aforementioned randomised trial of 240 patients, the only complication

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was one case of tamponade (in the PVI group) and the incidence of post-ablation atrial flutter did not differ between groups.34

Figure 5: Novel Ablation Catheter Technologies A

Novel Ablation Technologies

Balloon

Cryoballoon Ablation PVI is an effective approach for the ablation of AF but its success depends heavily on the complete isolation of the pulmonary veins. This requires very meticulous point-by-point delivery of lesions for which radiofrequency energy source is used. The cryoballoon ablation technology, on the other hand, delivers a single circumferential isolation lesion with the use of a catheter-guided cryotherapy balloon. Advantages include the lower risk of certain complications, such as pulmonary vein stenosis and atrio-oesophageal fistulae, and the significantly reduced procedural time. Additionally, cryolesions are more homogeneous and are considered less arrhythmogenic than RF lesions. The first cryoballoon ablation system received Food and Drug Administration (FDA) approval in the United States in 2010 and its use has been steadily growing. The pivotal Sustained Treatment of Paroxysmal Atrial Fibrillation (STOP-AF) trial (2001–5) showed that PVI with the first-generation cryoballoon effectively eliminated paroxysmal AF in 82 % of patients during a mean follow-up of ~3 years. The overall complication rate was 4 % in that trial.35 A metaanalysis of 23 randomised and observational studies showed acute procedural success rate of almost 100 % among patients achieving complete PVI with the first-generation cryoballoon system and 1-year single-procedure success of 60 % off any antiarrhythmic drugs.36 Acute and long-term efficacy results appear to be even more promising with the second-generation cryoballoon system, which is characterised by more homogeneous balloon temperature.37,38 This may, however, be at the expense of higher rates of complications such as phrenic nerve palsy and oesophageal thermal injury.37,39 The comparative effectiveness and safety of cryoballoon and radiofrequency ablation are also of great interest. The recently published FreezeAF randomised trial indicated the non-inferiority of cryoballoon ablation with regards to 1-year recurrence-free rates, but procedural complications, in particular phrenic nerve palsy, were more common with cryoballoon ablation.40 Further insights into the cryoballoon versus radiofrequency ablation comparison are expected from the ongoing FIRE AND ICE trial.41

Visually-guided Laser Balloon Ablation The visually-guided laser balloon (VGLB) ablation catheter (HeartLight®, CardioFocus Inc) is the only catheter that allows direct visualisation of the target myocardium to be ablated which may in theory improve the rates of complete isolation and eventually decrease AF recurrences (see Figure 5A). Similar to the cryoballoon catheter, it can deliver more homogeneous circumferential isolation compared with the pointby-point radiofrequency ablation. The system consists of a variablediameter compliant balloon with a central shaft through which a 2 Fr endoscope allows real-time visualisation of target tissue. Ablation is performed with a manoeuvrable 30° light arc originating from the central shaft that can be targeted to any location along the surface of the balloon to deliver laser energy (980 nm). Isolation of the PV is then confirmed with the use of a different circular mapping catheter. While the system is currently used in clinical practice in Europe, it is not yet FDA-approved in the US. The first clinical study of the current generation VGLB system in 27 patients with paroxysmal AF was published in 2010 and demonstrated

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Flexible tip

Adjustable aiming point

C MASC

MAAC

A: Visually-guided laser balloon. The catheter consists of a variable diameter and compliant balloon, and an atraumatic and flexible tip. Reproduced with permission from Dukkipati, et al.42 B: Biplane fluoroscopic view of the circular pulmonary vein ablation catheter (PVAC) in the left superior pulmonary vein. Reproduced with permission from Boersma, et al.57 C: The multiarray septal catheter (MASC) and the multiarray ablation catheter (MAAC) that along with the PVAC (panel B) comprise the phased radiofrequency ablation system. Reproduced with permission from Scharf, et al.59

the feasibility of the approach.42 In a subsequent study of 56 patients, acute and 3-month isolation was documented in 98 % and 86 % of pulmonary veins, respectively,43 while another study of similar size demonstrated an arrhythmia-free rate of 60 % one year after ablation.44 This was in accordance with a multicentre study of 200 patients with paroxysmal AF in which freedom from atrial arrhythmias after one to two procedures was 60 % at 1 year, which is comparable to RF ablation.45 Tamponade and phrenic nerve injury rates of 2 % and 2.5 %, respectively, were raised as potential safety concerns in that study and, of note, associations between the lack of operator experience and longer procedure, ablation and fluoroscopy times were also demonstrated. Finally, the recently released results of the HeartLight US pivotal trial comparing VGLB versus radiofrequency ablation in 353 patients with paroxysmal AF demonstrated the non-inferiority of VGLB with regards to freedom from treatment failure at 12-month follow-up (61.1 % in the VGLB group versus 61.7 % in the radiofrequency ablation group). The overall rate of adverse events was also similar between the two groups but VGLB was associated with higher risk of diaphragmatic paralysis (3.5 % versus 0.6 %, p=0.05) and lower risk of pulmonary vein stenosis (0 % versus 2.9 %, p=0.03).46

Radiofrequency Hot Balloon Ablation The radiofrequency hot balloon catheter (Hayama Arrhythmia Institute) is another balloon-based ablation system aiming to achieve transmural circumferential PVI. The most updated version

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Diagnostic Electrophysiology & Ablation of this system is composed of a 1.8 MHz RF generator, a 13 F deflectable guiding sheath, a two-lumen catheter shaft and a highly elastic and compliant 20 μm thick polyurethane balloon which is inflated from 26–33 mm in diameter with ionised contrast medium diluted with normal saline. RF energy is delivered between a coil electrode inside the balloon and four cutaneous electrodes on the patient’s back to induce capacitive-type heating of the balloon. 47 The efficacy and safety of this system have been assessed in a proof-of-concept animal study48 and in three subsequent human studies in paroxysmal and persistent AF.47,49,50 In the largest of these studies, among 100 patients with drugresistant paroxysmal (n=63) or persistent (n=37) AF, 92 patients were free of AF without antiarrhythmic drugs at mean follow-up 11 months and there were no strokes or atrio-oesophageal fistulae, but there were three cases of asymptomatic PV stenosis50. In the most recent but smaller study of 30 patients, after a similar follow-up period, two thirds of patients were free of AF with a single procedure and there were no procedure-related short-term or long-term complications.47

Contact-force Sensing Catheters PV reconnection is a common cause of AF recurrence after PVI.51 Therefore the delivery of effective radiofrequency lesions that are likely to lead to permanent PVI is of paramount importance. In addition to the duration of lesion application, the contact force (CF) applied by the catheter tip on the myocardium is a major determinant of lesion size and depth. There is, however, a fine balance between too much CF that can lead to perforation and tamponade and too little CF that can lead to non-transmural or incomplete lesions. The need for better precision in CF application led to the development of two FDAapproved CF radiofrequency ablation catheters, which have become available in the last 2 years: ThermoCool® SmartTouch™ (Biosense Webster Inc) and TactiCath™ Quartz (St Jude Medical Inc). Using spring microdeformation or fibreoptic technologies, catheter tip direction and CF amplitude are sampled in rapid cycles of 50–100 msec and displayed in real-time. Several, mostly small studies have examined the clinical utility of the CF sensing catheters. In the randomised study by Kimura et al., CF-guided ablation (n=19 patients) was associated with significantly reduced procedure time and residual conduction gaps compared with non-CF-guided ablation (n=19 patients).52 In the prospective non-randomised ThermoCool SmartTouch Catheter for the Treatment of Symptomatic Paroxysmal Atrial Fibrillation (SMART-AF) study, which led to the FDA approval of the ThermoCool SmartTouch catheter, effective use of CF monitoring (defined as remaining within the pre-selected CF range ≥80 % of the time during radiofrequency application) was associated with significantly higher success rate (probability of freedom from recurrence of 81 % versus 66 %).53 It should be noted, however, that in that trial tamponade complicated 2.5 % of the procedures which was higher than anticipated.54 More conclusive data on the utility of the CF sensing technology may be derived from the recently published TactiCath Contact Force Ablation Catheter Study for Atrial Fibrillation (TOCCASTAR), in which 300 patients with paroxysmal AF were randomised to CF-guided ablation with the TactiCath Quartz catheter versus a standard radiofrequency ablation catheter.55 In this study, the non-inferiority of the CF catheter was proven, as the primary effectiveness endpoint was achieved in 68 % and 69 % of patients in the CF and control groups, respectively, while complication rates were similar. Efficacy was even higher when optimal CF was used (>90 % ablation with >10 g force). Results of

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all randomised and non-randomised studies were summarised in a recent meta-analysis that demonstrated a 37 % decrease of AF recurrences with use of CF sensing technologies.56

Multielectrode Ablation Catheters Multielectrode ablation catheters were designed to overcome some of the limitations of point-by-point radiofrequency ablation, namely the potential for non-contiguous and/or non-transmural ablation lesions and the risk of injury of adjacent structures with extensive unipolar radiofrequency energy application. The pulmonary vein ablation catheter (PVAC, Medtronic Ablation Frontiers) is a circular, decapolar mapping and ablation catheter with a 25 mm diameter array at the distal tip with adjustable diameter allowing positioning in PVs of variable diameter (see Figure 5B). The GENius™ multichannel, duty-cycled RF generator generates either unipolar or bipolar current with a fixed duty-cycle by a phase difference between the channels. This system showed 100 % success in isolating 369 PVs in 98 patients with paroxysmal AF with mean procedural and fluoroscopy times 84 and 18 minutes, respectively; these times are significantly shorter compared with conventional PVI. Six-month freedom from AF off antiarrhythmic medications was 83 %.57 More recently, results of the early clinical experience with another circular ablation catheter (nMARQ™, Biosense Webster) in 39 patients with paroxysmal AF were released.58 The nMARQ catheter has 10 openly irrigated electrodes arranged on a circle with adjustable diameter. Mapping is performed with the same catheter using the Carto® 3 system (BiosenseWebster) and RF energy can be delivered in unipolar or bipolar fashion (though only unipolar RF was used in this study). An impedance-based technology built in the mapping system provides real-time information on electrode-tissue contact for optimal RF delivery. Successful acute isolation was documented in 99 % of PVs with mean procedure duration 86 minutes. Single procedure success rate was 66 % at a mean follow-up of 140 days. Only one (3 %) procedural complication was noted (tamponade not related to the ablation catheter) and there were no late complications. In persistent AF, extensive substrate modification is required in addition to PVI, making the ablation procedure lengthy and complex. To increase procedural efficiency and efficacy, the PVAC catheter was combined with two additional catheters: the multiarray septal catheter, which contains three arms with six paired electrodes and is purposed for ablation of CFAEs in the septum, and the multiarray ablation catheter, which has four arms with eight paired electrodes and is purposed for LA mapping and ablation (see Figure 5C). Initial clinical results with this system were promising: in a multicentre study of 50 patients with persistent AF the 20-month success rate was 66 % (>80 % reduction in AF burden)59 and in a subsequent study of 89 patients 56 % were free of AF at 12 months after a mean 1.2 procedures.60 The Tailored Treatment of Persistent Atrial Fibrillation (TTOP-AF) study represents the only randomised evaluation of this ablation system to date.61 Patients with persistent AF were randomised to ablative management (n=138) or antiarrhythmic medications (n=72). The chronic effectiveness endpoint was met in 55.8 % patients in the ablation group (≥90 % reduction in cumulative AF and atrial flutter burden at 6 months) versus 26.4 % in the medical management group. Significant differences were also observed in quality of life and symptom severity in favour of the ablation group. However, the trial did not meet its predefined acute safety endpoint, an effect that was mainly due to the peri-procedural stroke rate of 2.9 % (4 of 138 patients undergoing ablation). This higher-thananticipated stroke rate was attributed to lack of operator experience

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and inadequate anticoagulation strategies in the study, in addition to intrinsic characteristics of the ablation system. While an increased risk of subclinical thromboembolic events with the PVAC catheter has been reported,62 other non-randomised studies using the multiarray ablation system have demonstrated clinical thromboembolic rates comparable to cryoballoon and irrigated RF ablation in mixed paroxysmal and persistent AF populations.63,64 On the basis of the TTOP-AF results, the Medtronic Ablation Frontiers system was not approved for use in the US; however, a large-scale real-world registry of the second-generation multiarray ablation system utilising the PVAC GOLD® catheter is currently underway in several European centres. In the PVAC GOLD catheter, the platinum electrodes are replaced by gold ones, which are associated with improved thermal efficiency. The second generation system is also considered less thrombogenic.

Hybrid Endocardial and Epicardial Ablation Addition of epicardial ablation lesions to conventional endocardial lesion sets may increase the success rates of the ablation procedure. While the traditional open surgical ablation for AF developed by Cox is highly efficacious, it is an invasive and lengthy procedure.65 In contrast, a pericardioscopic radiofrequency-based approach allows for direct access to the epicardium for delivery of ablation lines without the complexity and morbidity associated with open surgical ablation, and importantly without the need for cardiopulmonary bypass. A combined endocardial and minimally invasive epicardial procedure (so called hybrid or convergent ablation) may offer superior results to each individual procedure alone, especially in patients with longstanding AF, by bridging gaps, achieving more complete PVI and eliminating also additional electrophysiological targets.66 It has also been suggested that sequential hybrid ablation may be superior to repeat catheter ablation in patients who have already failed one

Haissaguerre M, Jais 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. PMID: 9725923 Calkins H, Reynolds MR, Spector P, et al. Treatment of atrial fibrillation with antiarrhythmic drugs or radiofrequency ablation: Two systematic literature reviews and metaanalyses. Circ Arrhythm Electrophysiol 2009;2:349–61. DOI: 10.1161/CIRCEP.108.824789; PMID: 19808490 Verma A, Jiang CY, Investigators SAI, et al. Approaches to catheter ablation for persistent atrial fibrillation. N Engl J Med 2015;372:1812–22. DOI: 10.1056/NEJMoa1408288; PMID: 25946280 Kalifa J, Tanaka K, Zaitsev AV, et al. Mechanisms of wave fractionation at boundaries of high-frequency excitation in the posterior left atrium of the isolated sheep heart during atrial fibrillation. Circulation 2006;113:626–33. PMID: 16461834 Ganesan AN, Kuklik P, Lau DH, et al. Bipolar electrogram Shannon entropy at sites of rotational activation: Implications for ablation of atrial fibrillation. Circ Arrhythm Electrophysiol 2013;6:48–57. DOI: 10.1161/CIRCEP.112.976654; PMID: 23264437 Narayan SM, Krummen DE, Rappel WJ. Clinical mapping approach to diagnose electrical rotors and focal impulse sources for human atrial fibrillation. J Cardiovasc Electrophysiol 2012;23:447–54. DOI: 10.1111/j.1540-8167.2012.02332.x; PMID: 22537106; PMCID: PMC3418865 Narayan SM, Shivkumar K, Krummen DE, et al. Panoramic electrophysiological mapping but not electrogram morphology identifies stable sources for human atrial fibrillation: Stable atrial fibrillation rotors and focal sources relate poorly to fractionated electrograms. Circ Arrhythm Electrophysiol 2013;6:58–67. DOI: 10.1161/CIRCEP.111.977264; PMID: 23392583; PMCID: PMC3746540 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. DOI: 10.1016/j.jacc.2012.05.022; PMID: 22818076; PMCID: PMC3416917 Narayan 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

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endocardial attempt.67 Clinical evidence on the efficacy and safety of the hybrid approach has emerged in recent years from small or moderate sized series of patients, but no randomised trials have yet been published assessing the comparative performance of this combined approach to catheter ablation only or surgical ablation only.68–73 In the largest published series to-date by Gehi et al., 101 patients with predominantly persistent or long-standing persistent AF (83 % of patients) underwent single-procedure hybrid ablation. Twelve-month arrhythmia-free survival was 66.3 % and 70.5 % with a single and with repeat ablation procedure, respectively.69 The success rate at 1 year (defined as sinus rhythm without antiarrhythmic therapy or repeat ablation) was higher (83 %) in another smaller series though the small sample size (n=26) limits the ability to draw reliable conclusions.70 Importantly, 6 (6 %) early post-operative major complications were documented in the Gehi et al. study, including two deaths (one due to atrio-oesophageal fistula and one sudden death without obvious aetiology identified). In a more recent series of the staged hybrid procedure in 50 patients, the incidence of major complications after the surgical phase reached 13.7 %, while there were no major complications after the catheter ablation phase.68 These rates may exceed the major complication rate of conventional catheter ablation for AF in the contemporary era.74

Conclusions and Future Directions Continued innovation can help meet the urgent need to improve the outcomes of the nonpharmacological management of AF.75 The novel mapping and ablation technologies discussed in this review show great promise to that direction. Operator learning curve, costs and, most importantly, superior safety and effectiveness profiles compared with established strategies will be important for the widespread adoption of new technologies which should be tested and confirmed in multicentre prospective randomised trials. n

with or without focal impulse and rotor modulation). J Am Coll Cardiol 2014;63:1761–8. doi: 10.1016/j.jacc.2014.02.543; PMID: 24632280; PMCID: PMC4008643 Jarman JW, Wong T, Kojodjojo P, et al. Spatiotemporal behavior of high dominant frequency during paroxysmal and persistent atrial fibrillation in the human left atrium. Circ Arrhythm Electrophysiol 2012;5:650–8. DOI: 10.1161/ CIRCEP.111.967992; PMID: 22722660 Hansen BJ, Zhao J, Csepe TA, et al. Atrial fibrillation driven by micro-anatomic intramural re-entry revealed by simultaneous sub-epicardial and sub-endocardial optical mapping in explanted human hearts. Eur Heart J 2015;36:2390–401. DOI: 10.1093/eurheartj/ehv233; PMID: 26059724; PMCID: PMC4568403 Benharash P, Buch E, Frank P, et al. Quantitative analysis of localized sources identified by focal impulse and rotor modulation mapping in atrial fibrillation. Circ Arrhythm Electrophysiol 2015;8:554–61. doi: 10.1161/CIRCEP.115.002721 PMID: 25873718; PMCID: PMC4655205 Share M, Shivkumar K, Buch E. Clinical outcomes of focal impulse and rotor modulation for treatment of atrial fibrillation: Single-center experience. Abstract. Circulation 2014;130:A14906. Guillem MS, Climent AM, Castells F, et al. Noninvasive mapping of human atrial fibrillation. J Cardiovasc Electrophysiol 2009;20:507–13. DOI: 10.1111/j.1540-8167.2008.01356.x; PMID: 19017334 Guillem MS, Climent AM, Millet J, et al. Noninvasive localization of maximal frequency sites of atrial fibrillation by body surface potential mapping. Circ Arrhythm Electrophysiol 2013;6:294–301. DOI: 10.1161/CIRCEP.112.000167; PMID: 23443619; PMCID: PMC4292880 Haissaguerre M, Hocini M, Shah AJ, et al. Noninvasive panoramic mapping of human atrial fibrillation mechanisms: A feasibility report. J Cardiovasc Electrophysiol 2013;24:711–7. DOI: 10.1111/jce.12075; PMID: 23373588 Haissaguerre M, Hocini M, Denis A, et al. Driver domains in persistent atrial fibrillation. Circulation 2014;130:530–8. DOI: 10.1161/CIRCULATIONAHA.113.005421; PMID: 25028391 Knecht S. Successful ablation of persistent AF based on a non-invasive mapping to identify AF drivers. The AFACART multicenter study. Poster. Heart Rhythm On Demand, 2014 Verma A, Wazni OM, Marrouche NF, et al. Pre-existent left atrial scarring in patients undergoing pulmonary vein antrum

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isolation: An independent predictor of procedural failure. J Am Coll Cardiol 2005;45:285–92. PMID: 15653029 Oakes RS, Badger TJ, Kholmovski EG, et al. Detection and quantification of left atrial structural remodeling with delayed-enhancement magnetic resonance imaging in patients with atrial fibrillation. Circulation 2009;119:1758–67. DOI: 10.1161/CIRCULATIONAHA.108.811877; PMID: 19307477; PMCID: PMC2725019 Mahnkopf C, Badger TJ, Burgon NS, et al. Evaluation of the left atrial substrate in patients with lone atrial fibrillation using delayed-enhanced MRI: Implications for disease progression and response to catheter ablation. Heart Rhythm 2010;7:1475– 81. DOI: 10.1016/j.hrthm.2010.06.030; PMID: 20601148; PMCID: PMC3106345 Marrouche NF, Wilber D, Hindricks G, et al. Association of atrial tissue fibrosis identified by delayed enhancement MRI and atrial fibrillation catheter ablation: The decaaf study. JAMA 2014;311:498–506. DOI: 10.1001/jama.2014.3; PMID: 24496537 Ling LH, McLellan AJ, Taylor AJ, et al. Magnetic resonance post-contrast T1 mapping in the human atrium: Validation and impact on clinical outcome after catheter ablation for atrial fibrillation. Heart Rhythm 2014;11:1551–9. DOI: 10.1016/j. hrthm.2014.06.012; PMID: 24931636 Nazarian S, Kolandaivelu A, Zviman MM, et al. Feasibility of real-time magnetic resonance imaging for catheter guidance in electrophysiology studies. Circulation 2008;118:223–9. DOI: 10.1161/CIRCULATIONAHA.107.742452; PMID: 18574048; PMCID: PMC2826501 Vergara GR, Vijayakumar S, Kholmovski EG, et al. Real-time magnetic resonance imaging-guided radiofrequency atrial ablation and visualization of lesion formation at 3 tesla. Heart Rhythm 2011;8:295–303. DOI: 10.1016/j.hrthm.2010.10.032; PMID: 21034854; PMCID: PMC3118671 Ranjan R, Kholmovski EG, Blauer J, et al. Identification and acute targeting of gaps in atrial ablation lesion sets using a real-time magnetic resonance imaging system. Circ Arrhythm Electrophysiol 2012;5:1130–5. DOI: 10.1161/CIRCEP.112.973164; PMID: 23071143; PMCID: PMC3691079 Hunter RJ, Jones DA, Boubertakh R, et al. Diagnostic accuracy of cardiac magnetic resonance imaging in the detection and characterization of left atrial catheter ablation lesions: A multicenter experience. J Cardiovasc Electrophysiol 2013;24:396–403. DOI: 10.1111/jce.12063; PMID: 23293924 Pappone C, Santinelli V, Manguso F, et al. Pulmonary vein

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29.

30.

31.

32.

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34.

35.

36.

37.

38.

39.

40.

41.

42.

43.

denervation enhances long-term benefit after circumferential ablation for paroxysmal atrial fibrillation. Circulation 2004;109:327–34. PMID: 14707026 Lin J, Scherlag BJ, Niu G, et al. Autonomic elements within the ligament of marshall and inferior left ganglionated plexus mediate functions of the atrial neural network. J Cardiovasc Electrophysiol 2009;20:318–24. DOI: 10.1111/j.15408167.2008.01315.x.; PMID: 19261040 Lemery R, Birnie D, Tang AS, et al. Feasibility study of endocardial mapping of ganglionated plexuses during catheter ablation of atrial fibrillation. Heart Rhythm 2006;3:387–96. PMID: 16567283 Katritsis D, Giazitzoglou E, Sougiannis D, et al. Anatomic approach for ganglionic plexi ablation in patients with paroxysmal atrial fibrillation. Am J Cardiol 2008;102:330–4. DOI: 10.1016/j.amjcard.2008.03.062; PMID: 18638596 Pokushalov E, Romanov A, Shugayev P, et al. Selective ganglionated plexi ablation for paroxysmal atrial fibrillation. Heart Rhythm 2009;6:1257–64. DOI: 10.1016/j. hrthm.2009.05.018.; PMID: 19656736 Katritsis DG, Giazitzoglou E, Zografos T, et al. Rapid pulmonary vein isolation combined with autonomic ganglia modification: A randomized study. Heart Rhythm 2011;8:672–8. DOI: 10.1016/j.hrthm.2010.12.047; PMID: 21199686 Katritsis DG, Pokushalov E, Romanov A, et al. Autonomic denervation added to pulmonary vein isolation for paroxysmal atrial fibrillation: A randomized clinical trial. J Am Coll Cardiol 2013;62:2318–25. DOI: 10.1016/j.jacc.2013.06.053; PMID: 23973694 Packer DL, Kowal RC, Investigators SAC, et al. Cryoballoon ablation of pulmonary veins for paroxysmal atrial fibrillation: First results of the north american arctic front (stop af) pivotal trial. J Am Coll Cardiol 2013;61:1713–23. DOI: 10.1016/j. jacc.2012.11.064; PMID: 23500312 Andrade JG, Khairy P, Guerra PG, et al. Efficacy and safety of cryoballoon ablation for atrial fibrillation: A systematic review of published studies. Heart Rhythm 2011;8:1444–51. DOI: 10.1016/j.hrthm.2011.03.050; PMID: 21457789 Chierchia GB, Di Giovanni G, Ciconte G, et al. Secondgeneration cryoballoon ablation for paroxysmal atrial fibrillation: 1-year follow-up. Europace 2014;16:639–44. DOI: 10.1093/europace/eut417; PMID: 24478116 Koektuerk B, Yorgun H, Hengeoz O, et al. Cryoballoon ablation for pulmonary vein isolation in patients with persistent atrial fibrillation: One-year outcome using second generation cryoballoon. Circ Arrhythm Electrophysiol 2015;8:1073–9. DOI: 10.1161/CIRCEP.115.002776; PMID: 26286935 Casado-Arroyo R, Chierchia GB, Conte G, et al. Phrenic nerve paralysis during cryoballoon ablation for atrial fibrillation: A comparison between the first- and second-generation balloon. Heart Rhythm 2013;10:1318–24. DOI: 10.1016/j. hrthm.2013.07.005; PMID: 23891574 Luik A, Radzewitz A, Kieser M, et al. Cryoballoon versus open irrigated radiofrequency ablation in patients with paroxysmal atrial fibrillation: The prospective, randomised, controlled, non-inferiority FreezeAF study. Circulation 2015;132:1311–9. doi: 10.1161/CIRCULATIONAHA.115.016871; PMID: 26283655; PMCID: PMC4590523 Furnkranz A, Brugada J, Albenque JP, et al. Rationale and design of FIRE and ICE: A multicenter randomized trial comparing efficacy and safety of pulmonary vein isolation using a cryoballoon versus radiofrequency ablation with 3d-reconstruction. J Cardiovasc Electrophysiol 2014;25:1314–20. DOI: 10.1111/jce.12529; PMID: 25146732 Dukkipati SR, Neuzil P, Skoda J, et al. Visual balloonguided point-by-point ablation: Reliable, reproducible, and persistent pulmonary vein isolation. Circ Arrhythm Electrophysiol 2010;3:266–73. DOI: 10.1161/CIRCEP.109.933283; PMID: 20504945 Dukkipati SR, Neuzil P, Kautzner J, et al. The durability of pulmonary vein isolation using the visually guided laser balloon catheter: Multicenter results of pulmonary vein remapping studies. Heart Rhythm 2012;9:919–25. DOI: 10.1016/j. hrthm.2012.01.019; PMID: 22293143

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44. Metzner A, Schmidt B, Fuernkranz A, et al. One-year clinical outcome after pulmonary vein isolation using the novel endoscopic ablation system in patients with paroxysmal atrial fibrillation. Heart Rhythm 2011;8:988–93. DOI: 10.1016/j. hrthm.2011.02.030; PMID: 21354329 45. 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;6:467–72. DOI: 10.1161/CIRCEP.113.000431; PMID: 23559674 46. 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. DOI: 10.1016/j.jacc.2015.07.036; PMID: 26383722 47. Sohara H, Satake S, Takeda H, et al. Radiofrequency hot balloon catheter ablation for the treatment of atrial fibrillation: A 3-center study in Japan. J Arrhythmia 2013;29:20–7. DOI:10.1016/j.joa.2012.07.005 48. 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. PMID: 11738318 49. Satake S, Tanaka K, Saito S, et al. Usefulness of a new radiofrequency thermal balloon catheter for pulmonary vein isolation: A new device for treatment of atrial fibrillation. J Cardiovasc Electrophysiol 2003;14:609–15. PMID: 12875422 50. 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. DOI: 10.1161/CIRCEP.108.817205; PMID: 19808472 51. Wang XH, Liu X, Sun YM, et al. Early identification and treatment of PV re-connections: Role of observation time and impact on clinical results of atrial fibrillation ablation. Europace 2007;9:481–6. PMID: 17522081 52. Kimura T, Takatsuki S, Oishi A, et al. Operator-blinded contact force monitoring during pulmonary vein isolation using conventional and steerable sheaths. Int J Cardiol 2014;177:970–6. DOI: 10.1016/j.ijcard.2014.09.189; PMID: 25449509 53. 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. DOI: 10.1016/j.jacc.2014.04.072; PMID: 25125294 54. Calkins H. When it comes to radiofrequency catheter ablation of atrial fibrillation, have all of our wishes been granted? A perspective on the smart-af trial. J Am Coll Cardiol 2014;64:657–9. DOI: 10.1016/j.jacc.2014.04.071; PMID: 25125295 55. Reddy VY, Dukkipati SR, Neuzil P, et al. A randomized controlled trial of the safety and effectiveness of a contact force sensing irrigated catheter for ablation of paroxysmal atrial fibrillation: Results of the TOCCASTAR study. Circulation 2015;132:907–15. DOI: 10.1161/CIRCULATIONAHA.114.014092; PMID: 26260733 56. Afzal MR, Chatta J, Samanta A, et al. Use of contact force sensing technology during radiofrequency ablation reduces recurrence of atrial fibrillation: A systematic review and meta-analysis. Heart Rhythm 2015;12:1990–6. DOI: 10.1016/j. hrthm.2015.06.026; PMID: 26091856 57. Boersma LV, Wijffels MC, Oral H, et al. Pulmonary vein isolation by duty-cycled bipolar and unipolar radiofrequency energy with a multielectrode ablation catheter. Heart Rhythm 2008;5:1635–42. DOI: 10.1016/j.hrthm.2008.08.037; PMID: 19084796 58. Zellerhoff S, Daly M, Lim HS, et al. Pulmonary vein isolation using a circular, open irrigated mapping and ablation catheter (NMARQ): A report on feasibility and efficacy. Europace 2014;16:1296–303. PMID: 19084796 59. Scharf C, Boersma L, Davies W, et al. Ablation of persistent atrial fibrillation using multielectrode catheters and dutycycled radiofrequency energy. J Am Coll Cardiol 2009;54:1450–6. DOI: 10.1016/j.jacc.2009.07.009; PMID: 19796739

60. Mulder AA, Wijffels MC, Wever EF, Boersma LV. Pulmonary vein isolation and left atrial complex-fractionated atrial electrograms ablation for persistent atrial fibrillation with phased radio frequency energy and multi-electrode catheters: Efficacy and safety during 12 months follow-up. Europace 2011;13:1695–702. DOI: 10.1093/europace/eur204; PMID: 21750096 61. Hummel J, Michaud G, Hoyt R, et al. Phased RF ablation in persistent atrial fibrillation. Heart Rhythm 2014;11:202–9. DOI: 10.1016/j.hrthm.2013.11.009; PMID: 24239841 62. Herrera Siklody C, Deneke T, Hocini M, et al. Incidence of asymptomatic intracranial embolic events after pulmonary vein isolation: Comparison of different atrial fibrillation ablation technologies in a multicenter study. J Am Coll Cardiol 2011;58:681–8. DOI: 10.1016/j.jacc.2011.04.010; PMID: 21664090 63. Scharf C, Ng GA, Wieczorek M, et al. European survey on efficacy and safety of duty-cycled radiofrequency ablation for atrial fibrillation. Europace 2012;14:1700–7. DOI: 10.1093/ europace/eus188; PMID: 22772054; PMCID: PMC3501283 64. Andrade JG, Dubuc M, Rivard L, et al. Efficacy and safety of atrial fibrillation ablation with phased radiofrequency energy and multielectrode catheters. Heart Rhythm 2012;9:289–96. DOI: 10.1016/j.hrthm.2011.09.009; PMID: 21907169 65. Cox JL, Schuessler RB, D’Agostino HJ, et al. The surgical treatment of atrial fibrillation. Iii. Development of a definitive surgical procedure. J Thorac Cardiovasc Surg 1991;101:569–83. PMID: 2008095 66. Gelsomino S, Van Breugel HN, Pison L, et al. Hybrid thoracoscopic and transvenous catheter ablation of atrial fibrillation. Eur J Cardiothorac Surg 2014;45:401–7. DOI: 10.1093/ ejcts/ezt385; PMID: 23904136 67. Mahapatra S, LaPar DJ, Kamath S, et al. Initial experience of sequential surgical epicardial-catheter endocardial ablation for persistent and long-standing persistent atrial fibrillation with long-term follow-up. Ann Thorac Surg 2011;91:1890–8. DOI: 10.1016/j.athoracsur.2011.02.045; PMID: 21619988; PMCID: PMC3117201 68. Bulava A, Mokracek A, Hanis J, et al. Sequential hybrid procedure for persistent atrial fibrillation. J Am Heart Assoc 2015;4:e001754. DOI: 10.1161/JAHA.114.001754; PMID: 25809548; PMCID: PMC4392449 69. Gehi AK, Mounsey JP, Pursell I, et al. Hybrid epicardialendocardial ablation using a pericardioscopic technique for the treatment of atrial fibrillation. Heart Rhythm 2013;10:22–8. DOI: 10.1016/j.hrthm.2012.08.044; PMID: 23064043 70. Pison L, La Meir M, van Opstal J, et al. Hybrid thoracoscopic surgical and transvenous catheter ablation of atrial fibrillation. J Am Coll Cardiol 2012;60:54–61. DOI: 10.1016/j. jacc.2011.12.055; PMID: 22742400 71. Bisleri G, Rosati F, Bontempi L, et al. Hybrid approach for the treatment of long-standing persistent atrial fibrillation: Electrophysiological findings and clinical results. Eur J Cardiothorac Surg 2013;44:919–23. DOI: 10.1093/ejcts/ezt115; PMID: 23475587 72. Muneretto C, Bisleri G, Bontempi L, Curnis A. Durable staged hybrid ablation with thoracoscopic and percutaneous approach for treatment of long-standing atrial fibrillation: A 30-month assessment with continuous monitoring. J Thorac Cardiovasc Surg 2012;144:1460–5; discussion 1465. DOI: 10.1016/j.jtcvs.2012.08.069; PMID: 23062968 73. Zembala M, Filipiak K, Kowalski O, et al. Minimally invasive hybrid ablation procedure for the treatment of persistent atrial fibrillation: One year results. Kardiol Pol 2012;70:819–28. PMID: 22933215 74. Arbelo E, Brugada J, Hindricks G, et al. The atrial fibrillation ablation pilot study: A European survey on methodology and results of catheter ablation for atrial fibrillation conducted by the European Heart Rhythm Association. Eur Heart J 2014;35:1466–78. DOI: 10.1093/eurheartj/ehu001; PMID: 24487524 75. Siontis KC, Ioannidis JP, Katritsis GD, et al. Radiofrequency ablation versus antiarrhythmic drug therapy for atrial fibrillation: Meta-analysis of quality of life, morbidity, and mortality. J Am Coll Cardiol EP 2016;2:170–80. DOI:10.1016/j.jacep.2015.10.003.

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Device Therapy

Pacing and Defibrillators in Complex Congenital Heart Disease Henry Chubb, 1,2 Mark O’Neill 1,3 and Eric Rosenthal 2,3 1. Division of Imaging Sciences and Biomedical Engineering, King’s College London, London, UK; 2. Department of Congenital Heart Disease, Evelina Children’s Hospital, London, UK; 3. Adult Congenital Heart Disease Group, Departments of Cardiology at Guy’s and St Thomas’ NHS Foundation Trust and Evelina Children’s Hospital, London, UK

Abstract Device therapy in the complex congenital heart disease (CHD) population is a challenging field. There is a myriad of devices available, but none designed specifically for the CHD patient group, and a scarcity of prospective studies to guide best practice. Baseline cardiac anatomy, prior surgical and interventional procedures, existing tachyarrhythmias and the requirement for future intervention all play a substantial role in decision making. For both pacing systems and implantable cardioverter defibrillators, numerous factors impact on the merits of system location (endovascular versus non-endovascular), lead positioning, device selection and device programming. For those with Fontan circulation and following the atrial switch procedure there are also very specific considerations regarding access and potential complications. This review discusses the published guidelines, device indications and the best available evidence for guidance of device implantation in the complex CHD population.

Keywords Congenital heart disease, pacing, implantable cardioverter defibrillator, arrhythmia, sudden cardiac death, cardiac resynchronisation therapy Disclosure: The authors have no conflicts of interest to declare. Received: 14 January 2016 Accepted: 10 March 2016 Citation: Arrhythmia & Electrophysiology Review 2016;5(1):57–64 Access at: www.AERjournal.com DOI: 10.15420/AER.2016.2.3 Correspondence: Prof E Rosenthal, Department of Congenital Heart Disease, Evelina Children’s Hospital, Westminster Bridge Road, London, SE1 7EH, UK; E:eric.rosenthal@gstt.nhs.uk

Device therapy is increasingly employed in the management of complex congenital heart disease (CHD). Bradycardias, most often related to sinus nodal dysfunction (SND) or atrioventricular nodal (AVN) block, may necessitate the implantation of pacing devices, while malignant arrhythmias may be treated by appropriate use of implantable cardioverter defibrillators (ICDs). However, there is a complex interplay between these classical device indications and associated supraventricular tachyarrhythmias, failure of ventricular function and ventricular dyssynchrony. These considerations, alongside the technical demands of implantation in the context of complex anatomy, necessitate a tailored and nuanced approach in the use of device therapy in the complex CHD population. This review focuses on patients with CHD of moderate and severe complexity, including those with single ventricle circulation and transposition of the great arteries.1 The management of congenital complete heart block is not addressed directly in this review, but shares many of the management principles discussed for the paediatric group.

The incidence of sinus nodal and atrioventricular (AV) nodal dysfunction in the more common complex CHD lesions is summarised in Table 2. It is clear that a significant proportion of these patients will require pacing, in addition to those with intra-atrial conduction block and HisPurkinje disease. Sinoatrial and AV nodal dysfunction may be congenital in conditions such as left atrial isomerism (LAI) and congenitallycorrected transposition of the great arteries (ccTGA; L-transposition), but more frequently the cause is iatrogenic following corrective or palliative surgery. It is also important to note the association of indications for pacing with the increased incidence of atrial and ventricular tachycardias.3 SND, AV dyssynchrony and ventricular bradycardia predispose to the triggering of tachyarrhythmias, and the common pathogeneses of abnormal conduction, surgical scar and progressive myocardial fibrosis are evident. Therefore, device therapy should not be considered in isolation, and a multimodal approach is necessary, combining antiarrhythmic medication, catheter ablation and anti-tachycardia pacemaker (ATP) therapies.2

Pacing Devices in Complex CHD Guidelines and Prevalence of Pacing Indications

Endocardial versus Epicardial Pacing and Number of Leads

Guidelines for pacing in the complex CHD cohort are limited by a lack of prospective randomised trials, and the marked heterogeneity of the group. The indications for permanent cardiac pacing in adult patients with complex CHD are summarised in Table 1, but in children the majority of prospective data relate to patients with congenital complete heart block, and practices are generally extrapolated from those principles.

Epicardial pacing systems possess obvious advantages for patients with complex CHD. They do not rely upon venous access, may be placed during concurrent surgery, avoid endovascular leads and associated thromboembolic events19 and present fewer concerns regarding lead extraction. However, these factors need to be weighed up against increased lead failure rates and pacing thresholds, with a

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Device Therapy Table 1: Recommendations for Permanent Pacing in Adults with Complex CHD Class

Clinical Indication

Level of

Class I

Symptomatic SND, including documented sinus

Table 2: Prevalence of Indications for Pacing Therapy and ICD Therapy in Selected Congenital Heart Disease of Moderate and Severe Complexity

Evidence bradycardia or chronotropic incompetence that is intrinsic or secondary to required drug therapy Symptomatic bradycardia in conjunction with any

Intervention ToF

Surgical repair

1–2 %4,5

D-TGA

Post-Mustard

60–82 %6–8

Post-Senning

%7–9

Ventricular

5 %5

2–15 %4,5

arrhythmias

2 %6

4 %10

7 %4

1 %11

1–2 %10,11

<1 %11

<5 %12

20–25 %12,13 <1 %12

switch ccTGA (L-TGA)

All

non-invasive or invasive means, due to sinus

Ebstein’s Anomaly All

Minimal data 4 %14

1 %15

bradycardia or loss of AV synchrony

LAI

19–80 %16,17

16 %16

Minimal data

Dependent

4 %4,18

Sinus or junctional bradycardia for the prevention

All Fontan

ventricular pauses >3 seconds C

5–27

%4,18

on baseline anatomy

heart rate (sinus or junctional) <40 bpm or Adults with CHD of moderate complexity and an

Univentricular

All

heart

of recurrent IART Adults with complex CHD and an awake resting

Class IIb

Post-arterial

AV block that is not expected to resolve Impaired haemodynamics, as assessed by

22–35

All atrial switch

presumed to be because of AV block

Class IIa

AV block

dysfunction

degree of AV block or with ventricular arrhythmias Postoperative high-grade second- or third-degree

SA node

AV = atrioventricular; ccTGA = congenitally-corrected transposition of the great arteries; D-TGA = transposition of the great arteries with d-looping (right-hand topology); LAI = left atrial isomerism; L-TGA = transposition of the great arteries with l-looping (left-hand topology); SA = sinoatrial; ToF = tetralogy of Fallot.

awake resting heart rate (sinus or junctional) <40 bpm or ventricular pauses >3 seconds History of transient postoperative complete AV

block, and residual bifascicular block Class III

Pacing is not indicated in asymptomatic adults

with CHD and bifascicular block with or without first-degree AV block in the absence of a history of transient complete AV block Endocardial leads are generally avoided in adults

with CHD and intracardiac shunts AV = atrioventricular; CHD = congenital heart disease; IART = intra-atrial re-entrant tachycardia; SND = sinus node dysfunction. Adapted from Khairy, et al., 2014. 2

consequent reduction in system longevity.14,19,20 In a retrospective study of 287 patients with CHD, Silvetti et al. found a clear survival benefit of transvenous leads (10-year lead survival 71 % versus 95 %, p<0.0001).20 Steroid eluting leads are improving the efficacy of epicardial leads, and the potentially life-threatening implications of lead failure are mitigated to some degree by newer technologies such as transtelephonic monitoring and auto capture algorithms, providing a degree of safety during the early failure period. However, the decision for endocardial versus epicardial pacing should be made on a case-by-case basis. For the smallest patients, epicardial systems are generally recommended (see Table 3), and minimally invasive epicardial pacemaker approaches are also now being employed at some centres.21 However, selected patients <10 kg may continue to be treated with an endovascular system.22 For those in whom an endovascular approach is most appropriate, a comprehensive evaluation of shunts (or potential shunts) by echocardiography or angiography should be undertaken before lead implantation (Class 1C recommendation),3 in order to evaluate for thromboembolic risk. Thin lumenless pacing leads (model 3830 SelectSecure®, Medtronic Inc.) may reduce complications in smaller patients and those with limited venous lumens. These 4.1 Fr leads were first introduced in 2004 and are catheter delivered: conventionally using an 8.4 Fr delivery system, but the use of smaller 5 Fr sheaths has also been reported. They have demonstrated a good electrical performance and low complication rate,23 and may be more straightforward to

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extract than conventional leads despite the absence of a lumen for locking stylet.24 In addition, it should be borne in mind that generally fewer leads implanted will result in fewer complications. For children with AV block and normal ventricular function, VVIR may be the pacing mode of choice. DDD pacing with transvenous leads is technically feasible in small children, but may not be needed.25 There are also other situations in which the benefit of additional leads are outweighed by risk. As for patients with structurally normal hearts, single chamber AAI(R) pacing is frequently indicated for the large cohort of CHD patients with SND. However, those with difficult access to the ventricle, such as Fontan circulation, also stand to derive minimal overall benefit from an additional ventricular lead if the indication is marginal (see below). Device selection should also include the requirement for future magnetic resonance (MR) imaging. MR conditional pacing systems are now being widely adopted, with growing evidence of safety in a 1.5T MR environment,26 but artefact within the field of view has a substantial impact upon image quality.27 Therefore pre-emptive MR imaging prior to implantation should be considered, particularly for functional and scar assessment.

Lead Positioning Pacing site selection is now dictated by a multitude of factors, and simply adequate sensing and pacing thresholds are no longer sufficient. Directable delivery sheaths and active fixation leads mean that most endocardial targets are accessible, while epicardial lead positioning has also been shown to be increasingly important in determining long-term outcome.29 Preservation of ventricular function should be taken into consideration in all decisions for lead placement. In general, atrial lead placement is less critical, but atrial septal pacing may reduce unnecessary ventricular pacing when compared with appendage pacing.30 Ventricular lead placement is highly dependent upon the cardiac anatomy and whether an endocardial or epicardial approach has been adopted. For endocardial pacing in the AV

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Pacing and Defibrillators in Complex Congenital Heart Disease

concordant biventricular heart, there is some evidence for optimal site selection. Pacing from the right ventricle (RV) apex results in marginally better left ventricle (LV) ejection fraction than non-RV apical sites (e.g. right ventricular outflow tract, mid-septum and upperseptum)29 and this finding is replicated on systematic review.31 It is also clear that RV free wall pacing is inferior.29,32 Further lead-implant guidance techniques that include evaluation of ventricular function, via pressure-volume loops or the first derivative of systolic pressure (dP/ dt), may also optimise chronic paced ventricular function and have demonstrated that there is no single optimal site for endovascular lead placement.33,34 In studies of epicardial lead placement, Janousek et al. performed a non-randomised retrospective trial of lead placement in 178 children undergoing permanent pacing, with structurally normal heart, and there was a demonstrated benefit to placement of the epicardial ventricular lead at the LV apex or midlateral wall.29 The only prospective study of LV apex or free-wall pacing was conducted in neonates and infants with congenital complete AVB and showed good ventricular systolic function and synchrony after one year of pacing.35 Trials in complex CHD are generally lacking, and the evidence base for optimal lead positioning is small, but again the RV free wall should be avoided if possible.

Resynchronisation Therapy Cardiac resynchronisation therapy (CRT) has been shown to be a useful therapy for adult patients with selected forms of electrical dyssynchrony and heart failure with reduced ejection fraction, but patient selection and technical issues create significant challenges in the setting of CHD.36 Most cases of CRT in the paediatric and CHD population do not have left bundle branch block, but instead it is performed as an upgrade to conventional ventricular pacing because of pacing-associated heart failure (>60 % of cases), or with a failing systemic RV.37 In recent guidelines, indications for CRT in CHD are generally Class IIa and IIb, but should not be considered in adults with narrow QRS complex (<120 ms) or life expectancy <1 year (Class III).2

Assessing Dyssynchrony and CRT indications Electrical activation delay, with bundle branch block on the side of the systemic ventricle (left bundle branch block for systemic LV, right bundle branch block for systemic RV), identifies the group of patients that are most likely to respond to CRT.32 However, the further assessment and definition of dyssynchrony in many forms of repaired CHD are controversial. Mechanical dyssynchrony, as assessed by echocardiography, is the most widely used measure, but there are no universally adopted or validated selection criteria in CHD.37 As well as conventional echocardiographic modalities, strain assessment, speckle tracking and 3-dimensional volume assessment of both the LV and RV are likely to play a significant role in assessment for CRT in the future.38,39 It should also be noted that, within the normal cardiac anatomy population, the use of echocardiography measures of dyssynchrony to select patients for CRT has not been found to be robust, with a lack of reproducibility from centre-to-centre and also little evidence that much is added beyond traditional measures of QRS duration and morphology.40 Non-echocardiographic parameters, such as those derived from cardiac MR imaging or electrocardiographic imaging,41 may also play a role. Overall, the efficacy of CRT in CHD is likely to rely upon a multitude of factors, and identifying potential responders and non-responders will be highly dependent upon anatomy and valvular function as much as systolic function and dyssynchrony alone. However, objective

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Table 3: Consensus Panel Recommendations on Preferred Pacemaker Implantation Access, Pacing Modes and Ventricular Lead Placement in Paediatric Patients With AV Block, Systemic LV and Absence of Intracardiac Shunts Patient

Access

Pacing Mode

Epicardial

VVIR or DDD(R)a LV apex

Endocardial–in specific

VVIR or DDD(R)a RV septum

Size <10 kg

Ventricular Lead Placement

situations (failed epicardial, centre preference) 10–20 kg

>20 kg

Epicardial

VVIR or DDD(R)a LV apex

Endocardial

VVIR or DDD(R)a RV septum

Epicardial–specific situations VVIR or DDD(R)

LV apex or free

(e.g. concomitant with other

wall- based on

cardiac surgery)

surgical feasibility

Endocardial

VVIR or DDD(R)

RV septum

aIn

case of specific haemodynamic indication. LV = left ventricular; RV = right ventricular. Adapted from Brugada, et al., 2013.28

assessment will become an increasingly pressing issue, with a recent review by the European Heart Rhythm Association recommending dyssynchrony assessment and consideration of CRT in a wide range of patients.28

Technical Challenges and Outcomes from Resynchronisation There are often significant technical challenges in achieving CRT in complex CHD, particularly via the endocardial route. Even if the coronary sinus is accessible, pacing of the systemic ventricle may not be achievable via this route, for example following atrial switch for TGA with d-looping, i.e. right-hand topology (both the venous baffle and the coronary sinus lead to the LV, with no access to the RV). Access may also be complicated by surgical repairs and baffles, and therefore an epicardial or hybrid approach may be required.39 Outcome data for CRT in CHD are generally limited to small studies in the acute postoperative setting, or longer term follow-up studies with a variety of surrogate endpoints (6-minute walk test, hospitalisations, quality of life, ventricular stroke volume/ejection fraction). In general, the systemic LV is more likely to respond to CRT than the systemic RV,42 and patients listed for transplant may respond to a sufficient degree to enable delisting.43 In multisite pacing of the single ventricle, with widely spaced electrodes, the benefit is reduced but there are still reports of improvement.42,44 A recent study from Osaka, evaluating the outcome in patients with a systemic RV, has suggested that the leads should be placed at furthest sites in the longitudinal RV direction, unless there is substantial short axis dyssynchrony, in which case the leads are best placed laterally on opposite sides of the ventricles.45 Further CRT optimisation, including refinement of AV and VV (interventricular) delay, may also be considered, but there is an absence of evidence in the CHD population for the optimisation guidance modality and settings.

Programming of pacing devices Beyond the decision for single, dual or multisite pacing, there are also considerations for pacing programming. The general principle of minimising ventricular pacing applies in CHD as much as the general population, and novel algorithms have been developed by major manufacturers that incorporate a strategy to allow extended AV delays, and thus reduce ventricular pacing (Boston Scientific: AV search

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Device Therapy Table 4: Predictors of Appropriate ICD Therapy in Primary Preventative ICD Therapy in Tetralogy Of Fallot (Univariate Analysis) HR

95 % CI

p-value

Prior palliative shunt

2.6

0.7–9.4

0.13

Inducible sustained VT

2.1

0.6–7.6

0.24

QRS duration, per 1 ms

1.01

0.99–1.03

0.21

QRS ≥180 ms

2.0

0.7–5.9

0.22

Ventriculotomy incision

2.4

0.9–6.1

0.071

Nonsustained VT

2.7

1.0–7.2

0.053

RV systolic pressure, per 1 mmHg

1.06

1.01–1.11

0.0301

Mean PAP, per 1 mmHg

1.16

1.05–1.35

0.0032

LVEDP, per 1 mmHg

1.21

1.08–1.35

0.0008

LVEDP ≥12 mmHg

15.1

1.9–123.7

0.0114

HR = hazard ratio; VT = ventricular tachycardia; PAP = pulmonary artery pressure; LVEDP = left ventricular end diastolic pressure. Adapted from Khairy, et al., 2008.48

hysteresis; St Jude: autointrinsic conduction search). Medtronic Inc. have employed an alternative technique (managed ventricular pacing) that incorporates a mode-switching strategy between AAI(R) and backup ventricular/DDD(R) pacing with loss of AV conduction.39 Recent consensus guidelines on pacing in CHD generally class minimisation of ventricular pacing as a Class IB recommendation.2 In addition, further basic programming principles should be considered in the CHD population, including limiting upper tracking rate in patients at risk of intra-atrial re-entrant tachycardia (IART). Strong consideration should also be given for implantation of systems capable of administering ATP therapies, particularly in those with a documented history of IART. A dual chamber system is generally required for atrial ATP, and a recent study of 80 implants in patients with CHD found ATP to be successful in terminating 57 % of IARTs, with high success rates in atrial switch patients.46 In patients with a single ventricle where an endocardial ventricular lead cannot be placed, we plug the ventricular port to give an open circuit on the ventricular channel allowing effective ATP.

Implantable Cardioverter Defibrillators in Complex CHD Indications and Guidelines There is now a reasonable body of literature that details the risk of sudden cardiac death in complex CHD, and the subsequent indications for ICD implantation. Implantation after a cardiac arrest or sustained spontaneous ventricular tachycardia (secondary prevention) is generally a Class IB indication for ICD implantation in CHD, where no reversible cause is identified.2,3,28,47 However, evidence for selection for primary preventative therapy is limited in the complex CHD population.36 The most detailed data relate to those with repaired tetralogy of Fallot (ToF). A raised left ventricular end diastolic pressure, pulmonary artery pressure and RV systolic pressure are the strongest predictors of appropriate shock therapy. The significance of inducible sustained ventricular tachycardia at electrophysiology study is unclear, with a trend towards increased incidence of appropriate shocks in inducible patients,48,49 but it is symptomatic non-sustained ventricular tachycardia that is the more important prognostic indicator.49 An annual appropriate shock rate for primary preventative ICDs in ToF has been reported to be as high as

AER5.1_Rosenthal_FINAL.indd 60

7.7 % but with an inappropriate shock rate of 5.8 % per year and other system complications occurring in nearly 30 %.48 The ‘appropriate shock rate’ may also include transient non-haemodynamically disturbing arrhythmias that may not have needed treatment. Outside the ToF population, the indications are less well delineated, reflected in a significantly lower appropriate shock rate in the adult population.50 Conventional non-CHD indications may be applicable for those with biventricular circulation,2 but the systemic RV systolic function cut-off value that defines benefit is likely to be lower than the 35 % for the LV.51 The largest study of ICD therapy in CHD is that of Berul et al. in 2008.52 In a review of 443 patients (69 % of whom had structural heart disease), 48 % were for primary prevention. Of these, 18 % received appropriate shocks but 20 % received inappropriate shocks. The impact of an ICD in the generally younger CHD population should not be underestimated, with the likelihood of multiple generator and lead replacements, other complications and psychosocial stressors related to ICD therapy. It is also suggested that the inappropriate shock rate is increased in young and active CHD patients, aggravating concerns of lead fracture, particularly in those with Fidelis leads (Medtronic Inc.).52,53

Devices and Access Issues regarding access for ICD therapy are similar to those for conventional pacing, but complicated by larger lead sizes. Patients with univentricular hearts or post-atrial switch may also benefit from ICD therapy but pose further access difficulties,39,51,54 and pericardial, pleural or subcutaneous lead placement of the standard transvenous coils should be considered55,56 combined with endocardial or epicardial sensing leads. In addition, there may be a role for individualised calculation of optimal generator placement site, based upon the cardiac anatomy, and early work has been performed in computing ICD configuration based on cardiac MR-derived anatomy.57

Subcutaneous ICD There is increasing evidence for the use of subcutaneous ICD (S-ICD; Boston Scientific), avoiding the potential intravascular and lead complications of other systems. They are, however, relatively bulky and do not allow for conventional pacing or ATP, and therefore may generally be more appropriate for channelopathies and other arrhythmias not associated with structural CHD. Early evidence of efficacy and complications is beginning to emerge, with relatively promising results.58–61 Initial concerns regarding sensing issues, inappropriate shocks and failure of conversion of malignant arrhythmias seem to have been broadly overcome with appropriate programming and placement, but S-ICD remains a technology in its early phases with very little evidence in the structural CHD population.59 However, its implementation in patient groups with no venous access to the heart, particularly after a Fontan operation, is attractive if pacing is not required.

ICD Programming Considerations Inappropriate shock rates are relatively high, largely related to supraventricular arrhythmias, T-wave oversensing and increased lead failure rate.53 As with all ICDs, the task of balancing overtreatment against delaying therapy is a delicate one. The relatively slow atrial arrhythmias, predisposing to 1:1 conduction, may necessitate the implementation of manufacturer-specific discriminator algorithms, such as PR Logic® (Medtronic Inc.), morphology and onset analysis. These should be used with caution, however, as supraventricular tachycardia characteristics may vary widely from episode to episode.62

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Pacing and Defibrillators in Complex Congenital Heart Disease

Faster cut-off rates, longer detection times and customised ATP sequences should also be considered.

Figure 1: Pacing Solutions in Patients with Hemi-Fontan Circulation, or Similar Hemi-Fontan

Considerations for Devices in Complex CHD The implanting physician must have a detailed understanding of the patientâ&#x20AC;&#x2122;s cardiac and central vascular anatomy, alongside the prior procedures and diagnostic reports. Further cross-sectional imaging and assessment of vascular patency may often be required in patients who have undergone multiple prior procedures. In addition, haemodynamic concerns such as residual shunts or baffle patency should also be carefully considered prior to implantation. The need for concomitant or subsequent interventional or surgical procedures, as part of the overall management of the patient, must also be weighed up prior to device implantation.

Single Ventricle Circulations

Kawashima D

SVC

LPA

RPA

Azygos vein

LA RA

Patch closure SVC/RA junction

Hepatic vein

IVC

Interrupted IVC

Superior Cavo-pulmonary Connections One and one-half ventricle circulations, with hemi-Fontan or Glenn, may preclude conventional placement of the atrial lead. However, in the hemi-Fontan there is frequently atrial tissue remaining on the pulmonary artery side of the patch, and successful long-term pacing has been reported (Figure 1).63 The Glenn anastamosis tends not to have any residual atrial tissue on the pulmonary side, and in this case puncture from the pulmonary artery to atrial mass would have to be considered (see below). The Kawashima circulation, in which venous drainage from the lower half of the body is to the superior vena cava via the azygos vein with interrupted IVC, represents a further complication (Figure 1: D). This arrangement is most commonly encountered in patients with LAI, who are at markedly increased risk of complete heart block. Unfortunately, access to the ventricle in particular can be extremely challenging, and transhepatic access may be required,64 unless the technique of Arif et al.

F V

is used (Figure 2E and F).66 V

Total Cavopulmonary Circulation Atrial pacing in the classic atriopulmonary Fontan and lateral tunnel Fontan generally poses relatively few problems in terms of access to atrial myocardium. In those with extra-cardiac conduit epicardial pacing is generally required. However, transpulmonary artery pacing may be an alternative, puncturing through the inferior aspect of the left65 or right66 pulmonary artery into the common atrium (Figure 2F). Ventricular pacing in most Fontan anatomies is more easily achieved via epicardial leads, but multiple prior surgical procedures often render this approach unattractive and other endovascular techniques may be considered. For patients with atriopulmonary Fontan, and occasionally lateral tunnel Fontan, the coronary sinus may be accessed from the venous side (Figure 2B).67 Alternatively, the lead may be placed endocardially via a fenestration or baffle puncture, but endocardial lead placement evaulation should be made taking into account the substantial thromboembolic risk,19 and we would always anticoagulate these patients. ICD therapy in Fontan patients is often best served by non-transvenous systems (epicardial or subcutaneous). The use of a conventional subcutaneous system is limited by the absence of pacing capabilities, and may necessitate two devices (Figure 2D). As an alternative, shock coils may be placed in the pericardial or pleural space, with the ICD generator usually placed abdominally. The non-transvenous ICD system is likely to have significantly shorter longeivity than transvenous,55 but circumvents many of the potentially severe complications and may still

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AER5.1_Rosenthal_FINAL.indd 61

Left panels. (A) Hemi-Fontan anatomy, with patch closure of SVC/RA junction. (B) Angiogram following contrast injection in the SVC, and the SVC/RA stump is clearly seen (arrow). (C) Lead position for dual chamber system. The atrial lead [A] lies within the venous side, but is fixed to residual atrial tissue. The ventricular lead [V] has been placed in the systemic ventricle following patch puncture and lifelong anti-coagulation was required. Right panels. (D) Kawashima circulation. PA (E) and lateral (F) views of transhepatic vein atrial [A] and left ventricular [V] lead placement in a patient with left atrial isomerism and a Kawashima circulation (see text) to enable biventricular pacing for severe heart failure several years after right ventricular (black star) epicardial lead placement. The patient has now been delisted from cardiac transplantation for 10 years. IVC = inferior vena cava; LA = left atrium; LPA = left pulmonary artery; PA = posterior-anterior; RA = right atrium; RPA = right pulmonary artery; SVC= superior vena cava. Adapted from Rosenthal, et al., 2005.64

have a role to play in the Fontan or hemi-Fontan patient, even with the advent of licensed subcutanous ICD systems.28

Atrial Switch Procedures Atrial lead placement following the atrial switch procedure should be performed bearing in mind that the baffle tends to direct the pacing lead to the lateral wall of the LA, close to the left phrenic nerve (Figure 3). In addition, there is a high incidence of systemic venous obstruction, particularly of the superior limb following the Mustard procedure (>40Â % of patients)8 and consideration should be given to stenting of the baffle, if required, prior to lead insertion. Baffle leaks are also highly prevalent, and systemic anticoagulation or baffle leak occlusion may be required.19 The ventricular lead placement is to the smooth LV, and active lead fixation has greatly improved pacing success. The lead should

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Device Therapy Figure 2: Pacing in Patients with a Fontan Circulation Classical (AP) Fontan

Lateral tunnel

Extra-cardiac conduit

SVC SVC

SVC

LPA

RPA PA

RAA RA

Lat. tunnel

Extra-cardiac conduit

IVC

LPA

RPA

IVC

new lead in atrial roof

old endocardial lead

Left panels. (A) Classical atriopulmonary Fontan. (B) Dual chamber pacemaker in this anatomy, where ventricular pacing has been achieved via the coronary sinus. White cross indicates previous native pulmonary artery closure device. Middle panels. (C) Lateral tunnel Fontan. Atrial tissue is accessible within the lateral tunnel, enabling atrial pacing without puncture. (D) Subcutaneous ICD (white star) with single chamber (atrial) pacing system (white cross) implanted for treatment of beta-blocker-induced bradycardia after an out-of-hospital cardiac arrest. Right panels. (E) Extra-cardiac conduit. (F) Following puncture from the right pulmonary artery into the atrial mass, the atrial pacing lead is positioned in the atrial roof. The ‘old endocardial lead’ had been placed directly into the atrium at the time of the extra-cardiac conduit placement. Ao = aorta; ICD = implantable cardioverter defibrillator; IVC = inferior vena cava; LA = left atrium; LPA = left pulmonary artery; LV = left ventricle; PA = pulmonary artery; RA = right atrium; RAA = right atrial appendage; RPA = right pulmonary artery; SVC = superior vena cava. F reproduced with permission from Arif, et al., 2016.66

ideally be placed on the septum to avoid pacing the left ventricular free wall that may cause diaphragmatic pacing and dyssynchrony. However, resynchronisation therapy cannot be performed via a coronary sinus lead, as the default ventricular lead position is already within the LV. CRT is therefore likely to require a hybrid epicardialendocardial approach, or baffle pucture with the long term risk of placement of a pacing lead within the systemic ventricle. The use of RF energy to perforate the baffle and enable lead placement in the systemic RV has been described, for both CRT-pacing and CRT-defibrillator therapy. Access was generally via the subclavian approach with transoesophageal echocardiographic guidance, with good haemodynamic results.68 For those undergoing primary ICD placement, a relatively high complication rate (27 %) and low appropriate shock rate has been reported. Careful risk stratification is therefore required before implantation, particularly in view of the bulky leads that must cross the superior venous baffle.69

Device-Related Complications and Lead Extraction Complications of Permanent Pacing in CHD Permanent cardiac pacing in CHD is linked with a higher rate of pacing complications than in non-CHD. In a review of epicardial and endocardial pacing in CHD by McLeod et al.,14 it was found that the overall long-term complication rate in CHD was close to 40 %, compared with 5 % (or 0.5 % per year) in non-CHD. Epicardial systems were linked to lead failure, particularly exit block and lead fracture, whilst endocardial systems were more durable but susceptible to

AER5.1_Rosenthal_FINAL.indd 62

dislodgement and insulation leaks. A study of the paediatric population by Fortescue et al.70 made similar findings of high incidence of lead failures in all groups, but suggested a general move towards transvenous pacing where possible. In those that have undergone endocardial pacing, though, in addition to the spectre of lead extraction, two further potential complications should also be considered: venous occlusion and thromboembolic events. Venous occlusion is generally accepted to be a significant risk in smaller patients, but its incidence is dependent upon patient and lead size and difficult to define: a figure of around 5–10 % has been quoted at long-term follow-up.19,71 Regarding thromboembolic events in patients with an intracardiac shunt, the risk is more than doubled in patients with endocardial systems from 0.6 % per year (in patients with no permanent pacemaker or an epicardial system) to around 2 % per year.19

Lead Extraction The need for lead extraction remains a major concern for those placing systems in younger patients and in systemic chambers, and the risks and benefits need to be weighed up at the time of potential extraction. Conventional lead extraction guidelines also apply to the complex CHD population,2,72 but the benefit of extraction of non-functioning leads is likely to be greater in younger patients. There are generally limited data on lead extraction specifically in the complex CHD population. A retrospective study by McCanta et al. (2013)73 reviewed 24 laser lead extractions (LLE) in CHD patients, compared with matched non-CHD patients. They found a significantly lower extraction

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Pacing and Defibrillators in Complex Congenital Heart Disease

success rate in the CHD cohort (74 % versus 92 %) using LLE, but many of the remaining leads were then removed using other techniques, and there were no significant complications. On the other hand, Cecchin et al.74 found no significant difference between the CHD and non-CHD patients, using a combination of simple extraction with a non-locking stylet with complex techniques such as the radiofrequency-powered sheath when required, as did Khairy et al. using LLE.75

Figure 3: Pacing Following Atrial Switch Procedure A

Ao PA

Five-year View Device therapy in complex CHD has always necessitated ingenious, creative and sometimes brave approaches to adapt pacemakers and defibrillators that have been designed for the normal adult heart. Smaller leads and devices have assisted the progression of the field in the paediatric group, but there are further future innovations that promise to be highly applicable for those with complex CHD.

LV RV Baffle

There are a number of solutions that are close on the horizon. These include drug-eluting coatings for pacemakers to reduce infections, advanced imaging processing to guide planning and implantation, and a growing understanding of the capabilities of telemonitoring and how to harness the strengths of the technology. Leadless pacemakers have already been licensed in Europe for implantation in the RV, and are close to FDA approval. However, device size, extraction concerns and lack of dual chamber capabilities need to be resolved before extensive use in the complex CHD population. The combination of a leadless atrial device with subcutaneous-ICD, though, may be closer on the horizon and could prove invaluable if ATP is available.

Conclusion Device placement in the patient with complex CHD is not an isolated procedure, and should be viewed in the context of the patient as a whole. Multidisciplinary discussion prior to implantation is almost invariably required, with input from congenital cardiac surgeons, interventionalists, imaging specialists and electrophysiologists informing a balanced approach with appropriate long-term considerations. The heterogeneity of the patient group means that almost every implantation decision

Warnes CA, Williams RG, Bashore TM, et al. ACC/AHA 2008 Guidelines for the management of adults with congenital heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2008;118:e714–e833. DOI: 10.1161/CIRCULATIONAHA.108.190690; PMID: 18997169 Khairy P, Van Hare GF, Balaji S, et al. PACES/HRS expert consensus statement on the recognition and management of arrhythmias in adult congenital heart disease. Heart Rhythm 2014;11:e102–e65. DOI: 10.1016/j.hrthm.2014.05.009; PMID: 24814377 Bhatt AB, Foster E, Kuehl K, et al. Congenital Heart Disease in the Older Adult A Scientific Statement From the American Heart Association. Circulation 2015;131:1884-931. DOI: 10.1161/ CIR.0000000000000204; PMID: 25896865 Czosek RJ, Anderson J, Khoury PR, et al. Utility of ambulatory monitoring in patients with congenital heart disease. Am J Cardiol 2013;111:723–30. DOI: 10.1016/j.amjcard.2012.11.021; PMID: 23246250 Khairy P, Aboulhosn J, Gurvitz MZ, et al, for the Alliance for Adult Research in Congenital Cardiology (AARCC). Arrhythmia burden in adults with surgically repaired tetralogy of Fallot: A Multi-Institutional Study. Circulation 2010;122:868–75. DOI: 10.1161/CIRCULATIONAHA.109.928481; PMID: 20713900 Gelatt M, Hamilton RM, McCrindle BW, et al. Arrhythmia and mortality after the Mustard procedure: a 30-year single-center experience. J Am Coll Cardiol 1997;29:194–201. DOI:10.1016/S0735-1097(96)00424-X; PMID: 8996314 Helbing WA, Hansen B, Ottenkamp J, et al. Long-term results of atrial correction for transposition of the great arteries. Comparison of Mustard and Senning operations. J Thorac Cardiovasc Surg 1994;108:363–72. PMID: 8041184 Khairy P, Landzberg MJ, Lambert J, Donnell CPO. Long-term outcomes after the atrial switch for surgical correction of transposition: a meta-analysis comparing the Mustard and

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10.

11.

12.

13.

14.

15.

16.

(A) Atrial switch anatomy (Senning or Mustard). (B) Significant stenosis of the superior venous baffle in a patient following Senning atrial switch and failed epicardial atrial pacing. (C) Stenting of the baffle, immediately prior to (D) placement of atrial pacing lead in the roof of the left atrium. Ao = aorta; LA = left atrium; LV = left ventricle; PA = pulmonary artery; RA = right atrium; RV = right ventricle.

requires tailoring to the patient. The evidence base for any individual approach, be it epicardial versus endocardial, dual chamber versus biventricular pacing, or pacing lead removal versus retention, is difficult to apply and there is no substitute for a detailed understanding of the patient anatomy, prior procedures and device indications. The need for concomitant or subsequent interventional or surgical procedures as part of the overall management of the patient may tailor the approach more substantially than device considerations alone. n

Senning procedures. Cardiol Young 2004;14:284–92. DOI: http:// dx.DOI.org/10.1017/S1047951104003063; PMID: 15680022 Deanfield J, Camm J, Macartney F, Cartwright T, et al. Arrhythmia and late mortality after Mustard and Senning operation for transposition of the great arteries. An eight-year prospective study. J Thorac Cardiovasc Surg 1988;96:569–76. PMID: 3172804 Rhodes LA, Wernovsky G, Keane JF, et al. Arrhythmias and intracardiac conduction after the arterial switch operation. J Thorac Cardiovasc Surg 1995;109:303–10. DOI: http://dx.DOI. org/10.1016/S0022-5223(95)70392-6; PMID: 7853883 Khairy P, Clair M, Fernandes SM, et al. Cardiovascular outcomes after the arterial switch operation for d-transposition of the great arteries. Circulation 2013;127:331–9. DOI: 10.1161/ CIRCULATIONAHA.112.135046; PMID: 23239839 Rutledge JM, Nihill MR, Fraser CD, et al. Outcome of 121 patients with congenitally corrected transposition of the great arteries. Pediatr Cardiol 2002;23:137–45. DOI: 10.1007/ s00246-001-0037-8; PMID: 11889523 Huhta JC, Maloney JD, Ritter DG, et al. Complete atrioventricular block in patients with atrioventricular discordance. Circulation 1983;67:1374–7. DOI: 10.1161/01. CIR.67.6.1374; PMID: 6851033 McLeod CJ, Jost CHA, Warnes CA, et al. Epicardial versus endocardial permanent pacing in adults with congenital heart disease. J Interv Card Electrophysiol 2010;28:235–43. DOI: 10.1007/s10840-010-9494-4; PMID: 20563634 Reich JD, Auld D, Hulse JE, et al. The Pediatric Radiofrequency Ablation Registry’s experience with Ebstein’s anomaly. J Cardiovasc Electrophysiol 1998;9:1370–7. DOI: 10.1111/j.1 540-8167.1998.tb00113.x; PMID: 9869537 Eronen MP, Aittomäki KAU, Kajantie EO, Sairanen HI. Outcome of left atrial isomerism at a single institution. Pediatr Cardiol 2012;33:596–600. DOI: 10.1007/s00246-012-0184-0; PMID: 22311570

17. Miyazaki A, Sakaguchi H, Ohuchi H, et al. The incidence and characteristics of supraventricular tachycardia in left atrial isomerism: a high incidence of atrial fibrillation in young patients. Int J Cardiol 2013;166:375–80. DOI: 10.1016/j. ijcard.2011.10.118; PMID: 22082714 18. Stephenson EA, Lu M, Berul CI, et al. Arrhythmias in a contemporary Fontan cohort: prevalence and clinical associations in a multicenter cross-sectional study. J Am Coll Cardiol 2010;56:890–6. DOI: 10.1016/j.jacc.2010.03.079; PMID: 20813285 19. Khairy P, Landzberg MJ, Gatzoulis MA, et al. Transvenous pacing leads and systemic thromboemboli in patients with intracardiac shunts: a multicenter study. Circulation 2006;113:2391–7. DOI: 10.1161/CIRCULATIONAHA.106.622076; PMID: 16702467 20. Silvetti MS, Drago F, Di Carlo D, et al. Cardiac pacing in paediatric patients with congenital heart defects: transvenous or epicardial? Europace 2013;15:1280–6. DOI: 10.1093/europace/eut029; PMID: 23439868 21. Costa R, Scanavacca M, da Silva K et al. Novel approach to epicardial pacemaker implantation in patients with limited venous access. Heart Rhythm 2013;10:1646–52. DOI: 10.1016/j. hrthm.2013.08.002; PMID: 23920077 22. Konta L, Chubb MH, Bostock J, et al. Twenty-seven years experience with transvenous pacemaker implantation in children weighing <10 kg. Circ Arrhythmia Electrophysiol 2016;9:e003422. DOI: 10.1161/CIRCEP.115.003422; PMID: 26857908 23. Garnreiter J, Whitaker P, Pilcher T, et al. Lumenless pacing leads: performance and extraction in pediatrics and congenital heart disease. Pacing Clin Electrophysiol 2015;38:42–7. DOI: 10.1111/pace.12508; PMID: 25224253 24. Shepherd E, Stuart G, Martin R, Walsh MA. Extraction of SelectSecure leads compared to conventional pacing leads in patients with congenital heart disease and congenital

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Device Therapy atrioventricular block. Heart Rhythm 2015;12:1227–32. DOI: 10.1016/j.hrthm.2015.03.004; PMID: 25748672 25. Silvetti MS, Drago F, Grutter G, et al. Twenty years of paediatric cardiac pacing: 515 pacemakers and 480 leads implanted in 292 patients. Europace 2006;8:530–6. DOI: http://dx.DOI.org/10.1093/europace/eul062 530-536; PMID: 16798767 26. Wilkoff BL, Bello D, Taborsky M, et al. Magnetic resonance imaging in patients with a pacemaker system designed for the magnetic resonance environment. Heart Rhythm 2011;8:65–73. DOI: 10.1016/j.hrthm.2010.10.002; PMID: 20933098 27. Bhandiwad AR, Cummings KW, Crowley M, Woodard PK. Cardiovascular magnetic resonance with an MR compatible pacemaker. J Cardiovasc Magn Reson 2013;15:18. DOI: 10.1186/1532-429X-15-18; PMID: 23409835 28. Brugada J, Blom N, Sarquella-Brugada G, et al. Pharmacological and non-pharmacological therapy for arrhythmias in the pediatric population: EHRA and AEPC-Arrhythmia Working Group joint consensus statement. Europace 2013;15:1337–82. DOI: 10.1093/europace/eut082; PMID: 23851511 29. Janoušek J, van Geldorp IE, Krupickova S, et al, for the Working Group for Cardiac Dysrhythmias and Electrophysiology of the Association for European Pediatric Cardiology. Permanent cardiac pacing in children: choosing the optimal pacing site: a multicenter study. Circulation 2013;127:613–23. DOI: 10.1161/ CIRCULATIONAHA.112.115428; PMID: 23275383 30. Acosta H, Viafara LM, Izquierdo D, et al. Atrial lead placement at the lower atrial septum: a potential strategy to reduce unnecessary right ventricular pacing. Europace 2012;14:1311–6. DOI: 10.1093/europace/eus043; PMID: 22454410 31. 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 2012;14:81–91. DOI: 10.1093/europace/eur240; PMID: 21798880 32. Janoušek J. Device therapy in children with and without congenital heart disease. Herzschrittmacherther Elektrophysiol 2014;25:183–7. DOI: 10.1007/s00399-014-0335-5; PMID: 25070934 33. Padeletti L, Pieragnoli P, Ricciardi G, et al. Acute hemodynamic effect of left ventricular endocardial pacing in cardiac resynchronization therapy: assessment by pressurevolume loops. Circ Arrhythmia Electrophysiol 2012;5:460–7. DOI: 10.1161/CIRCEP.111.970277; PMID: 22589286 34. Karpawich PP, Singh H, Zelin K. Optimizing paced ventricular function in patients with and without repaired congenital heart disease by contractility-guided lead implant. Pacing Clin Electrophysiol 2015;38:54–62. DOI: 10.1111/pace.12521; PMID: 25311823 35. Silvetti MS, Di Carlo D, Ammirati A, et al. Left ventricular pacing in neonates and infants with isolated congenital complete or advanced atrioventricular block: short- and medium-term outcome. Europace 2015;17:603–10. DOI: 10.1093/europace/euu180; PMID: 25115169 36. Tracy CM, Epstein AE, Darbar D, et al. 2012 ACCF/AHA/HRS focused update of the 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2012;60:1297–313. DOI: 10.1016/j.jacc.2012.07.009; PMID: 22975230 37. Janousek J. Cardiac resynchronisation in congenital heart disease. Heart 2009;95:940–7. DOI: 10.1136/hrt.2008.151266; PMID: 19443484 38. Raedle-Hurst TM, Mueller M, Rentzsch A, et al. Assessment of left ventricular dyssynchrony and function using real-time 3-dimensional echocardiography in patients with congenital right heart disease. Am Heart J 2009;157:791–8. DOI: 10.1016/j. ahj.2008.12.015; PMID: 19332212 39. Abadir S, Khairy P. Electrophysiology and adult congenital heart disease: advances and options. Prog Cardiovasc Dis 2011;53:281–92. DOI: 10.1016/j.pcad.2010.07.003; PMID: 21295670 40. Chung ES, Leon AR, Tavazzi L, et al. Results of the Predictors of Response to CRT (PROSPECT) Trial. Circulation 2008;117:2608–16. DOI: 10.1161/ CIRCULATIONAHA.107.743120; PMID: 18458170 41. Silva JN, Ghosh S, Bowman TM, et al. Cardiac

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resynchronization therapy in pediatric congenital heart disease: Insights from noninvasive electrocardiographic imaging. Heart Rhythm 2009;6:1178–85. DOI: 10.1016/j. hrthm.2009.04.017; PMID: 19632630 Janousek J, Gebauer RA, Abdul-Khaliq H, et al. Cardiac resynchronisation therapy in paediatric and congenital heart disease: differential effects in various anatomical and functional substrates. Heart 2009;95:1165–71. DOI: 10.1136/ hrt.2008; PMID: 19307198 Dubin AM, Janousek J, Rhee E, et al. Resynchronization therapy in pediatric and congenital heart disease patients: an international multicenter study. J Am Coll Cardiol 2005;46:2277– 83. DOI:10.1016/j.jacc.2005.05.096; PMID: 16360058 Cecchin F, Frangini PA, Brown DW, et al. Cardiac resynchronization therapy (and multisite pacing) in pediatrics and congenital heart disease: five years experience in a single institution. J Cardiovasc Electrophysiol 2009;20:58–65. DOI: 10.1111/j.1540-8167.2008.01274.x; PMID: 18775051 Miyazaki A, Sakaguchi H, Kagisaki K, et al. Optimal pacing sites for cardiac resynchronization therapy for patients with a systemic right ventricle with or without a rudimentary left ventricle. Europace 2016;18:100–12. DOI: 10.1093/europace/ euu401; PMID: 25745073 Kamp AN, Lapage MJ, Serwer GA, et al. Antitachycardia pacemakers in congenital heart disease. Congenit Heart Dis 2015;180–4. DOI: 10.1111/chd.12230; PMID: 25376944 Epstein AE, DiMarco JP, Ellenbogen KA, et al. ACC/AHA/ HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/ AHA/NASPE 2002 Guideline. J Am Coll Cardiol 2008;51:e1–e62. DOI: 10.1016/j.hrthm.2008.04.014; PMID: 18534360 Khairy P, Harris L, Landzberg MJ, et al. Implantable cardioverter-defibrillators in tetralogy of Fallot. Circulation 2008;117:363–70. DOI: 10.1161/ CIRCULATIONAHA.107.726372; PMID: 18172030 Koyak Z, de Groot JR, Bouma BJ, et al. Symptomatic but not asymptomatic non-sustained ventricular tachycardia is associated with appropriate implantable cardioverter therapy in tetralogy of Fallot. Int J Cardiol 2013;167:1532–5. DOI: 10.1016/j.ijcard.2012.04.103; PMID: 22608897 Kella DK, Merchant FM, Veledar E, et al. Lesion-specific differences for implantable cardioverter defibrillator therapies in adults with congenital heart disease. Pacing Clin Electrophysiol 2014;37:1492–8. DOI: 10.1111/pace.12434; PMID: 24889130 Khairy P, Harris L, Landzberg MJ, et al. Sudden death and defibrillators in transposition of the great arteries with intra-atrial baffles: A multicenter study. Circ Arrhythmia Electrophysiol 2008;1:250–7. DOI: 10.1161/CIRCEP.108.776120; PMID: 19808416 Berul CI, Van Hare GF, Kertesz NJ, et al. Results of a multicenter retrospective implantable cardioverterdefibrillator registry of pediatric and congenital heart disease patients. J Am Coll Cardiol 2008;51:1685–91. DOI: 10.1016/j.jacc.2008.01.033; PMID: 18436121 Atallah J, Erickson CC, Cecchin F, et al. Multi-institutional study of implantable defibrillator lead performance in children and young adults: results of the Pediatric Lead Extractability and Survival Evaluation (PLEASE) study. Circulation 2013;127:2393–402. DOI: 10.1161/ CIRCULATIONAHA.112.001120; PMID: 23694966 Yap S-C, Roos-Hesselink JW, Hoendermis ES, et al. Outcome of implantable cardioverter defibrillators in adults with congenital heart disease: A multi-centre study. Eur Heart J 2007;28:1854–61. DOI: http://dx.DOI.org/10.1093/eurheartj/ ehl306 1854-1861; PMID: 17030523 Radbill AE, Triedman JK, Berul CI, et al. System survival of nontransvenous implantable cardioverter-defibrillators compared to transvenous implantable cardioverterdefibrillators in pediatric and congenital heart disease patients. Heart Rhythm 2010;7:193–8. DOI: 10.1016/j. hrthm.2009.10.014; PMID: 20022820 Tomaske M, Prêtre R, Rahn M, Bauersfeld U. Epicardial and pleural lead ICD systems in children and adolescents maintain functionality over 5 years. Europace 2008;10:1152–6. DOI: 10.1093/europace/eun214; PMID: 18701602 Rantner LJ, Vadakkumpadan F, Spevak PJ, et al. Placement of implantable cardioverter-defibrillators in paediatric and congenital heart defect patients: A pipeline for model generation and simulation prediction of optimal

configurations. J Physiol 2013;17:4321–34. DOI: 10.1113/ jphysiol.2013.255109; PMID: 23798492 58. Jarman JWE, Lascelles K, Wong T, et al. Clinical experience of entirely subcutaneous implantable cardioverterdefibrillators in children and adults: cause for caution. Eur Heart J 2012;33:1351–9. DOI: 10.1093/eurheartj/ehs017; PMID: 22408031 59. Köbe J, Reinke F, Meyer C, et al. Implantation and followup of totally subcutaneous vs conventional implantable cardioverter-defibrillators: A multicenter case-control study. Heart Rhythm 2013;10:29–36. DOI: 10.1016/j. hrthm.2012.09.126; PMID: 23032867 60. Pettit SJ, McLean A, Colquhoun I, et al. Clinical experience of subcutaneous and transvenous implantable cardioverter defibrillators in children and teenagers. Pacing Clin Electrophysiol 2013;36:1532–8. DOI: 10.1111/pace.12233; PMID: 24033753 61. Griksaitis MJ, Rosengarten JA, Gnanapragasam JP, et al. Implantable cardioverter defibrillator therapy in paediatric practice: a single-centre UK experience with focus on subcutaneous defibrillation. Europace 2013;15:523–30. DOI: 10.1093/europace/eus388; PMID: 23333943 62. Khairy P, Mansour F. Implantable cardioverter-defibrillators in congenital heart disease: 10 programming tips. Heart Rhythm 2011;8:480–3. DOI: 10.1016/j.hrthm.2010.10.046; PMID: 21056119 63. Rosenthal E, Konta L. Transvenous Atrial Pacing from the Superior Vena Cava Stump after the Hemi-Fontan Operation-A New Approach. Pacing Clin Electrophysiol 2013;37:531–6. DOI: 10.1111/pace.12305; PMID: 24883447 64. Rosenthal E. Biventricular pacing in children: Indications and technique. Turkish J Arrhythmia, Pacing Electrophysiol 2005;3:41–5. 65. Moore JP, Shannon KM. Transpulmonary atrial pacing: An approach to transvenous pacemaker implantation after extracardiac conduit fontan surgery. J Cardiovasc Electrophysiol 2014;25:1028–31. DOI: 10.1111/jce.12447; PMID: 24786766 66. Arif S, Clift PF, De Giovanni J V. Permanent trans-venous pacing in an extra-cardiac Fontan circulation. Europace 2016;18:304–7. DOI: 10.1093/europace/euv110; PMID: 25995386 67. Rosenthal E, Qureshi SA, Crick JC. Successful long-term ventricular pacing via the coronary sinus after the Fontan operation. Pacing Clin Electrophysiol 1995;18:2103–5. DOI: 10.1111/j.1540-8159.1995.tb03874.x; PMID: 8552527 68. Chakrabarti S, Szantho G, Turner MS, et al. Use of radiofrequency perforation for lead placement in biventricular or conventional endocardial pacing after mustard or senning operations for D-transposition of the great arteries. Pacing Clin Electrophysiol 2009;32:1123–9. DOI: 10.1111/j.1540-8159.2009.02453.x; PMID: 19719487 69. Bouzeman A, Marijon E, de Guillebon M, et al. Implantable cardiac defibrillator among adults with transposition of the great arteries and atrial switch operation: Case series and review of literature. Int J Cardiol 2014;177:301–6. DOI: 10.1016/j.ijcard.2014.09.015; PMID: 25499397 70. Fortescue EB, Berul CI, Cecchin F, et al. Patient, procedural, and hardware factors associated with pacemaker lead failures in pediatrics and congenital heart disease. Heart Rhythm 2004;1:150–9. DOI: http://dx.DOI.org/10.1016/j. hrthm.2004.02.020; PMID: 15851146 71. Alexander ME. Transvenous pacing in infants: a faith based initiative? Pacing Clin Electrophysiol 2004;27:1463–5. DOI: 10.1111/j.1540-8159.2004.00662.x; PMID: 15546299 72. Wilkoff BL, Love CJ, Byrd CL, et al. Transvenous lead extraction: Heart rhythm society expert consensus on facilities, training, indications, and patient management. Heart Rhythm 2009;6:1085–104. DOI: 10.1016/j. hrthm.2009.05.020; PMID: 19560098 73. McCanta AC, Kong MH, Carboni MP, et al. Laser lead extraction in congenital heart disease: a case-controlled study. Pacing Clin Electrophysiol 2013;36:372–80. DOI: 10.1111/ pace.12071; PMID: 23305443 74. Cecchin F, Atallah J, Walsh EP, et al. Lead extraction in pediatric and congenital heart disease patients. Circ Arrhythm Electrophysiol 2010;3:437–44. DOI: 10.1161/CIRCEP.110.957324; PMID: 20729392 75. Khairy P, Roux J-F, Dubuc M, et al. Laser lead extraction in adult congenital heart disease. J Cardiovasc Electrophysiol 2007;18:507–11. DOI: 10.1111/j.1540-8167.2007.00782.x; PMID: 17343721

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Cardiac Implantable Electronic Device Infection in Patients at Risk K ha ldoun G Ta ra k ji, 1 C hri s t o p h e r R E l l i s, 2 Pa s c a l D e f a y e 3 a n d Ch a r l e s Ke n n e r g r e n 4 1. Heart and Vascular Institute, Cleveland Clinic, Ohio, US; 2. Vanderbilt Heart and Vascular Institute at Vanderbilt University, Nashville, Tennessee, US; 3. Centre Hospitalier Universitaire de Grenoble, La Tronche, France; 4. Sahlgrenska University Hospital, Gothenburg, Sweden

Abstract The incidence of infection following implantation of cardiac implantable electronic devices (CIEDs) is increasing at a faster rate than that of device implantation. Patients with a CIED infection usually require hospitalisation and complete device and lead removal. A significant proportion die from their infection. Transvenous lead extraction (TLE) is associated with rare but serious complications including major vascular injury or cardiac perforation. Operator experience and advances in lead extraction methods, including laser technology and rotational sheaths, have resulted in procedures having a low risk of complication and mortality. Strategies for preventing CIED infections include intravenous antibiotics and aseptic surgical techniques. An additional method to reduce CIED infection may be the use of antibacterial TYRX™ envelope. Data from non-randomised cohort studies have indicated that antibacterial envelope use can reduce the incidence of CIED infection by more than 80 % in high-risk patients and a randomised clinical trial is ongoing.

Keywords Cardiovascular implantable electronic device infections, implantable cardioverter-defibrillators, antibacterial envelope, pacemaker, transvenous lead extraction Disclosure: Professor Tarakji has received speaker fees and consulting honoraria from Medtronic, Professor Ellis has received advisory board/consultant fees from Atricure, SentreHeart, Boston Scientific, Medtronic and Spetranetics, and research grants from Medtronic, Atricure, Boston Scientific, Thoratec and HeartWare. Professor Defaye has no conflicts of interest to declare. Professor Kennergren has presented on behalf of, advised and/or performed scientific studies with Boston Scientific, Biotronic, ELA/Sorin, Medtronic/Vitatron/ TYRX, Mentice, Sim Suite and St Jude. Acknowledgements: Medical Media Communications (Scientific) Ltd provided medical writing and editing support to the author, funded by Medtronic and Spectranetics. Received: 30 November 2015 Accepted: 14 March 2016 Citation: Arrhythmia & Electrophysiology Review 2016;5(1):65–71 Access at: www.AERjournal.com DOI: 10.15420/aer.2015.27.2 Correspondence: Charles Kennergren, Department of Cardiothoracic Surgery, Sahlgrenska University Hospital, S 413 65 Goteborg, Sweden. E: charles.kennergren@vgregion.se

Over the last few decades an increasing body of evidence has supported the role of cardiovascular implantable electronic devices (CIEDs) including permanent pacemakers (PPMs), implantable cardioverter-defibrillators (ICDs) and cardiac resynchronisation therapy (CRT-D [with defibrillator] and CRT-P [without defibrillator]) in improving quality of life and survival.1 In addition, there has been a significant increase in the number of implantation procedures and subsequent replacements, revisions and upgrades.2 Between 1993 and 2008, 4.2 million patients underwent implantation of a CIED.3 A worldwide cardiac pacing and ICD survey, which included more than 80 % of all the pacemakers and ICDs implanted worldwide during 2009, reported 737,840 new implants and 264,824 replacements, a significant rise compared with a similar survey conducted in 2005.4 However, the cost and complications of device implantation, including infection or hardware malfunction in patients receiving CIEDs, have led to the concern that negative outcomes may partially counteract the expected benefits. The rate of CIED infection has been estimated at 0.5 % with primary implants and 1–7 % with secondary interventions.3,5–8 It is difficult to give accurate estimates of infection rates, given the fact that figures are partly based on retrospective series of varying duration, and that different definitions of infection exist. However, the incidence of CIED infection is increasing out of proportion to CIED implantation.3,5,9 A US study reported a 12 % increase in the number of CIED implantations from 2004 to 2006,

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with a 57 % increment in CIED infections during the same period.9 Reasons for this rise in CIED infections include the fact that younger patients are receiving CIEDs, and therefore surviving long enough to require more pulse generator changes and lead revisions, which are associated with a higher infection rate.7,10 In addition, there has been an increase in comorbidities, such as diabetes and kidney disease, resulting in poor wound healing and diminished immune responses.3,9,11,12 Expanding indications for CIED use, coupled with an ageing population with more comorbidities, mean this trend is likely to increase.2 Better awareness and improved reporting of CIED infections may, however, help to decrease the higher complication rates noted in recent years. CIED infections also impose a substantial financial burden resulting from prolonged hospital stays, long duration of antibiotic therapy, management of sepsis and complications, device extraction and reimplantation.3 These infections typically cost at least $52,00013 and may exceed $100,000.14 This article will review strategies for management and prevention of CIED infections, including lead extraction and the use of an absorbable antibacterial envelope.

Risk Factors for Cardiac Implantable Electronic Device Infections Risk factors for CIED infections include patient factors such as medical comorbidities,15 renal failure,15–17 heart failure,16,18 diabetes,16,18 fever within

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Device Therapy Figure 1: Images of Pocket Infection Over Two Years

blood cultures.31 Less commonly, the intravascular portion of the CIED can become infected as a result of haematogenous seeding from another infection site, and vegetations on the leads are frequently detected by transoesophageal echocardiography (TOE).33 Early presentations typically result from wound infections, MRSA or MSSA. Late presentations are more likely to be related to vascular access.12,34 It can be hard to diagnose CIED infections since numerous conditions can present with the same symptoms. Clinical manifestations of CIED range from local device pocket erosion to full-blown sepsis,25 and include symptoms such as erythema, warmth, tenderness, purulent discharge, erosion of generator or protrusion of leads through the skin (see Figure 1).26,35 Furthermore, up to 30 % of patients present with nonspecific symptoms only, such as fever and malaise.

Source: Tarakji and Wilkoff, 2013.35

24 hours before the implantation,7 anticoagulation17 and steroid use.19 Important device-related risk factors include device revision or upgrade,8 the use of more than two pacing leads and the need for early pocket re-exploration.7,19 The presence of multiple leads increases the risk of central venous thrombosis in the area of the leads and is a potential site of secondary seeding of bacteria.20 Procedure-related factors include procedure time, temporary pacemaker use prior to implantation, early re-intervention and postoperative haematoma at the device pocket site.21 ICD replacement is associated with a 2.5x greater incidence of pocket-related events, and the need for re-intervention increases with every consecutive replacement.10 A registry study found that PPM and ICD generator replacements were associated with a substantial complication risk, particularly those with lead additions.8 A study of 122 ICD patients undergoing generator replacement or surgical lead revision between January 2006 and July 2008 found that one-third of patients had an asymptomatic bacterial colonisation of the generator pocket. After revision, 7.5 % of these patients developed a device infection over 108 ± 73 days with the same species of microorganism.22 However, these risk factors have mostly been derived from small, single-centre studies. There is a need for larger, more representative studies to identify the most important factors that are responsible for the development of CIED infection. There is no consensus definition of patients at high risk of CIED infection; a composite risk score has been proposed,23 but definitions of high-risk patients vary across studies.

Pathogenesis, Presentation and Diagnosis of Cardiac Implantable Electronic Device Infection CIED-related infections are mainly due to local contamination during implantation; breach of the skin barrier introduces bacteria into the device pocket.24 The majority (88 %) of CIED infections are caused by Gram-positive organisms;24–26 the most common organism is methicillinsensitive Staphylococcus aureus (MSSA; 30.8 %), followed by coagulasenegative Staphylococcus (20.5 %). Around half of these Staphylococcus infections are methicillin-resistant Staph. aureus (MRSA).25,27 The majority (60 %) of CIED infections are pocket infections, characterised by erythema, tenderness, warmth and erosion,28 but infection can track along the intravascular portion of the leads, leading to intravascular infection, manifesting as bacteraemia and endocarditis.29–32 A study found that, even when infection symptoms were limited to the device pocket, in 72 % of cases the intravascular segments of the leads had positive

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In order to diagnose systemic CIED infection, two sets of blood cultures should be obtained before initiating antibiotic therapy (class I recommendation). Percutaneous aspiration of the pocket should not be performed (class III recommendation). The use of transthoracic echocardiogram (TTE) should be mandatory to investigate the possibility of endocarditis.28 The results should be interpreted according to the individual patient; for example a positive echo density does not always indicate infection and a lack of vegetation in the blood culture does not eliminate the possibility of CIED-related bacteraemia. Patients with bacteraemia but no evidence of device pocket infection or endocarditis represent a diagnostic challenge. The use of TOE is essential in this group of patients as TTE lacks the necessary specificity.36 The diagnosis may only be confirmed if infection relapses or persists after completion of the antibiotic course, particularly in the case of Gram-positive organisms other than Staph. aureus.28,37 Given the increasing prevalence of CIED infections and the occasionally challenging nature of diagnosis, particularly in the absence of pocket involvement and with negative TOE, other diagnostic techniques have been investigated. Several show promise, including the use of 18F-fluorodeoxyglucose–PET/CT.38,39

Management of Cardiac Implantable Electronic Device Infection Correct management of patients with CIED infection depends on the clinical presentation and the causative pathogen. In mild cases such as superficial incision site infection or stitch abscess, conservative management strategies may suffice, such as 7–10 days of antimicrobial therapy and removal of the stitches.40 When CIED infection is restricted to the pocket site, an American Heart Association (AHA) scientific statement recommends 7–10 days of therapy after device removal if no inflammatory changes are seen, otherwise 10–14 days of antimicrobial treatment is recommended.28 At least one of the authors would extend the treatment until complete wound healing. Antibiotic treatment in cases of systemic CIED infection is more uniform, usually involving 4–5 weeks of IV treatment, also depending on the type of causative bacteria. The Heart Rhythm Society (HRS) and European Heart Rhythm Association (EHRA) recommend complete device and lead removal in all patients with definite CIED systemic infection as evidenced by valvular endocarditis, lead endocarditis and sepsis. It is also recommended for all patients with CIED pocket infection as evidenced by pocket abscess, device erosion, skin adherence or chronic draining sinus without clinically evident involvement of the transvenous portion, patients with valvular

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endocarditis without definite involvement of the leads and/or device and in patients with occult Gram-positive bacteria.41,42 Complete device and lead removal is also reasonable in patients with persistent occult Gram-negative bacteria, but is not indicated for superficial or incisional infection without involvement of the device and/or leads, nor to treat chronic bacteraemia due to a source other than the CIED, when the source could not be eliminated and long-term antibiotic treatment is required.41 Satisfactory control of the infection is required before implantation of a replacement device may be considered.

Figure 2: Causes of Cardiac Implantable Electronic Devices Infection Mortality

11 %

25% 5%

Renal failure n=1 Heart failure n=2

11 % 32 %

15% 11 %

60%

Transvenous device system explantation is the preferred technique; intraprocedural risks include haemothorax, laceration of the superior vena cava, damage to the tricuspid valve and cardiac tamponade.25,26,28 However, without system removal the rate of relapse is high: rates of 50–100 % have been reported, compared with 0–4.2 % for complete system removal.26,27,31,43,44 Mortality can be as high as 31–66 % if the device is not removed.30,45 Using a combined approach with antibiotic and CIED removal, the one-year mortality is still approximately 20 %.30,45,46 Data from the National Hospital Discharge Survey from 1996–2003 demonstrated that CIED infection doubles the rate of in-hospital mortality.47 In one study that included 412 patients with CIED infection, the causes of in-hospital mortality are shown in Figure 2.Of note, only two out of the 19 in-hospital deaths were related to CIED extraction.25 Delays to treatment and incomplete system removal are associated with higher mortality.3,14 Recent data from the European multicentre study on lead extraction (ELECTRA) also show a significant in-hospital mortality of CIED infection patients, however only a minority of deaths were related to the extraction procedure.48 In a study investigating the clinical predictors of short- and long-term mortality in patients with CIED infection, the following risk factors were identified: patient age (hazard ratio [HR] 1.20, 95 % CI [1.06–1.36]), heart failure (HR 2.01, 95 % CI 1.42–2.86), metastatic malignancy (HR 5.99, 95 % CI [1.67–21.53]), corticosteroid therapy (HR 1.97, 95 % CI [1.22–3.18]), renal failure (HR 1.94, 95 % CI [1.37–2.74]), and CIED-related endocarditis (HR 1.68, 95 % CI [1.17–2.41]).49 The need for transvenous lead extraction (TLE) has been increasing in proportion to the increased number of CIED implantations. In a study of patients undergoing TLE, a total of 5,973 (4,436 [74.3 %] PPM and 1,537 [25.7 %] ICD) leads were extracted during 3,258 TLE procedures.50 Among these, 25 (0.8 %) patients experienced major complications requiring emergent surgical or endovascular intervention. Twenty patients (0.6 %) underwent sternotomy (n=18) or thoracotomy (n=2) for superior vena cava laceration (n=15) and right atrial (n=2) or ventricular (n=3) perforation. Two patients required vascular repair at the access site for subclavian vein or artery laceration. In-hospital mortality was 36 % including six procedural/operative deaths (0.2 %).50 Factors associated with increased procedural complications (not mortality) risk include body mass index (BMI) <25 kg/m2, damaged leads and ICD leads.42 Predictors of major complications associated with TLE include cerebrovascular disease, ejection fraction ≤15 %, lower platelet count, international normalised ratio ≥1.2, mechanical sheaths and powered sheaths.51 Thirty-day all-cause mortality following TLE has been associated with BMI, haemoglobin, end-stage renal disease left ventricular ejection fraction, New York Heart Association (NYHA) functional class, extraction for infection, number of prior lead extractions performed by the operator and extraction of a dual-coil defibrillator lead.52 Procedural success can be enhanced in lead extraction by the use of several tools and techniques such as locking stylets (Cook Medical and Spectranetics), powered and non-powered sheaths

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Sepsis n=6 Stroke n=2 Multi-organ system failure n=2

10% 32 %

Extraction related n=2

Source: Tarakji, 2010.25

(Evolution ® , Cook Medical and TightRail™, Spectranetics) and laser technology53,54 such as the Excimer and GlideLight™ (Spectranetics). An observational retrospective study concluded that lead extraction employing laser sheaths is highly successful with a low procedural complication rate, and that increasing experience is associated with greater success. 32 Several reports have described the effectiveness of the Evolution sheath.55–58 The use of locking stylets placed in the lead to facilitate the application of traction and to stabilise the lead during sheath dissection of fibrotic tissue is essential. 59 However, the use of the electrosurgical technique for lead extraction seems to be decreasing according to data from the ELECTRA study.48 Although TLE intraprocedural mortality is very low, postprocedural and long-term mortality when extraction is performed for the indication of infection remain significant.60–62 A recent study reviewed records of all patients with infected CIEDs who underwent TLE at a tertiary care centre between 2002 and 2008. Patients (n=502) were stratified into two groups: those presenting with pocket infection (n=289, 58 %), and those who presented with bacteraemia, with or without vegetation, and a pocket that appeared benign, termed endovascular infection (EVI) (n=213, 42 %). The one-year mortality rate was 20 %; EVI was associated with significantly higher one-year mortality (HR 2.1, p=0.0008). Among patients with EVI, 100 had vegetation on TOE however there was no difference in one-year mortality between patients with EVI and vegetation compared with patients with EVI and no vegetation. Risk factors for one-year mortality among patients with EVI included chronic renal insufficiency or history of renal insufficiency, end stage renal disease, NYHA functional class III or IV, prior valve surgery, diabetes and bleeding requiring transfusion. The presence of vegetations was not associated with increased one-year mortality (see Figure 3).63 A study of autopsy findings of patients with CIEDs found other issues relating to leads such as thrombi on ventricular/atrial leads (48 %), bipolar lead rings fixed by fibrous tissue (22 %), connective tissue bridges or tunnels in ventricle/atrium (71 %) and ventricular leads fixed to valve or penetrating chordae (46 %).64 Depending on their location, such connective tissue surrounding the leads, as well as leads partially positioned outside the vessels or the heart, may increase the risk of complications during lead extraction. The present HRS and EHRA recommendations do not fully cover the timing of reimplantion or the treatment of pacemaker and ICD dependent patients, partially due to lack of studies comparing strategies. Amendments to the recommendations regarding these issues are highly desirable. Contralateral reimplantation in CIED infection patients is however always recommended, when possible. In summary, advances in TLE

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Device Therapy Figure 3: Kaplan-Meier Survival Curves for One-year Mortality Among Patients with Cardiac Implantable Electronic Devices Undergoing Transvenous Lead Extraction 1.0

The most common strategy to reduce infections is intravenous prophylaxis using antibiotics.74 A double-blind clinical trial randomised patients (n=649) to prophylactic antibiotics (intravenous administration of 1 g cefazolin immediately before the procedure) or placebo. The trial was terminated early after a significantly lower rate of infection was observed in the antibiotic arm (0.63 % in antibiotic arm versus control [3.28 %]; RR=0.19; p=0.016).74 However, all infections in this study were caused by cefazolin-sensitive isolates and the study population had a low prevalence of methicillin resistance compared with US hospitals (13 % Staph. aureus and 60 % coagulase-negative Staphylococcus species in study versus 55–60 % and 80–90 % in US hospitals).

Survival

0.9 0.8 0.7 0.6

1 versus 2, p<0.001 1 versus 3, p<0.001

0.5 0

120

180

240

300

360

Days 1. Pocket infection with negative blood cultures and no vegetations 2. Pocket infection with positive blood cultures and vegetations 3. Endovascular infection (EVI) Source: Tarakji, 2010.25

have improved procedural safety for patients with CIED infection, but overall mortality remains high and there is a need for further studies to optimise treatment of at-risk patients.

Strategies to Prevent Cardiac Implantable Electronic Device Infection The first preventive strategy against CIED infection is not reopening a CIED pocket unless necessary. ICD pulse generators in primary prevention systems may not always need replacement. It is possible to maximise battery longevity by setting the lower rate limit (LRL) at 50 bpm, choosing a better LV lead impedance vector for CRT, using devices with quadripolar LV leads or selecting high battery capacity devices, particularly with CRT-D systems. In addition, central lines (vascular catheters) should be avoided in patients with CIED devices, because they may be associated with higher risk of mortality from infection.34 Leadless pacemaker technology provides an alternative that does not require pockets or leads65,66,67 and therefore avoids many of the problems associated with intravascular lead use, including pocket infection. This represents an important therapeutic advance in suitable patients.68 In addition, subcutaneous ICDs (SICD) are now available. The SICD is implanted inferior and lateral to the left breast in mid-axillary line, and the lead is placed under the skin along the left side of the sternum. Therefore the lead is not intravascular or in contact with cardiac tissue, minimising intravascular infection risk.69 However, to date, no comparative studies between the SICD and conventional ICDs have been reported. Therefore, the impact of SICD use on CIED infection rate is not yet known. Various prophylaxis strategies have been suggested, including skin and nasal infection treatment, device pocket irrigation and operative prep skin barriers, but there is no evidence to support their use in preventing CIED infections. Preoperative cleansing of the patient’s skin with chlorhexidine–alcohol has been found to be superior to cleansing with povidone–iodine for preventing abdominal surgical site infection.70 However, two recent studies showed no significant difference in infection risk among patients undergoing CIED procedure using chlorhexidine–

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alcohol or povidone–iodine for skin preparation.71,72 In addition, the antimicrobial treatment of pacemaker casings with antiseptics has been investigated in vitro and early studies showed promising results.73

The use of postoperative antibiotics has been investigated in two recent studies. In a prospective randomised, single-centre study, patients (n=1,008) received standard systemic antibiotic prophylaxis and were then randomised into four groups receiving either povidone-iodine, neomycin, a sterile non-adherent pad or placebo ointment after procedure. All patients were followed for at least 12 months. Surgical site inflammation and infection were graded based on degree of inflammation, discharge, wound culture and blood culture. The surgical site infection rate was more than doubled in those with longer procedural time (HR=2.3, p=0.01) but the use of topical antibiotics after closure did not show significant benefit.75 A prospective database on patients undergoing PPM implantation from 1991–2009 (n=3,253) found that over 19 years the incidence of CIED infections fell from 3.6 % with no antibiotics to 2.9 % (perioperative antibiotics), to 0.4 % (peri- plus postoperative antibiotics), suggesting that perioperative followed by postoperative antibiotics may minimise infections.76 However, the REPLACE registry found no difference in infection rate between those who received postoperative antibiotics and those who did not.6 The Prevention of Arrhythmia Device Infection Trial (PADIT) clinical trial is currently recruiting and aims to compare a centre-wide policy of incremental antibiotic therapy with conventional antibiotic prophylaxis in high-risk patients undergoing CIED implantation. Centres (not patients) will be randomised to either conventional antibiotic therapy (cefazolin or vancomycin for penicillin-allergic patients) or incremental antibiotic therapy comprising a single preoperative dose of cefazolin and vancomycin (vancomycin only in patients allergic to penicillin), an intraoperative bacitracin pocket wash then two days of postoperative antibiotic therapy comprising cefalexin or cephadroxil (clindamycin in penicillin-allergic patients). Centres will be randomised to one therapy and then crossover after 6, 12 and 18 months. During each treatment period the randomised antibiotic therapy will be used on all patients undergoing a device implant procedure.77,78 An additional strategy to combat pocket infection involves the use of an antibiotic envelope. The TYRX™ non-absorbable envelope (Medtronic) has shown substantial efficacy in clinical studies in reducing the infection rate.23,79,80 This has led to the development of the TYRX absorbable envelope, which is constructed from a fully bioabsorbable multifilament mesh (see Figure 4). The envelope holds the CIED in place, preventing device migration, elutes antimicrobial agents minocycline and rifampicin for a minimum of 7 days; and then is fully absorbed approximately 9 weeks after implantation.

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Cardiac Implantable Electronic Device Infection in Patients at Risk

A growing body of evidence has demonstrated the efficacy of the TYRX envelopes in the prevention of CIED infections. In a singlecentre retrospective cohort study, the infection rate in patients with ≥2 risk factors for CIED infection was compared in patients receiving the TYRX absorbable envelope (n=135), the TYRX non-absorbable envelope (n=353) and controls who did not receive an envelope (n=636). After a minimum 300 days, CIED infections were reported in 0 % of patients receiving the absorbable TYRX, 0.3 % for the nonabsorbable TYRX, and 3.1 % for controls (p=1 for absorbable versus non-absorbable TYRX; p=0.03 for absorbable TYRX versus controls, and p=0.002 for non-absorbable TYRX versus controls; see Figure 5). This represents a very low prevalence of infection in subjects at risk and suggests that the use of the TYRX absorbable antibacterial envelope is a promising strategy.81 Two large (n=1,129) prospective multicentre cohort studies are currently investigating the impact of the TYRX non-absorbable envelope on CIED major infections and mechanical complication rates. The Citadel (TYRX Envelope for Prevention of Infection Following Replacement with an Implantable Cardioverter-Defibrillator) and Centurion (TYRX Envelope for Prevention of Infection Following Replacement with a Cardiac Resynchronisation Therapy Device) studies aim to compare the rate of CIED infection and mechanical complication after CIED replacement with an ICD or CRT. Recently presented data indicated that the TYRX antibacterial envelope reduces the infection rate by 80 % compared with historical control data.82 However, it should be noted that the comparison of data with historical controls has well-known limitations, and there is a need for randomised study data to confirm the effect of the TYRX envelope. The Worldwide Randomised Antibiotic Envelope Infection Prevention Trial (WRAP-IT) is a multicentre, single-blinded, randomised study that aims to evaluate the ability of the TYRX absorbable antibiotic envelope to reduce major CIED infections during 12 months following CIED generator replacement, upgrade, revision or de novo CRT-D implant.78 Patients (around 7,000) will be randomised 1:1 to envelope versus no envelope. The primary endpoint is the rate of major CIED infections leading to one or more of the following: CIED system removal, CIED pocket revision, antibiotic therapy or death. Secondary objectives include all cause mortality and CIED removal due to pain without obvious infection. The study also aims to determine the one-year incidence rate of CIED infection among a large cohort of patients undergoing CIED procedures, as well as elucidating risk factors for CIED infection. A recent retrospective study analysed data from patients who underwent CIED implantations, with (n=365) or without (n=1,111) the TYRX envelope. In the non-TYRX group, 19 infections were observed (1.7 %), versus 0 in the TYRX group (p=0.006). It was estimated that the TYRX prevented 6.2 additional infections costing approximately $340,000. This cost was similar to the actual cost of the envelopes in the TYRX group, estimated at $320,000.83 Therefore use of an antibacterial envelope as standard care appears to be economically reasonable.

Discussion As a result of the increasing incidence and complexity of CIED treatment, infection is frequently encountered in clinical practice and is associated with significant morbidity and mortality. Moreover, the

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Figure 4: The TYRX™ Absorbable Antibacterial Envelope

Photo courtesy of Dr Christopher R Ellis. Previously published in Ellis et al, 2011.84

Figure 5: Efficacy of TYRX™ Antibacterial Envelope in High-risk Subjects 1.00 Log rank p=0.001

Probability of infection-free survival

The TYRX envelope received US Food and Drug Administration clearance in May 2013 and the CE Mark in September 2014.

0.95

0.90

0.85

0.80 0

365

730

1,095

1,460

Days since cardiovascular implantable electronic device procedure Antibacterial envelope used

Yes

Number at risk Envelope

488

252

160

110

No envelope

636

434

375

308

180

Source: Kolek et al, 2015.81

infection rate is rising faster than the rate of CIED implantation. Many questions remain unanswered, including the true infection incidence, clear infection definitions, better understanding of risk factors and the impact of implantation practices and techniques. More experience and advances in TLE including laser technology and rotational sheaths have reduced procedural complications; however device infection, despite lead extraction, is associated with long-term mortality of 15–25 % at one year. The mortality risk is higher with endovascular infection than with pocket infection. There is a need for further studies aimed at elucidating the complication and mortality risks associated with device and lead extraction: these may help guide CIED and lead management as well as extraction tool and technique development.

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Device Therapy In terms of preventing CIED infections, interim data from non-randomised studies indicate that the use of the TYRX antibacterial envelope appears to be one promising and cost-effective strategy in preventing

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CIED infections. The WRAP IT study will help assess the efficacy of the absorbable TYRX envelope in reducing infection in a prospective randomised large clinical trial. n

DOI: 10.1093/eurheartj/ehp421; PMID: 19875388. 22. Kleemann T, Becker T, Strauss M, et al. Prevalence of bacterial colonization of generator pockets in implantable cardioverter defibrillator patients without signs of infection undergoing generator replacement or lead revision. Europace 2010;12:58–63. DOI: 10.1093/europace/eup334; PMID: 19861383. 23. Mittal S, Shaw RE, Michel K, et al. Cardiac implantable electronic device infections: incidence, risk factors, and the effect of the AigisRx antibacterial envelope. Heart Rhythm 2014;11:595–601. DOI: 10.1016/j.hrthm.2013.12.013; PMID: 24333543. 24. Da Costa A, Lelievre H, Kirkorian G, et al. Role of the preaxillary flora in pacemaker infections: a prospective study. Circulation 1998;97:1791–5. PMID: 9603533. 25. Tarakji KG, Chan EJ, Cantillon DJ, et al. Cardiac implantable electronic device infections: presentation, management, and patient outcomes. Heart Rhythm 2010;7:1043–7. DOI: 10.1016/j. hrthm.2010.05.016; PMID: 20470904. 26. Sohail MR, Uslan DZ, Khan AH, et al. Management and outcome of permanent pacemaker and implantable cardioverter-defibrillator infections. J Am Coll Cardiol 2007;49:1851–9. PMID: 17481444. 27. Margey R, McCann H, Blake G, et al. Contemporary management of and outcomes from cardiac device related infections. Europace 2010;12:64–70. DOI: 10.1093/europace/ eup362; PMID: 1991031. 28. Baddour LM, Epstein AE, Erickson CC, et al. Update on cardiovascular implantable electronic device infections and their management: a scientific statement from the American Heart Association. Circulation 2010;121:458–77. DOI: 10.1161/ CIRCULATIONAHA.109.192665; PMID: 20048212. 29. Greenspon AJ, Rhim ES, Mark G, et al. Lead-associated endocarditis: the important role of methicillin-resistant Staphylococcus aureus. Pacing Clin Electrophysiol 2008;31:548–53. DOI: 10.1111/j.1540-8159.2008.01039.x; PMID: 18439167. 30. Klug D, Lacroix D, Savoye C, et al. Systemic infection related to endocarditis on pacemaker leads: clinical presentation and management. Circulation 1997;95:2098–107. PMID: 9133520. 31. Klug D, Wallet F, Lacroix D, et al. Local symptoms at the site of pacemaker implantation indicate latent systemic infection. Heart 2004;90:882–6. PMID: 15253959. 32. Wazni O, Epstein LM, Carrillo RG, et al. Lead extraction in the contemporary setting: the LExICon study: an observational retrospective study of consecutive laser lead extractions. J Am Coll Cardiol 2010;55:579–86. DOI: 10.1016/j jacc.2009.08.070; PMID: 20152562. 33. Golzio PG, Fanelli AL, Vinci M, et al. Lead vegetations in patients with local and systemic cardiac device infections: prevalence, risk factors, and therapeutic effects. Europace 2013;15:89–100. DOI: 10.1093/europace/eus240; PMID: 22968846. 34. Kim DH, Tate J, Dresen WF, et al. Cardiac implanted electronic device-related infective endocarditis: clinical features, management, and outcomes of 80 consecutive patients. Pacing Clin Electrophysiol 2014;37:978–85. DOI: 10.1111/ pace.12452; PMID: 25060820. 35. Tarakji KG, Wilkoff BL. Management of cardiac implantable electronic device infections: the challenges of understanding the scope of the problem and its associated mortality. Expert Rev Cardiovasc Ther 2013;11:607–16. DOI: 10.1586/erc.12.190; PMID: 23621142. 36. Rundstrom H, Kennergren C, Andersson R, et al. Pacemaker endocarditis during 18 years in Göteborg. Scand J Infect Dis 2004;36:674–9. PMID: 15370655. 37. Madhavan M, Sohail MR, Friedman PA, et al. Outcomes in patients with cardiovascular implantable electronic devices and bacteremia caused by Gram-positive cocci other than Staphylococcus aureus. Circ Arrhythm Electrophysiol 2010;3:639–45. DOI: 10.1161/CIRCEP.110.957514; PMID: 20852296. 38. Sarrazin JF, Philippon F, Tessier M, et al. Usefulness of fluorine-18 positron emission tomography/computed tomography for identification of cardiovascular implantable electronic device infections. J Am Coll Cardiol 2012;59:1616–25. DOI: 10.1016/j.jacc.2011.11.059; PMID: 22538331. 39. Ahmed FZ, James J, Cunnington C, et al. Early diagnosis of cardiac implantable electronic device generator pocket infection using (1)(8)F-FDG-PET/CT. Eur Heart J Cardiovasc Imaging 2015;16:521–30. DOI: 10.1093/ehjci/jeu295. Epub 2015 Feb 3; PMID: 25651856. PMCID: PMC4407104. 40. Sohail MR, Sultan OW, Raza SS. Contemporary management of cardiovascular implantable electronic device infections. Expert Rev Anti Infect Ther 2010;8:831–9. DOI: 10.1586/eri.10.54; PMID: 20586567. 41. Wilkoff BL, Love CJ, Byrd CL, et al. Transvenous lead extraction: Heart Rhythm Society expert consensus on facilities, training, indications, and patient management. Heart Rhythm 2009;6:1085–104. DOI: 10.1016/j. hrthm.2009.05.020; PMID: 19560098. 42. Deharo JC, Bongiorni MG, Rozkovec A, et al. Pathways for training and accreditation for transvenous lead extraction: a European Heart Rhythm Association position paper. Europace

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