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Arrhythmia & Electrophysiology Review Volume 7 • Issue 1 • Spring 2018

Volume 7 • Issue 1 • Spring 2018

www.AERjournal.com

Unmissable Electrophysiology Papers from 2017, Compiled by the Editors Demosthenes Katritsis, Andrew Grace, Angelo Auricchio, Karl-Heinz Kuck

Non-invasive Cardiac Radiation for Ablation of Ventricular Tachycardia: a New Therapeutic Paradigm in Electrophysiology Eun-Jeong Kim, Giovanni Davogustto, William G Stevenson and Roy M John

Systematic Screening for Atrial Fibrillation in the Community: Evidence and Obstacles Ngai-Yin Chan

The Significance of Drug–Drug and Drug–Food Interactions of Oral Anticoagulation Pascal Vranckx, Marco Valgimigli and Hein Heidbuchel

Techniques for Preventing Oesophageal Injury During Ablation

Managing Arrhythmias in Patients with Pulmonary Hypertension

Isolating Inferior Pulmonary Veins for Cryoballoon Ablation

ISSN – 2050-3369

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Volume 7 • Issue 1 • Spring 2018

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

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

Carsten W Israel

Carlo Pappone

Lankenau Institute for Medical Research, Wynnewood, USA

JW Goethe University, Germany

IRCCS Policlinico San Donato, Milan, Italy

Carina Blomström-Lundqvist

Warren Jackman

Uppsala University, Uppsala, Sweden

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

Sunny Po

Johannes Brachmann Klinikum Coburg, II Med Klinik, Germany

Pierre Jaïs

Pedro Brugada

University of Bordeaux, CHU Bordeaux, France

University of Brussels, UZ-Brussel-VUB, Belgium

Josef Kautzner

Josep Brugada,

Institute for Clinical and Experimental Medicine, Prague, Czech Republic

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

Alfred Buxton

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

Beth Israel Deaconess Medical Center, Boston, USA

Samuel Lévy

Hugh Calkins

Aix-Marseille University, France

John Hopkins Medical Institution, Baltimore, USA

Cecilia Linde

David J Callans

Karolinska University, Stockholm, Sweden

University of Pennsylvania, Philadelphia, USA

Gregory YH Lip

A John Camm

University of Birmingham, UK

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

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

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

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

Richard Schilling Barts Health NHS Trust, London, UK

William Stevenson Vanderbilt School of Medicine, USA

Richard Sutton

St George’s University of London, UK

Francis Marchlinski

Riccardo Cappato

University of Pennsylvania Health System, Philadelphia, USA

IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy

John Miller

Ken Ellenbogen

Indiana University School of Medicine, USA

National Heart and Lung Institute, Imperial College London, UK

Panos Vardas Heraklion University Hospital, Greece

Marc A Vos

Virginia Commonwealth University, Richmond, VA, USA

Fred Morady

Sabine Ernst

Cardiovascular Center, University of Michigan, USA

University Medical Center Utrecht, The Netherlands

Royal Brompton and Harefield NHS Foundation Trust, London, UK

Sanjiv M Narayan

Hein Wellens

Stanford University Medical Center, USA

University of Maastricht, The Netherlands

Hein Heidbuchel

Andrea Natale

Katja Zeppenfeld

Antwerp University and University Hospital, Antwerp, Belgium

Austin, Texas

Leiden University Medical Center, The Netherlands

Gerhard Hindricks

Mark O’Neill

Douglas P Zipes

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

University of Leipzig, Germany

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

Junior Associate Editor Dr Afzal Sohaib Imperial College London, UK Managing Editor Rita Som • Production Helena Clements • Design Tatiana Losinska Sales & Marketing Executive William Cadden • New Business & Partnership Director Rob Barclay Publishing Director Leiah Norcott • Commercial Director David Bradbury Chief Executive Officer David Ramsey • Chief Operating Officer Liam O'Neill •

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Editorial Contact Rita Som rita.som@radcliffecardiology.com Circulation & Commercial Contact David Ramsey david.ramsey@radcliffecardiology.com •

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Lifelong Learning for Cardiovascular Professionals Published by Radcliffe Cardiology. All information obtained by Radcliffe Cardiology and each of the contributors from various sources is as current and accurate as possible. However, due to human or mechanical errors, Radcliffe Cardiology and the contributors cannot guarantee the accuracy, adequacy or completeness of any information, and cannot be held responsible for any errors or omissions, or for the results obtained from the use 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 © 2018 All rights reserved ISSN: 2050-3369 • eISSN: 2050–3377 © RADCLIFFE CARDIOLOGY 2018

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Established: October 2012

Aims and Scope •  Arrhythmia & Electrophysiology Review aims to assist time-pressured physicians to keep abreast of key advances and opinion in the arrhythmia and electrophysiology sphere. •  Arrhythmia & Electrophysiology Review comprises balanced and comprehensive articles written by leading authorities, addressing the most pertinent developments in the field. •  Arrhythmia & Electrophysiology Review provides comprehensive updates on a range of salient issues to support physicians in continuously developing their knowledge and effectiveness in day-to-day clinical practice. • The journal endeavours, through its timely teaching reviews, to support the continuous medical education of both specialist and general cardiologists, and disseminate knowledge of the field to the wider cardiovascular community.

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

Frequency: Quarterly

Current Issue: Spring 2018

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

Submissions and Instructions to Authors • Contributors are identified by the Editor-in-Chief with the support of the Section Editors and Managing Editor, and guidance from the Editorial Board. •  Following acceptance of an invitation, the author(s) and Managing Editor, in conjunction with the Editor-in-Chief, formalise the working title and scope of the article. • Subsequently, the Managing Editor provides an ‘Instructions to Authors’ document and additional submission details. •  The journal is always keen to hear from leading authorities wishing to discuss potential submissions, and will give due consideration to any proposals. Please contact the 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 Editorial Expertise Arrhythmia & Electrophysiology Review is supported by various levels of expertise: • Overall direction from an Editor-in-Chief, supported by Section Editors and an Editorial Board comprising leading authorities from a variety of related disciplines. • Invited contributors who are recognised authorities in their respective fields. • Peer review – conducted by members of the journal’s Peer Review Board as well as other experts appointed for their experience and knowledge of a specific topic. • An experienced team of Editors and Technical Editors.

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

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

Copyright and Permission Peer Review • On submission, all articles are assessed by the Editor-in-Chief or Managing Editor to determine their suitability for inclusion. •  The Managing Editor, following consultation with the Editor-in-Chief, Section Editors and/or a member of the Editorial Board, sends the manuscript to members of the Peer Review Board, who are selected on the basis of their specialist knowledge in the relevant area. All peer review is conducted double-blind. • Following review, manuscripts are either accepted without modification, accepted pending modification, in which case the manuscripts are returned to the author(s) to incorporate required changes, or rejected outright. The Editor-in-Chief reserves the right to accept or reject any proposed amendments.

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

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

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

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

www.AERjournal.com

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

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

www.ECRjournal.com

Resistant Hypertension: A Real Entity Requiring Special Treatment? Stefano Taddei and Rosa Maria Bruno

Advances in Cardiovascular MRI using Quantitative Tissue Characterisation Techniques: Focus on Myocarditis US Cardiology Review

Rocio Hinojar, Eike Nagel and Valentina O Puntmann

Role of the Thyroid System in the Dynamic Complex Network of Cardioprotection Alessandro Pingitore, Giorgio Iervasi and Francesca Forini www.ICRjournal.com

Volume 13 • Issue 1 • Spring 2018

Atrial Fibrillation, Cognitive Decline and Dementia

Volume 12 • Issue 1 • Spring 2018

Interventional Cardiology Review Volume 13 • Issue 1 • Spring 2018

European Cardiology Review Volume 11 • Issue 1 • Summer 2016

Volume 11 • Issue 1 • Summer 2016

Alvaro Alonso and Antonio P Arenas de Larriva

Minimally Invasive Surgical Mitral Valve Repair: State of the Art Review Alexander Meyer,D Axel Unbehaun, A Karel M Van Praet, Christof B Stamm, Simon H Sündermann, C Matteo Montagner, Timo Z Nazari Shafti, Stephan Jacobs, Volkmar Falk and Jörg Kempfert

Transcatheter Treatment of Functional Tricuspid Regurgitation Using the Trialign Device

Artery

Christian Besler, Christopher U Meduri and Philipp Lurz

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Is Complete Revascularisation Mandated for all Patients with Multivessel F G H Coronary Artery Disease?

Understanding Neurologic Complications Following TAVR Mohammed Imran Ghare and Alexandra Lansky

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T1 mapping using the modified look-locker sequence

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Fulminant Myocarditis: A Review of the Current Literature

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Interventional Echocardiography: Field of Advanced Imaging to Support Structural Heart Interventions

Smooth muscle cell

Roy Arjoon, MD, Ashley Brogan, MD, and Lissa Sugeng, MD, MPH

Pericyte

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Catheter Ablation for Ventricular Tachycardia in Patients with Structural Heart Disease

Pericyte-derived MSC

Timothy M Markman, MD Daniel A McBride, MD and Jackson J Liang, DO

Collagen

Carlo De Innocentiis, Marco Zimarino and Raffaele De Caterina

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Recognition, Diagnosis, and Management of Heart Failure with Preserved Ejection Fraction

Emily Seif, MD, Leway Chen, MD, MPH, and Bruce Goldman, MD

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Origin of potential stem cells

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Baseline Appearance of 23 mm Magna BPV after Deployment of 26 mm Medtronic Evolut R THV

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Transcatheter Treatment of Severe Tricuspid Regurgitation With the Trialign Device

Heart valve surgery for removing expandable transcatheter aortic valve implantation

Anatomic location and sensing vectors of the subcutaneous implantable cardioverterdefibrillator system

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Contents

Foreword

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“What Cannot be Missed”: a New Service of Arrhythmia and Electrophysiology Review Demosthenes Katritsis, Editor-in-Chief Hygeia Hospital, Athens, Greece

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Unmissable EP Papers Demosthenes Katritsis, Editor-in-Chief, AER, Hygeia Hospital, Athens, Greece Andrew Grace, Section Editor – Arrhythmia Mechanisms/ Basic Science, AER, University of Cambridge, UK Angelo Auricchio, Section Editor – Implantable Devices, AER, Fondazione Cardiocentro Ticino, Lugano, Switzerland Karl-Heinz Kuck, Section Editor – Clinical Electrophysiology and Ablation, AER, Asklepios Klinik St Georg, Hamburg, Germany

Expert Opinions

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Non-invasive Cardiac Radiation for Ablation of Ventricular Tachycardia: a New Therapeutic Paradigm in Electrophysiology Eun-Jeong Kim,* Giovanni Davogustto,* William G Stevenson and Roy M John Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA *Both authors contributed equally to this work

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Practical Techniques in Cryoballoon Ablation: How to Isolate Inferior Pulmonary Veins Shaojie Chen, Boris Schmidt, Stefano Bordignon, Fabrizio Bologna, Takahiko Nagase, Laura Perrotta and K R Julian Chun Cardioangiologisches Centrum Bethanien (CBC), Medical Clinic III, Frankfurt am Main, Germany

Electrophysiology and Ablation

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How to Prevent, Detect and Manage Complications Caused by Cryoballoon Ablation of Atrial Fibrillation Nitin Kulkarni1, Wilber Su2 and Richard Wu1 1. University of Texas Southwestern Medical Center, Dallas, TX, USA; 2. Banner University Medical Center, University of Arizona, Phoenix, AZ, USA

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Oesophageal Injury During AF Ablation: Techniques for Prevention Jorge Romero,1 Ricardo Avendano,1 Michael Grushko,1 Juan Carlos Diaz,1 Xianfeng Du,2 Carola Gianni,3 Andrea Natale1,3 and Luigi Di Biase1,3 1. Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, USA; 2. Department of Cardiology, Ningbo First Hospital, Zhejiang Sheng, China; 3. Texas Cardiac Arrhythmia Institute, St David’s Medical Center, Austin, USA

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Asymptomatic Ventricular Pre-excitation: Between Sudden Cardiac Death and Catheter Ablation Josep Brugada1 and Roberto Keegan2 1. Cardiovascular Institute, Hospital Clinic and Paediatric Arrhythmia Unit, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain; 2. Electrophysiology Service, Private Hospital of the South, Bahia Blanca, Argentina

Clinical Arrhythmias

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Systematic Screening for Atrial Fibrillation in the Community: Evidence and Obstacles Ngai-Yin Chan Department of Medicine and Geriatrics, Princess Margaret Hospital, Hong Kong, China

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Atrial Arrhythmias in Pulmonary Hypertension: Pathogenesis, Prognosis and Management Brett Wanamaker, Thomas Cascino, Vallerie McLaughlin, Hakan Oral, Rakesh Latchamsetty, Konstantinos C Siontis University of Michigan, Ann Arbor, MI, USA

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Drivers of Atrial Fibrillation: Theoretical Considerations and Practical Concerns Ian Mann, Belinda Sandler, Nick Linton and Prapa Kanagaratnam Imperial College Healthcare NHS Trust, London, UK

Drugs and Devices

55

The Significance of Drug–Drug and Drug–Food Interactions of Oral Anticoagulation Pascal Vranckx,1 Marco Valgimigli2 and Hein Heidbuchel3 1. Hartcentrum Hasselt, Faculty of Medicine and Life Sciences, Hasselt University, Hasselt, Belgium; 2. Swiss Cardiovascular Center Bern, Bern University Hospital, Bern, Switzerland; 3. Antwerp University and Antwerp University Hospital, Antwerp, Belgium

Letters

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Unravelling the Mysteries of the Human AV Node Maria Kokladi Athens Euroclinic, Athens, Greece

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The Risks of Electric Currents at Home Boghos L Artinian Private Practice, Salam Building, Beirut, Lebanon

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Hybrid Approach for Atrial Fibrillation Ablation: the Jury is Still Out Georgios Giannopoulos & Spyridon Deftereos Yale School of Medicine, New Haven, CT, USA

© RADCLIFFE CARDIOLOGY 2018

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Foreword

“What Cannot be Missed”: a New Service of Arrhythmia and Electrophysiology Review

P

revious editorials in Arrhythmia and Electrophysiology Review have discussed the impressive range of developments in electrophysiology, and the consequent revolutionary speed of dissemination of relevant information.1,2

Critical assessment of all this prolific production, and presentation of what is really clinically useful or scientifically unmissable, is a crucial task of the editors of every scientific journal. This is the very essence of existence for a review journal. The novel initiative of the Editors of Arrhythmia and Electrophysiology Review, “What Cannot Be Missed”, is aimed at serving the busy clinician in this particular context:

the most important papers on arrhythmia from the year past, as chosen by the section editors and myself, will be presented and discussed in a dedicated article. It is not our intention to present everything that is new. We intend to choose and present just what is necessary for practicing evidence-based medicine in the field of arrhythmias or what, in our opinion, delineates the future in basic science. Needless to say, this is not an enterprise restricted to the editors’ tastes. Editorial board members and readers of the journal are encouraged to write to the Editor expressing their preferences and choices in this respect. Opinions will be collected and considered throughout the year and the first full collection of what is vital compiled as this year draws to a close. Overleaf the editors and I present a list of the unmissable papers from 2017. The Editors of Arrhythmia and Electrophysiology Review look forward to receiving your valued opinions. n Demosthenes G Katritsis Editor-in-Chief, Arrhythmia and Electrophysiology Review Hygeia Hospital, Athens, Greece

1. 2.

Katritsis D. Clinical electrophysiology: a glimpse into the future. Arrhythm Electrophysiol Rev 2017;6:40. DOI: 10.15420/aer.2017:6:2:ED1; PMID: 28835833. Katritsis D. Time for practical clinical tools. Arrhythm Electrophysiol Rev 2017;6:103. DOI: 10.15420/AER.2017.6.3.FO1; PMID: 29018512.

DOI: 10.15420/aer.2018.7.1.FO1

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Foreword

Unmissable Papers, 2017 The most important papers on arrhythmias and electrophysiology published in 2017, selected by the editors of Arrhythmia and Electrophysiology Review (AER).

CLINICAL PRACTICE 1. Ortiz M, Martín A, Arribas F, et al. Randomized comparison of intravenous procainamide vs. intravenous amiodarone for the acute treatment of tolerated wide QRS tachycardia: the PROCAMIO study. Eur Heart J 2017;38:1329–35. DOI: 10.1093/ eurheartj/ehw230; PMID: 27354046. 2. Khan SU, Winnicka L, Saleem MA, et al. Amiodarone, lidocaine, magnesium or placebo in shock refractory ventricular arrhythmia: a Bayesian network meta-analysis. Heart Lung 2017;46:417–24. DOI: 10.1016/j.hrtlng.2017.09.001; PMID:28958592. 3. Mazzanti A, Maragna R, Vacanti G, et al. Hydroquinidine prevents life-threatening arrhythmic events in patients with short QT syndrome. J Am Coll Cardiol 2017;70:3010–5. DOI: 10.1016/j.jacc.2017.10.025; PMID: 29241489. 4. Boersma L, Barr C, Knops R, et al.; EFFORTLESS Investigator Group. Implant and midterm outcomes of the Subcutaneous Implantable Cardioverter-Defibrillator Registry: the EFFORTLESS study. J Am Coll Cardiol 2017;70:830–41. DOI: 10.1016/j. jacc.2017.06.040; PMID: 28797351. 5. Leyva F, Zegard A, Acquaye E, et al. Outcomes of cardiac resynchronization therapy with or without defibrillation in patients with nonischemic cardiomyopathy. J Am Coll Cardiol 2017;70:1216–27. DOI: 10.1016/j.jacc.2017.07.712; PMID: 28859784. 6. Al-Khatib SM, Gillis AM, Curtis AB. Centers for Medicare and Medicaid Services' decision to reconsider coverage indications for ICDs: where to now? Circulation 2018;137:317–9. DOI: 10.1161/CIRCULATIONAHA.117.031786; PMID: 29070501. 7. Bongiorni MG, Kennergren C, Butter C, et al.; ELECTRa Investigators. The European Lead Extraction ConTRolled (ELECTRa) study: a European Heart Rhythm Association (EHRA) registry of transvenous lead extraction outcomes. Eur Heart J 2017;38:2995–3005. PMID: 28369414. 8. Calkins H, Willems S, Gerstenfeld EP, et al.; RE-CIRCUIT Investigators. Uninterrupted dabigatran versus warfarin for ablation in atrial fibrillation. N Engl J Med 2017;376:1627–36. DOI: 10.1056/NEJMoa1701005; PMID: 28317415. 9. Kapel GF, Sacher F, Dekkers OM, et al. Arrhythmogenic anatomical isthmuses identified by electroanatomical mapping are the substrate for ventricular tachycardia in repaired Tetralogy of Fallot. Eur Heart J 2017;38:268–76.; PMID: 28182233. 10. Pappone C, Brugada J, Vicedomini G, et al. Electrical substrate elimination in 135 consecutive patients with Brugada syndrome. Circ Arrhythm Electrophysiol 2017;10:e005053. DOI: 10.1161/CIRCEP.117.005053; PMID: 28500178.

THE FUTURE 1. Cuculich PS, Schill MR, Kashani R, et al. Noninvasive cardiac radiation for ablation of ventricular tachycardia. N Engl J Med 2017;377:2325–36. DOI: 10.1056/NEJMoa1613773; PMID: 29236642. 2. Reddy VY, Miller MA, Neuzil P, et al. Cardiac resynchronization therapy with wireless left ventricular endocardial pacing: the SELECT-LV study. J Am Coll Cardiol 2017;69:2119–29. DOI: 10.1016/j.jacc.2017.02.059; PMID: 28449772. 3. Trayanova NA, Pashakhanloo F, Wu KC, Halperin HR. Imaging-based simulations for predicting sudden death and guiding ventricular tachycardia ablation. Circ Arrhythm Electrophysiol 2017;10:e004743. DOI: 10.1161/CIRCEP.117.004743; PMID: 28696219. 4. Baruscotti M, Bucchi A, Milanesi R, et al. A gain-of-function mutation in the cardiac pacemaker HCN4 channel increasing cAMP sensitivity is associated with familial inappropriate sinus tachycardia. Eur Heart J 2017;38:280–8. DOI: 10.1093/ eurheartj/ehv582; PMID: 28182231. 5. Chu M, Novak SM, Cover C, et al. Increased cardiac arrhythmogenesis associated with gap junction remodeling with upregulation of RNA-binding protein FXR1. Circulation 2018;137:605–18. DOI: 10.1161/CIRCULATIONAHA.117.028976; PMID: 29101288. Demosthenes Katritsis, Editor-in-Chief, AER, Hygeia Hospital, Athens, Greece Andrew Grace, Section Editor – Arrhythmia Mechanisms/ Basic Science, AER, University of Cambridge, UK Angelo Auricchio, Section Editor – Implantable Devices, AER, Fondazione Cardiocentro Ticino, Lugano, Switzerland Karl-Heinz Kuck, Section Editor – Clinical Electrophysiology and Ablation, AER, Asklepios Klinik St Georg, Hamburg, Germany

DOI: 10.15420/aer.2018.7.1.FO2

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Expert Opinion

Non-invasive Cardiac Radiation for Ablation of Ventricular Tachycardia: a New Therapeutic Paradigm in Electrophysiology Eun-Jeong Kim,* Giovanni Davogustto,* William G Stevenson and Roy M John Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA *Both authors contributed equally to this work

Abstract Non-invasive ablation of cardiac tissue to control ventricular tachycardia (VT) is a novel therapeutic consideration in the management of ventricular arrhythmias associated with structural heart disease. The technique involves the use of stereotactic radiotherapy delivered to VT substrates. Although invasive mapping can be used to identify the target, the use of non-invasive ECG and imaging techniques combined with multi-electrode body-surface ECG recordings offers the potential of a completely non-invasive approach. Early case series have demonstrated a consistent decrease in VT burden and sufficient early safety to allow more detailed multicenter studies. Such studies are currently in progress to further evaluate this promising technology.

Keywords Ventricular tachycardia, ablation, non-invasive, stereotactic body radiation therapy Disclosure: William Stevenson is coholder of a patent for the needle ablation electrode consigned to the Brigham and Women’s Hospital. Roy John has received lecture honoraria from Biosense Webster and Medtronic. Received: 13 February 2018 Accepted: 20 February 2018 Citation: Arrhythmia & Electrophysiology Review 2018;7(1):8–10. DOI: 10.15420/aer.7.1.EO1 Correspondence: Roy M John, MBBS, PhD, FRCP, Division of Cardiology, Department of Medicine, Vanderbilt University Medical Center, 2220 Pierce Avenue, 383 Preston Research Building, Nashville, TN 37232-6300, USA. E: roy.john@vanderbilt.edu

Myocardial scars from infarction or replacement fibrosis in nonischaemic cardiomyopathies are the common substrate for sustained monomorphic ventricular tachycardia (VT).1,2 In selected patients at high risk of ventricular arrhythmias, placement of an implantable cardioverter-defibrillator (ICD) is effective for prevention of sudden cardiac death.2 Although ICDs are effective in terminating VT and preventing sudden cardiac death, shocks from ICDs reduce quality of life, and multiple shocks are associated with post-traumatic stress disorder.3,4 Most importantly, ventricular arrhythmia episodes and ICD shocks are also associated with increased overall mortality and progression of HF, although the extent to which arrhythmia recurrences actually contribute to adverse outcomes versus being markers for deteriorating cardiac status is not clear.5 In any case, preventing sustained ventricular arrhythmia and associated ICD shocks is a major focus in the management of patients with ICDs. Both antiarrhythmic agents and catheter ablation have been used to reduce VT recurrences. A recent trial showed that VT ablation in patients with ischaemic cardiomyopathy reduced the composite outcome of death, VT storm and ICD shock compared with escalation of antiarrhythmic drug therapy.6 However, even in the catheter ablation group, more than half of patients had recurrent VT. Depending on the nature of the underlying heart disease, acute success rates in eliminating inducible VT range from 55–89 %, with VT recurrence rates ranging between 16–63 %.2 Catheter ablation for VT has limited efficacy when the VT substrate is not easily accessible due to deep intramural locations or when catheter access is precluded by the presence of mechanical valve prosthesis or intracavitary thrombus. Furthermore, its invasive nature and potential complications make it less attractive for patients with multiple comorbidities and haemodynamic

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compromise. A relatively non-invasive technique to ablate defined areas of myocardium involved in arrhythmogenesis has appeal if it can be shown to be safe and effective. Early feasibility studies of single-fraction stereotactic body radiotherapy have demonstrated encouraging results.7 VT substrates for such focussed radiotherapy can potentially be identified using imaging techniques that incorporate electrophysiological data.

Stereotactic Body Radiation Therapy: Basic Concepts and Applications Stereotactic radiotherapy involves directing highly focused external beam radiation therapy to target a well-defined and demarcated volume of tissue.8 Its use was first described to treat brain tumours with the goal of delivering a high therapeutic dose to the lesion of interest while minimising radiation to the surrounding normal tissue.9 The application of this technology to other organs in the body was initially limited by physiological motion and difficulties in accurate targeting.10 However, with advances in imaging, gating, tracking and intensity modulation, the use of stereotactic radiation has been expanded to other organs, and is now referred to as stereotactic body radiation therapy (SBRT).11 Megavoltage photons and protons can be used for SBRT, and during irradiation, multiple static beams or rotational beams are generally oriented to an isocentre. The key requirements of SBRT are accurate target delineation and motion compensation strategies.10,11 Accurate target delineation requires use of advanced imaging strategies that allow differentiating healthy from affected tissue. Motion compensation can be achieved with: • d  ampening/inhibition, which aims to limit respiratory motion using abdominal compression or breath-hold manoeuvres;

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Non-invasive Ablation of Ventricular Tachycardia • g ating, which follows the respiratory cycle to deliver radiation during a specific segment of this cycle; or •  tracking systems, which move the radiation beam to follow a moving target.12 SBRT has emerged as standard therapy for early stage lung cancer, as well as for localised prostate cancer and primary pancreas, liver, kidney and breast cancer, as well as for limited metastatic disease.12,13 Its extension to cardiac tissue came with the recognition that stereotactic therapy gated to cardiac motion can effectively treat defined volumes in the heart. SBRT for cardiac arrhythmias is termed stereotactic arrhythmia radioablation (STAR). In experimental models, STAR (the CyberHeart system; CyberHeart Inc.) was used to create atrioventricular block, conduction block in the cavotricuspid isthmus and lesions in the veno-atrial junctions of the pulmonary veins.14 Unlike catheter-directed radiofrequency or cryoablation, in which tissue destruction is effected by thermal injury, radiotherapy uses gamma-rays or x-rays directed in high doses (typically 25–30 Gy) to a three-dimensional volume of target tissue. The radiobiology of SBRT remains to be completely characterised. The mechanism of tissue injury is likely multifactorial, being in part the consequence of double-strand breaks in DNA, leading to apoptosis, but also of vascular damage and ischaemic cell death. Unlike with catheter-based thermal injury, which produces immediate effects, the results of radiotherapy-related ablation can take days to months to manifest fully.14 In experimental studies of cardiac ablation, conduction block in ablated tissue was not seen until 30 days after therapy. Clinical effects in patients have been observed earlier, with a reduction in arrhythmia burden within days or weeks of therapy.7

Imaging the Arrhythmia Substrate In scar-related ventricular arrhythmias, the arrhythmia origin is usually related to the ventricular scar containing surviving myocyte bundles, or its border zones.15 The 12-lead morphology of a VT offers clues to its origin. Identification of myocardial scars can be achieved by the use of delayed enhanced MRI, nuclear perfusion imaging or even CT or echocardiographic identification of wall thinning or wall motion abnormality. However, the entire region of scar may not be participating in arrhythmogenesis. Conventionally, scar-related electrophysiology and definition of critical areas involved in re-entrant arrhythmias is obtained by invasive electro-anatomical mapping prior to catheterbased ablation. This can be done prior to radiotherapy, and the target defined by mapping can be used to construct the target volume for radiotherapy. An alternative, totally non-invasive approach uses MRI or CT to define the scar area, and then incorporating information obtained from the body-surface ECG to define the arrhythmia substrate. Multielectrode ECGs, referred to as body-surface mapping, can potentially refine the electrophysiological information beyond what can be inferred from the standard ECG.16

information of the CT, the specialised ECGI algorithm calculates unipolar epicardial electrograms projected onto the surface of the ventricles. From these projections, epicardial isochronal maps can be created. Electrogram amplitude, electrogram fractionation and late potentials, which are evidence of arrhythmia substrate and scar, can be detected and used to define potential ablation targets. The abnormal areas of myocardium defined by ECGI can be correlated with areas of scar identified with MRI and single-photon emission CT as well. When the ECGI recording is obtained during VT, the epicardial VT exit sites can be identified and used to formulate an ablation strategy. A limitation of this approach is that ECGI provides information largely about the epicardial depolarisation and repolarisation of the heart, but the arrhythmia substrate is often endocardial or intramural. However, endocardial substrate locations can likely be inferred from epicardial mapping data, although this is an area of continuing research.17

Stereotactic Radioablation for VT: Clinical Experience Early experience with the use of stereotactic radiotherapy as palliation for VT has been encouraging, but it should be noted that these reports are limited to very small numbers of patients.7,18,19 In the largest series, five patients with refractory VT who failed two antiarrhythmic drugs and had either at least one traditional invasive ablation procedure that failed or a contraindication to ablation procedures underwent non-invasive therapy for VT.7 Of these, four underwent a combined anatomical imaging study and non-invasive ECGI during VT induced by their implanted cardioverter-defibrillator. VT exit points were identified by ECGI and the target volume for radiotherapy defined based on the ECGI or previously defined electro-anatomic maps from prior EP studies. After mapping, simulation and planning, the patients received a single fraction of 25 Gy while awake (mean ablation time 14 minutes). Over 46 patient-months following a blanking period of 6  weeks, a marked reduction in total VT burden was noted in all patients compared with baseline. In addition to these dramatic reductions in VT, the short-term safety profile was encouraging.7 Mild inflammatory changes in the adjacent lung tissue was observed on CT scans and resolved on follow-up imaging at 12  months. One patient suffered a fatal stroke 3 weeks after treatment. This might have been related to AF and inability to anticoagulate, but a direct effect of SBRT cannot be excluded. The targeted volume of myocardium in this series ranged between 17 and 81 cc and was large enough to have demonstrated potential collateral damage, but in the 12  months of follow-up in the four surviving patients, there was no evidence for papillary muscle dysfunction, new conduction abnormalities or loss of left ventricular function. In addition, SBRT had no discernible adverse effects on the patients’ implanted cardiac defibrillators. These investigators have initiated a prospective phase I/II trial of SBRT in patients with VT who have failed standard therapies and have a 1-year survival below 20 % (ClinicalTrials.gov identifier: NCT02919618). A second trial, sponsored by CyberHeart Inc., will evaluate safety and efficacy in 10 patients with refractory VT (ClinicalTrials.gov identifier: NCT02661048).

Electrocardiographic Imaging Electrocardiographic imaging (ECGI) is a recently refined method of obtaining detailed electrophysiological information from the bodysurface recordings.16,17 Electrodes (n=256) incorporated into strips are applied to the torso of the patient, with CT markers attached to each electrode. A thoracic non-contrast gated CT scan is performed, which allows the distance between the heart and each electrode to be determined. Body-surface unipolar electrograms are recorded from the surface electrodes. From the electrograms and the anatomical

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The immediate attraction of non-invasive SBRT for VT ablation is its applicability to a wider patient population, particularly sicker patients with severe left ventricular dysfunction or mechanical prosthesis, and VT substrates that are not accessible to current methodologies.1 However, the limitations of non-invasive radioablation will need to be carefully considered. The long-term toxic effect of radiotherapy on the cardiac structures is well documented and derived from experiences with mantle field radiation for treatment of lymphomas.20

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Expert Opinion Damage to the coronary arteries, conduction system, valve structures, myocardium and pericardium can emerge years later. Its acute and chronic effects on thinned-out areas of myocardium is not known. Although SBRT is designed to minimise toxicity to adjacent structures, respiratory and cardiac motion increases the risk of offtarget delivery. This risk profile, while acceptable when SBRT is used as palliation, might be more concerning for patients who have longer survival. Secondly, identification of arrhythmia substrates in the nonischaemic cardiomyopathies is more challenging. Myocardial scars are often less confluent and distributed throughout the mid-myocardium or subepicardium, and localisation using invasive or non-invasive

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J ohn RM, Stevenson WG. Noninvasive ablation of ventricular tachycardia. N Engl J Med 2017;377:2388–90. DOI: 10.1056/ NEJMe1713245; PMID: 29236632. Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Heart Rhythm 2017; DOI: 10.1016/j.hrthm.2017.10.035; PMID: 29097320; epub ahead of press. Schron EB, Exner DV, Yao Q, et al. Quality of life in the antiarrhythmics versus implantable defibrillators trial: impact of therapy and influence of adverse symptoms and defibrillator shocks. Circulation 2002;105:589–94. DOI: 10.1161/ hc0502.103330; PMID: 11827924. Perini AP, Kutyifa V, Veazie P, et al. Effects of implantable cardioverter/defibrillator shock and antitachycardia pacing on anxiety and quality of life: a MADIT-RIT substudy. Am Heart J 2017;189:75–84. DOI: 10.1016/j.ahj.2017.03.009; PMID: 28625384. Poole JE, Johnson GW, Hellkamp AS, et al. Prognostic importance of defibrillator shocks in patients with heart failure. N Engl J Med 2008;359:1009–17. DOI: 10.1056/ NEJMoa071098; PMID: 18768944. Sapp JL, Wells GA, Parkash R, et al. Ventricular tachycardia ablation versus escalation of antiarrhythmic drugs. N Engl J Med 2016;375:111–21. DOI: 10.1056/NEJMoa1513614; PMID: 27149033. Cuculich PS, Schill MR, Kashani R, et al. Noninvasive cardiac

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techniques can prove difficult. Furthermore, arrhythmia substrates can occur in close proximity to the basal septum, where the conduction tissue is exposed to the risk of collateral damage. Finally, the delayed effect of SBRT makes it unsuitable for rapid control of ventricular arrhythmias, such as VT storms. Despite its limitations, non-invasive stereotactic radioablation has undoubtedly extended the therapeutic horizon for ventricular arrhythmias and clearly warrants further investigation. Until its safety and efficacy can be established in larger trials, there should be cautious optimism. n

radiation for ablation of ventricular tachycardia. N Engl J Med 2017;377:2325–36. DOI: 10.1056/NEJMoa1613773; PMID: 29236642. P otters L, Kavanagh B, Galvin JM, et al.; American Society for Therapeutic Radiology and Oncology; American College of Radiology. American Society for Therapeutic Radiology and Oncology (ASTRO) and American College of Radiology (ACR) practice guideline for the performance of stereotactic body radiation therapy. Int J Radiat Oncol Biol Phys 2010;76:326– 32. DOI: 10.1016/j.ijrobp.2009.09.042; PMID: 20117285. Leksell L. The stereotaxic method and radiosurgery of the brain. Acta Chir Scand 1951;102:316–9. PMID: 14914373. Timmerman RD, Herman J, Cho LC. Emergence of stereotactic body radiation therapy and its impact on current and future clinical practice. J Clin Oncol 2014;32:2847–54. DOI: 10.1200/ jco.2014.55.4675; PMID: 25113761. Lax I, Blomgren H, Näslund I, Svanström R. Stereotactic radiotherapy of malignancies in the abdomen. Methodological aspects. Acta Oncol 1994;33:677–83. PMID: 7946448. Timmerman RD, Kavanagh BD, Cho LC, et al. Stereotactic body radiation therapy in multiple organ sites. J Clin Oncol 2007;25:947–52. DOI: 10.1200/jco.2006.09.7469; PMID: 17350943. Folkert MR, Timmerman RD. Stereotactic ablative body radiosurgery (SABR) or stereotactic body radiation therapy (SBRT). Adv Drug Deliv Rev 2017;109:3–14. DOI: 10.1016/j. addr.2016.11.005; PMID: 27932046. Sharma A, Wong D, Weidlich G, et al. Noninvasive stereotactic radiosurgery (CyberHeart) for creation of ablation lesions in the atrium. Heart Rhythm 2010;7:802–10. DOI: 10.1016/j. hrthm.2010.02.010; PMID: 20156591.

15. A  liot EM, Stevenson WG, Almendral-Garrote JM, et al. EHRA/ HRS Expert Consensus on Catheter Ablation of Ventricular Arrhythmias: developed in a partnership with the European Heart Rhythm Association (EHRA), a Registered Branch of the European Society of Cardiology (ESC), and the Heart Rhythm Society (HRS); in collaboration with the American College of Cardiology (ACC) and the American Heart Association (AHA). Heart Rhythm 2009;6:886–933. DOI: 10.1016/j.hrthm.2009.04.030; PMID: 19467519. 16. Cuculich PS, Zhang J, Wang Y, et al. The electrophysiological cardiac ventricular substrate in patients after myocardial infarction: noninvasive characterization with electrocardiographic imaging. J Am Coll Cardiol 2011;58:1893– 902. DOI: 10.1016/j.jacc.2011.07.029; PMID: 22018301. 17. Rudy Y, Plonsey R. A comparison of volume conductor and source geometry effects on body surface and epicardial potentials. Circ Res 1980;46:283–91. PMID: 6444278. 18. Loo BW Jr, Soltys SG, Wang L, et al. Stereotactic ablative radiotherapy for the treatment of refractory cardiac ventricular arrhythmia. Circ Arrhythm Electrophysiol 2015;8: 748–50. DOI: 10.1161/circep.115.002765; PMID: 26082532. 19. Zei PC, Soltys S. Ablative radiotherapy as a noninvasive alternative to catheter ablation for cardiac arrhythmias. Curr Cardiol Rep 2017;19:79. DOI: 10.1007/s11886-017-0886-2; PMID: 28752279. 20. Yusuf SW, Sami S, Daher IN. Radiation-induced heart disease: a clinical update. Cardiol Res Pract 2011;2011:317659. DOI: 10.4061/2011/317659; PMID: 21403872.

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Expert Opinion

Practical Techniques in Cryoballoon Ablation: How to Isolate Inferior Pulmonary Veins Shaojie Chen, Boris Schmidt, Stefano Bordignon, Fabrizio Bologna, Takahiko Nagase, Laura Perrotta and K R Julian Chun Cardioangiologisches Centrum Bethanien (CBC), Medical Clinic III, Frankfurt, Germany

Abstract Catheter ablation is the most effective treatment option for patients suffering from symptomatic atrial fibrillation. Electrical isolation of the pulmonary veins is the procedural cornerstone. Point-by-point radiofrequency current energy ablation in combination with a 3D electro-anatomical mapping system is the established approach to ablation. In contrast, cryoballoon ablation uses a single-shot approach to facilitate pulmonary vein isolation. However, fixed cryoballoon diameters (28 mm or 23 mm) and non-balloon compliance can lead to technical difficulties in isolating variable pulmonary vein anatomies. This review focuses on key procedural aspects and illustrates practical techniques in cryoballoon pulmonary vein isolation to shorten the learning curve without compromising safety and efficacy. It has a special emphasis on inferior pulmonary veins.

Keywords Atrial fibrillation, catheter ablation, cryoballoon, cryoablation, technique Disclosure: The authors have no conflict of interests to declare. Received: 8 January 2018 Accepted: 21 February 2018 Citation: Arrhythmia & Electrophysiology Review 2018;7(1):11–7. DOI: 10.15420/aer.2018;1;2 Correspondence: Cardioangiologisches Centrum Bethanien (CCB), Frankfurt am Main, Medizinische Klinik III, Agaplesion Markus Krankenhaus, Wilhelm-Epstein Straße 4, 60431 Frankfurt, Germany; E: drsjchen@126.com; j.chun@ccb.de

Atrial fibrillation (AF) is the most common sustained tachyarrhythmia. Catheter ablation is the most effective treatment for AF, and pulmonary vein isolation (PVI) is the cornerstone of all AF ablation strategies. The use of a radiofrequency (RF) catheter in combination with a 3D electroanatomical mapping system is the most well established approach to AF ablation. However, manipulating a RF catheter to create continuous and effective circumferential lesions in a point-by-point fashion is challenging. Single-shot ablation systems have been developed to facilitate the ablation procedure. Of these, the cryoballoon (CB) ablation system has been investigated in the greatest depth. In recent years, balloon-based ablation has emerged as an encouraging alternative to RF ablation and is at least equivalent for PVI in patients with paroxysmal and persistent AF.1

Cryoablation in Atrial Fibrillation Cryoablation is a safe and effective approach for the treatment of AF with a high rate of durable PVI and favourable mid-to-long term freedom from AF.2–10 It has a single procedure one-year success rate in paroxysmal AF of >80 % in patients no longer taking antiarrhythmic drugs.2–10 A large multicentre ablation registry study from Germany showed that the overall rates of major complications were similar in cryoablation and RF.11 We compared the results of 3,000 RF and balloon PVI procedures for AF and found a significantly reduced risk of cardiac tamponade in balloon ablation; no cardiac tamponade was observed in the cryoablation group.12 Different CB ablation techniques have been introduced – particularly for inferior pulmonary veins (PVs) – that aim to achieve acute PVI.3 These techniques are increasingly being utilised in different centres. The recent multicentre randomised Cryoballoon or Radiofrequency Ablation for Paroxysmal Atrial Fibrillation (FIRE AND ICE) trial aimed to determine whether CB ablation was non-inferior to RF ablation

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in symptomatic patients with drug-refractory paroxysmal AF. After a mean 1.5 years of follow-up, the CB and RF groups had similar success rates and safety profiles. The results confirmed the comparable role of CB in PVI as an alternative to conventional RF ablation for paroxysmal AF.13 In a previous study with long-term follow up, success rate of 61.6 % was reported at median follow-up of 30 months in a group of 605 AF patients (579 with paroxysmal AF) who had undergone a single cryoablation procedure and were off antiarrhythmic drugs.14

Preparing the Patient for Ablation In this review, we discuss current best practice and describe our centre´s procedural techniques using the CB ablation system for PVI, with a special emphasis on inferior PVs. The CB ablation system consists of a 15F steerable sheath (FlexCath™, Medtronic) and the CB, which is available in two different but fixed sizes (28 mm and 23 mm). The console delivers liquid N2O into the balloon. An intraluminal-mapping catheter (eight poles, 15 mm and 20 mm, Achieve™, Medtronic) serves as a guide wire along with PV mapping during CB ablation. The patient is asked to actively swallow an oesophageal temperature probe. Deep sedation is then induced using boluses of midazolam and a continuous infusion of propofol (1 %). Vital parameters, such as non-invasive blood pressure and oxygen saturation, are constantly monitored. For CB PVI procedures, we perform two right-sided venous punctures: one for the transseptal sheath and one to introduce a steerable diagnostic multipolar catheter that is subsequently positioned in the coronary sinus and superior vena cava for phrenic nerve (PN) stimulation.

Transseptal Puncture Transseptal puncture is performed using a standard needle via a standard sheath. The transseptal needle is connected with a

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Expert Opinion Figure 1: Selective Pulmonary Vein Angiography and Sequence of Cryoablation

Practical Techniques for Cryoballoon Ablation of Inferior Pulmonary Veins After a single transseptal puncture, selective PV angiographies are performed (using a 6F multipurpose catheter) to determine the PV and atrial anatomy. PV angiographies are performed using standardised angulations: right anterior oblique (RAO) 30° and left anterior oblique (LAO) 40°. Typically, the CB ablation follows a clockwise sequence: left superior PV (LSPV) then left inferior PV (LIPV), followed by RIPV and finally right superior PV (RSPV), see Figure 1. The rationale for this ablation sequence is discussed below.

Identification of LIPV and RIPV

(1, 3 and 4) 30°. (2) 40°. CS = coronary sinus; LAO = left anterior oblique; LIPV = left inferior pulmonary vein; LSPV = left superior pulmonary vein (LSPV); RAO = right anterior oblique; RIPV = right inferior pulmonary vein; RSVP = right superior pulmonary vein.

Figure 2: Cryoballoon Ablation of the Right Inferior Pulmonary Vein using the Direct Approach

Typically, inferior PVs are located posterior to superior PVs.15 Therefore, after LSPV ablation the steerable sheath is curved and rotated in a clockwise fashion in a posterior direction based on the baseline LIPV angiogram in left anterior oblique 40°. The intraluminal Achieve catheter should be advanced to intubate the LIPV while continuously analysing local electrical information. This mapping strategy can help safely navigate through the left atrium (LA). After LIPV isolation, the CB should be pulled back into the sheath while the Achieve catheter remains in the LA and protecting the sheath. Again, clockwise rotation and curving of the sheath based on the RIPV angiogram (RAO 30°) should result in identification of the RIPV.

Ablation Techniques In principle there are four different CB techniques that have been described: the direct approach, the hockey stick approach, pull-down and pull away.

Direct Approach If the CB directly occludes the PV ostium, we use the term ‘direct approach’. This manoeuvre is typically used for LSPV and RSPV. It may be considered for selected RIPVs, see Figure 2. However, based on our experience this approach should not be the first choice for inferior PVs.

Hockey Stick and Pull-down

RAO 30 = right anterior oblique 30°; RIPV = right inferior pulmonary vein.

pressure monitor. We recommend a low and relatively anterior transseptal puncture as it offers greater mechanical advantages for the CB and Achieve mapping catheter when accessing PVs. Such a puncture allows more space for the CB to be rotated posteriorly to the right inferior PV (RIPV). A low puncture location can also improve balloon contact with inferior aspects of the inferior PV. Fluoroscopy and pressure monitoring are used to assist the transseptal puncture procedure. In difficult transseptal cases, use of transoesophageal echocardiography or intracardiac echocardiography is recommended.

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The so-called hockey stick alone or in combination with a pulldown manoeuvre is commonly used in LIPV and RIPV. A careful PV angiogram is required and the most caudal branch of the inferior PV should be wired with the spiral mapping catheter. After CB inflation, the sheath should be curved down and pushed up, with the bending point at the LA roof. The CB should then be advanced to improve contact with the inferior aspect of the inferior PV, resulting in a hockey stick figure on fluoroscopy, see Figure 3. Importantly, the CB should not slide into a distal PV position. The orientation of the steerable sheath should be aligned with the course of the spiral catheter; this may require a second look at the corresponding fluoroscopic angulation, see Figure 4. We also advance the steerable sheath to the proximal part of the CB to minimise potential CB and sheath dislocation, see Figure 4B. After optimal CB positioning, we carefully flip back the spiral catheter to increase PV signal visualisation without compromising the CB position. If an inferior gap remains, we combine the hockey stick with a pulldown manoeuvre (CB and sheath) after 60 seconds. At this point in time, the CB is frozen to the superior aspect of the inferior PV and a typical response consists of an additional CB temperature drop. During freezing, the CB temperature profile is carefully monitored. If such a sequential PV occlusion has been achieved by the pull-down manoeuvre, PVI is

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Practical Techniques in Cryoballoon Ablation Figure 3: Dynamic Manoeuvring During the Hockey Stick Technique in the Left Inferior Pulmonary Vein

LAO 40 = left anterior oblique 40°; LIPV = left inferior pulmonary vein; PN = phrenic nerve.

expected to occur within the next 20 seconds, see Figure 5. However, if neither a temperature drop nor PVI occurs, freezing should be terminated and a different CB position obtained. The pull-down technique can also be combined with the direct approach for superior and inferior PVs.

Figure 4: Cross-checking Pulmonary Vein Occlusion During the Hockey Stick Manoeuvre

Pull Away The so-called pull away manoeuvre should be considered whenever the operator suspects an increased risk of PN palsy due to a short distance between the CB and the PN.16 Typically, during the initial phase of a freeze the CB is pushed towards the PV ostium. This may result in a distorted LA anatomy, thereby reducing the distance between the CB and the PN. Therefore, during CB freezing of RIPV or RSPV, the CB may be pulled away after about 60 seconds based on the idea of increasing the distance between the CB and the potential course of the PN.

Optimal CB Ablation/Dosing Parameters that may be associated with effective CB lesions include PV occlusion, CB temperature profile, time to PVI and duration of freezing. CB freezing times can vary from 2 to 5 minutes per freezing cycle. A standard freeze duration of 4 minutes was utilised in the Clinical Study of the Arctic Front Cryoablation Balloon for the Treatment of Paroxysmal Atrial Fibrillation (STOP-AF) using a first-generation CB.17 In the FIRE AND ICE trial, an empiric 4-minute bonus freeze was applied to all PVs after acute PVI. Since the advent of the second-generation CB, a reduction in the duration of freezing to 3 minutes has been suggested. Investigators reported an 80 % success rate with 3 minutes of freezing in 143 patients in a single arm, non-controlled study.9

(A) Right anterior oblique 30°. (B) Left anterior oblique 40°. CS = coronary sinus; LIPV = left inferior pulmonary vein.

Real-time Pulmonary Vein Isolation Recently, Wei and colleagues assessed real-time PV potential recordings during cryoablation in 180 AF patients. Real-time assessment of PV disconnection was achieved in 85.9 % of PVs.19 The third-generation CB with a short tip has been developed to improve the visualisation of real-time PVI recording; the rate of real-time PVI recording during cryoablation ranges from 74  % to 89.2  % in third-generation CB studies.20–23 In the ICE-T trial using second-generation CBs, real-time PVI was recorded in 80 % of PVs.18

Safety In the prospective randomised Individualised Cryoballoon Energy Pulmonary Vein Isolation Guided by Real-time Pulmonary Vein Recordings (ICE-T) trial, which included 100 patients with paroxysmal AF, we studied the impact of time to PVI where the duration of freezing was 4 minutes. If the time to PVI was <75 seconds, patients did not receive an empiric bonus freeze. Interestingly, the ICE-T protocol was associated with significantly reduced CB ablations while preserving the favourable rhythm outcome after 12 months.18 Procedure-related complications were numerically reduced in the ICE-T arm. Therefore, the ICE-T concept (time to PVI <75 seconds during 4-minute freeze with no empiric bonus) has been adopted as our institutional standard for CB AF ablation.

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Phrenic Nerve Function Due to the anatomical proximity of the PN to the PVs (particularly the RSPV), CB ablation in the respective PVs can potentially lead to collateral PN injury. The incidence of transient right PN palsy as a complication of CB ablation of AF can reach around 20 % but persistent PN palsy remains uncommon, with a reported incidence 0–4  %.4-7,14 Most recently, Okishige and colleagues assessed left PN injury during cryoablation of the left PVs and reported transient and persistent left PN palsy rates of 6.5 % and 0.2 %, respectively.24 Before freezing, particularly for RSPV and RIPV, the PN should be paced at twice the capture threshold using a deflectable catheter

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Expert Opinion Figure 5: Pulmonary Vein Isolation using the Pull-down Technique

Image A and B show hockey stick plus pull-down maneuvre to isolate the LIPV. CS = coronary sinus; LAO 40 = left anterior oblique 40°; LIPV = left inferior pulmonary vein; PV = pulmonary vein.

Figure 6: Phrenic Nerve Palsy Monitored by Compound Motor Action Potential (CMAP)

CS = coronary sinus; PV = pulmonary vein. Modified from the Cardiolangiological Centre Bethanien Frankfurt CRYO database.

to monitor PN function. An optimal site for right PN capture is near the junction of the superior vena cava (SVC) and the right subclavian vein or the anterolateral portion of the SVC near the atrial–SVC

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junction. For left PN capture, the optimal pacing site is the left subclavian vein with a pacing output exceeding the threshold by 10–20 %. 24

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Practical Techniques in Cryoballoon Ablation PN function can be monitored via manual palpation to determine the strength of the diaphragmatic excursion during PN pacing or by monitoring the diaphragmatic compound motor action potential (CMAP) during PN pacing (sensitive, early detection). One study reported that combining CMAP and palpation can decrease the incidence of PN palsy to <1.5 %.25

Figure 7: Oesophageal Temperature Probe (A) and Monitor (B)

The concept of CMAP-guided ablation is relatively new. It has been demonstrated that a reduction in CMAP amplitude precedes diaphragmatic dysfunction.26 We recommend carefully monitoring both CMAP potential amplitude and diaphragmatic excursion (manual palpation). Observing CMAP has the added benefit that co-workers from the control room can assess the diaphragmatic muscle potential independently from the operator. An example of CMAP monitoring during cryoablation is shown in Figure 6. The CMAP is implemented using a modified ECG lead I technique. The right-arm surface ECG electrode is placed 5 cm above the xiphoid, and the left-arm surface ECG electrode is placed 16 cm from the xiphoid along the costal margin. A recent study suggested that a larger PV dimension was associated with an increased risk of PN injury.27 Data from our group demonstrated that persistent PN palsy occurred in 2.8 % of patients undergoing firstgeneration CB and 1.9 % of patients undergoing second-generation CB ablation. First- and second-generation CB ablation resulted in transient PN injury (with full recovery before discharge) in 5.9  % and 3.8  % of patients, respectively. Complete recovery of phrenic function occurred after 29 + 11 days in first-generation CB ablation and 259 + 137 days in second-generation CB ablation.28

Ablation Sequence We always perform CB ablation of the RIPV before the RSPV, see Figure 1. This sequence is based on the knowledge that CB RIPV ablation is associated with a lower risk of PN palsy as there is a greater distance to the PN. In addition, PVI typically precedes PN injury in the RSPV during CB ablation. Therefore, despite potential PN weakening at the RSPV, all four PVs can be isolated if the clockwise ablation sequence is selected.

CS = coronary sinus; ESO = oesophagus; LAO 40 = left anterior ascending 40°; SVC = superior vena cava.

Freezing Temperature It is important to monitor the CB temperature during the procedure. The operator should understand and determine when to terminate a freeze cycle. The temperature displayed on the CryoConsole™ (Medtronic) is not the tissue temperature but a return gas temperature measurement. The balloon–tissue interface temperature is typically −70 to −80°C, whereas the temperature on the CryoConsole often ranges between −40 and −50°C. A steep and rapid drop in temperature (<–40°C within 30 seconds) and nadir temperature of −55 to −65°C are potential indicators that the CB is in a deep PV position rather than an antral position. In this case, freezing should be terminated and the CB position re-confirmed. For inferior PV, the nadir temperature achieved is normally between −35 and −45°C. Typically, an additional temperature drop can be observed after the pull-down manoeuvre.

Oesophageal Temperature The temperature in the oesophagus should be constantly measured during CB ablation.29,30 The individual course of the oesophagus may not be predictable, but typically the region around the inferior PVs (LIPV) is

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the most common site for atrio-oesophageal fistula formation.29 A soft temperature probe, as shown in Figure 7, should be used with multiple thermocouples and a cut-off value of 15°C. This has been associated with a significantly reduced rate of post-ablation oesophageal lesions.30

Oesophageal Lesions and Atrio-oesophageal Fistulas CB ablation can extended beyond the LA posterior wall and increase the potential risk of damaging neighbouring structures, such as the oesophagus. A 12–19 % incidence of oesophageal lesions after second-generation CB ablation and a correlation between lesions and the lowest endoluminal oesophageal temperature during freezing have been reported.31 Although most oesophageal lesions are asymptomatic and resolve after ablation, in rare cases oesophageal damage may result in a fatal atrio-oesophageal fistula. John and colleagues reviewed all documented cases of atrio-oesophageal fistula associated with CB ablation and found that it was most commonly related to the LIPV.29 Monitoring of the luminal oesophageal temperature is therefore highly recommended, particularly during CB ablation of inferior PVs. A recent study from our group reported that interruption of CB ablation based

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Expert Opinion on endoluminal oesophageal temperature at a cut-off value of 15°C was associated with a very low (1.5 %) incidence of oesophageal injury.30 We recommend oesophageal temperature monitoring in CB cases and early termination of freezing whenever the oesophageal temperature drops to 15°C. We suggest that patients routinely receive 2 weeks of proton-pump inhibitors after cryoablation.

as the reason for haemoptysis. Erosion can also be detected during bronchoscopy.37–39 Based on the evidence, both the clinical symptoms and findings appear to be self-limiting, with gradual resolution over time. No evidence has shown that these cases have been associated with catastrophic complications, such as the formation of a fistula.

Advantages and Limitations Fluoroscopy and Procedure Times Mean fluoroscopy times reported from previous studies using secondgeneration CBs range from 13 to 29 minutes.7,32–34 In the FIRE AND ICE trial, the mean procedure time was shorter in the CB group than in the RF group (124 versus 141 minutes) and the mean total fluoroscopy time was shorter in the RF group than in the CB group (17 versus 22 minutes, p<0.001).13 In our recent ICE-T trial, the mean procedure time using the suggested techniques was 89±21 minutes and the fluoroscopy time was 12.7±5.5 minutes.18

PV Stenosis Matsuda and colleagues evaluated the PVs of AF patients before and after cryoablation using cardiac-enhanced multidetector CT technology. The study found that PV stenosis occurred in 2.5 % of all the PVs analysed and all the stenoses were classified as being minimal (<25 %) or mild (25–50 %). The PV stenoses characterised by CT imaging did not progress further during the extended follow-up period.35 Narui and colleagues studied the PVs of patients who underwent CB ablation for paroxysmal AF using contrast-enhanced CT both before and 3 months after the procedure. There were reductions in the dimensions of PVs with mild (25–50  %), moderate (50–75  %) and severe (≥75  %) values in 29.3  %, 4.7  %, and 1  % of the PVs analysed, respectively; a larger PV ostium and lower minimum freezing temperature during CB ablation were independently associated with PV narrowing.36

Haemoptysis and Lung Injury Haemoptysis has been reported following cryoablation of AF; however, it remains uncommon, with an incidence ranging between 0 and 2 %.37–39 Transient interruption of vascular integrity, perhaps within the pulmonary capillary system due to cryoinjury, has been postulated

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 chmidt B, Neuzil P, Luik A, et al. Laser balloon or S wide-area circumferential irrigated radiofrequency ablation for persistent atrial fibrillation: a multicenter prospective randomized study. Circ Arrhythm Electrophysiol 2017;10:pii:e005767. DOI: 10.1161/CIRCEP.117.005767; PMID: 29217521. Reddy VY, Sediva L, Petru J, et al. Durability of pulmonary vein isolation with cryoballoon ablation: results from the Sustained PV Isolation with Arctic Front Advance (SUPIR) study. J Cardiovasc Electrophysiol 2015;26:493–500. DOI: 10.1111/ jce.12626; PMID: 25644659. Chun KR, Schmidt B, Metzner A, et al. The ‘single big cryoballoon’ technique for acute pulmonary vein isolation in patients with paroxysmal atrial fibrillation: a prospective observational single centre study. Eur Heart J 2009;30:699–709. DOI: 10.1093/eurheartj/ehn570; PMID: 19109353. Aytemir K, Oto A, Canpolat U, et al. Immediate and mediumterm outcomes of cryoballoon-based pulmonary vein isolation in patients with paroxysmal and persistent atrial fibrillation: single-centre experience. J Interv Card Electrophysiol 2013;38:187–95. DOI: 10.1007/s10840-013-9834-2; PMID: 24113850.  Aryana A, Morkoch S, Bailey S, et al. Acute procedural and cryoballoon characteristics from cryoablation of atrial fibrillation using the first- and second-generation cryoballoon: a retrospective comparative study with follow-up outcomes. J Interv Card Electrophysiol 2014;41:177–86. DOI: 10.1007/ s10840-014-9942-7; PMID: 25227868.  Straube F, Dorwarth U, Schmidt M, et al. Comparison of the first and second cryoballoon: high-volume single-center safety and efficacy analysis. Circ Arrhythm Electrophysiol 2014;7:293–9. DOI: 10.1161/CIRCEP.113.000899; PMID: 24610739.  Fürnkranz A, Bordignon S, Dugo D, et al. Improved 1-year clinical success rate of pulmonary vein isolation with the

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Advantages of cryoablation for AF include: a homogenous and extended lesion; it is less arrhythmogenic; it enables real-time PV isolation without the need for a 3D mapping system; and it reduces the procedure time. Currently, cryoablation is limited to instances of nonPV trigger, additional substrate modification and special PV anatomies. A recent study reported using a CB catheter to achieve large-area atrial substrate modification in persistent and long-standing persistent AF. The success rate at 12 months was 71 % in patients with persistent AF and 55 % in patients with long-standing persistent AF.40 Akkaya and colleagues reported a 70.3  % success rate at 37 months in patients who had undergone PVI plus left atrial roof-line ablation using a CB.41 Patients with a left common pulmonary vein (LCPV) can be a challenge for PVI using CB technology due to the size of the CB. Antral level isolation of the LCPV ostium was achieved in half of the patients within the LCPV group in a recent trial; in patients where antral PVI could not be obtained, sequential isolation of the first superior and inferior PV branches was applied. The follow-up data showed comparable results with regard to clinical success and the durability of PVI in patients with or without LCPV.42

Summary CB PV isolation has been established in AF ablation. This review focuses on key procedural aspects and illustrates practical techniques in CB PVI to shorten the learning curve without compromising safety and efficacy, with special emphasis on inferior PVs. Specific CB manoeuvres and safety measures should be adopted for inferior PVs, thereby facilitating the endpoint of PVI. It should be mentioned that the techniques suggested in this paper are based on the procedural experience of a high-volume centre and further studies are warranted. n

second-generation cryoballoon in patients with paroxysmal atrial fibrillation. J Cardiovasc Electrophysiol 2014;25:840–4. DOI: 10.1111/jce.12417; PMID: 24654794. Metzner A, Reissmann B, Rausch P, et al. One-year clinical outcome after pulmonary vein isolation using the secondgeneration 28-mm cryoballoon. Circ Arrhythm Electrophysiol 2014;7:288–92. DOI: 10.1161/CIRCEP.114.001473; PMID: 24610797. Ciconte G, de Asmundis C, Sieira J, et al. Single 3-minute freeze for second-generation cryoballoon ablation: oneyear follow-up after pulmonary vein isolation. Heart Rhythm 2015;12:673–80. DOI: 10.1016/j.hrthm.2014.12.026; PMID: 25542427.  Aryana A, Singh SM, Kowalski M, et al. Acute and long-term outcomes of catheter ablation of atrial fibrillation using the second-generation cryoballoon versus open-irrigated radiofrequency: a multicenter experience. J Cardiovasc Electrophysiol 2015;26:832–9. DOI: 10.1111/jce.12695; PMID: 25917655.  Schmidt M, Dorwarth U, Andresen D, et al. Cryoballoon versus RF ablation in paroxysmal atrial fibrillation: results from the German Ablation Registry. J Cardiovasc Electrophysiol 2014;25:1–7. DOI: 10.1111/jce.12267; PMID: 24134539.  Chun KRJ, Perrotta L, Bordignon S, et al. Complications in catheter ablation of atrial fibrillation in 3,000 consecutive procedures: balloon versus radiofrequency current ablation. JACC: Clinical Electrophysiology 2017;3:154–61. DOI: 10.1016/j. jacep.2016.07.002. Kuck KH, Brugada J, Fürnkranz A, et al. FIRE AND ICE Investigators. Cryoballoon or radiofrequency ablation for paroxysmal atrial fibrillation. N Engl J Med 2016;374:2235–45. DOI: 10.1056/NEJMoa1602014; PMID: 27042964. Vogt J, Heintze J, Gutleben KJ, et al. G. Long-term outcomes after cryoballoon pulmonary vein isolation: results from

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a prospective study in 605 patients. J Am Coll Cardiol 2013;61:1707–12. DOI: 10.1016/j.jacc.2012.09.033; PMID: 23199518. Schmidt B, Ernst S, Ouyang F, et al. External and endoluminal analysis of left atrial anatomy and the pulmonary veins in three-dimensional reconstructions of magnetic resonance angiography: the full insight from inside. J Cardiovasc Electrophysiol 2006;17:957–64. DOI: 10.1111/j. 1540-8167.2006.00548.x; PMID: 16948739.  Martins RP, Hamon D, Césari O, et al. Safety and efficacy of a second-generation cryoballoon in the ablation of paroxysmal atrial fibrillation. Heart Rhythm 2014;11:386–93. DOI: 10.1016/j. hrthm.2014.01.002; PMID: 24389575. Packer DL, Kowal RC, Wheelan KR, et al. STOP AF Cryoablation Investigators. 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.  Chun KR, Stich M, Fürnkranz A, et al. Individualized cryoballoon energy pulmonary vein isolation guided by real-time pulmonary vein recordings, the randomized ICE-T trial. Heart Rhythm 2017;14:495–500. DOI: 10.1016/j. hrthm.2016.12.014; PMID: 27956248.  Wei HQ, Guo XG, Zhou GB, et al. Pulmonary vein isolation with real-time pulmonary vein potential recording using second-generation cryoballoon: Procedural and biophysical predictors of acute pulmonary vein reconnection. Pacing Clin Electrophysiol 2018;41:14–21. DOI: 10.1111/pace.13230; PMID: 29087000.  Heeger CH, Wissner E, Mathew S, et al. Short tip-big difference? First-in-man experience and procedural efficacy of pulmonary vein isolation using the third-generation cryoballoon. Clin Res Cardiol 2016;105:482–8. DOI: 10.1007/

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Practical Techniques in Cryoballoon Ablation

s00392-015-0944-y; PMID: 26608161. 21. M  ugnai G, de Asmundis C, Hünük B, et al. Improved visualisation of real-time recordings during third generation cryoballoon ablation: a comparison between the novel shorttip and the second generation device. J Interv Card Electrophysiol 2016;46:307–14. DOI: 10.1007/s10840-016-0114-9; PMID: 26873259. 22. Chierchia GB, Mugnai G, Ströker E, et al. Incidence of realtime recordings of pulmonary vein potentials using the thirdgeneration short-tip cryoballoon. Europace 2016;18:1158–63. DOI: 10.1093/europace/euv452; PMID: 26857185.  23. Aryana A, Kowalski M, O’Neill PG, et al. Cryo-DOSING Investigators. Catheter ablation using the third-generation cryoballoon provides an enhanced ability to assess time to pulmonary vein isolation facilitating the ablation strategy: Short- and long-term results of a multicenter study. Heart Rhythm 2016;13:2306–13. DOI: 10.1016/j.hrthm.2016.08.011; PMID: 27503480. 24. Okishige K, Aoyagi H, Nishimura T, et al. Left phrenic nerve injury during electrical isolation of left-sided pulmonary veins with the second-generation cryoballoon. Pacing Clin Electrophysiol 2017;40:1426–31. DOI: 10.1111/pace.13201; PMID: 28940496. 25. Mondésert B, Andrade JG, Khairy P, et al. Clinical experience with a novel electromyographic approach to preventing phrenic nerve injury during cryoballoon ablation in atrial fibrillation. Circ Arrhythm Electrophysiol 2014;7:605–11. DOI: 10.1161/CIRCEP.113.001238; PMID: 25017398. 26. Franceschi F, Dubuc M, Guerra PG, et al. Diaphragmatic electromyography during cryoballoon ablation: a novel concept in the prevention of phrenic nerve palsy. Heart Rhythm 2011;8:885–91. DOI: 10.1016/j.hrthm.2011.01.031; PMID: 21256978. 27. Ströker E, de Asmundis C, Saitoh Y, et al. Anatomic predictors of phrenic nerve injury in the setting of pulmonary vein isolation using the 28-mm second-generation cryoballoon. Heart Rhythm 2016;13:342–51. DOI: 10.1016/j.hrthm.2015.10.017;

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PMID: 26573972. 28. F  ürnkranz A, Bordignon S, Schmidt B, et al. Incidence and characteristics of phrenic nerve palsy following pulmonary vein isolation with the second-generation as compared with the first-generation cryoballoon in 360 consecutive patients. Europace 2015;17:574–8. DOI: 10.1093/europace/euu320; PMID: 25564551. 29. John RM, Kapur S, Ellenbogen KA, Koneru JN. Atrioesophageal fistula formation with cryoballoon ablation is most commonly related to the left inferior pulmonary vein. Heart Rhythm 2017;14:184–9. DOI: 10.1016/j.hrthm.2016.10.018; PMID: 27769853. 30. Fürnkranz A, Bordignon S, Böhmig M, et al. Reduced incidence of esophageal lesions by luminal esophageal temperature-guided second-generation cryoballoon ablation. Heart Rhythm 2015;12:268–74. DOI: 10.1016/j.hrthm.2014.10.033; PMID: 25446159. 31. Metzner A, Burchard A, Wohlmuth P, et al. Increased incidence of esophageal thermal lesions using the secondgeneration 28-mm cryoballoon. Circ Arrhythm Electrophysiol 2013;6:769–75. DOI: 10.1161/CIRCEP.113.000228; PMID: 23748208. 32. Fürnkranz A, Bordignon S, Schmidt B, et al. Improved procedural efficacy of pulmonary vein isolation using the novel second-generation cryoballoon. J Cardiovasc Electrophysiol 2013;24:492–7. DOI: 10.1111/jce.12082; PMID: 23398599. 33. Straube F, Dorwarth U, Schmidt M, et al. Comparison of the first and second cryoballoon: high-volume single-center safety and efficacy analysis. Circ Arrhythm Electrophysiol 2014;7:293–9. DOI: 10.1161/CIRCEP.113.000899; PMID: 24610739. 34. Conti S, Moltrasio M, Fassini G, et al. Comparison between first- and second-generation cryoballoon for paroxysmal atrial fibrillation ablation. Cardiol Res Pract 2016;2016:5106127. DOI: 10.1155/2016/5106127; PMID: 27069711. 35. Matsuda J, Miyazaki S, Nakamura H, et al. Pulmonary vein stenosis after second-generation cryoballoon ablation.

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J Cardiovasc Electrophysiol 2017;28:298–303. DOI: 10.1111/ jce.13155; PMID: 28032927. Narui R, Tokuda M, Matsushima M, et al. Incidence and factors associated with the occurrence of pulmonary vein narrowing after cryoballoon ablation. Circ Arrhythm Electrophysiol 2017;10:pii:e004588. DOI: 10.1161/ CIRCEP.116.004588; PMID: 28630168. Martí-Almor J, Jauregui-Abularach ME, Benito B, et al. Pulmonary hemorrhage after cryoballoon ablation for pulmonary vein isolation in the treatment of atrial fibrillation. Chest 2014;145:156–7. DOI: 10.1378/chest.13-0761; PMID: 24394827. Kumar N, Timmermans C, Das M, et al. Hemoptysis after cryoablation for atrial fibrillation: truth or just a myth? Chest 2014;146:e173–5. DOI: 10.1378/chest.14-1600; PMID: 25367491. Bhagwandien R, van Belle Y, de Groot N, Jordaens L. Hemoptysis after pulmonary vein isolation with a cryoballoon: an analysis of the potential etiology. J Cardiovasc Electrophysiol 2011;22:1067–9. DOI: 10.1111/j.1540-8167.2011.02031.x; PMID: 21352395. Su WW, Alzubaidi M, Tseng R, et al. Novel usage of the cryoballoon catheter to achieve large area atrial substrate modification in persistent and long-standing persistent atrial fibrillation. J Interv Card Electrophysiol 2016;46:275–85. DOI: 10.1007/s10840-016-0120-y; PMID: 26936265.  Akkaya E, Berkowitsch A, Zaltsberg S, et al. Secondgeneration cryoballoon ablation for treatment of persistent atrial fibrillation: Three-year outcome and predictors of recurrence after a single procedure. J Cardiovasc Electrophysiol 2018;29:38–45. DOI: 10.1111/jce.13372; PMID: 29064127. Heeger CH, Tscholl V, Wissner E, et al. Acute efficacy, safety, and long-term clinical outcomes using the second-generation cryoballoon for pulmonary vein isolation in patients with a left common pulmonary vein: A multicenter study. Heart Rhythm 2017;14:1111–8. DOI: 10.1016/j.hrthm.2017.05.003; PMID: 28495652. 

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Electrophysiology and Ablation

How to Prevent, Detect and Manage Complications Caused by Cryoballoon Ablation of Atrial Fibrillation Nitin Kulkarni 1 , Wilber Su 2 and Richard Wu 1 1. University of Texas Southwestern Medical Center, Dallas, TX, USA; 2. Banner University Medical Center, University of Arizona, Phoenix, AZ, USA

Abstract Atrial fibrillation is the most common cardiac arrhythmia and the prevalence is increasing every year. Patients who fail to maintain sinus rhythm with use of anti-arrhythmic drug therapy are referred for catheter ablation. Cryoballoon (CB) ablation has emerged as an effective and alternative treatment option to traditional point-by-point radiofrequency ablation, but there can be complications. This article reviews the incidence, presentation, risk factors, management and preventative strategies of three major complications associated with CB ablation: phrenic nerve injury, atrial oesophageal fistula and bronchial injury. Although these complications are rare, electrophysiologists should institute measures to identify high-risk patients, implement best-practice techniques to minimise risks and maintain a high index of suspicion to recognise the complications quickly and implement correct treatment strategies.

Keywords Atrial fibrillation, atrio-oesophageal fistula, bronchial injury, catheter ablation, cryoablation, cryoballoon, dosing, phrenic nerve injury Disclosure: Research, travel, and honorarium from Medtronic Inc. for Wilber Su and Richard Wu. Received: 20 September 2017 Accepted: 20 December 2017 Citation: Arrhythmia & Electrophysiology Review 2018;7(1):18–23 DOI: 10.15420/aer.2017.32.1 Correspondence: Richard Wu, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9047, USA. E: Richard.Wu@UTSouthwestern.edu

Atrial fibrillation (AF) is the most common cardiac arrhythmia and the prevalence is increasing every year; it is expected to affect 12 million Americans by the year 2030.1 A significant portion of patients fail to maintain sinus rhythm with use of anti-arrhythmic drug therapy and are referred for catheter ablation. Ablation is currently indicated for patients with paroxysmal (class I) or persistent (class IIa) AF who are intolerant or refractory to drug therapy.2 Cryoballoon (CB) ablation has emerged as an effective and alternative treatment option to traditional point-by-point radiofrequency (RF) ablation.3,4 In addition to the traditional major complications associated with AF ablation – stroke, cardiac tamponade and atrial oesophageal fistula (AEF) – CB ablation is also associated with phrenic nerve and bronchial injury. Knowledge of the close anatomical relationships between the pulmonary veins, the right phrenic nerve, oesophagus and the bronchial tree is critical to understanding why these structures are prone to collateral injury during CB ablation. Additionally, techniques to minimise the cryoablation dose, such as titration of freezing time utilising a time-toisolation (TTI) strategy, can also help minimise collateral damage and, therefore, complications. In this article, we review the incidence, presentation, risk factors, management and preventative strategies of three major complications associated with CB ablation: phrenic nerve injury (PNI), AEF and bronchial injury (Table 1, Table 2).

Phrenic Nerve Injury The incidence of PNI with CB ablation has decreased over the years, probably resulting from increased operator experience and improved techniques for early detection. In the STOP-AF trial, a randomised trial comparing drug therapy versus CB ablation utilising the first generation CB (Arctic FrontTM , Medtronic), the rate

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of PNI was noted to be 13.5 %. 5 In Freeze AF, a randomised control trial comparing first generation CB ablation versus radiofrequency ablation, 5.8 % of patients in the CB arm were noted to have phrenic nerve palsy and zero patients in the RF arm. In a single centre study of 500 consecutive patients from 2012 to 2015 who underwent CB ablation using the second generation CB, PNI was noted in 7.2 % of patients. 6 In more recently published data utilising contemporary techniques, rates of PNI appear to be lower. In the landmark FIRE AND ICE trial, in which both first and second generation CB (Arctic Front Advance TM , Medtronic) were used, 3.2  % of patients experienced PNI. 3 The anatomical relationship between the phrenic nerves and pulmonary vein anatomy is fundamental to pathogenesis of PNI. The left phrenic nerve courses anteriorly across the left atrial appendage during its descent to the diaphragm.7 The right phrenic nerve descends parallel along the anterolateral aspect of the superior vena cava, and then courses posteriorly in between the right pulmonary veins and the superior vena cava–right atrial junction. Histological studies have shown that there may be as few as 2.1 mm (±0.4) and 7.8 mm (±1.2) of distance between the right phrenic nerve and the anterior wall of the right superior pulmonary vein and the right inferior pulmonary vein, respectively.8 This close proximity accounts for why the PNI risk is highest during ablation of the right superior pulmonary vein. However, there are case reports of left PNI during CB ablation of the left superior pulmonary vein.9 Multiple risk factors have been associated with the development of PNI. The common theme among these risk factors is inadvertent deep seating of the CB, which has been shown to distort pulmonary vein anatomy leading to an even shorter distance between the vein and the phrenic nerve.10 These risk factors include:

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Complications of Cryoballoon Ablation Table 1: Overview of Cryoballoon Complications Complication

Incidence

Mechanism

Risk Factors

Phrenic nerve injury

3.2–13.5 %3,5,6

• Deep seating of CB in RSPV

• Distance between RSPV and right phrenic nerve • Larger ostial vein size • Circular shape pulmonary vein ostium rather than eccentric shape • Greater obtuse angle between RSPV and LA

Atrial oesophageal fistulae

0.016–0.03 %22,24,29,43

• Collateral injury of oesophagus during CB ablation • Continued oesophageal injury post ablation due to acid reflux and mechanical trauma

• Low body mass index • General anaesthesia • Low nadir luminal oesophageal temperature • Longer cumulative CB ablation time (multiple and/or longer freeze applications)

Bronchial injury

1.7–3.6 %49

• Deep seating of CB in LSPV • Collateral injury of left mainstem bronchus during CB ablation

• Low nadir balloon temperature

CB = cryoballoon; LA = left atrium; LSPV = left superior pulmonary vein; RSPV = right superior pulmonary vein.

• the distance between the right superior pulmonary vein and right phrenic nerve as assessed on pre-operative imaging;11 • larger ostial vein size;12,13 • a more circular shape pulmonary vein ostium rather than eccentric shaped ostium;12 and • an obtuse angle between the right superior pulmonary vein and left atrium (i.e. minimal angulation of the vein and left atrium).13 A vein with a large, circular-shaped ostium with an obtuse take off can inadvertently lead to a more deeply seated CB, and thus higher rates of PNI. Care should be taken to avoid deep seating of the CB by noting the position of the balloon relative to the cardiac silhouette – a greater portion of the CB lying outside the cardiac shadow has been associated with higher rates of PNI.14 Multiple methods for phrenic nerve monitoring during CB ablation have been published.15–19 It is imperative that the patient not be under any paralytics during this portion of CB ablation. All methods use a pacing catheter to capture the phrenic nerve cranial to the site of CB ablation. Although any catheter can be used, our institution uses a deflectable multipolar catheter placed at the right brachiocephalic vein and superior vena cava junction paced at a cycle length between 1 and 2 seconds at twice the capture threshold. It is important to maintain stable catheter position since loss of capture can be mistaken as PNI during CB ablation. During phrenic pacing, various techniques have been described to assess for impending PNI. These can be classified as a qualitative or quantitative methods. The most common qualitative method used is palpation of diaphragmatic excursion at the costal margin, with either diminishment in strength or loss of excursion considered of concern for PNI. Visualisation of diaphragmatic excursion with either fluoroscopy or intracardiac echocardiography has also been described. 16 The most well described quantitative method for assessment of PNI is the monitoring of diaphragmatic compound motor action potential (CMAP), in which diminishment in signal amplitude of CMAP considered of concern for PNI. The diaphragmatic CMAP can be recorded using a modified surface lead I17 or a quadrapolar catheter in the hepatic vein.18 Another objective method for phrenic nerve monitoring is the use of venous pressure waveform monitoring, in which a venous sheath is attached to a pressure transducer;19 in this case, reduction in pressure signal amplitude is considered of concern for PNI. Although there are no prospective

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Table 2: Strategies to Prevent Collateral Damage Phrenic nerve injury • Intra-procedural monitoring for phrenic nerve injury during phrenic nerve pacing ° Palpation of diaphragmatic excursion at the costal margin °  Visualisation of diaphragmatic excursion with fluoroscopy or intracardiac echocardiography ° Monitoring of diaphragmatic compound motor action potential ° Venous pressure waveform monitoring • Avoid deep seating of CB in RSPV during ablation ° Avoid positioning of CB outside cardiac silhouette on fluoroscopy ° Utilisation of proximal seal technique Atrial oesophageal fistulae • Monitoring of luminal oesophageal temperature • Avoid excessive CB ablation dose by monitoring TTI and adjusting dose accordingly • Use of proton pump inhibitors post-procedure Bronchial injury • Avoid low nadir balloon temperature • Avoid deep seating of CB in LSPV with use of proximal seal technique CB = cryoballoon; LSPV = left superior pulmonary vein; RSPV = right superior pulmonary vein; TTI = time to isolation.

randomised control trials comparing the effectiveness of strategies, most experts agree that at least two methods should be used for phrenic nerve monitoring.15 If PNI is suspected, an immediate balloon deflation, rather than merely stopping refrigerant flow to the balloon, is the recommended course of action.20 If PNI persists at the end of the case, the diagnosis is confirmed by the visualisation of an elevated hemidiaphragm on inhalation/ exhalation chest X-ray. The overall prognosis for this condition is good – a majority of the patients have phrenic nerve recovery within 1 year. In a post-approval study of patients enrolled in the STOP-AF trial, fewer than 1 % of patients had persistent PNI after 12 months.21 The use of a ‘proximal seal technique’ to increase the distance between the phrenic nerve and the CB may reduce the likelihood of PNI.22 Proximal seal is achieved by first injecting the contrast during the occlusion (Figure 1A). If good occlusion is observed, one should not immediately initiate ablation, but slowly relax the sheath or withdraw the catheter and allow the CB to retract until contrast leaks around the true pulmonary vein ostium (Figure 1B). Often, a

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Electrophysiology and Ablation Figure 1: Proximal Seal Technique A

B

(A) After inflation of cryoballoon, contrast injected into the right superior pulmonary vein (RSPV) demonstrates location of the balloon is inside the pulmonary vein distal to the ostium. The anticipated fluoroscopic course of the phrenic nerve (PN) is annotated by yellow dots using a 3D mapping system and was identified by pacing from the superior vena cava to localise sites of PN. Cryoablation at this location increases risk of PN injury. (B) The cryoballoon is pulled back until contrast leak is observed in order to identify the pulmonary vein ostium. Minimal pressure is reapplied to the balloon to obtain occlusion of the RSPV ostium prior to ablation. Cryoablation can also be initiated just prior to re-advancing the balloon to full inflation in order to position the balloon more proximal in the PV antrum. This method increases the distance to the PN (course annotated with yellow dots) and lessens the risk of PN injury when used in combination with PN pacing and monitoring of PN function.

large right superior pulmonary vein may have a deep engagement with the CB and the initial occlusion without balloon deformation may appear ostial; however, the CB may be a few centimetres deeper than intended. Only apply the minimal amount of pressure to regain occlusion before ablation. This will also likely reduce the risk of collateral injury and ablate in the true antrum of the pulmonary vein. Multicentre experience of CB ablation using the proximal seal method combined with time-to-isolation dosing has reduced the incidence of PNI to 0.34 % when performed with monitoring of phrenic nerve function.23

Atrial Oesophageal Fistulae AEF is a deadly complication of CB ablation; the mortality rate is well over 80 %.24 Patients with AEF may present with something relatively benign, like odynophagia, or more serious clinical conditions, such as gastrointestinal bleeding, endocarditis, severe sepsis or cerebrovascular accident.25–27 Stroke, secondary to air or food embolism, is the most common clinical presentation among patients with AEF.24 Given the variety of clinical presentations, a high index of suspicion after recent AF ablation is needed to make a diagnosis. The pathogenesis of AEF is related to the close proximity of the oesophagus to the posterior wall of the left atrium. However, the precise mechanism is unclear. A proposed hypothesis is that oesophageal injury during AF ablation is the triggering event, with progressive inflammation and injury resulting from swallowing and gastric reflux, leading to continued oesophageal injury, perforation, and fistulae formation.28 The theory of oesophageal injury leading to AEF, rather than left atrial perforation, is consistent with the delayed time course of the disease. Patients appear to present approximately 19 days after ablation, with some patients presenting as early as 6 days and as late as 59 days.29 Fortunately, the incidence of AEF is quiet low. In a survey of 405 physicians from 2013 to 2014 who had performed a total of 191,215 AF ablations, 31 cases of AEF were reported – a rate of 0.016 %.29 An older physician survey notes a slightly higher rate of AEF. In a survey of 585 physicians from 2004 to 2005 who had performed 20,425 AF ablations, six cases of AEF were reported – a rate of 0.03 %.24 Of note, these rates of AEF are largely with RF ablation. The risk of AEF formation with CB

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ablation is unknown but much lower, and an AEF after CB ablation is a case-reportable event.30–33 Some authors estimate that although the risk of AEF with RF ablation is between 1:400 and 1:1000, the risk with CB ablation is 1:10,000.22 Despite the low incidence, given the high mortality associated with this condition, strategies to identify high-risk patients and techniques to avoid this complication are warranted. Although much of the research has been in patients who have undergone RF ablation, some of the results can be extrapolated to the CB ablation patient. In a study of 104 patients who underwent RF ablation followed by upper endoscopy within 48 hours, 9.6 % of patients were found to have asymptomatic oesophageal injury. On multiple regression analysis, the only risk factor that was significant for oesophageal injury was low body mass index.34 Another risk factor appears to be the use of general anaesthesia. In a study of 50 patients undergoing RF ablation in which patients were randomised to general anaesthesia versus conscious sedation, the rate of oesophageal injury as assessed by capsule endoscopy was 48 % in the general anaesthesia arm and only 4  % in the conscious sedation arm.35 The authors attributed this finding to reduced motility and peristalsis during general anaesthesia, exposing the same oesophageal tissue to RF energy. The most common intra-procedural strategy to minimise oesophageal injury is the use of luminal oesophageal temperature (LET) monitoring, with cessation of ablation when oesophageal temperature becomes too low. However, there is no consensus of what nadir oesophageal temperature should be used as a safety cut-off. In a study of 32 patients who underwent CB ablation with the second generation catheter utilising two 240 seconds applications for each vein, the authors noted that a minimal LET of ≤12°C was associated with higher rates of oesophageal injury as assessed by postoperative upper endoscopy.36 In a more recently published study with a larger study cohort (92 patients), the same authors found that a higher cut-off of 15°C further reduced oesophageal injury.37 Another study utilising deflectable and non-deflectable temperature probes and a single 3-minute freeze with the second generation CB found a similar temperature cut-off (12.8°C) to decrease risk of oesophageal injury.38 However, one study found an even lower temperature cut-off of 10°C utilising the second generation CB and two 240 s freezes.39 It is worth noting that in all these studies, the oesophageal lesions were healing on follow-up endoscopy, and no patients developed AEF. It is thought these oesophageal ulcers or injuries are precursors to AEF. Although further studies may help to help establish a safety cut-off LET, it is important to emphasise that oesophageal ulceration or AEF may occur without a measured drop in LET.40 We can only say that when the oesophageal temperature is low, oesophageal ulceration or injury is more likely to occur. However, when the measured oesophageal temperature is not low, it does not exclude the possibility of AEF formation. Interestingly, the left inferior pulmonary vein appears to be the most common culprit in AEF formation after CB ablation. In a recently published case control study in which the authors obtained 11 AEF cases from the Manufacturer and User Facility Device Experience database, 10 of the cases of AEF involved the left pulmonary veins, and eight of the 10 involved the left inferior pulmonary vein.41 The left inferior pulmonary vein often requires more posteriorly directed forces to achieve isolation. These posteriorly directed forces shorten the left atrium-to-oesophagus distance, which has been found to be a risk factor in the development of oesophageal injury.42 Given these findings,

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Complications of Cryoballoon Ablation proceduralists should practice extra precaution when ablating the left inferior pulmonary vein.

Figure 2: Cardiac Computed Tomography Scan

The incidence of AEF is also related to the freezing time or cryoablation dose. The initial clinical trials used traditional 240 seconds freeze–thaw–freeze (two cycles per pulmonary vein at the same location) ablation for the first generation balloon. When the same protocol was used for the second generation CB, the highest incidence of AEF (7/30,000 reported cases) was observed.43 After reducing the standard dosing to 180 seconds, which was based on consensus user experience, AEF is now rarely observed (1/120,000 reported cases) when using two conventional applications per pulmonary vein.43 However, multiple consecutive applications, longer cumulative CB ablation time and higher ‘dosing’ for a single pulmonary vein are still considered incremental risk factors for collateral injury, including AEF.40 Some studies suggest adjusting CB ablation dose based on the timeto-isolation (TTI) of the pulmonary vein may reduce collateral injury or AEF. Observing the physiology of pulmonary vein isolation using an intraluminal circular mapping catheter (AchieveTM, Medtronic) positioned between the left atrium and proximal pulmonary vein during CB ablation may be the most important factor in determining the permanence of pulmonary vein isolation. To better observe the pulmonary vein electrogram of interest, the circular AchieveTM can be positioned in the ostium of the pulmonary vein or prolapsed in front of the inflated CB to assess TTI. Predictors of permanent pulmonary vein isolation are a TTI of less than 30 to 60 seconds. If a rapid TTI is seen with less than 30 seconds, the total ablation time may be reduced to 150 seconds.22 Experimental canine data have shown that permanent pulmonary vein isolation can be reproduced with a TTI of 20 seconds, with the total ablation time of only 80 seconds.44 Conversely, a long TTI of greater than 90 seconds with an additional 180-second freeze is generally not able to permanently isolate the vein, even though initial acute isolation was seen. Longer CB application time beyond 180 seconds will create a deeper lesion and increase the risk of collateral injury or AEF, but not improve pulmonary vein isolation efficacy. Therefore, we do not recommend increasing ablation time when acute isolation does not occur with the first CB application. If TTI does not occur within 90 seconds, we recommend stopping the application and repositioning the CB catheter to modify tissue contact, confirm pulmonary vein occlusion before freezing and aim for TTI < 60 seconds to achieve permanent pulmonary vein isolation.22,44 Reducing application time during a repeat freeze to 150 seconds or less may be warranted due to faster temperature decline on the repeat freeze, which may also avoid deep tissue injury. Repeated ablation more than twice at the identical location or same CB catheter position should be avoided to prevent collateral injury. Although there are no clinical data to support the use of proton pump inhibitors (PPIs) after AF ablation, most physicians prescribe a short course of these medications to reduce AEF risk.45 Additionally, in the studies entailing endoscopic evaluations after CB ablation, most practitioners prescribed PPIs, and all patients with oesophageal injury were noted to have healing or healed lesions on follow-up.36–38 It is a routine practice in our institution to prescribe 4 weeks of PPI since there are only minimal side effects of a short course of PPI, and we believe that the benefits outweigh the risks.

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Intravenous iodinated contrast in sagittal view demonstrating the close proximity of the left superior pulmonary vein and the left main stem bronchus, a structure susceptible to collateral damage during cryoballoon ablation. AA = ascending aorta; DA = descending aorta; LA = left atrium; LIPV = left inferior pulmonary vein; LMSB = left main stem bronchus; LSPV = left superior pulmonary vein; PA = pulmonary artery.

Patients with suspected AEF require rapid evaluation and treatment. Given the lack of specific findings, a high index of suspicion is required to make a diagnosis. An upper endoscopy is absolutely contraindicated given the risk of massive air embolism after air insufflation during endoscopy.27,45 Either computed tomography (CT) or magnetic resonance imaging (MRI) of the chest is needed to make the diagnosis when air is found in the mediastinum, pericardium or left atrium.26,27 While oesophageal stenting is a therapeutic option, surgery offers the best chance of survival.26,46–48 In addition to AEF, CB ablation has been associated with various upper gastrointestinal dysmotility syndromes, including gastroesophageal reflux and gastroparesis.49 The hypothesised mechanism is injury to the parasympathetic nerve inputs that overly the oesophagus during ablation. The exact incidence of these injuries is unknown because symptoms may be subclinical and practitioners may not have the necessary index of suspicion to make the diagnosis. In small observational studies, the incidence of gastroparesis in patients undergoing CB ablation was approximately 9–17 %.50–52 In one study of 66 consecutive patients undergoing CB ablation, all six patients were asymptomatic and the diagnosis was made on postprocedure upper endoscopy as part of the study protocol.51 A larger study of 144 patients who underwent upper endoscopy as per study protocol found 18 patients with gastric hypomotility, all of whom were asymptomatic.52 Lastly, in a study of 58 patients undergoing CB ablation, the six patients who reported gastrointestinal symptoms intra-procedure had prospective evaluation to make the diagnosis and all six patients had symptomatic recovery within 2 months.50 Further large-scale studies are warranted to identify the true incidence, develop strategies to minimise collateral risk and examine the long-term prognosis of these injuries.

Bronchial Injury Bronchial erosion and injury is becoming recognised as another serious complication of CB ablation. Although the exact incidence is not known, small single-centre studies have reported rates of 1.7 % and 3.6  %.53 Patients can present with a cough and production of blood tinged sputum54,55 or frank haemoptysis.56–58 Onset of symptoms can be variable. Patients may become symptomatic during the procedure58 on postoperative Day 154,55,57 or even a day later.56,57,59

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Electrophysiology and Ablation Although the exact mechanism of injury is not known, case reports suggest that these injuries result from extremely low nadir temperatures (–60°C or lower) and deep seating of the CB 54,56 leading to collateral thermal injury of the bronchial tree. Radiological studies have shown the close proximity of the bronchial system to the pulmonary veins, making this structure prone to injury during CB ablation (Figure 2).60,61 A recently published case series of CB ablation patients who underwent real-time bronchoscopy found ice formation in the left main stem bronchus in 70 % of patients during ablation of the left superior pulmonary vein (average nadir CB temperature of –48.5°C).62 These findings of thermal injury have been replicated in pig studies, where lower nadir temperature during CB application (–66°C vs –45°C) showed increased bronchial mucosal oedema, erythema and inflammation in post-ablation bronchoscopy.63

up. 54–57 However, rare catastrophic cases of atriobronchial fistula have been reported.59,64

Conclusion Cryoballoon ablation has become a widely accepted tool for the management of atrial fibrillation. However, cryoballoon ablation can lead to collateral extra-cardiac damage, which can lead to catastrophic complications: phrenic nerve injury, atrial oesophageal fistula and bronchial injury. Although these complications are rare, electrophysiologists should institute measures to identify high-risk patients, implement best-practice techniques to minimise risks and maintain a high index of suspicion to recognise the complications quickly and implement correct treatment strategies. n

Clinical Perspectives No definitive recommendations exist for the management of bronchial injury. Protocol at our institution for suspected bronchial injury entails anticoagulation reversal with protamine, urgent bronchoscopy and, at times CT of the chest to evaluate for consolidation suggestive of pulmonary haemorrhage. Bronchoscopy findings can range from mucosal petechiae, 54 bronchial wall erosion56 to haematoma formation. 55 Lastly, cough suppressants may play a role in the management of bronchial injury. 55 Although the prognosis is not precisely known given limited data, on the basis of case reports it appears that most patients do well on follow1.

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selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design: a report of the Heart Rhythm Society (HRS) Task Force on Catheter and Surgical Ablation of Atrial Fibrillation. Developed in partnership with the European Heart Rhythm Association (EHRA), a registered branch of the European Society of Cardiology (ESC) and the European Cardiac Arrhythmia Society (ECAS); and in collaboration with the American College of Cardiology (ACC), American Heart Association (AHA), the Asia Pacific Heart Rhythm Society (APHRS), and the Society of Thoracic Surgeons (STS). Endorsed by the governing bodies of the American College of Cardiology Foundation, the American Heart Association, the European Cardiac Arrhythmia Society, the European Heart Rhythm Association, the Society of Thoracic Surgeons, the Asia Pacific Heart Rhythm Society, and the Heart Rhythm Society. Heart Rhythm 2012;9:632–96. Mohanty S, Santangeli P, Mohanty P, et al. Outcomes of atrioesophageal fistula following catheter ablation of atrial fibrillation treated with surgical repair versus esophageal stenting. J Cardiovasc Electrophysiol 2014;25:579–84. DOI: 10.1111/ jce.12386; PMID: 25013875. Zhou B, Cen XJ, Qian LY, et al. Treatment strategy for treating atrial-esophageal fistula: esophageal stenting or surgical repair? A case report and literature review. Medicine 2016;95:e5134. DOI: 10.1097/MD.0000000000005134; PMID: 27787367. Singh SM, d’Avila A, Singh SK, et al. Clinical outcomes after repair of left atrial esophageal fistulas occurring after atrial fibrillation ablation procedures. Heart Rhythm 2013;10:1591–7. DOI: 10.1016/j.hrthm.2013.08.012; PMID: 23954269. Garg L, Garg J, Gupta N, et al. Gastrointestinal complications associated with catheter ablation for atrial fibrillation. Int J Cardiol 2016;224: 424–30. DOI: 10.1016/j.ijcard.2016.09.069; PMID: 27690340. Aksu T, Golcuk S, Guler TE, et al. Gastroparesis as a complication of atrial fibrillation ablation. Am J Cardiol 2015;116:92–7. DOI: 10.1016/j.amjcard.2015.03.045; PMID: 25933733. Guiot A, Savoure A, Godin B, et al. Collateral nervous damages after cryoballoon pulmonary vein isolation. J Cardiovasc Electrophysiol 2012;23:346–51. DOI: 10.1111/j.15408167.2011.02219.x; PMID: 22081875. Miyazaki S, Nakamura H, Taniguchi H, et al. Gastric hypomotility after second-generation cryoballoon ablationUnrecognized silent nerve injury after cryoballoon ablation. Heart Rhythm 2017;14:670–7. DOI: 10.1016/j.hrthm.2017.01.028; PMID: 28434448.

53. K  umar N, Timmermans C, Pison L, et al. Hemoptysis: deja vu for cryoballoon use for pulmonary vein isolation for atrial fibrillation ablation. Chest 2014;145:1435. DOI: 10.1378/ chest.14-0236; PMID: 24889450. 54. Marti-Almor J, Jauregui-Abularach ME, Benito B, et al. Pulmonary hemorrhage after cryoballoon ablation for pulmonary vein isolation in the treatment of atrial fibrillation. Chest 2014;145: 156–7. DOI: 10.1378/chest.13-0761; PMID: 24394827. 55. Desai AK, Osahan DS, Undavia MB, et al. Bronchial injury post-cryoablation for atrial fibrillation. Ann Am Thorac Soc 2015;12:1103–4. DOI: 10.1513/AnnalsATS.201503-135LE; PMID: 26203613. 56. van Opstal JM, Timmermans C, Blaauw Y, et al. Bronchial erosion and hemoptysis after pulmonary vein isolation by cryoballoon ablation. Heart Rhythm 2011;8:1459. DOI: 10.1016/ j.hrthm.2010.06.024; PMID: 20601153. 57. Bhagwandien R, Belle YV, deGroot N, et al. Hemoptysis after pulmonary vein isolation with a cryoballoon: an analysis of the potential etiology. J Cardiovasc Electrophysiol 2011;22:1067–9. DOI: 10.1111/j.1540-8167.2011.02031.x; PMID: 21352395. 58. Aksu T, Ebru Golcuk S, Yalin K. Haemoptysis and pulmonary haemorrhage associated with cryoballoon ablation. Europace 2015;17:1240. DOI: 10.1093/europace/euu407; PMID: 25712979 59. Cuoco F, Wharton MJ, Gold MR. Delayed formation of an atrial bronchial fistula following cryoballoon ablation for atrial fibrillation. P001-150. Heart Rhythm 2016. 60. Wu MH, Wongcharoen W, Tsao HM, et al. Close relationship between the bronchi and pulmonary veins: implications for the prevention of atriobronchial fistula after atrial fibrillation ablation. J Cardiovasc Electrophysiol 2007;18:1056–9. DOI: 10.1111/j.1540-8167.2007.00915.x; PMID: 17666059. 61. Li YG, Yang M, Li Y, et al. Spatial relationship between left atrial roof or superior pulmonary veins and bronchi or pulmonary arteries by dual-source computed tomography: implication for preventing injury of bronchi and pulmonary arteries during atrial fibrillation ablation. Europace 2011;13: 809–14. DOI: 10.1093/europace/eur034; PMID: 21345923. 62. Verma N, Gillespie CT, Argento AC, et al. Bronchial effects of cryoballoon ablation for atrial fibrillation. Heart Rhythm 2017; 14:12–6. DOI: 10.1016/j.hrthm.2016.10.012; PMID: 28007093. 63. Aryana A, Bowers MR, Hayatdavoudi SM, et al. Impact of pulmonary vein cryoballoon ablation on bronchial injury. J Cardiovasc Electrophysiol 2016;27:861–7. DOI: 10.1111/jce.12983; PMID: 27062526. 64. Doshi RN, Cesario DA, Shivkumar K. Atriobronchial fistula formation as a devastating complication of left atrial catheter ablation for atrial fibrillation. [Abstract] Heart Rhythm 2006.

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Electrophysiology and Ablation

Oesophageal Injury During AF Ablation: Techniques for Prevention Jorge Romero, 1 Ricardo Avendano, 1 Michael Grushko, 1 Juan Carlos Diaz, 1 Xianfeng Du, 2 Carola Gianni, 3 Andrea Natale 1,3 and Luigi Di Biase 1,3 1. Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, USA; 2. Department of Cardiology, Ningbo First Hospital, Zhejiang Sheng, China; 3. Texas Cardiac Arrhythmia Institute, St David’s Medical Center, Austin, USA

Abstract Atrial fibrillation remains the most common arrhythmia worldwide, with pulmonary vein isolation (PVI) being an essential component in the treatment of this arrhythmia. In view of the close proximity of the oesophagus with the posterior wall of the left atrium, oesophageal injury prevention has become a major concern during PVI procedures. Oesophageal changes varying from erythema to fistulas have been reported, with atrio-oesophageal fistulas being the most feared as they are associated with major morbidity and mortality. This review article provides a detailed description of the risk factors associated with oesophageal injury during ablation, along with an overview of the currently available techniques to prevent oesophageal injury. We expect that this state of the art review will deliver the tools to help electrophysiologists prevent potential oesophageal injuries, as well as increase the focus on research areas in which evidence is lacking.

Keywords Atrial fibrillation, pulmonary vein isolation, ablation, oesophageal injury, transoesophageal echocardiogram Disclosure: Luigi Di Biase is a consultant for Biosense Webster, Stereotaxis, Boston Scientific and Abbott. He has received speaker honoraria/travel costs from Medtronic, AtriCure, EPiEP, Pfizer and Biotronik. Received: 20 October 2017 Accepted: 15 January 2018 Citation: Arrhythmia & Electrophysiology Review 2018;7(1):24–31. DOI: 10.15420/aer.2017.46.2 Correspondence: Luigi Di Biase, Division of Cardiology, Montefiore-Einstein Center for Heart and Vascular Care, Montefiore Medical Center, Albert Einstein College of Medicine, 1111 East 210th Street, Bronx, NY 10467, USA. E: dibbia@gmail.com

Oesophageal injury prevention has become a major concern in the field of electrophysiology since the first case of atrio–oesophageal fistula was reported as a complication of endocardial surgical radiofrequency ablation (RFA),1 with Scanavacca et al. and Pappone et al. subsequently reporting this complication in patients who underwent percutaneous pulmonary vein isolation (PVI) for AF.2,3 It is well recognised that oesophageal wall injury, varying from erythema to ulceration, is common and has been described by endoscopy in up to 47 % of patients following PVI.4,5 The potential of atrio–oesophageal fistulas is a limiting factor for optimal ablation in a considerable number of PVI cases, as close contact between the oesophagus and the posterior left atrial wall limits the amount of energy delivered in this area. In the vast majority of patients undergoing AF ablation, a large contact area between the left atrium (LA) and oesophagus can be observed. The mean vertical contact length is 4.4 cm and the mean distance between the anterior wall of the oesophagus and the posterior LA endocardium is only approximately 2.6 mm (range: 1.4–6.0 mm).6 In addition, the thickness of the pulmonary veins (PV) wall and PV antrum has been reported to be as little as 2–3 mm, generally thinner than the atrial myocardium at the posterior or anterior free walls (Figure 1).7 From an engineering study using a theoretical model, oesophageal injury results exclusively from thermal conduction from the atrium and is mainly influenced by the thickness of the intervening connective tissue.8 Additionally, damage of the vagal plexus coursing along the oesophagus can result in gastric hypomotility and gastroparesis.9 As such, techniques to prevent oesophageal damage during AF ablation have generated considerable interest during the last decade.

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Magnitude of the Problem Despite initial reports from intraoperative RFA that reported atriooesophageal fistula incidence as high as 1 %9,10 and subsequent reports from surveys reporting an incidence ranging from 0.03 to 0.5  %,11,12 the true incidence remains unknown. It is noteworthy that in larger cohorts, such as the retrospective study performed by Cappato et al., which included 45,115 catheter ablation procedures in 32,569 patients, the incidence of atrio–oesophageal fistula was 0.01  % (451 patients), with a 100  % fatality rate if left untreated.13 Strikingly, even if no oesophageal wall injury is seen (Figure 2), morphological changes of the peri-oesophageal connective tissue and the posterior wall of the LA are diagnosed in almost one-third of the patients by endosonography.14 In a more recent article published by Barbhaiya et al., results were published from a global survey regarding oesophageal perforation and fistula completed by 405 physicians who performed 191,215 AF ablations. Oesophageal perforation without fistula was reported in 0.016  % patients. Mortality in those with atrio–oesophageal fistula was 70  % and in those without fistula was 13  %, with those surviving the fistula requiring surgical procedure.15 As a result, most electrophysiologists have opted for a reduction in maximum catheter ablation power and lesion duration on the posterior LA in an attempt to avoid this devastating complication, increasing the chance of PV/posterior wall reconnection and arrhythmia recurrence.9

Risk Factors, Oesophageal Localisation and Injury Prevention Although no major prospective studies are available delineating risk factors for the development of oesophageal damage, Martinek et al.

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Oesophageal Injury During AF Ablation Figure 1: Anatomical Relationship Between the Oesophagus and the Left Atrium A

B

(A) Three-dimensional electroanatomic map of the left atrium and the oesaphagus using the CARTO-Sound (Biosense) technology. (B) Sagittal view of a chest computed tomography showing the close proximity of the left atrium to the oesophagus.

Figure 2: Different Extent of Thermal Injuries Along the Course of the Oesophagus of Different Patients who Underwent Radiofrequency Ablation A

B

C

(A) Mucosal erythema with adherent exudate. (B) Shallow ulceration covered with black coagulum. (C) Deep ulceration with adherent clot. Source: Keshishian, et al., 2012.65

retrospectively reported in patients diagnosed with persistent AF, who underwent additional ablation lines, had LA enlargement, were exposed to high oesophageal temperatures, received increased power during energy delivery on the posterior wall, had a short atrium-to-oesophagus distance (defined as a distance of <2 mm), were exposed to the use of nasogastric tubes, and underwent general anaesthesia to be at increased risk of oesophageal injury and stroke risk.16,17 Interestingly, Good et al. reported that the oesophagus naturally shifts sideways by ≥2 cm in most patients undergoing PVI via conscious sedation.18 These observations led to the development of intraoperative monitoring tools to prevent and/or decrease potential oesophageal damage during ablation.

increases in intraluminal temperature, magnitude and duration of local tissue heating, energy delivery, catheter tip size, contact pressure and atrial thickness.7,8,26 Different methods are available to help mitigate oesophageal injury, including intra-procedural oesophageal temperature monitoring, titration of delivered energy, mechanical displacement of the oesophagus to avoid direct damage (with the objective of increasing ablation time on the posterior wall), and using post-procedural proton pump inhibitors (PPI) and sucralfate to prevent inflammatory changes associated with these RF lesions. These will be reviewed in the following sections.

Oesophageal Temperature Monitoring Assessing the anatomic relationship between the LA and the oesophagus can be categorised into non-real-time and real-time methods. Non-real-time methods, such as computed tomography (CT) or cardiac magnetic resonance (CMR), provide pre-procedural information about the course of the oesophagus and its location relative to the LA (Figure 1). Real-time methods provide imaging during RFA energy delivery and include repetitive fluoroscopic visualisation of the oesophageal lumen along with the help of intraluminal temperature monitoring and/or barium administration.19–21 Additionally, 2D and 3D intracardiac ultrasound,22–24 and/or anatomical delineation with a mapping/ablation catheter, are imaging modalities available to assess oesophageal position (Figure 1).25

Techniques to Prevent Oesophageal Injury The blood supply, nerves and surface of the oesophagus can be affected when RFA is applied on the posterior wall of the LA. When performing RFA, important factors to consider are thermal conduction,

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As described above, oesophageal injury appears to be mainly driven by contact force (CF), connective tissue thickness and the extent of thermal damage.8 Given the variability of energy delivery and tissue damage despite constant adjustments of the RF generator settings, several studies have examined the importance of the proximity of the oesophagus to the LA and the rise in temperature during ablation.19 Cummings et al. performed PVI in 81 patients with the use of a standard oesophageal temperature-monitoring probe, CT scan to assess oesophageal course, and endoscopic evaluation preand post-procedure to assess any microscopic luminal changes. As expected, oesophageal temperature was significantly higher during lesion application over the course of the oesophagus than lesions applied elsewhere (38.9 ± 1.4°C, 36.8 ± 0.5°C, p<0.01), and lesions that generated early changes of oesophageal injury had higher oesophagus temperatures than those that did not (39.3 ± 1.5°C, 38.5 ± 0.9°C, p<0.01).21 In a larger cohort of 359 patients undergoing PVI, Kuwahara et al. compared perioesophageal nerve injury leading to oesophageal

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Electrophysiology and Ablation Figure 3: Different Types of Oesophageal Temperature Probes A

B

(A) 12-sensor, sinusoidal temperature probe. (B) Fluoroscopy image showing the 12-sensor sinusoidal (arrow) and a single sensor temperature probe (circle). Source: Tschabrunn, et al., 2015.37

dysfunction in patients receiving oesophageal temperature monitoring with a deflectable probe placed in proximity to the ablation electrode compared to those without temperature monitoring. Gastric hypomotility owing to perioesophageal nerve damage was observed in three patients in the non-monitored group, and none in the monitored group (p=0.02).27 However, oesophageal temperature monitoring is not without controversy. Deneke et al. initially suggested that routine monitoring may contribute to oesophageal damage caused by thermal effect.28 In a prospective study conducted by Muller et al., 80 patients with drug refractory or longstanding persistent AF underwent posterior wall ablation with a limited power output of less than 25 W and received either continuous oesophageal temperature monitoring or no oesophageal probe. The incidence of oesophageal injury assessed by endoscopy was higher in patients with temperature monitoring compared to those without (30 % versus 3.5  %, p<0.01) and multivariate regression analysis showed that the use of an oesophageal temperature probe is the only independent predictor for the development of oesophageal damage (OR 16.7, p<0.01).29 However, there is controversy about the existence of this so-called “antenna effect”: while Nguyen et al. reported that ablation in close proximity to metal resulted in higher temperatures in surrounding tissues leading to significant tissue heating,30 this was not confirmed in a computational modelling study by Pérez et al. in which no electrical and/or thermal interaction was found between the ablation catheter and the oesophageal temperature probe.31 According to the 2017 AF ablation consensus statement, there is general agreement that it is reasonable to use an oesophageal temperature probe during RF ablation procedures to monitor oesophageal temperature and help guide energy delivery (Class IIA, LOE-C).32 Currently, it is common practice to stop ablation when a rise of 1–2°C in intraluminal temperature from baseline occurs, or a temperature of 39–40°C is reached during ablation. Nonetheless, the role of temperature monitoring as a sole predictor for oesophageal injury is debatable. Despite the well-established relationship between energy delivery and oesophageal temperature elevation, other factors associated with oesophageal lesion formation are at play.21,27 Tissue contact force has been described as having a key role for injury development.33 Because factors such as LA thickness and distance between the oesophagus and the LA vary among patients, they have been implicated as determinants of the amount of heat that is being transferred to the oesophagus.7,34 One of the most prevailing

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arguments against the use of an oesophageal temperature probe is that it can create a false sense of security. Owing to the size of the oesophagus, the ablation electrode might not align with the temperature probe, leading to a spuriously low temperature reading, which in turn could lead to increased power delivery or ablation duration on the posterior wall.35 Different probes are currently available with significant variations in temperature reading, , including multi-sensor, single-sensor and stethoscope models. Thus, the level of intraluminal temperature cut-off that can be considered safe has major variations according to the probe used (Figure 3).36 However, Tschabrunn et al. reported that multisensor self-expandable probes appear to provide greater sensitivity (100 % versus 60  %) and similar specificity (60  %) for the detection of oesophageal ulceration than single electrode probes.37 More evidence is needed to fully evaluate the role of oesophageal temperature monitoring in AF ablation, as well as to compare the different types of monitors and energy delivery.

Energy Delivery Current treatment for AF requires creation of effective ablative lesions by energy delivery to a thin atrial tissue layer, with potential serious adverse events such as oesophageal damage, including ulcerations, perforation and fistulas. Factors that influence this energy delivery include impedance, power, thrombus formation, tissue CF, tissue/ electrode interface temperatures and time of energy application. As stated above, thermal injury has been well described to play a key role in oesophageal damage.8 To reduce heat conduction to the oesophagus, different modalities have been tested. Martinek et al. randomised 175 AF ablation patients to one of three different techniques aimed at limiting oesophageal damage during RFA (ablation without visualisation of the oesophagus, limiting power to 25 W in the posterior wall; ablation guided by direct visualisation of the oesophagus using barium with a maximum power of 15 W; and ablation with 25 W using direct visualisation and application duration of less than 5 seconds, known as “short burns”). The authors found that oesophageal ulcerations were rare when using a “short burn” approach, defined as lesions with an output of 25 W up to a maximum of 5 seconds.16 However, despite reducing the incidence of oesophageal ulcerations, the clinical short-term success of the procedure using this approach was lower than that in the control group (51.6 % versus 58.5 %, respectively).16 It is important to note that different ablation catheters have different energy delivery efficacy, and that power, time and CF cut-offs should be individualised. For example, Deneke et al. studied the safety of a novel multipolar irrigated RF ablation catheter (nMARQ™), capable of performing “single shot” PVI through a decapolar electrode, which synchronously applies ablative energy. Despite a high effectiveness in achieving PVI, a high incidence of oesophageal lesions (33  %) was reported, especially in patients in whom a rise in intraluminal oesophageal temperature was observed.38 The incidence appeared to be higher in comparison with other ablative techniques.28,39 Given the lack of robust clinic trials for this modality and without irrefutable evidence for reduction in oesophageal injury, nMARQ AF ablation is not currently recommended in the US.38,40 Open irrigation is associated with deeper and larger lesions, as irrigated catheters minimise the risk of thrombus formation by cooling the catheter surface, thus allowing the use of higher power settings and longer durations.41 Though more efficient for tissue ablation, this may increase the risk of suffering oesophageal damage. Several attempts have been made to mitigate these untoward effects of open

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Oesophageal Injury During AF Ablation irrigation ablation. Sato et al. demonstrated that increasing the number of irrigation channels in an ablation catheter is associated with a slower increase in oesophageal temperature, thus providing a potential strategy to reduce the risk of oesophageal lesions.42 With non-irrigated ablation, lesion width and depth increases linearly as a function of electrode-tissue interface temperature up to 90°C. Nevertheless, coagulum formation on the catheter tip occurs with temperatures exceeding 80°C and sudden impedance rises can occur, frequently limiting the duration of RF delivery and thus the extent of energy delivery to tissue. Producing deep lesions with irrigated ablation may not be optimal in thin-walled tissues such as the posterior LA, which lies in close proximity with structures vulnerable to collateral injury, such as the oesophagus and the lungs. On the posterior LA, the deep lesions produced by irrigated ablation catheters may expose the oesophagus to much higher temperatures without increasing the success of ablation, since a sufficient endocardial lesion could be achieved with non-irrigated catheters (Figure 4). In an experimental clinical study by Kumar et al.,43 the authors hypothesised that short duration, low-flow irrigated radiofrequency ablation of the posterior LA would allow creation of transmural lesions with a maximum diameter at the endocardial surface, without compromising safety or efficacy. Biophysical parameters and pathology measurements were compared between open irrigation at low flow (2 mL/min) versus conventional flow rates (17 mL/min) during irrigated catheter ablation in 20 swines, along with biophysical parameters in 60 patients undergoing de-novo catheter ablation for AF. Low flow ablation compared to control in swine had larger impedance decreases (median 20 Ω versus 8 Ω, p<0.001), higher incidence of loss of pace capture (44 % versus 18  %, p<0.001), more electrogrambased transmural lesions (57 % versus 9 %; p<0.001), and more visible lesions on anatomic inspection (75 % versus 41 %, p=0.007). Low flow, compared to standard higher flow irrigation, also produced a more rapid impedance drop with shorter RF applications, while achieving a higher incidence of electrical inexcitability with pacing. This was noted in both swine and human studies. Importantly, no evidence of an abrupt rise in impedance, steam pops, or coagulum formation was noted with low-flow ablation at 20–25 W and limited duration (i.e. 10–15 seconds). The greater tissue and catheter tip temperatures seen with low-flow lesions seem to be responsible for the larger impedance decreases, which may partially explain why impedance alone is not a good predictor of overall lesion size, rather a better predictor of surface heating. In the human ablation analysis, the extent of impedance decrease, the loss of pace capture, and achievement of transmurality post-ablation strongly favoured low-flow lesions, therefore supporting this approach to posterior LA ablation to prevent oesophageal damage.

Mechanical Displacement of the Oesophagus Another potential intervention for oesophageal protection during LA ablation is actual mechanical oesophageal displacement. Proper identification of structures that lie in close proximity to the oesophagus is a critical step before mechanical displacement is considered. The oesophagus has been reported to be a highly mobile organ, without a serosal layer, and although fixed in the mediastinum (primarily in the pharynx and gastro-oesophageal junction), its position can be variable. Good et al., using barium paste and digital fluoroscopic imaging, reported that under conscious sedation the oesophagus shifts sideways at least 2 cm.18 Oesophageal movement varies along the LA surface, with a mean displacement of 2.0 ± 0.8

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Figure 4: Difference in Lesion Size and Geometry between Normal-flow and Low-flow Ablation Representative lesions High flow lesions

Low flow lesions

Lesion volume 12.6 mm3

Lesion volume 15.6 mm3

Endocardial surface 2.2 ± 0.7c Epicardial surface

5.1 ± 1.1f

4.8 ± 1.1a 5.9 ± 1b

6.1 ± 0.9e

1.5 ± 0.7d

1.6 ± 0.8h

P<0.05 P=NS a vs. b a vs. f c vs. h b vs. g d vs. i f vs. g e vs. j c vs. h when a vs. e corrected for tissue f vs. j thickness

5.3 ± 1g

0.04 ± 0.2i

4.3 ± 1j

Non-irrigated ablation produce lesions mainly limited to the endocardium, with less collateral oesophageal injury than with irrigated lesions in which maximal tissue temperatures are reached near the epicardial surface. Source: Kumar, et al., 2017.43 https://creativecommons. org/licenses/by-nc-nd/4.0/

Figure 5: Oesophageal Displacement with a Transoesophageal Echocardiography (TOE) Probe

(A) Contrast injection into the left common pulmonary vein trunk (LAO). (B,C) Barium‐ opacified oesophagus in LAO and RAO projections. (D,E) TOE probe in the LAO and RAO projections deflecting the oesophagus by ~1.5 cm (LAO) and ~0.2 cm (RAO) for safer radiofrequency energy application. The left vertical line aligns the left spinal border and the right sternal border in the LAO and RAO projections, respectively. LAO = left anterior oblique; RAO = right anterior oblique. Source: Herweg, et al., 2006.46

cm (range: 0.3–3.8 cm) in the superior portion of the oesophagus, 1.7 ± 0.8 cm (range: 0.1–3.5 m) at the mid-oesophagus, and 2.1 ± 1.2 cm (range: 0.1–4.5 cm) inferiorly. Accordingly, two small studies were published with the aim of addressing possible techniques for mechanical oesophageal displacement. Chugh et al. aimed to determine the feasibility of mechanical displacement through the help of an endoscope with a flexible tip in 12 patients during AF catheter ablation.44 In 9 of the 12 patients, this was a redo procedure

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Electrophysiology and Ablation Figure 6: Oesophageal Displacement with the EsoSure Device

The distance of deflection of the right border of the oesophagus (green dashed line), from right deflection to left deflection, was ~33 mm. The distance of deflection of the left edge of the oesophagus (blue dashed line), when measured from the left deflection to right deflection, was ~25 mm. Image courtesy of Steve Miller, EPreward president, 2017.

performed because of an incomplete PVI and recurrent arrhythmia detection due to an unfavourable LA–oesophageal relationship during a prior ablation procedure. In 10 (83 %) of the patients, the oesophagus was displaced toward the left and right to a maximum of 2.4 and 2.1 cm, respectively. In two (22 %) of the nine patients in whom a prior procedure was unsuccessful due to rise in intraluminal oesophageal temperature, the displacement facilitated effective energy delivery at target site. The downside of this technique is that there is a theoretical concern that RF energy might be shifted from the ablation catheter to the endoscope. Therefore, RF ablation is only performed if the oesophagus remains in the same place after the probe has been removed. Using a different approach, Koruth et al. placed an endotracheal stylet within a chest tube to mechanically deviate the oesophagus in a cohort of 20 consecutive patients undergoing RFA or laser balloon for AF (there was no control group).45 Leftward oesophageal deviation of 2.8 ± 1.6 cm and rightward deviation of 2.8 ± 1.8 cm was observed. Temperature rose to more than 38.5°C in three (15  %) of the patients. There was no rise of temperature greater than 40°C. Post ablation, all of the patients had an upper gastrointestinal endoscopy to evaluate for ulcer formation. Of the 19 patients analysed, 18 (95  %) showed no ulceration from thermal injury. Overall, 12 patients (63  %) showed lesions that were classified as mild (9) and moderate (3) intensity oesophageal instrumentation-related trauma. During follow-up (mean 40.6 days), no patient developed dysphagia or gastrointestinal bleeding. Transoesophageal echocardiogram (TOE) has also been used to mechanically displace the oesophagus during AF ablation procedures. Herwerg et al. used a TOE transducer to move the oesophagus away from the ablation sites in a total of three of six patients who underwent AF ablation via fluoroscopy.46 The increased distance created by the deflection allowed for a targeted RF energy at critical sites of the posterior LA wall. No patient showed evidence of oesophageal injury, and only one of the patients presented with mild pharyngeal oedema (Figure 5). In a recent study, Parikh et al. evaluated the safety and efficacy of a novel mechanical oesophageal deviation tool, the EsoSure (NEScientific).47 In a multicenter trial, EsoSure was used to displace the oesophagus in 85 patients who underwent PVI and in whom the increase in oesophageal temperature limited the desired energy delivery at the posterior wall. All PVs were successfully isolated without a rise in oesophageal temperature (Figure 6). At 3-month follow-up, 7  % of patients reported self-limited dysphagia; no other

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major complications were seen. A randomised clinical trial testing a new investigational oesophageal deviation device by Reddy et al. (NCT01546168) was stopped due to lack of statistical significance after an interim analysis was performed. No difference was found between the use of this device for mechanical displacement and oesophageal temperature monitoring alone; results have yet to be published. Mechanical displacement of the oesophagus appears promising and safe, and should allow for complete LA PVI, especially in patients with a thinner posterior atrial wall. Nevertheless, when performing displacement of the oesophagus, its complete anatomy should be delineated, as elegantly reported by Palanisway et al. Some probes have the disadvantage of not properly identifying the trailing edge of the oesophagus, which could lead to inadvertent injury.48 In addition, given the mobile nature of the oesophagus, trauma has been reported when a stiff stylet is used for mechanical displacement.45 Large prospective randomised clinical trials are still lacking, and therefore a more robust measure of efficacy and safety is yet to be determined.

Epicardial Balloon Protection of the oesophagus can also be accomplished by inflating a balloon catheter (18 mm × 4 cm balloon dilation catheter; Meditech [Boston Scientific]) in the pericardial space. Buch et al. initially described this procedure during epicardial ventricular tachycardia ablation in a patient with repetitive drug refractory monomorphic ventricular tachycardia to mechanically distance the phrenic nerve.49 More recently, the same group described using this technique to protect the oesophagus and right phrenic nerve during AF ablation in a porcine model and in humans, thus allowing safe complete isolation of all four PVs.50,51 The distance between the oesophagus and posterior LA balloon inflation increased by 12.3 ± 4.0 mm, considerably attenuating the luminal oesophageal temperature increase during endocardial RFA (i.e. 6.1 °C versus 1.2 °C; p<0001).51 Similarly, after displacement of the right phrenic nerve with the intrapericardial balloon, nerve capture was abolished in 91 % of sites previously stimulated by pacing (Figure 7).51 This technique, while effective, does require epicardial access with its inherent risks.

Initiation of Proton Pump Inhibitors Initial studies performed in canine models by Yokoyama et al. evaluated whether concomitant states of inflammation of the oesophagus, such as gastro-oesophageal reflux disease, may be a potential risk factor for oesophageal injury during LA ablation.52 Prior to this, Martinek

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Oesophageal Injury During AF Ablation et al. assessed the acute effect of RFA on distal oesophageal acidity.53 In this study, 31 patients with a diagnosis of paroxysmal AF were enrolled. Oesophagoscopy was used to evaluate for any injury prior to and after the ablation. No patient was on a PPI or had oesophageal acidity problems. Of 26 patients evaluated after ablation, 5 patients (19.2 %) demonstrated a significant pathological increase in the DeMeester acid reflux score evaluation. However, only one patient with asymptomatic reflux developed oesophageal ulceration. As a result of these findings, multiple centres are using PPIs or H2 blockers as a common clinical practice before and after the ablation procedure, with emphasis given to those with an history of gastro-oesophageal reflux disease.14,54 Gastric acid reflux is very common among patients undergoing RFA, and experimental studies have reported a correlation between reflux and the progression of oesophageal ulcers created by ablation (Figure 2).55 In patients undergoing lengthy ablation and/or multiple lines, assessment for previous history of reflux disease should be performed, and if positive or probable, post-ablation PPIs should be initiated.4 The efficacy of sucralfate (acid buffer) as a prophylactic treatment has not been tested extensively. Based on these findings, PPIs as a singular preventive treatment is recommended by the 2017 AF ablation consensus statement.32

Figure 7: Positioning of the Intrapericardial Balloon for Oesophageal Protection A

B

C

(A) Anterior-posterior (AP) and left anterior oblique (LAO) views of the intrapericardial balloon positioned after a posterior pericardial access. (B) Intrapericardial balloon positioned after an anterior pericardial access, requiring deflectable sheath guidance. (C) In vivo photographs of inflated intrapericardial balloon (yellow arrow); the phrenic nerve along the pericardium is indicated by the dashed white arrow. ESO = oesophageal mapping catheter; PV Map = pulmonary vein mapping catheter. Source: Nakahara, et al., 2010.51

Oesophagus Cooling Systems Other Techniques As an alternative strategy to RFA, the use of cryoablation for targeting AF triggers has been proposed in multiple studies. Ripley et al. applied cryotherapy in bovine oesophagus in vivo.56 Compared to the disruption of normal cellular architecture seen in RFA, macroscopic and histologic findings after cryotherapy showed no cellular change, chronic ulceration, or fistula formation. This is corroborated by an experimental study demonstrating that cryothermal ablation preserved the extracellular matrix and endothelial integrity.57 Clinically, in a prospective study by the OPIPAF group (Ostial Pulmonary vein Isolation in Paroxysmal Atrial Fibrillation), 70 patients underwent cryotherapy as the preferred treatment for PVI.58 No PV stenosis or oesophageal injury was detected during follow-up of 33 ± 15 months post ablation. Regarding efficacy, however, 49 % of the patients achieved complete initial success, with 11 % (8) of patients showing sporadic episodes of AF post ablation. Initially it was thought that cryotherapy would not be associated with PV stenosis, oesophageal perforation, or thromboembolic events. However, in a well-reported systematic review by Andrade et al., the procedure was found not to be free of serious complications, the most common of which was phrenic nerve paralysis, with an overall incidence of 6.38 % (86 of 1349 procedures) despite the high acute procedural success rate (91.67  % complete PVI in 19 studies and 94.85  % complete PVI of targeted veins in 18 studies).59 Also seen were pericardial effusions, which occurred in 1.46  % of cases, and thromboembolic complications in 0.57 % of cases. However, no cases of left atrio-oesophageal fistulas were reported. Nonetheless, Ahmed et al., reported oesophageal ulcerations in 17 % of the 35 % of patients in whom endoscopic evaluation was performed after CB ablation.60 More recent evidence has been published verifying that CB ablation is not free of oesophageal damage. John et al. reported that the incidence of atrio-oesophageal fistulas with CB ablation is similar to that of RF ablation (<1 in 10,000).12,61 Of note, they noted that there was a particular relationship between the left inferior pulmonary vein ablation and fistula formation. Prolonged CB inflation times were noted in the fistula occurrences. The authors proposed that real-time monitoring for temperature decline in the oesophagus should quickly prompt limiting energy delivery through this method.

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Oesophageal cooling systems are used to mitigate conductive heating to the oesophagus (therefore preventing ulceration due to thermal damage). Arruda et al. conducted an experimental model of an oesophagus cooling system, and the results were promising.62 By circulating fluid constantly at 5 or 10 °C and using a compliant system with adjustable circulating volume to avoid displacement of the oesophagus, high power (45 W) could be achieved. In a recent randomised controlled study, 100 patients who underwent RF ablation of AF were assigned to either oesophageal cooling with 5 mL of iced water or ablation without oesophageal cooling.63 The authors found that oesophageal lesions assessed by endoscopy might be less severe in the cooling group; however, no difference in the incidence was reported (20 and 22 %, respectively). Studies in larger populations are still needed to evaluate the true effectiveness of this method, and the practice is not currently recommended as routine according to the most recent consensus statement on AF ablation.32

Early Identification of a Suspected Atriooesophageal Injury In a recently published article by Kapur et al, a stepwise algorithm to an early detection of a potential atrio-oesophageal injury is described. A non-emergent evaluation that includes performing an upper endoscopy during the 72 hours following the procedure should be considered in patients with extreme temperature registered at the oesophageal probe during the procedure, have symptoms immediately after ablation and have a pre-existing oesophageal pathology.64 On the contrary, an emergent evaluation should be performed in all patients who present during the 6 weeks following the ablation with symptoms such as chest pain, fever or gastrointestinal or neurological symptoms along with the abovementioned characteristics for a non-emergent procedure. This emergent evaluation should include blood laboratory, transthoracic cardiac echocardiogram and chest CT with IV contrast.64 Despite the low incidence of fistula formation, early diagnosis and rapid surgical treatment are cornerstone in the management of this complication.

Conclusion Though rare, serious oesophageal injury during PVI and posterior wall ablation is still a major concern among electrophysiologists, particularly

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Electrophysiology and Ablation if left untreated, with a mortality rate of up to 100 % associated with atrio-oesophageal fistulas. In our practice and experience, we rely on a stepwise approach to prevent these potential complications. Several techniques have been described to prevent such injuries. We suggest obtaining pre- and intra-procedural oesophageal imaging to provide valuable information for ablation, given the high variability of oesophageal anatomy among patients. Despite its controversy, our group encourages the routine use of oesophageal intraluminal temperature monitoring probes during AF ablation. Mechanical displacement of the oesophagus appears feasible, safe and efficacious; nevertheless, randomised data are missing to evaluate the different tools available. Consistently in our procedures, when performing ablation lesions to the posterior wall, we prefer to use low irrigation parameters as this technique has been shown to be effective and seems to be a promising way to avoid oesophageal damage. We do not routinely use cryothermal energy ablation; however, it has been shown to have a lower incidence of oesophageal injury,64 though the data is not without debate and efficacy may be less than RFA. Given the low incidence of clinically significant events, such as atriooesophageal fistula, the development of strategies for the prevention of these potential complications is limited. As discussed in this review,

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 illinov AM, Pettersson G, Rice TW. Esophageal injury during G radiofrequency ablation for atrial fibrillation. J Thorac Cardiovasc Surg 2001;122:1239–40. PMCID: PMC3424480. Scanavacca MI, D’ÁVila A, Parga J, Sosa E. Left atrialesophageal fistula following radiofrequency catheter ablation of atrial fibrillation. J Cardiovasc Electrophysiol 2004;15:960–962. DOI: 10.1046/j.1540-8167.2004.04083.x; PMID: 15333097. Pappone C, Oral H, Santinelli V, et al. Atrio-esophageal fistula as a complication of percutaneous transcatheter ablation of atrial fibrillation. Circulation 2004;109:2724–6. DOI: 10.1161/01. CIR.0000131866.44650.46; PMID: 15159294. Schmidt M, Nolker G, Marschang H, et al. Incidence of oesophageal wall injury post-pulmonary vein antrum isolation for treatment of patients with atrial fibrillation. Europace 2008;10:205–9. DOI: 10.1093/europace/eun001; PMID: 18256125. Di Biase L, Saenz LC, Burkhardt DJ, et al. Esophageal capsule endoscopy after radiofrequency catheter ablation for atrial fibrillation: documented higher risk of luminal esophageal damage with general anesthesia as compared with conscious sedation. Circ Arrhyth Electrophysiol 2009;2:108–12. DOI: 10.1161/ CIRCEP.108.815266; PMID: 19808454. Helms A, West JJ, Patel A, et al. Real-time rotational ICE imaging of the relationship of the ablation catheter tip and the esophagus during atrial fibrillation ablation. J Cardiovasc Electrophysiol 2009;20:130–7. DOI: 10.1111/j.15408167.2008.01277.x; PMID: 18775048. Ho SY, Sanchez-Quintana D, Cabrera JA, et al. Anatomy of the left atrium: implications for radiofrequency ablation of atrial fibrillation. J Cardiovasc Electrophysiol 1999;10:1525–33. PMID: 10571372. Berjano EJ, Hornero F. What affects esophageal injury during radiofrequency ablation of the left atrium? An engineering study based on finite-element analysis. Physiol Meas 2005;26:837–48. DOI: 10.1088/0967-3334/26/5/020; PMID: 16088072. Shah D, Dumonceau JM, Burri H, et al. Acute pyloric spasm and gastric hypomotility: an extracardiac adverse effect of percutaneous radiofrequency ablation for atrial fibrillation. J Am Coll Cardiol 2005;46:327–30. DOI: 10.1016/j.jacc.2005.04.030; PMID: 16022963. Doll N, Borger MA, Fabricius A, et al. Esophageal perforation during left atrial radiofrequency ablation: Is the risk too high? J Thorac Cardiovasc Surg 2003; 125:836–42. DOI: 10.1067/ mtc.2003.165; PMID: 12698146. Cummings JE, Schweikert RA, Saliba WI, et al. Brief communication: atrial-esophageal fistulas after radiofrequency ablation. Ann Intern Med 2006;144:572–4. PMID: 16618954. Ghia KK, Chugh A, Good E, et al. A nationwide survey on the prevalence of atrioesophageal fistula after left atrial radiofrequency catheter ablation. J Interv Card Electrophysiol 2009;24:33–6. DOI: 10.1007/s10840-008-9307-1; PMID: 18836822. Cappato R, Calkins H, Chen SA, et al. Prevalence and causes of fatal outcome in catheter ablation of atrial fibrillation. J Am Coll Cardiol 2009;53:1798–803. DOI: 10.1016/j.jacc.2009.02.022; PMID: 19422987. Zellerhoff S, Ullerich H, Lenze F, et al. Damage to the esophagus after atrial fibrillation ablation: Just the tip of the iceberg? High prevalence of mediastinal changes diagnosed by endosonography. Circ Arrhythm Electrophysiol 2010;3:155–9. DOI: 10.1161/CIRCEP.109.915918; PMID: 20194799.

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the use of different surrogates, such as variation in oesophageal luminal temperature, remains controversial and more studies are needed to evaluate oesophageal injury prevention systems. n

Clinical Perspectives • O  esophageal injury prevention has become a major concern in the field of electrophysiology. • Oesophageal wall injury varies from erythema to ulceration, is common and has been described by endoscopy in up to 47 % of patients following pulmonary vein isolation (PVI). • Assessment of the anatomic relationship between the LA and the oesophagus prior to the procedure is of major importance. • Different techniques, including mechanical displacement of the oesophagus, intraluminal temperature monitoring, and adjusting to low irrigation parameters are options to be considered when performing lesions to the posterior wall in an attempt to avoid any potential injury. •  Emergent diagnostic procedures should be performed in patients with high suspicion of atrio-oesophageal fistula.

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Oesophageal Injury During AF Ablation

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Electrophysiology and Ablation

Asymptomatic Ventricular Pre-excitation: Between Sudden Cardiac Death and Catheter Ablation Josep Brugada 1 and Roberto Keegan 2 1. Cardiovascular Institute, Hospital Clinic and Paediatric Arrhythmia Unit, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain; 2. Electrophysiology Service, Private Hospital of the South, Bahia Blanca, Argentina

Abstract Debate about the best clinical approach to the management of asymptomatic patients with ventricular pre-excitation and advice on whether or not to invasively stratify and ablate is on-going. Weak evidence about the real risk of sudden cardiac death and the potential benefit of catheter ablation has probably prevented the clarification of action in this not infrequent and sometimes conflicting clinical situation. After analysing all available data, real evidence-based medicine could be the alternative strategy for managing this group of patients. According to recent surveys, most electrophysiologists invasively stratify. Based on all accepted risk factors – younger age, male, associated structural heart disease, posteroseptal localisation, ability of the accessory pathway to conduct anterogradely at short intervals of ≤250 milliseconds and inducibility of sustained atrioventricular re-entrant tachycardia and/or atrial fibrillation – a shared decisionmaking process on catheter ablation is proposed.

Keywords Wolff–Parkinson–White syndrome, pre-excitation, asymptomatic, sudden cardiac death, catheter ablation Disclosure: The authors have no conflicts of interest to declare. Received: 7 November 2017 Accepted: 15 February 2018 Citation: Arrhythmia & Electrophysiology Review 2018;7(1):32–8. DOI: 10.105420/aer.2017.51.2 Correspondence: Roberto Keegan, Servicio de Electrofisiologia, Hospital Privado del Sur y Hospital Español, Bahia Blanca, Argentina. E: robertokeegan@gmail.com

The best clinical approach to managing asymptomatic patients with ventricular pre-excitation has yet to be established. The clinical benefit of identifying and treating asymptomatic patients at risk of sudden cardiac death (SCD) has been debated since catheter ablation became effective and safe for the treatment of accessory pathways (APs). Data supporting current recommendations are mostly derived from observational studies, with few data coming from randomised clinical trials, and most studies only include a small number of patients. The very low incidence of SCD in asymptomatic patients reported by most studies has also contributed to the debate. As most patients are healthy young people who are expected to have a long life, a large, long-term randomised clinical trial evaluating mortality (no treatment versus catheter ablation) could provide the necessary evidence-based information to support recommendations. The impact that the low risk of SCD in asymptomatic patients with a chronic heart abnormality has on quality of life, career options and patients’ work life could also be considered. Evidencebased medicine has formed the basis of teaching and clinical practice for >20 years,1 but real evidence-based medicine has recently been proposed as a different approach to clinical decision-making based on expert judgment and sharing decisions with patients through meaningful conversations.2 This approach, taking into account the limitations of available evidence, could provide an alternative strategy for managing asymptomatic patients with ventricular pre-excitation.

Risk of Sudden Cardiac Death The prevalence of Wolff–Parkinson–White (WPW) syndrome in the general population has been estimated to be one to three per 1,000 individuals3–9 and 5.5 per 1,000 among the first-degree relatives of an index case.10 However, a recent nationwide retrospective study

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showed a lower general prevalence of 0.36 per 1,000 in the general population aged <50 years.11 Sixty per cent of asymptomatic patients with ventricular pre-excitation are estimated to be adolescents and 40 % are thought to be individuals >30 years.12–16 Anterograde conduction through the AP disappears in 40 % of patients in the first year of life12 and in a similar percentage of cases supraventricular tachycardia (SVT) becomes non-inducible, suggesting loss of retrograde conduction.17 In children and adolescents, the probability of losing pre-excitation varies from 0 to 26  %,18–20 while 13–30  % of adults lose anterograde conduction during 5-year follow-up.21,22 The rate of spontaneous arrhythmia observed during the follow-up of asymptomatic patients ranges from 8 to 21  %.15,23–26 Studies of people with WPW syndrome have found that atrial fibrillation (AF) develops in 15  % of adults and children followed up for 10 years.27,28 The assumed mechanism of SCD and ventricular fibrillation (VF) is rapid stimulation of the ventricles due to AF rapidly conducted through the AP.29 The incidence of SCD in WPW syndrome is reported to be between 0  % and 0.6  % per year.15,24,30,31 In symptomatic patients, the risk is 3–4 % over a lifetime (approximately 0.25 % per year);15,30 higher than in asymptomatic patients.32 Although most asymptomatic patients with pre-excitation have a good prognosis, there is also a lifetime risk of malignant arrhythmias and SCD, estimated to be 0.1 % per patient year.23,33–35 More worrisome is the fact that this event can be the first manifestation of the disease in up to 53 % of patients.12,29,36,37 Table 1 shows all-cause mortality in patients with WPW syndrome compared with matched individuals without the condition. Borregaard

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Between Sudden Cardiac Death and Catheter Ablation Table 1: All-cause Mortality in Patients with Wolff–Parkinson–White (WPW) Syndrome Compared to Matched Controls without WPW Paper

Study Type

Borregaard et al., 201438

Observational, single centre

Bunch et al., 201539

Retrospective, multicentre

Groups

No. of

Follow-up

All-cause

Participants

(years)

Mortality (%)

Ablation WPW

362

8.8

5.3

Control (no WPW)

3,619

Ablation WPW

872

p-value

Estimated Annual

NS

0.6

<0.0001

0.78

0.19

1.8

Mortality (%)

5.3 7.9 ± 5.4

6.1

No-ablation WPW

1,461

7.9 ± 6.2

19.6

Ablation + no-ablation WPW

2,333

7.9 ± 5.9

12.9

Control (no WPW)

11,175

7.5 ± 5.5

14.0

2.5

2.0

WPW = Wolff-Parkinson-White, NS = non-significant.

et al. found no difference between patients with WPW syndrome who underwent radiofrequency ablation when compared to an age- and gender-matched control group.38 However, different results were found by a recent multicentre system-wide retrospective study comparing the long-term results in three groups of patients: those with WPW who underwent ablation; those with WPW who did not undergo ablation; and age- and gender-matched individuals without WPW.39 The patients who underwent ablation were younger (39.2 ± 17.0 years) than those who did not (46.4 ± 19.6 years) and those in the control group (43.4 ± 19.0 years). They were less likely to have hypertension, diabetes, renal failure and coronary artery disease. The total mortality and cardiac arrest rates were similar between WPW patients (ablation and no ablation) and the control group. However, cardiac death was significantly higher in the WPW population than the control group (7 % versus 4.6  %, respectively; p<0.0001). The WPW patients who did not undergo ablation had a higher risk of death in the long-term, with a trend towards more cardiac arrests and cardiac deaths than patients who did receive ablation. In the propensity analysis, the ablated group had significantly lower mortality and cardiac death rates than the non-ablated group (6.1  % versus 11.6  % and 2.8  % versus 5.9  %, respectively). A large nationwide retrospective observational study including 6,086 WPW patients aged <50 years (41.5  % ablated) showed a low mortality of 0.69 % at 11 years.11 When catheter ablation was included in the risk analysis, this variable was associated with a significantly lower risk of mortality. A recent meta-analysis of 20 clinical studies40 showed an incidence of 0.85 SCD events (SCD/aborted or SCD/ventricular fibrillation) per 1,000 person-years, with individual rates ranging from 0.7 to 4.5 per 1,000 person-years. Although the incidence was higher in paediatric than adult patients (1.93 versus 0.86 per 1,000 person-years), this difference was not statistically significant (p=0.07). Interestingly, the risk of events was significantly higher in Italian studies (2.16 per 1,000 person-years) than in non-Italian studies (0.14 per 1,000 person-years) (p=0.008).40

Risk Factors Some clinical variables such as gender, younger age, structural heart disease and septal localisation of AP have been associated with a higher risk of SCD.

control group (87 % versus 67  %, p≤0.05).41 Added to this, the risk of SCD in female patients was markedly lower than in male patients in a recent meta-analysis.40

Age Fan et al. showed that some electrophysiological (EP) properties of the AP were associated with a higher risk of SCD. A shorter anterograde effective refractory period (AERP) of the bypass tract and pre-excited R-R interval during AF were significantly less prevalent in the older group (>50 years versus <30 years).42 However, in a group of 92 asymptomatic patients (10–69 years), Brembilla-Perrot et al. demonstrated that although STV was not inducible by trans-oesophageal stimulation in any patients aged 50–69 years, rapid conduction was seen throughout the AP in all groups (21 % in 10–69 year olds: 27 % in 20–29 year olds, 27 % in 30–39 year olds, 6 % in 40–49 year olds and 23 % in 50–69 year olds).43 They concluded that older patients remain at risk of threatening arrhythmias.

Physiology Structural heart disease is more frequent in patients with VF than those without VF in some32,41 but not all studies.44 Septal localisation (left posteroseptal, midseptal, anteroseptal and right posteroseptal) is significantly more frequent in patients with VF when compared with individuals with no VF.37 However, Klein et al. demonstrated that the localisation was no different between these groups.32 More recently, Pappone et al. found that a posteroseptal AP was present in 85 % of asymptomatic patients who experience VF (11/13) as a unique AP (7/11) or multiple APs (4/11).44

Electrophysiological Properties of AP As clinical variables have a modest power to identify patients at high risk of SCD, risk stratification has focused on the EP properties of the AP, see Table 2. The following characteristics have been related to the risk of developing AF with rapid conduction to the ventricles: • the ability to conduct anterogradely at very short intervals (≤ 250 milliseconds); •  the ability to sustain an atrioventricular reciprocant tachycardia (AVRT) for >1 minute (inducibility). This arrhythmia is the mechanism of AF initiation in most of patients with WPW syndrome; and • multiple APs.

Gender Timmermans et al. demonstrated that male gender was associated with a significantly higher rate of events than female gender (13 out of 15 events, p=0.04).37 Montoya et al. observed that male gender was significantly more prevalent in patients with VF than the

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Anterograde AP Conduction at Short Intervals Clinical and EP evaluations have been used to determine the anterograde AP conduction: • spontaneous exercise- or drug-induced loss of pre-excitation;

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Electrophysiology and Ablation Table 2: Risk Factors for Sudden Cardiac Death Clinical Risk Factor Male38,51,52 Age <30 years53 Structural heart disease33,51 Septal localisation38,55 Electrophysiological Properties of Accessory Pathways Anterograde accessory pathway conduction: • Loss of pre-excitation57,59 • Anterograde effective refractory periods ≤250 ms22,51 • Shortest pre-excited RR interval ≤250 ms33,63 Inducibility • A  trioventricular reciprocant tachycardia or atrial fibrillation lasting ≥1 min20,22 Multiple accessory pathways33,37,66,67

• A  ERP by programmed atrial stimulation (transvenous or transoesophageal EP study); • the shortest cycle length with one-to-one conduction by incremental atrial stimulation (transvenous or trans-oesophageal EP study); and • the shortest pre-excited R-R interval (SPERRI) during spontaneous or induced AF. Loss of pre-excitation observed spontaneously (intermittent preexcitation) during an electrocardiogram (ECG) or electrocardiographic monitoring (e.g. Holter) can be observed in up to 67 % of patients45 and is considered a predictor of poor anterograde conduction and low risk of SCD.46 However, although rare, cardiac arrest in patients with intermittent pre-excitation has been observed.25 Kiger et al. recently found that intermittent pre-excitation was present in 23.4 % of paediatric patients aged 1–18 years (13.2 % on baseline ECG and 10.2 % on exercise testing or Holter monitoring). They also found an absence of statistically significant differences in the prevalence of high-risk APs (AERP, block cycle length or SPERRI during AF of ≤250  milliseconds) between patients with intermittent and persistent pre-excitation. They concluded that intermittent pre-excitation in children cannot be considered a low-risk marker according to EP criteria.47 The abrupt and complete loss of pre-excitation seen during exercise testing has been demonstrated to correlate with a long AERP. 48 Two recent studies have evaluated exercise testing in 152 children with pre-excitation.49,50 Although the sudden loss of ventricular preexcitation during exercise had a specificity and positive predictive value of 100  %, its sensitivity was low (17.7  %). Consequently, most patients who undergo an exercise stress test will need complementary risk stratification. Furthermore, although infrequent, the sudden disappearance of pre-excitation during exercise was observed in a patient with a SPERRI of 180  milliseconds.51 On the other hand, sometimes the exercise stress test shows intermittent pre-excitation at rest and persistent pre-excitation during exercise, making risk stratification confusing.52 Sodium channel-blocking agents (procainamide, propafenone and ajmaline) have been used to determine the anterograde AP conduction. Loss of pre-excitation under these drugs has been correlated with a longer AERP.51,53,54 However, these pharmacological tests are now rarely used.

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An AERP ≤250 milliseconds is a frequent finding in patients with documented VF. A significantly shorter AERP was observed in 22 patients with VF (229 ± 51 milliseconds) compared to 100 patients without VF (280 ± 67 milliseconds).41 It was also observed in all three asymptomatic patients in a study who experienced VF during a mean follow-up of 37.7 months.22 Although most patients with VF have an AERP <250 milliseconds, the clinical utility of the AERP is limited as there is overlap between patients with and without VF.32 Sharma et al. observed an AERP of >250 milliseconds in 55 % of WPW patients with VF (5/9).55 Another potential limitation is the impossibility of measuring AERP because anterograde AP conduction frequently persists up to the atrial refractory period. Timmermans et al. were only able to measure the AERP in five out of 15 patients with VF.37 The shortest cycle length with one-to-one conduction by incremental atrial stimulation has been used to differentiate groups of patients with and without VF. Although all patients in the VF group were capable of anterograde conduction over the accessory pathway at cycle lengths of ≤300 ms, considerable overlap between groups was observed by Klein et al.32 Another possible limitation is the fact that sometimes it is not possible to evaluate this measurement because of the appearance of arrhythmias during incremental atrial pacing. Probably the most useful finding in risk stratification is SPERRI during AF. In a group of 25 patients with documented VF, the SPERRI was significantly shorter than in the 73 individuals in the control group (240 ± 63 milliseconds versus 180 ± 29 milliseconds) and did not exceed 250 milliseconds in any patient in the VF group.32 Sharma et al. found a mean SPERRI of 176 ± 33 milliseconds in WPW patients with VF and a SPERRI of ≤250 milliseconds in 78 % of these patients (7/9) compared to 52 % of those without VF (30/58).55

Inducibility In 2003, Pappone et al. published data from 212 asymptomatic patients with ventricular pre-excitation (mean age 33.6 ± 14 years, 64.8 % male) evaluated with a baseline EP study.22 At the end of a mean follow-up of 37.7 ± 16.1 months (range 14–60 months), 15.6 % of the group (33/212) had developed arrhythmic events. Of the patients that completed the follow-up EP study after 5 years, 29  % (47/162) were inducible, 10.5  % had non-sustained AF (2.5  % with isoproterenol), 12  % had sustained AVRT (5.5  % with isoproterenol) and the remaining 6.5  % had AVRT that degenerated into totally pre-excited sustained AF. Of the 20  % of patients that became symptomatic due to spontaneous arrhythmias (33/162, mean age 20 ± 8.6 years), SVT was documented in three-quarters (25/162) and AF in a quarter (8/162). VF was documented in 1.8  % of patients (3/162), all of whom had previously documented AF; two were aborted SCDs and one was a sudden death. The group of patients that became symptomatic were younger and had a significantly shorter AERP (246.6 ± 27.5 milliseconds) than patients who continued to be asymptomatic (283 ± 29.9 milliseconds). Inducibility (sustained AVRT or AVRT triggering AF) was found to be a better predictor of arrhythmic events than AERP. All three patients who experienced VF had multiple APs, an AERP ≤250 milliseconds and were inducible (SVT triggering AF). Only 3.5 % of non-inducible patients (4/115) became symptomatic during follow-up, suggesting that noninducibility has a good negative predictive value. In 2009, Santinelli et al. presented the results of a longer prospective observational study of 293 adults with asymptomatic pre-excitation (median age 36 years, 61.4  % male) in whom a baseline EP study

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Between Sudden Cardiac Death and Catheter Ablation evaluating inducibility was performed (reproducible induction of AVRT or AF lasting at least 1 minute).20 The occurrence of a first arrhythmic event was determined during a median follow-up of 67 months (range 8–90 months). Arrhythmic events appeared within a median followup of 27 months (range 8–55 months) in 10.5 % of patients (31/293) with a median age of 25 years: 5 % had AVRT (14/293) and 5.5 % had potentially life-threatening arrhythmias (1.5  % AVRT degenerating into AF and 4  % with AF). In the multivariate Cox analysis, younger age, AERP ≤250 milliseconds and inducibility were predictors of total and potentially life-threatening events. There was a high predictive positive value of 80 % when all three factors were present. In the most recent, largest and longest single-centre, prospective, observational study by Pappone et al., 2,169 symptomatic and asymptomatic patients were divided into two groups according to their decision whether or not to undergo catheter ablation.44 At the end of the follow-up period (>8 years), a total of 756 patients (35  %) were asymptomatic: 206 that were ablated and 550 that were not. After a median follow-up of 22 months (range 15–41 years), 13 non-ablated asymptomatic patients developed VF (aborted cardiac arrest in all cases). An additional 48 asymptomatic patients experienced AF with a SPERRI ≤250 milliseconds after a median follow-up of 46.5 months (range 36.0–58.5 months). All of these patients were successfully ablated immediately after the event. All 13 asymptomatic patients that experienced VF had a SPERRI ≤240 milliseconds, multiple APs were present in 31 % (4/13) and 69 % (9/13) were inducible for AVRT triggering AF. Cox proportional hazards model showed that VF and AF with a SPERRI ≤250 milliseconds were independently associated with short AERP (≤240 milliseconds) and inducibility of AVRT degenerating into AF. Di Mambro et al. showed that the EP properties of APs, including the SPERRI, assessed by trans-oesophageal EP study in asymptomatic paediatric patients (n=73) were similar to symptomatic patients (n=51).56 The only difference was a higher rate of orthodromic AVRT non-rest inducibility (mostly isoproterenol infusion) in symptomatic patients. They concluded that the potential risk of SCD in asymptomatic patients based on SPERRI measurement seems to be similar to that in symptomatic patients but that asymptomatic individuals were ‘protected’ by a lower rate of AVRT inducibility.

Isoproterenol Challenge Observational data have shown that isoproterenol can modify the EP properties of APs and inducibility of supraventricular arrhythmia in patients with ventricular pre-excitation. Pauriah et al. demonstrated a significantly shorter atrial CL with one-to-one conduction (194 ± 15 milliseconds versus 223 ± 30 milliseconds) and AERP (191 ± 18 versus 225 ± 28) under isoproterenol in severely symptomatic adult patients while no difference in inducibility was found.57 De Ponti et al. observed a significantly shorter SPERRI and AERP in a group of 40 asymptomatic patients with persistent pre-excitation at exercise stress test who had a SPERRI >250 milliseconds and no AVRT inducible at baseline.58 Kubus et al. identified an additional 36.4  % of high-risk patients (SPERRI/shortest cycle length with one-to-one conduction ≤250 milliseconds or AERP ≤250 milliseconds; or STV inducibility) with isoproterenol when high-risk parameters were absent at baseline EP study in a group of 85 asymptomatic paediatric patients with persistent pre-excitation at maximum exercise.59 According to the recommendations for competitive sports participation in athletes with cardiovascular disease, asymptomatic athletes with pre-excitation and a SPERRI <220 milliseconds during effort or isoproterenol infusion

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are considered to be at increased risk of SCD.60 When conscious sedation/general anaesthesia is used, particularly in children, the use of isoproterenol may evoke real adrenergic stimulation and can better characterise the anterograde conduction of the AP. Although the role of isoproterenol challenge has yet to be clearly defined, it seems reasonable to look for high-risk EP parameters under isoproterenol when they are absent at baseline EP study.

Multiple Accessory Pathways The recognition of multiple APs can be difficult without a complete EP study. Although in some studies this variable was not associated with higher risk,37,61 most of the data have shown that the presence of multiple APs is a risk factor for SCD.32,36,62,63

Catheter Ablation Catheter ablation is an effective and safe method of curing arrhythmias related to APs. Data derived from single-centre experience, multicentre prospective studies and registries have shown a success rate ≥90 % and a low rate of complications (≤ 5 %).64–71 However, fatal complications related to the procedure have been communicated. Hindricks et al. reported 0.13 % mortality in a group of 222 patients: one patient died because of massive stroke 8 days after ablation, another patient developed lethal cardiac tamponade 3 days after the procedure and one patient died suddenly 24 days after ablation.66 Scheinman et al. reported four deaths following a total of 5,427 AP ablations (0.08  %).67 Lu et al. reported 0.16  % mortality associated with WPW ablation (4/2,527 in an 11-year period).11 More recently, one death due to embolism in a patient with Ebstein’s anomaly was reported in 4,603 AP ablations (0.08  %) by the First Latin American Catheter Ablation Registry.71 The result of prophylactic catheter ablation in asymptomatic patients was first evaluated in a randomised clinical trial of patients from two centres in 2003.26 A total of 76 high-risk patients (≤35 years old with reproducibly-induced arrhythmias) out of 224 eligible patients were enrolled. In the final analysis, 35 control patients and 37 ablation patients were compared. In a median of 27 months (range 9–60 months) of follow-up, there were two arrhythmic events (5  %) in the ablation group where the atrioventricular nodal re-entrant tachycardia was successfully ablated. After a median follow-up of 15 months (range 8–53 months), 60 % of the control group patients had experienced an arrhythmic event (15 had SVT, five had AF and one had VF as a first manifestation with previous AVRT triggering AF, a SPERRI of 200  milliseconds and multiple septal APs). The estimated 5-year arrhythmic event rate was significantly higher in the control group (77  %) than the ablation group (7  %); ablation led to a risk reduction of 92 %. No major complications were observed in the ablation group and no patients died. In 2004, a randomised clinical trial evaluated the results of prophylactic catheter ablation in children with asymptomatic preexcitation.63 Out of 165 eligible patients aged 5–12 years, 60 high-risk patients (with reproducibly-induced ARVT or AF) were randomised to control or ablation. During a median follow-up of 34 months (range 19–44 months), 27 control patients and 20 ablation patients were compared. One 11-year-old ablation patient had an atrioventricular reciprocant tachycardia (AVRT) 21 months after the ablation of two APs. In contrast, after a median follow-up of 19 months (range 16–22 months), an arrhythmic event was detected in 44  % of the control patients (12/27). Of these, symptomatic arrhythmias (AVRT in five

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Electrophysiology and Ablation Table 3: Incidence of Sudden Cardiac Death Population

0.05–0.94

group (among the 1,168 patients, 206 were asymptomatic), no deaths were associated with the procedure and there was a very low rate of major complications (complete atrioventricular block in 0.08 %). Kaplan–Meier analysis at 8 years showed that catheter ablation was associated with a significantly better survival free from malignant arrhythmias (AF lasting >1 minute with a SPERRI ≤250  milliseconds) and from VF.

0.09

Discussion

Sudden Cardiac Death Rate*

Asymptomatic pre-excitation Including Italian studies55 • Excluding Italian studies52

2.4

General population • 0–35 years72 • 1–35 years

• 14–35 years

Loss of pre-excitation (e.g. ECG, Holter monitoring, exercise stress test, etc)

There are varying epidemiological data on the risk of SCD in the natural history of asymptomatic patients. When some populations are excluded (i.e. Italian studies), the rate of SCD is similar to that observed in the general population. Therefore, it is possible that the real incidence of SCD is still unknown, see Table 3.44,72-75 Although low or very low, the presence of pre-excitation in an asymptomatic, generally young, healthy people adds a definite risk of SCD. There is also a very low but definite risk of mortality associated with catheter ablation. Although evidence from randomised clinical trials demonstrates the benefit of catheter ablation, it may not support a Class I indication because these studies are not multicentre trials and the number of patients included is low.26,63 Consequently, a large, long-term, multicentre randomised clinical trial of catheter ablation in asymptomatic patients would provide the best evidence on which to recommend treatment. However, for many reasons, this kind of study maybe never be performed.

No high-risk factors

Chevalier et al. performed a sensitivity analysis to compare two management strategies in asymptomatic patients: no treatment and catheter ablation. The hypothetical study – which was scheduled to run for 10 years – was based on a decision tree model, the hypothetical population – aged between 20 and 40 years – did not undergo an initial risk stratification, and the risk of recurrence after initially successful catheter ablation and cryotherapy were not taken into consideration.76

0.028

73

74

• 35–49 years75

0.032 0.13

*Per 1,000 person-years.

Figure 1: ‘Real’ Evidence-based Medicine Approach to Treating Asymptomatic Patients Asymptomatic pre-excitation

NO loss of pre-excitation (e.g. ECG, Holter monitoring, exercise stress test, etc)

Electrophysiology study

High-risk factors present*

Catheter ablation

Follow-up

*Structural heart disease; anterograde accessory pathway conduction at intervals ≤250 ms (anterograde effec-tive refractory period or shortest pre-excited RR interval during atrial fibrillation); inducibility (sustained atrioventricular reciprocant tachycardia or atrial fibrillation); and multiple accessory pathways. ECG = electrocardiogram.

patients and AF in two patients) were documented in 26 % of patients (six boys and one girl) and Holter-documented silent episodes of sustained AF were observed in 18  % (five patients). After declining radiofrequency ablation, one 10-year-old died suddenly and another two patients experienced VF. All three patients were boys, had multiple APs and inducible AVRT and AF. The freedom from arrhythmic events was significantly higher in the ablation group compared with the control group. Independent predictors of arrhythmic events were the absence of prophylactic ablation (hazard ratio [HR] 69.4; 95  % confidence interval [CI] 5.1–950; p=0.001) and multiple accessory pathways (HR 12.1; 95 % CI 1.7–88.2; p=0.01). The estimated number of high-risk patients needed to treat to prevent arrhythmic events in one patient was two (95 % CI 1.4 to 3.1). Although there was a high percentage of total complications associated with EP study (15  %) and catheter ablation (5  %), most were minor complications and no death occurred. In the largest and longest single-centre, prospective, observational study, Pappone et al. observed a success rate of 98.5 % in the ablation

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They concluded that when the risk of sudden death was at least 1.5 out of 1,000 patients per year, radiofrequency catheter ablation with a success rate of 95 % is superior to abstention. However, the result of this study has not been widely accepted.76 Limitations in current evidence have led to continued debate about what to recommend these patients. Current guidelines recommend an EP study as a Class IIA (level of evidence B/C) indication when loss of pre-excitation is not observed during non-invasive risk stratification. Catheter ablation is a Class IIA (level of evidence B/C) indication for young asymptomatic patients (aged 8–21 years) with WPW pattern when a SPERRI is ≤250 ms during induced AF at an EP study, whatever the risk of the procedure when localisation of the APs has been taken into account.77 The most recent American College of Cardiology/American Heart Foundation/Heart Rhythm Society guideline recommends catheter ablation as a Class IIA recommendation in asymptomatic patients when an EP study (also a Class IIA recommendation) stratifies the patient at high-risk for arrhythmic events or if the pre-excitation precludes specific employment (such as pilots). Although the level of evidence supporting the indication is considered B-NR (moderate-quality evidence from nonrandomised, observational or registry studies), one of the studies included is the only randomised clinical trial demonstrating the benefit of prophylactic catheter ablation in patients of ≥13 years of age. A recent systematic review, including nine previously analysed studies (eight uncontrolled prospective cohort studies), concluded that an EP study for risk stratification along with AP ablation in cases with a high risk of future arrhythmias may be beneficial.78

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Between Sudden Cardiac Death and Catheter Ablation The main argument against studying and treating asymptomatic patients has been the poor predictive accuracy (low specificity and low positive predictive value) of non-invasive and invasive risk stratifiers due to the low event rate of SCD. Many patients would be unnecessarily treated and exposed to the risks of EP study and catheter ablation if all such asymptomatic patients were treated. A negative predictive value of <100 % will leave some patients exposed to an avoidable risk of SCD and according to published surveys, in clinical practice most electrophysiologists choose to invasively stratify and ablate this group of asymptomatic patients.79,80 Pappone et al. showed that 70  % of electrophysiologists performed an EP study for risk stratification and prophylactic ablation 80 and Campbell et al. that 84 % of paediatric electrophysiologists used some form of

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 vidence-Based Medicine Working Group. EvidenceE based medicine. A new approach to teaching the practice of medicine. JAMA 1992;268:2420–5. DOI: 10.1001/ jama.268.17.2420; PMID: 1404801. Greenhalgh T, Howick J, Maskrey N. Evidence Based Medicine Renaissance Group. Evidence based medicine: a movement in crisis? BMJ 2014;348:g3725. DOI: 10.1136/bmj.g3725; PMID: 24927763. Hejtmancik MR, Herrmann GR. The electrocardiographic syndrome of short P-R interval and broad QRS complexes; a clinical study of 80 cases. Am Heart J 1957;54:708–21. DOI: 10.1016/0002-8703(57)90425-8. Averill KH, Fosmoe RJ, Lamb LE. Electrocardiographic findings in 67,375 asymptomatic subjects. IV. Wolff-Parkinson-White syndrome. Am J Cardiol 1960;6:108–29. DOI: 10.1016/0002-9149(60)90041-2. Manning GW. An electrocardiographic study of 17,000 fit, young Royal Canadian Air Force aircrew applicants. Am J Cardiol 1960;6:70–5. DOI: 10.1016/0002-9149(60)90037-0; PMID: 14420704. Hiss RG, Lamb LE. Electrocardiographic findings in 122,043 individuals. Circulation 1962;25:947–61. DOI: 10.1161/01. CIR.25.6.947; PMID: 13907778. Swiderski J, Lees MH, Nadas AS. The Wolff-Parkinson-White syndrome in infancy and childhood. Br Heart J 1962;24:561–80. DOI: 10.1136/hrt.24.5.561; PMID: 13979704. Davidoff R, Schamroth CL, Myburgh DP. The Wolff-ParkinsonWhite pattern in health aircrew. Aviat Space Environ Med 1981;52:554–8. PMID: 7283906. Guize L, Soria R, Chaouat JC, et al. Prevalence and course of Wolf-Parkinson-White syndrome in a population of 138,048 subjects. Ann Med Interne (Paris) 1985;136:474–8 [in French]. PMID: 4083638. Vidaillet HJJ, Pressley JC, Henke E, et al. Familial occurrence of accessory atrioventricular pathways (preexcitation syndrome). N Engl J Med 1987;317:65–9. DOI: 10.1056/ NEJM198707093170201; PMID: 3587328. Lu CW, Wu MH, Chen HC, et al. Epidemiological profile of Wolff-Parkinson-White syndrome in a general population younger than 50 years of age in an era of radiofrequency catheter ablation. Int J Cardiol 2014;174:530–4. DOI: 10.1016/j. ijcard.2014.04.134; PMID: 24798784. Deal BJ, Keane JF, Gillette PC, Garson A, Jr. Wolff-ParkinsonWhite syndrome and supraventricular tachycardia during infancy: management and follow-up. J Am Coll Cardiol 1985;5:130–5. DOI: 10.1016/S0735-1097(85)80095-4; PMID: 3964800. Becquart J, Vaksmann G, Becquart V, Dupuis C. Prognosis of Wolff-Parkinson-White syndrome in infants. Apropos of 31 cases. Arch Mal Coeur Vaiss 1988;81:695–700 [in French]. PMID: 3136732. Soria R, Guize L, Chretien JM, et al. The natural history of 270 cases of Wolff-Parkinson-White syndrome in a survey of the general population. Arch Mal Coeur Vaiss 1989;82:331–6 [in French]. PMID: 2502088. Munger TM, Packer DL, Hammill SC, et al. A population study of the natural history of Wolff-Parkinson-White syndrome in Olmsted County, Minnesota, 1953-1989. Circulation 1993;87:866–73. DOI: 10.1161/01.CIR.87.3.866; PMID: 8443907. Goudevenos JA, Katsouras CS, Graekas G, et al. Ventricular pre-excitation in the general population: a study on the mode of presentation and clinical course. Heart 2000;83:29–34. DOI: 10.1136/heart.83.1.29; PMCid:PMC1729271. Benson DW, Dunnigan A, Benditt DG. Follow-up evaluation of infant paroxysmal atrial tachycardia: transesophageal study. Circulation 1987;75:542–9. DOI: 10.1161/01.CIR.75.3.542; PMID: 3815766. Perry JC, Garson A. Supraventricular tachycardia due to WolffParkinson-White syndrome in children: early disappearance and late recurrence. J Am Coll Cardiol 1990;16:1215–20. DOI: 10.1016/0735-1097(90)90555-4; PMID: 2229769. Sarubbi B, Scognamiglio G, Limongelli G, et al. Asymptomatic ventricular pre-excitation in children and adolescents: a 15 year follow up study. Heart 2003;89:215–7. DOI: 10.1136/ heart.89.2.215.

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EP study to risk-stratify asymptomatic children with ventricular preexcitation.79 Consequently, and taking into account these data, most electrophysiologists are managing asymptomatic patients according to ‘real’ evidence-based medicine. 2 After a critical analysis of the available evidence, expert judgment, discussing the risks and benefits of the procedure – including potential benefits beyond mortality, such as better quality of life – an EP study to stratify risk and an ablation procedure should be considered when accepted high-risk factors are present and whenever the risk of complications judged by localisation is low (i.e. atrioventricular block risk in the para-Hisian and mid-septal regions), see Figure 1. This strategy seems to be more accepted than conservative management in clinical practice. n

20. S  antinelli V, Radinovic A, Manguso F, et al. The natural history of asymptomatic ventricular pre-excitation a long-term prospective follow-up study of 184 asymptomatic children. J Am Coll Cardiol 2009;53:275-80. DOI: 10.1016/j.jacc.2008.09.037; PMID: 19147045. 21. Klein GJ, Prystowsky EN, Yee R, et al. Asymptomatic Wolff-Parkinson-White. Should we intervene? Circulation 1989;80:1902–5. DOI: 10.1161/01.CIR.80.6.1902; PMID: 2486558. 22. Pappone C, Santinelli V, Rosanio S, et al. Usefulness of invasive electrophysiologic testing to stratify the risk of arrhythmic events in asymptomatic patients with WolffParkinson-White pattern: results from a large prospective long-term follow-up study. J Am Coll Cardiol 2003;41:239–44. DOI: 10.1016/S0735-1097(02)02706-7; PMID: 12535816. 23. Berkman NL, Lamb LE. The Wolff-Parkinson-White electrocardiogram. A follow-up study of five to twentyeight years. N Engl J Med 1968;278:492–4. DOI: 10.1056/ NEJM196802292780906; PMID: 5636675. 24. Leitch JW, Klein GJ, Yee R, Murdock C. Prognostic value of electrophysiology testing in asymptomatic patients with Wolff-Parkinson-White pattern. Circulation 1990;82:1718–23. DOI: 10.1161/01.CIR.82.5.1718; PMID: 2225373.  25. Fitzsimmons PJ, McWhirter PD, Peterson DW, Kruyer WB. The natural history of Wolff-Parkinson-White syndrome in 228 military aviators: a long-term follow-up of 22 years. Am Heart J 2001;142:530–6. DOI: 10.1067/mhj.2001.117779; PMID: 11526369.  26. Pappone C, Santinelli V, Manguso F, et al. A randomized study of prophylactic catheter ablation in asymptomatic patients with the Wolff-Parkinson-White syndrome. N Engl J Med 2003;349:1803–11. DOI: 10.1056/NEJMoa035345; PMID: 14602878.  27. Fukatani M, Tanigawa M, Mori M, et al. Prediction of a fatal atrial fibrillation in patients with asymptomatic WolffParkinson-White pattern. Jpn Circ J 1990;54:1331–9. DOI: 10.1253/jcj.54.10_1331; PMID: 2277412.  28. Pietersen AH, Andersen ED, Sandoe E. Atrial fibrillation in the Wolff-Parkinson-White syndrome. Am J Cardiol 1992;70:38A– 43A. DOI: 10.1016/0002-9149(92)91076-G 29. Dreifus LS, Haiat R, Watanabe Y, et al. Ventricular fibrillation. A possible mechanism of sudden death in patients and WolffParkinson-White syndrome. Circulation 1971;43:520–7. DOI: 10.1161/01.CIR.43.4.520; PMID: 5573385. 30. Flensted-Jensen E. Wolff-Parkinson-White syndrome. A longterm follow-up of 47 cases. Acta Med Scand 1969;186:65–74. PMID: 5807647  31. Soria R, Guize L, Chretien JM, et al. The natural history of 270 cases of Wolff-Parkinson-White syndrome in a survey of the general population. Arch Mal Coeur Vaiss 1989;82:331–6 [in French]. PMID: 2502088. 32. Klein GJ, Bashore TM, Sellers TD, et al. Ventricular fibrillation in the Wolff-Parkinson-White syndrome. N Engl J Med 1979; 301:1080–5. DOI: 10.1056/NEJM197911153012003; PMID: 492252. 33. Smith RF. The Wolff-Parkinson-White syndrome as an aviation risk. Circulation 1964;29:672–9. DOI: 10.1161/01.CIR.29.5.672; PMID: 14153940.  34. Guize L, Soria R, Chaouat JC, et al. Prevalence and course of Wolf-Parkinson-White syndrome in a population of 138,048 subjects. Ann Med Interne (Paris) 1985;136:474–8 [in French]. PMID: 4083638. 35. Milstein S, Sharma AD, Klein GJ. Electrophysiologic profile of asymptomatic Wolff-Parkinson-White pattern. Am J Cardiol 1986;57:1097–100. DOI: 10.1016/0002-9149(86)90681-8; PMID: 3706161. 36. Della Bella P, Brugada P, Talajic M, et al. Atrial fibrillation in patients with an accessory pathway: importance of the conduction properties of the accessory pathway. J Am Coll Cardiol 1991;17:1352–6. DOI: 10.1016/S0735-1097(10)80146-9; PMID: 2016453. 37. Timmermans C, Smeets JL, Rodriguez LM, et al. Aborted sudden death in the Wolff-Parkinson-White syndrome. Am J Cardiol 1995;76:492–4. DOI: 10.1016/S0002-9149(99)80136-2; PMID: 7653450. 38. Borregaard R, Lukac P, Gerdes C, et al. Radiofrequency

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Electrophysiology and Ablation PMID: 7137035. 55. S  harma AD, Yee R, Guiraudon G, Klein GJ. Sensitivity and specificity of invasive and noninvasive testing for risk of sudden death in Wolff-Parkinson-White syndrome. J Am Coll Cardiol 1987;10:373–81. DOI: 10.1016/S0735-1097(87)80021-9; PMID: 3598007. 56. Di Mambro C, Russo MS, Righi D, et al. Ventricular preexcitation: symptomatic and asymptomatic children have the same potential risk of sudden cardiac death. Europace 2015;17:617–21. DOI: 10.1093/europace/euu191; PMID: 25142741. 57. Pauriah M, Cismaru G, Sellal JM, et al. Is isoproterenol really required during electrophysiological study in patients with Wolff-Parkinson-White syndrome? J Electrocardiol 2013;46:686– 92. DOI: 10.1016/j.jelectrocard.2012.12.019; PMID: 23313385. 58. De Ponti R, Marazzi R, Doni LA, et al. Invasive electrophysiological evaluation and ablation in patients with asymptomatic ventricular pre-excitation persistent at exercise stress test. Europace 2015;17:946–52. DOI: 10.1093/europace/ euu324; PMID: 25600768. 59. Kubus P, Vit P, Gebauer RA, et al. Electrophysiologic profile and results of invasive risk stratification in asymptomatic children and adolescents with the Wolff-Parkinson-White electrocardiographic pattern. Circ Arrhythm Electrophysiol 2014;7:218–23. DOI: 10.1161/CIRCEP.113.000930; PMID: 24488978. 60. Pelliccia A, Fagard R, Bjornstad HH, et al. Recommendations for competitive sports participation in athletes with cardiovascular disease: a consensus document from the Study Group of Sports Cardiology of the Working Group of Cardiac Rehabilitation and Exercise Physiology and the Working Group of Myocardial and Pericardial Diseases of the European Society of Cardiology. Eur Heart J 2005;26:1422–45. DOI: 10.1093/eurheartj/ehi325; PMID: 15923204. 61. Mabo P, Lelong B, Kennxrec A, et al. Devenier à long terme d’une série hospitalière de patients ayant one voie de conduction accessoire auriculo-ventriculaire. Arch Mal Coeur Vaiss 1992;85:1535–43 [in French]. PMID: 1363771  62. Teo WS, Klein GJ, Guiraudon GM, et al. Multiple accessory pathways in the Wolff-Parkinson-White syndrome as a risk factor for ventricular fibrillation. Am J Cardiol 1991;67:889–91. DOI: 10.1016/0002-9149(91)90626-V; PMID: 2011990. 63. Pappone C, Manguso F, Santinelli R, et al. Radiofrequency ablation in children with asymptomatic Wolff-Parkinson-White syndrome. N Engl J Med 2004;351:1197–205. DOI: 10.1056/ NEJMoa040625; PMID: 15371577. 64. Calkins H, Sousa J, el-Atassi R, et al. Diagnosis and

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science. 2009;178(3):257-61. 75. M  orentin B, Audicana C. Population-based study of outof-hospital sudden cardiovascular death: incidence and causes of death in middle-aged adults. Revista española de cardiologia. 2011;64(1):28-34. 76. Chevalier P, Cadi F, Scridon A, et al. Prophylactic radiofrequency ablation in asymptomatic patients with Wolff-Parkinson-White is not yet a good strategy: a decision analysis. Circ Arrhythm Electrophysiol 2013;6:185–90. DOI: 10.1161/ CIRCEP.112.970459; PMID: 23362302. 77. Hamilton RM. Letter by Hamilton regarding article, “Prophylactic radiofrequency ablation in asymptomatic patients with Wolff-Parkinson-White is not yet a good strategy: a decision analysis”. Circ Arrhythm Electrophysiol 2013;6:e38. DOI: 10.1161/CIRCEP.113.000472; PMID: 23778253.  78. C ohen MI, Triedman JK, Cannon BC, et al. PACES/HRS expert consensus statement on the management of the asymptomatic young patient with a Wolff-Parkinson-White (WPW, ventricular preexcitation) electrocardiographic pattern: developed in partnership between the Pediatric and Congenital Electrophysiology Society (PACES) and the Heart Rhythm Society (HRS). Endorsed by the governing bodies of PACES, HRS, the American College of Cardiology Foundation (ACCF), the American Heart Association (AHA), the American Academy of Pediatrics (AAP), and the Canadian Heart Rhythm Society (CHRS). Heart Rhythm 2012;9:1006–24. DOI: 10.1016/j.hrthm.2012.03.050; PMID: 22579340.  79. Al-Khatib SM, Arshad A, Balk EM, et al. Risk Stratification for Arrhythmic Events in Patients With Asymptomatic PreExcitation: A Systematic Review for the 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. J Am Coll Cardiol 2016;67:1624–38. DOI: 10.1016/j. jacc.2015.09.018; PMID: 26409260. 80. Campbell RM, Strieper MJ, Frias PA, et al. Survey of current practice of pediatric electrophysiologists for asymptomatic Wolff-Parkinson-White syndrome. Pediatrics 2003;111:e245–7. DOI: 10.1542/peds.111.3.e245; PMID: 12612279.  81. Pappone C, Radinovic A, Santinelli V. Sudden death and ventricular preexcitation: is it necessary to treat the asymptomatic patients? Curr Pharm Des 2008;14:762–5. DOI: 10.2174/138161208784007662; PMID: 18393875. 

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Clinical Arrhythmias

Systematic Screening for Atrial Fibrillation in the Community: Evidence and Obstacles Ngai-Yin Chan Department of Medicine and Geriatrics, Princess Margaret Hospital, Hong Kong, China

Abstract With an ageing population globally, the burden of atrial fibrillation (AF) and its consequent complication of stroke and risk of mortality will continue to increase. Although opportunistic screening for AF by pulse check or ECG rhythm strip for people >65 years of age is currently recommended, data are now emerging that demonstrate the possible benefits of systematic community screening. Such screening is capable of identifying previously undiagnosed AF in 0.5–3.0 % of all those screened. The effectiveness of screening programmes will be markedly weakened by the lack of a structured downstream management pathway, making it a mandatory component in any AF screening programme for the general population. Different tools, especially smartphone-based devices, have made AF screening in the community more feasible. However, the sensitivities and positive predictive values of the current versions of automated diagnostic algorithms for AF have to be improved further to increase the cost-efficiency of screening programmes.

Keywords Atrial fibrillation, screening, stroke, community, smartphone ECG, prevention Disclosure: The author has no conflicts of interest to declare. Received: 6 November 2017 Accepted: 1 February 2018 Citation: Arrhythmia & Electrophysiology Review 2018;7(1):39–42. DOI: 10.15420/aer.2017.47.2 Correspondence: Dr Ngai-Yin Chan, Room 223, Block J, Princess Margaret Hospital, 2–10 Princess Margaret Hospital Road, Lai Chi Kok, Kowloon, Hong Kong, China. E: ngaiyinchan@yahoo.com.hk

Atrial fibrillation (AF) is the most common sustained heart rhythm disorder1 and in a recently conducted community screening programme in Hong Kong the total burden of AF in the population was estimated to be 0.77 % in 2016. This is predicted to increase to 1.1 % in 2030 due to population ageing, see Figure 1.2 As in other developed countries and regions with ageing populations, AF has become an epidemic condition. Although the risk of stroke related to AF can be reduced by 64–70  % by oral anticoagulation,3 underutilisation of this effective treatment and delayed diagnosis remain major obstacles. Around a quarter of patients have silent or asymptomatic AF4 and up to 25 % of patients with AF-related stroke only have this arrhythmia diagnosed at the time of the stroke.4–6 Current European Society of Cardiology guidelines recommend opportunistic screening for AF by pulse taking or ECG rhythm strip instead of a systematic approach in people >65 years of age.3 In fact, in a randomised controlled study, systematic and opportunistic screening in a primary care setting in England detected similar numbers of new AF cases.7 This review article therefore discusses the current evidence for and obstacles to systematic community screening for AF.

implantable loop recorders to document silent AF in stroke patients is a Class IIa indication. Lastly, systematic ECG screening to detect AF is only recommended as a Class IIb indication in those >75 years or who are at high stroke risk. Screening for AF has recently been tested in different settings using different tools.9 Various models of systematic community-based AF screening programmes have been reported on.

Systematic AF Screening in the Community Large-scale systematic AF screening in the community (>4,000 individuals) has been conducted in different countries and regions, see Table 2. In the US Cardiovascular Health Study, a population-based longitudinal study of risk factors for coronary artery disease and stroke, a random sample of citizens from Medicare eligibility lists from four communities was recruited.10 A response rate of 57.6 % was achieved and 12-lead ECG was performed in 5,151 patients. AF was detected in 277 (5.4 %) of participants, with 77 (1.5 %) previously being undiagnosed.

Current AF Screening Recommendations AF satisfies most of the World Health Organization criteria for a disease suitable for screening, see Table 1.8 The European Society of Cardiology guidelines recommend opportunistic screening for AF, as outlined above, short term followed by continuous ECG monitoring for at least 72 hours in patients with transient ischaemic attack or ischaemic stroke, and regular interrogation of pacemakers and implantable cardioverterdefibrillators for atrial high-rate episodes (Class I recommendations).3 Additional ECG monitoring by long-term non-invasive ECG monitors or

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The US Reasons for Geographic and Racial Differences in Stroke (REGARDS) study was designed to investigate the racial and regional disparities in stroke incidence.11 Individuals were recruited from a commercially available list of residents. Two groups of individuals known to have high stroke mortality rates, including black Americans and residents of the southeastern “stroke belt region”, were overrepresented in the total study sample. By using a combination of mail and telephone contact, a 49 % participation rate was achieved. Of the

Access at: www.AERjournal.com

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Clinical Arrhythmias Figure 1: Estimated Prevalence of Atrial Fibrillation in Hong Kong 1.2 48

Percentage of population

1 0.8

%

1.1 %

0.77 %

0.6 0.4 0.2 0

Year 2016

Year 2030

Table 1: Suitability of Atrial Fibrillation for Screening According to World Health Organization Criteria Criteria

Suitability

Important health problem with an accepted treatment

+

Facilities for diagnosis and treatment

+

Latent and symptomatic stage

+

Natural history is understood

±

Agreed policy on whom to treat

+

Cost of finding the condition is economically balanced with overall health benefits of treatment

±

Case-finding is a continuous process

+

Screening test is suitable and acceptable to the population

+

+ = suitable; ± = uncertain.

total 29,861 participants, AF was revealed in 432 people by seven- or 12-lead ECG. Of these, 174 (0.58 %) were previously undiagnosed. The population-based Gutenberg Health Study was performed to determine the incidence of cardiovascular morbidity and cardiovascular diseases such as AF and myocardial infarction.12 Persons aged between 35 and 74 from the city of Mainz and the region of MainzBingen in Germany were selected at random via the registration office and invited to take part in a 5-hour examination. The response rate was 60.4  %. Of the 5,000 participants, 161 (3.2  %) already had AF, as detected by a 12-lead ECG and/or diagnosed by a physician. Twentyfive participants (0.5 %) were first diagnosed during the study. The Irish Longitudinal Study on Ageing (TILDA) was a prospective cohort study of ageing comprised of community-dwelling citizens aged ≥50 years in the Republic of Ireland. The objectives of this study were to describe the social, economic and health status of older adults and determine the factors underlying healthy ageing.13 A nationally representative sample was drawn from a list of all residential addresses in the country. The response rate was 62 % and a total of 8,175 individuals were recruited. Of these, 4,890 underwent three-lead ECG recording. The prevalence of AF was 3 %. Forty-five (0.92 %) of those with ECG evidence of AF had not previously been diagnosed with the condition. The on-going Systematic NT-proBNP and ECG Screening for Atrial Fibrillation Among 75-year-old Subjects in the Region of Stockholm, Sweden (STROKESTOP) study aimed to determine whether systematic

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screening for untreated AF in the community with the initiation of oral anticoagulation could cost-effectively reduce the risk of ischaemic stroke over 5 years of follow up.14 Computerised 1:1 randomisation was performed in the 75- to 76-year-old population, with stratification for sex, year of birth and region. Those residing in Stockholm Country or the Halland region were eligible to participate. Individuals were identified by their unique civic registration numbers. They were randomised to the screening or non-screening arm. An invitation was sent by mail to those in the screening arm and non-responders were sent one or two reminder letters. The response rate was 53.8 % and 7,173 individuals participated in screening. A single-lead ECG recorder (Zenicor, Zenicor Medical Systems) was used for AF screening. AF was newly diagnosed in 0.5 % in the screened population on the first ECG and in 3 % of the screened population with repeated ECGs performed twice daily for 2 weeks and on palpitations. Chan et al. reported on a study to assess the feasibility of community screening for AF using smartphone ECG (AliveCor, AliveCor Inc.) and generate epidemiological data on AF prevalence and risk factors in Hong Kong.2 All citizens aged ≥18 years were eligible to participate. Of the 13,122 participants (mean age 64.7 years), AF was detected in 239 individuals (1.8 %). Of these, 101 (0.8 %) had newly diagnosed AF, with 66 (65.3  %) being asymptomatic. The mean CHA2DS2VASc score was 3.1 in patients with newly diagnosed AF and the number-needed-toscreen (NNS) for one case of newly diagnosed AF was 129. Proietti et al. reported on data obtained from Belgian Heart Rhythm Week, which is a national campaign including an untargeted voluntary AF screening programme organised by the Belgian Heart Rhythm Association.15 AF was diagnosed with a 30-second one-lead ECG recording with a hand-held machine (HeartScan HCG-801, Omron Healthcare). Of a total 65,747 participants in 2010–14, 911 (1.4 %) had AF and 603 (0.92 %) were previously undiagnosed. Chan et al. recently examined the effectiveness of the communitybased AFinder programme.16 This programme was initiated by a panel of cardiologists, led by the Hong Kong Council of Social Services and carried out by a group of trained lay volunteers. Individuals aged ≥50 years were eligible to participate. Among the 10,735 individuals (mean age 78.6 years) screened with interpretable smartphone ECGs (AliveCor), 244 (2.3 %) had AF and 74 (0.69 %) had newly diagnosed AF. The mean CHA2DS2VASc score was 3.9 in the latter group, and the NNS for one newly diagnosed AF was 145. A nurse followed-up the AF patients at 9 months by telephone and assessed their health-seeking behaviour. Those with indications for oral anticoagulation were asked whether they were receiving this treatment and whether they were compliant with it. Of the 72 newly diagnosed patients in this group, only 47 (65 %) had sought medical attention and, more disappointingly, only 17 (24 %) had been prescribed oral anticoagulants. Once they were given oral anticoagulation, most of them (16, 94  %) reported 100  % compliance with therapy. Compared with the NNS of 145 for a newly-diagnosed case of AF, the NNS for one patient receiving appropriate oral anticoagulation for newly diagnosed AF increased 3.6-fold to 671. This underscores the importance of a more structured management pathway being embedded in any AF screening programme.

Diagnostic Performance of New Tools for Community AF Screening With the advent of mobile and other technologies, many new tools for screening AF in the community have become available. The AFinder

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Systematic Screening for Atrial Fibrillation Table 2: Characteristics of Large-scale Systematic Community Atrial Fibrillation Screening Studies (>4,000 Individuals) Study

Number of

Target

Mean

Response

Screening

Confirmation

Total AF

Previously

Patients*

participants

population

age

rate (%)

tool

with 12-lead

detected,

undiagnosed

indicated and

ECG

n (%)

AF detected,

given OAC,

(years) Furberg et al. 199410

5,151

Random sample of citizens from Medicare eligibility lists from four US communities

Meschia et al. 201011

29,861

Schnabel et al. 201212

Frewen et al. 201313

n (%)

57.6

12-lead ECG N/A

277 (5.4)

77 (1.49)

N/A

67

Black 74.0 Americans and (median) residents of the southeastern ‘stroke belt region’ in the US

49.0

7- or 12-lead ECG

N/A

432 (1.4)

174 (0.58)

85 (48.9)

172

5,000

Persons aged 35–74 from the city of Mainz and MainzBingen region in Germany

52.2

60.4

12-lead ECG N/A

161 (3.2)

25 (0.5)

N/A

200

4,890

Communitydwelling citizens aged ≥50 years in the Republic of Ireland

63.8

37.1

3-lead ECG

No

118 (2.4)

45 (0.92)

N/A

109

Svennberg 7,173 et al. 201514

75–76-year-old population in Stockholm county or the Halland region in Sweden

N/A

53.8

1-lead ECG

No

884 (12.3) with history plus ECG

218 (3)

203 (93)

Single ECG: 200 Twice daily ECG for 2 weeks: 33

Chan et al. 13,122 20162

Untargeted voluntary participation by Hong Kong citizens aged ≥18 years

64.7

N/A

1-lead ECG

No

239 (1.8)

101 (0.8)

N/A

129

Untargeted 58.0 voluntary (median) participation by Belgian citizens

N/A

1-lead ECG

Yes when 1-lead ECG unclear

911 (1.4)

603 (0.92)

N/A

109

Untargeted voluntary participation by Hong Kong citizens aged ≥50 years

N/A

1-lead ECG

No

244 (2.3)

74 (0.69)

17 (24)

145

Proietti et al. 201615

65,747

Chan et al. 10,735 201716

N/A (≥65)

n (%)

NNS

78.6

*with previously undiagnosed AF. AF = atrial fibrillation; N/A = not applicable; NNS = number-needed-to-screen for one patient with newly diagnosed atrial fibrillation; OAC = oral anticoagulation.

programme used the Kardia mobile device (AliveCor), which produces a single-lead ECG.16 Compared to a reference diagnosis made following interpretation of the ECG by a cardiologist, the sensitivity and specificity of the automated algorithm in diagnosing AF were determined to be 75 % and 98.2 %, respectively. The positive and negative predictive values were 64.9  % and 99.5  %, respectively. It was concluded that the suboptimal sensitivity and positive predictive value of the current version of the algorithm makes doctors’ interpretation of smartphone ECGs essential.

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Different tools have also been studied in the primary care setting in Hong Kong.17,18 Chan et al. used a smartphone camera-based device capable of diagnosing AF by measuring photoplethysmographic pulse waveform (Cardiio Rhythm, Cardio Inc.). 17 Patients with hypertension and/or diabetes mellitus or who were ≥65 years of age were screened. AF was found in 28 (2.76 %) out of 1,013 participants, five (0.5 %) of which were newly diagnosed. Comparing against a reference diagnosis made by interpretation of the single-

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Clinical Arrhythmias lead ECG produced from the Kardia mobile device by two blinded and independent cardiologists, the sensitivity and specificity of the automated algorithm of the smartphone camera-based device were 92.9 % and 97.7 %, respectively. The positive and negative predictive values were 53.1  % and 99.8  %. The same group of researchers reported the use of an automated blood pressure measurement device (Microlife WatchBP Home A; Microlife USA, Dunedin, Florida, USA) capable of generating an irregularity index based on R-R intervals for AF screening in primary care.18 Similar to the study described above, they screened patients with hypertension and/ or diabetes mellitus or who were ≥65 years of age. Of the 5,969 patients recruited, AF was diagnosed in 72 (1.2 %) participants. The proportion of patients with newly diagnosed AF was not reported. Comparing against a reference diagnosis made by interpretation of the single-lead ECG produced from the Kardia mobile device by two blinded and independent cardiologists, the sensitivity and specificity of the Microlife WatchBP Home A device in diagnosing AF were 80.6  % and 98.7  % respectively, with a positive predictive value of 42.4 % and negative predictive value of 99.8 %. The overall diagnostic performance as determined by area under curve was 0.90.

As shown by AFinder, the effectiveness of a community AF screening programme will be significantly weakened by lack of a management pathway.16 The NNS for one patient receiving appropriate oral anticoagulation for newly diagnosed AF was 671 in AFinder compared to 209 in the STROKESTOP study, when such individuals were offered structured follow-up by a cardiologist.14 A structured downstream management pathway should thus be a mandatory component of any community AF screening programme. Mass AF screening of the general population has become more feasible with the availability of new tools, especially those capable of producing single-lead smartphone ECGs. The sensitivity and positive predictive value of the automated diagnostic algorithm of any ECG-producing tool, however, has to be high enough to save the intermediate step of interpretation by a doctor. Currently, the Cardiio Rhythm seems to provide the highest sensitivity, at 92.9 %.

Obstacles and Challenges

Data on the cost-effectiveness of systematic community AF screening programmes are, unfortunately, scarce.14,19 Data are, however, essential for health resource allocation by governments. In the STROKESTOP study, screening with smartphone ECG was shown to be cost-effective using a lifelong decision-analytic Markov model.14

Despite increasing data on community-based AF screening becoming available in recent years, questions remain regarding the most appropriate setting and tools. Large and appropriately powered randomised outcome studies to answer these questions and confirm that such programmes can indeed reduce the burden of stroke and consequent mortality are eagerly awaited. At this juncture, a few obstacles and challenges have already been identified.

Last but not least, there remains room for improvement in the response rates observed in different systematic community screening programmes for AF. Regular large-scale community AF awareness programmes highlighting the condition’s potentially disabling and fatal complication of stroke should be implemented to enhance the response rate. n

1.

2.

3.

4.

5.

6.

7.

 o AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed G atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA 2001;285:2390–5. PIMD: 1343485. Chan NY, Choy CC. Screening for atrial fibrillation in 13122 Hong Kong citizens with smartphone electrocardiogram. Heart 2017;103:24–31. DOI: 10.1136/heartjnl-2016-309993; PMID: 27733533. Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 2016;37:2893–962. DOI: 10.1093/ejcts/ezw313; PMID: 27663299. Friberg L, Rosenqvist M, Lindgren A, et al. High prevalence of atrial fibrillation among patients with ischemic stroke. Stroke 2014;45:2599–605. DOI: 10.1161/STROKEAHA.114.006070; PMID: 25034713. Wolf PA, Kannel WB, McGee DL, et al. Duration of atrial fibrillation and imminence of stroke: the Framingham study. Stroke 1983;14:664–7. PMID: 6658948. Siu CW, Lip GY, Lam KF, et al. Risk of stroke and intracranial hemorrhage in 9727 Chinese with atrial fibrillation in Hong Kong. Heart Rhythm 2014;11:1401–8. DOI: 10.1016/ j.hrthm.2014.04.021; PMID: 24747420. Fitzmaurice DA, Hobbs FDR, Jowett S, et al. Screening versus routine practice in detection of atrial fibrillation in patients aged 65 or over: cluster randomized

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8.

9.

10.

11.

12.

13.

14.

controlled trial. Br Med J 2007;335:383–6. DOI: 10.1136/ bmj.39280.660567.55; PMID: 17673732. Wilson J, Junger G. Principles and practice of screening for disease. In: Public Health Paper No. 34. Geneva: World Health Organization, 1968. Freedman B, Camm J, Calkins H, et al. AF-Screen Collaborators. Screening for atrial fibrillation: a report of the AF-SCREEN International Collaboration. Circulation 2017;135:1851–67. DOI: 10.1161/CIRCULATIONAHA.116.026693; PMID: 28483832. Furberg CD, Psaty BM, Manolio TA, et al. Prevalence of atrial fibrillation in elderly subjects (the Cardiovascular Health Study). Am J Cardiol 1994;74:236–41. PMID: 8037127. Meschia JF, Merril P, Soliman EZ, et al. Racial disparities in awareness and treatment of atrial fibrillation. The REasons for Geographic and Racial Differences in Stroke (REGARDS) Study. Stroke 2010;41:581–7. DOI: 10.1161/STROKEAHA.109.573907; PMID: 20190000. Schnabel RB, Wilde S, Wild PS, et al. Atrial fibrillation: Its prevalence and risk factor profile in the German general population. Dtsch Arztebl Int 2012;109:293–9. DOI: 10.3238/ arztebl.2012.0293; PMID: 22577476. Frewen J, Finucane C, Cronin H, et al. Factors that influence awareness and treatment of atrial fibrillation in older adults. Q J Med 2013;106:415–24. DOI: 10.1093/qjmed/hct060; PMID: 23504411. Svennberg E, Engdahl J, Al-Khalili F, et al. Mass screening for untreated atrial fibrillation. The STROKESTOP

15.

16.

17.

18.

19.

Study. Circulation 2015;131:2176–84. DOI: 10.1161/ CIRCULATIONAHA.114.014343; PMID: 25910800. Proietti M, Mairesse GH, Goethals P, et al. Belgian Heart Rhythm Week Investigators. A population screening program for atrial fibrillation: a report from the Belgian Heart Rhythm Week screening program. Europace 2016;18:1779–86. DOI: 10.1093/europace/euw069; PMID: 27170000. Chan NY, Siu CW, Choy CC, et al. Effectiveness of community atrial fibrillation screening in over 10,000 citizens using smartphone electrocardiogram- The AFinder Program. European Society of Cardiology Congress 2017, Barcelona, Spain, 29 August 2017. Chan PH, Wong CK, Poh YC, et al. Diagnostic performance of a smartphone-based photoplethysmographic application for atrial fibrillation screening in a primary care setting. J Am Heart Assoc 2016;5:e003428. DOI: 10.1161/ JAHA.116.003428; PMID: 27444506. Chan PH, Wong CK, Pun L, et al. Diagnostic performance of an automatic blood pressure measurement device, Microlife WatchBP Home A, for atrial fibrillation screening in a realworld primary care setting. BMJ Open 2017;7:e013685. DOI: 10.1136/bmjopen-2016-013685; PMID: 28619766. Hobbs FD, Fitzmaurice DA, Mant J, et al. A randomized controlled trial and cost-effectiveness study of systematic screening (targeted and total population screening) versus routine practice for the detection of atrial fibrillation in people aged 65 and over: the SAFE study. Health Technol Assess 2005;9:iii–iv, ix. PMID: 16202350.

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Clinical Arrhythmias

Atrial Arrhythmias in Pulmonary Hypertension: Pathogenesis, Prognosis and Management Brett Wanamaker, Thomas Cascino, Vallerie McLaughlin, Hakan Oral, Rakesh Latchamsetty, Konstantinos C Siontis University of Michigan, Ann Arbor, MI, USA

Abstract Atrial arrhythmias, including atrial fibrillation and atrial flutter, are common in patients with pulmonary hypertension and are closely associated with clinical decompensation and poor clinical outcomes. The mechanisms of arrhythmogenesis and subsequent clinical decompensation are reviewed. Practical implications and current evidence for the management of atrial arrhythmias in patients with pulmonary hypertension are summarised.

Keywords Atrial arrhythmia, pulmonary hypertension, prognosis, cather ablation, antiarrhythmia drug treatment, anticoagulation Disclosure: The authors have no conflicts of interest to declare. Received: 19 January 2018 Accepted: 20 February 2018 Citation: Arrhythmia & Electrophysiology Review 2018;7(1):43–8. DOI: 10.15420/aer.2018.3.2 Correspondence: Konstantinos C Siontis, Division of Cardiovascular Medicine, University of Michigan, East Medical Center Drive, Ann Arbor, MI 48109, USA. E: ksiontis@med.umich.edu

Pulmonary hypertension (PH) is a chronic condition that is characterised by elevated pulmonary vascular pressures and can be caused by several disease processes (see Table 1).1 Regardless of the aetiology, PH is a progressive disease with a clinical course characterised by frequent decompensations in advanced stages and often a poor prognosis despite the development of novel therapeutic agents.2 AF and atrial flutter are common in PH populations and have been shown to be associated with frequent decompensations, increased hospital admissions and poor quality of life. Failure to adequately address these arrhythmias may portend a particularly poor prognosis in an already devastating disease process.3–5 The purpose of this review is to discuss the epidemiology, pathophysiology, clinical significance and management of atrial arrhythmias, namely AF and atrial flutter, in patients with PH (see Figure 1). Whenever possible, this review is restricted to data from patients with World Health Organization (WHO) group I PH (pulmonary arterial hypertension [PAH] that may be idiopathic, hereditary, toxininduced or associated with connective tissue disease or infection) and group IV PH (chronic thromboembolic pulmonary hypertension [CTEPH]).1 In general, both processes reflect a primary disorder at the level of the pulmonary arterial circulation and have many common pathophysiological features.6

Epidemiology of Atrial Arrhythmias in Pulmonary Hypertension Most of the early data regarding the burden of sustained atrial arrhythmias in patients with PH were derived from retrospective singlecentre analyses. The first major observational study by Tongers et al. analysed 231 patients undergoing routine surface electrocardiograms as part of their regular outpatient clinic follow-up.7 The patient population was heterogeneous and included patients with PH due to congenital heart disease or inoperable chronic thromboembolic disease (WHO

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group IV). The annual incidence of atrial arrhythmias in this cohort was 2.8 % per year, with a cumulative incidence of 11.7  % by the end of the 6-year study (12 patients with atrial flutter, 12 with AF and three with atrioventricular nodal reentrant tachycardia). A similar series of 72 patients from an Italian center reported a 22  % incidence of atrial arrhythmias over 35 months; however, this cohort was also heterogeneous and included patients with WHO group III disease (n=12).8 More recent prospective studies have confirmed a relatively high incidence of atrial arrhythmias in PH patients and have attempted to characterise the clinical features of those patients at risk of developing such arrhythmias. Olsson et al. followed 239 patients with idiopathic PAH (n=157) or CTEPH (n=82) and restricted their analysis to AF and atrial flutter.9 This study found a cumulative atrial arrhythmia incidence of 25.1  % over 5 years of follow-up. Wen et al. studied 280 patients with idiopathic PAH and found a cumulative incidence of 15.8 % over 6 years.10 By comparison, the incidence of AF or atrial flutter in the general population based on the Rotterdam study was 0.1  % per year among people aged 55–60 years, rising to 2.7  % per year among those aged 80–85 years.11 The overall lifetime risk of developing AF or atrial flutter in the absence of heart failure or MI is estimated at approximately 16 % based on Framingham data.12 The variation in reported incidence of atrial arrhythmias in patients with PH may reflect differences in the risk profiles of the patient populations studied. Compared with the Wen et al. study,10 the patients in the Olsson study were generally older (mean 55 years versus 39 years) and had more advanced disease (79 % versus 65 % with WHO functional class III or worse).9 Age is an important independent risk factor for atrial arrhythmias.13 Existing analyses have relied on intermittent surveillance during clinic visits and hospitalisations due to decompensation or other PH-related

Access at: www.AERjournal.com

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Clinical Arrhythmias Table 1: Revised World Health Organization Classification of Pulmonary Hypertension Group I. Pulmonary arterial hypertension

1.1. Idiopathic 1.2. Familial 1.3. Associated with:    1.3.1. Connective tissue disorder    1.3.2. Congenital systemic-to-pulmonary shunts    1.3.3. Portal hypertension    1.3.4. HIV infection    1.3.5. Drugs and toxins    1.3.6. Other (thyroid disorders, glycogen storage disease, Gaucher’s disease, hereditary haemorrhagic telangiectasia, haemoglobinopathies, chronic myeloproliferative disorders, splenectomy) 1.4. Associated with significant venous or capillary involvement    1.4.1. Pulmonary veno-occlusive disease    1.4.2. Pulmonary capillary haemangiomatosis 1.5. Persistent pulmonary hypertension of the newborn

Group II. Pulmonary hypertension with left heart disease

2.1. Left-sided atrial or ventricular heart disease 2.2. Left-sided valvular heart disease

Group III. Pulmonary hypertension associated with lung diseases and/or hypoxemia

3.1. Chronic obstructive pulmonary disease 3.2. Interstitial lung disease 3.3. Sleep-disordered breathing 3.4. Alveolar hypoventilation disorders 3.5. Chronic exposure to high altitude 3.6. Developmental abnormalities

Group IV. Pulmonary hypertension due to chronic thrombotic and/or embolic disease

4.1. Thromboembolic obstruction of proximal pulmonary arteries 4.2. Thromboembolic obstruction of distal pulmonary arteries 4.3. Non-thrombotic pulmonary embolism (tumour, parasites, foreign material)

Group V. Miscellaneous

Sarcoidosis, histiocytosis X, lymphangiomatosis, compression of pulmonary vessels (adenopathy, tumour, fibrosing mediastinitis)

Source: Reprinted from Simonneau G et al. (2013) Updated Clinical Classification of Pulmonary Hypertension, Journal of the American College of Cardiology, 62(25), D34-D41, with permission from Elsevier.1

issues to detect incident atrial arrhythmias. There are no studies using long-term, continuous rhythm surveillance specifically in patients with PH, which would likely increase detection rates of atrial arrhythmias. In a recent study using 24-hour Holter monitoring in 36 patients with PAH or CTEPH, paroxysmal AF was detected in nearly one in three patients, suggesting that the true prevalence of asymptomatic arrhythmia may be much higher.14

Pathophysiology of Atrial Arrhythmias in the Setting of Elevated Right Heart Pressures The altered structural and electrophysiological properties of the left atrium in the setting of AF and left heart disease have been well described.15,16 In PH, enlargement of the right atrium (RA) is thought to reflect advancing disease and potential progression to right heart failure as elevated pulmonary and right ventricular pressures are transmitted to the RA.17,18 Observational studies suggest that RA pressure and chamber size are important risk factors for atrial arrhythmia development.9,10 Chronic RA pressure overload and stretching, along with chronic hypoxia, may alter the atrial substrate by promoting fibrosis and local tissue heterogeneities, which in turn predispose to a risk for AF.19 This is consistent with emerging data demonstrating a key role of atrial fibrosis in the pathogenesis of AF as documented by delayed enhancement on MRI.20,21 Figure 2 summarises potential mechanistic pathways contributing to the development of atrial arrhythmias in patients with PH. Electrophysiologic studies (EPSs) in patients with idiopathic PAH compared with control patients without PH demonstrate reproducible and quantifiable abnormalities in atrial conduction. In a study by Medi et al., EPSs were performed in eight patients with idiopathic PAH prior to starting PH therapies and the results were compared with those from 16 age-matched controls without PH undergoing EPS

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for supraventricular tachycardia.22 The group with PAH had slower conduction velocities throughout the RA and a significant generalised voltage reduction consistent with the presence of atrial fibrosis (see Figure 3). In addition, patients with PAH were found to have higher rates of AF inducibility (50 % versus 0 % in controls), defined as sustained AF >30 seconds. Similar electrical remodelling has been seen in the left and right atria of patients with mitral valve disease.23 Such altered atrial conduction can manifest on surface electrocardiograms as P-wave duration >110 milliseconds, a finding that has been associated with poor clinical outcomes in patients with PH.24 In addition to alterations of the RA substrate, derangements in autonomic tone may also play an important role in atrial arrhythmia development. Patients with PAH have been shown to have increased sympathetic activity,25 and reduction of this sympathetic input may improve functional status.26 The sympathetic autonomic system is recognised to play a significant role in the initiation and perpetuation of AF via enhanced automaticity, triggered activity and an increase in delayed afterdepolarizations, and may even represent a therapeutic target for AF.27,28 Using a canine animal model, Zhao and colleagues performed EPSs in animals with PAH and controls.29 Animals with PAH showed more AF/atrial flutter vulnerability and higher right atrial sympathetic nerve and beta1-adrenergic receptor density. Ablation of the right anterior ganglionic plexi (but not other intracardiac nerves) attenuated the arrhythmic potential, likely due to the withdrawal of local sympathetic input to the RA.

Clinical Significance and Prognostic Implications of Atrial Arrhythmias in Pulmonary Hypertension The development of AF is considered an independent predictor of adverse outcomes in various cardiac conditions including heart failure

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Atrial Arrhythmias in Pulmonary Hypertension Figure 1: Electrocardiogram of a 70-year-old Patient with AF and Severe Pulmonary Hypertension with Right Ventricular Dilatation/Dysfunction

Notable are the right axis deviation, incomplete right bundle branch block and dominant R waves in V1 suggestive of right ventricular hypertrophy.

with reduced or preserved ejection fraction, valvular disease, and hypertrophic cardiomyopathy.30–32 AF may be a marker of advanced disease or decompensated cardiac substrate, but it can also contribute to disease progression and exacerbation. Both are likely true in patients with PH. Atrial arrhythmias are strongly associated with markers of disease severity and deterioration in patients with PH. In the Tongers et al. cohort, 84 % of patients with atrial arrhythmias presented with clinical decompensation manifesting as worsened functional class or clinical right heart failure.7 Importantly, patients who converted to sinus rhythm improved clinically, while those refractory to rhythm control (all of whom had AF) had a mortality rate of 82 % over an average of 11 months post atrial arrhythmia diagnosis. This pattern of clinical decline in the setting of atrial arrhythmias was also seen in a similar retrospective cohort study, which showed reductions in 6-minute walk tests that recovered with restoration of sinus rhythm33 and in an Italian PH cohort that showed a significant worsening of echocardiographic measures of right heart function and an increase in brain natriuretic peptide levels among patients with atrial arrhythmias.8 The Olsson et al. study found that nearly all (97.5 %) patients with atrial arrhythmias developed clinical deterioration with worsened functional class or right heart failure.9 The 5-year mortality rate for patients with AF who were refractory to rhythm control was as high as 78  %, compared with 32  % in patients who remained arrhythmia free. There were no baseline differences in haemodynamic parameters, functional status or natriuretic peptide levels among those who achieved restoration of sinus rhythm and those who did not. Patients in whom a rhythm control strategy was successful experienced outcomes similar to those who had no incident arrhythmias. Recognising the limitations of observational studies, these data suggest that the maintenance of

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Figure 2: Mechanistic Pathways for the Pathogenesis of Atrial Arrhythmias in Pulmonary Hypertension and the Associated Pathophysiological Consequences

RA = right atrium; RV = right ventricle.

sinus rhythm, when feasible, should be considered a treatment goal in patients with PH. Multiple mechanisms may account for the clinical deterioration seen in PH patients who develop atrial arrhythmias (see Figure 2). The negative effect on cardiac output from the loss of atrial contraction, loss of atrioventricular synchrony, and ventricular irregularity has been described in patients with atrial arrhythmia and left heart failure.34,35 These effects may be particularly severe for patients with established right ventricular dysfunction or clinical right heart failure as a result of long-term PH. Echocardiographic data suggest that patients with PH rely on active, rather than passive, atrial emptying to a greater degree than matched controls.36 Aside from decreased contractility, the tachycardia from a rapid ventricular response increases both pulsatile and resistive components of right ventricle (RV) afterload.37 The RV is significantly more sensitive to changes in afterload compared

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Clinical Arrhythmias Figure 3: Voltage Map of the Right Atrium in a Patient with Pulmonary Hypertension and Multiple Tachycardias of Right Atrial Origin

theoretical considerations, although it is not clear to what extent the adverse outcomes seen in patients with structural heart disease44 may extend to patients with PH with or without RV dysfunction.

Catheter Ablation

Red indicates scar (bipolar voltage <0.1 mV). SVC = superior vena cava; TV = tricuspid valve.

with the left ventricle,38 and the resultant increase in RV wall stress may exacerbate the already tenuous supply–demand relationship of coronary perfusion in these patients.39 Left ventricular systolic dysfunction resulting from chronic tachycardia has also been well described,40 but it is unclear as to what degree the RV can be preferentially affected by this pathophysiology.

Management of Atrial Arrhythmias in Pulmonary Hypertension Rhythm Versus Rate Control The management of AF and atrial flutter in patients with severe PH represents a clinical challenge, especially in those with tenuous RV function or frankly decompensated right heart failure. In these settings rate-control agents with negative inotropic effects (betablockers, calcium channel blockers) are poorly tolerated. There are no randomised studies comparing rate and rhythm control specifically in PH populations and these patients have typically been excluded from clinical trials on AF therapy. Given the poor tolerance of these arrhythmias and their association with adverse outcomes, most observational studies of patients with PH and atrial arrhythmias report an initial attempt at rhythm control strategy.7–9,41 Rhythm control is currently recommended as the preferred approach in the European Society of Cardiology and European Respiratory Society guidelines for PH management.42 Rhythm control strategies have included pharmacological cardioversion with membrane-active antiarrhythmic drugs, electrical cardioversion and catheter ablation. All studies investigating rhythm control strategies to date have included small numbers of patients and, in general, no standardised approach to rhythm control has been described.

Antiarrhythmic Drug Therapy The use of class III agents such as amiodarone and sotalol has been reported in patients with PH,7–10 with amiodarone perhaps having an advantage due to its rather neutral effect on cardiac contractility. However, the long-term use of amiodarone may not be an option in patients with PH secondary to comorbid parenchymal lung disease and poor pulmonary function reserve. For patients treated with the endothelin receptor antagonist bosentan, amiodarone can increase bosentan levels via inhibition of cytochrome P450 (CYP)2C9 and should be used with caution.43 Dronedarone is contraindicated in patients who have advanced heart failure, including those in whom the heart failure is due to PH. Class IC agents such as propafenone or flecainide are

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Similar to patients without PH, catheter ablation is a first-line approach to the management of cavotricuspid isthmus (CTI)-dependent atrial flutter in patients with PH. Due to the RA and tricuspid annular dilation in patients with PAH, CTI ablation is often more technically challenging than in patients with structurally normal right heart chambers. In a retrospective analysis of a single-centre experience with CTI ablation in 38 patients with PAH, bidirectional block was achieved in all patients; however, the PAH group had significantly longer procedure times (mean 78 minutes versus 62 minutes; p=0.03), required a larger number of ablation lesions (26 versus 19; p=0.02) and had a longer total ablation time (mean 20 minutes versus 15 minutes; p=0.02) compared with the group of patients without PAH.45 A similar trend (yet not statistically significant) toward longer CTI ablation procedures in patients with PAH versus controls was reported in a smaller series of 12 patients.46 It is worth noting that PH with associated RA remodelling may alter the typical electrocardiographic presentation of CTI-dependent flutter, as the same study reported the classic saw tooth pattern in only 42 % of PAH cases as compared with 100  % of controls. In patients with PAH, flutter waves often had lower amplitude with a cycle length that was significantly longer compared with controls (295 ± 53 ms versus 252 ± 35 ms). Despite the technical challenges in these patients, the acute and long-term success of catheter ablation of CTI-dependent flutter is favourable. Although multiple randomised and non-randomised studies have investigated the use of catheter ablation in patients with AF, 47–49 the safety and efficacy of ablation techniques for AF specifically in the PH population is uncertain and no published reports of AF ablation (or other left atrial ablation) exist in this patient population to date. While the pulmonary veins (PVs) are still the most promising ablation targets in patients with PH, it is possible that non-PV triggers may play a more important role than in patients without PH due to ultrastructural and electrical remodelling of the RA. In an unselected population with paroxysmal and persistent AF, non-PV triggers were identified in approximately 11  % of cases.50 Approximately half of those non-PV triggers originated in the RA, including the crista terminalis/eustachian ridge, superior vena cava and tricuspid annulus. In a recent study of patients with obstructive sleep apnea (OSA) who underwent ablation procedures for paroxysmal AF, residual non-PV triggers were found in nearly 42 % of patients after PV isolation. 51 Notably, patients with OSA were found to have some of the electrophysiological abnormalities previously described in patients with PH (lower atrial voltage and slower conduction velocities). By extension, due to this phenotypic overlap between OSA and PH, patients with PH may also have a higher prevalence of non-PV triggers compared with the general AF population. In addition, focal atrial tachycardias, non-CTI-dependent atypical atrial flutters, and multiple flutter circuits are not uncommon in these patients due to the extensive atrial remodelling. Another special consideration in patients with severely elevated right heart pressures is the risk of complications from transseptal puncture and left atrial access for ablation procedures. This is particularly important with the use of the cryoballoon ablation system that requires a larger sheath for delivery than the standard radiofrequency ablation

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Atrial Arrhythmias in Pulmonary Hypertension Table 2: Management Recommendations of Atrial Arrhythmias in Patients with Pulmonary Hypertension General approach • When feasible, prompt restoration of sinus rhythm is preferable over rate control of atrial arrhythmias Antiarrhythmic drugs • Amiodarone should be used with caution in patients with PH secondary to pulmonary disease • Amiodarone should be used cautiously in patients concomitantly treated with bosentan for their PH because CYP2C9 inhibition can increase bosentan levels Catheter ablation • C  atheter ablation should be a first-line approach for management of CTI-dependent atrial flutter, despite the potential technical challenges of CTI ablation in PH patients with right-sided chamber dilation • In PH patients undergoing catheter ablation of AF, mapping of non-PV triggers, particularly in the RA, may improve outcomes in conjunction with traditional PVIbased approaches • The risk of clinical deterioration due to iatrogenic ASD with right-to-left shunting after transseptal access for left atrial ablation should be considered. This is particularly relevant in PH patients with baseline hypoxemia and with the use of large bore transseptal sheaths (cryoballoon) • Procedural anaesthesia for catheter ablation in patients with severe PH should be performed by providers with expertise in cardiac anaesthesiology Anticoagulants • Clinicians should be mindful of interactions between PH medications and anticoagulants used for AF-related stroke prophylaxis ASD = atrial septal defect; CTI = cavotricuspid isthmus; PH = pulmonary hypertension; PV = pulmonary veins; RA = right atrium.

catheters. While iatrogenic atrial septal defects (ASDs) are possible with any transseptal procedure, the cryoballoon technique has been associated with a significantly higher incidence of persistent ASD.52 The clinical consequences of these ASDs have not been established, but, in theory, a significant residual ASD in a patient with PH and elevated right heart filling pressures might result in clinically significant intracardiac right-to-left shunting and hypoxaemia, as well as an increased risk of paradoxical embolism. PH patients with baseline hypoxaemia due to ventilation-perfusion mismatch may suffer further clinical deterioration with a second insult. Lastly, patients with severe PH generally have a high anaesthetic risk53 that is partially attributable to the unfavourable cardiopulmonary circulatory changes associated with mechanical ventilation. Thus, the benefits of catheter ablation procedures in these patients should be carefully weighed against the risks of deep sedation or general anaesthesia. Procedural anaesthesia in patients with severe PH should be performed under the supervision of experienced personnel with expertise in cardiac anaesthesiology.

Anticoagulation A number of unresolved questions regarding the use of anticoagulation in patients with PH (with or without atrial arrhythmias) remain. It is unknown whether the presence of PH and right heart enlargement and/or dysfunction allows for reliable risk estimation with the use of the traditional CHA2DS2VASc score, which incorporates systemic hypertension and congestive heart failure.54 In terms of the choice of anticoagulation agent, there are no obvious contraindications to the use of direct oral anticoagulants in patients with PH. Patients with PH were not specifically excluded from the clinical trials that led to the establishment of direct oral anticoagulants as first-line agents for stroke risk reduction in the management of AF and these agents continue to be used for an expanding spectrum of indications, often with superior safety and efficacy profiles as compared with warfarin.55 However, safety and efficacy data for direct oral anticoagulants specifically pertaining to the PH population are lacking. Clinicians pursuing stroke prophylaxis with these agents also need to be mindful of potential drug–drug interactions relevant to PH therapies. For example, bosentan is a known inducer of CYP3A4, an important metabolic clearance

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pathway for rivaroxaban and apixaban.56 Use of additional CYP3A4 inducers or drugs affecting other degradation pathways may result in subtherapeutic anticoagulation with these agents. A summary of specific management recommendations of atrial arrhythmias in patients with PH is shown in Table 2.

Conclusions Atrial arrhythmias are common in patients with PH. Whether these arrhythmias are the cause or consequence of worsening RV failure in these patients is not certain; however, haemodynamic data suggest that PH patients are especially vulnerable to haemodynamic stress during tachycardia and loss of coordinated atrioventricular contraction. Regardless, atrial arrhythmias require prompt intervention as failure to adequately control these arrhythmias may be associated with an unfavourable clinical course in this patient population. Observational studies have shown that a variety of rhythm-control strategies are feasible. As novel pharmacological treatments for PH and the continued improvement of multidisciplinary care improve survival in these patients,57 arrhythmias are likely to become a more prevalent complication of the disease. Future investigation in the field should clarify the remaining questions related to atrial arrhythmias in patients with PH, including the role of ambulatory rhythm monitoring, the role and timing of rhythm-control strategies, and the technical aspects and outcomes of catheter ablation. n

Clinical Perspectives • P  ulmonary hypertension (PH) is a progressive disease that is commonly accompanied by the presence of atrial arrhythmias, which are associated with disease severity and deterioration in PH. •  European guidelines recommend that, where feasible, sinus rhythm control is the preferred first-line approach in the management of atrial arrhythmias in PH. •  In patients with PH and cavotricuspid isthmus-dependent atrial flutter in patients with PH, catheter ablation should be considered as first-line.

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22. M  edi C, Kalman JM, Ling LH, et al. Atrial electrical and structural remodeling associated with longstanding pulmonary hypertension and right ventricular hypertrophy in humans. J Cardiovasc Electrophysiol 2012;23:614–20. DOI: 10.1111/j.1540-8167.2011.02255.x; PMID: 22269035. 23. John B, Stiles MK, Kuklik P, et al. Electrical remodelling of the left and right atria due to rheumatic mitral stenosis. Eur Heart J 2008;29:2234–43. DOI: 10.1093/eurheartj/ehn329; PMID: 18621772. 24. Bandorski D, Bogossian H, Ecke A, et al. Evaluation of the prognostic value of electrocardiography parameters and heart rhythm in patients with pulmonary hypertension. Cardiol J 2016;23:465–72. DOI: 10.5603/CJ.a2016.0044; PMID: 27367480. 25. Velez-Roa S, Ciarka A, Najem B, et al. Increased sympathetic nerve activity in pulmonary artery hypertension. Circulation 2004;110:1308–12. DOI: 10.1161/01.CIR.0000140724.90898.D3; PMID: 15337703. 26. Chen SL, Zhang FF, Xu J, et al. Pulmonary artery denervation to treat pulmonary arterial hypertension: The single-center, prospective, first-in-man PADN-1 study (first-in-man pulmonary artery denervation for treatment of pulmonary artery hypertension). J Am Coll Cardiol 2013;62:1092–100. DOI: 10.1016/j.jacc.2013.05.075; PMID: 23850902. 27. 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. 28. Chen PS, Chen LS, Fishbein MC, et al. Role of the autonomic nervous system in atrial fibrillation: Pathophysiology and therapy. Circ Res 2014;114:1500–15. DOI: 10.1161/ CIRCRESAHA.114.303772; PMID: 24763467. 29. Zhao Q, Deng H, Jiang X, et al. Effects of intrinsic and extrinsic cardiac nerves on atrial arrhythmia in experimental pulmonary artery hypertension. Hypertension 2015;66:1042–9. DOI: 10.1161/HYPERTENSIONAHA.115.05846; PMID: 26418021. 30. Grigioni F, Avierinos JF, Ling LH, et al. Atrial fibrillation complicating the course of degenerative mitral regurgitation: determinants and long-term outcome. J Am Coll Cardiol 2002;40:84–92. PMID: 12103260. 31. Siontis KC, Geske JB, Ong K, et al. Atrial fibrillation in hypertrophic cardiomyopathy: Prevalence, clinical correlations, and mortality in a large high-risk population. J Am Heart Assoc 2014;3:e001002. DOI: 10.1161/ JAHA.114.001002; PMID: 24965028. 32. Sartipy U, Dahlstrom U, Fu M, Lund LH. Atrial fibrillation in heart failure with preserved, mid-range, and reduced ejection fraction. JACC Heart Fail 2017;5:565–74. DOI: 10.1016/j. jchf.2017.05.001; PMID: 28711451. 33. Ruiz-Cano MJ, Gonzalez-Mansilla A, Escribano P, et al. Clinical implications of supraventricular arrhythmias in patients with severe pulmonary arterial hypertension. Int J Cardiol 2011;146:105–6. DOI: 10.1016/j.ijcard.2010.09.065; PMID: 21056484. 34. Clark DM, Plumb VJ, Epstein AE, Kay GN. Hemodynamic effects of an irregular sequence of ventricular cycle lengths during atrial fibrillation. J Am Coll Cardiol 1997;30:1039–45. PMID: 9316536. 35. Pozzoli M, Cioffi G, Traversi E, et al. Predictors of primary atrial fibrillation and concomitant clinical and hemodynamic changes in patients with chronic heart failure: A prospective study in 344 patients with baseline sinus rhythm. J Am Coll Cardiol 1998;32:197–204. PMID: 9669270. 36. Willens HJ, Fertel DP, Qin J, et al. Effects of age and pulmonary arterial hypertension on the different phases of right atrial function. Int J Cardiovasc Imaging 2008;24:703–10. DOI: 10.1007/ s10554-008-9306-4; PMID: 18454278. 37. Metkus TS, Mullin CJ, Grandin EW, et al. Heart rate dependence of the pulmonary resistance x compliance (RC) time and impact on right ventricular load. PLoS One 2016;11:e0166463. DOI: 10.1371/journal.pone.0166463; PMID: 27861600. 38. Haddad F, Hunt SA, Rosenthal DN, Murphy DJ. Right ventricular function in cardiovascular disease, part I: Anatomy, physiology, aging, and functional assessment of the right ventricle. Circulation 2008;117:1436–48. DOI: 10.1161/ CIRCULATIONAHA.107.653576; PMID: 18347220. 39. Bogaard HJ, Abe K, Vonk Noordegraaf A, Voelkel NF. The right ventricle under pressure: Cellular and molecular mechanisms of right-heart failure in pulmonary hypertension. Chest 2009;135:794–804. DOI: 10.1378/chest.08-0492; PMID: 19265089. 40. Gopinathannair R, Etheridge SP, Marchlinski FE, et al. Arrhythmia-induced cardiomyopathies: Mechanisms,

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Clinical Arrhythmias

Drivers of Atrial Fibrillation: Theoretical Considerations and Practical Concerns Ian Mann, Belinda Sandler, Nick Linton and Prapa Kanagaratnam Imperial College Healthcare NHS Trust, London, UK

Abstract Understanding the mechanisms responsible for driving AF is key to improving the procedural success for AF ablation. In this review, we look at some of the proposed drivers of AF, the disagreement between experts and the challenges confronted in attempting to map AF. Defining a ‘driver’ is also controversial, but for the purposes of this review we will consider an AF driver to be either a focal or localised source demonstrating fast, repetitive activity that propagates outward from this source, breaking down in to disorganisation further away from its origin.

Keywords Arrhythmia, atrial fibrillation, mechanisms Disclosure: Dr Mann and Dr Sandler receive funding from the British Heart Foundation. Received: 22 October 2017 Accepted: 9 February 2018 Citation: Arrhythmia & Electrophysiology Review 2018;7(1):49–54. DOI: 10.15420/aer.2017.40.3 Correspondence: Prapa Kanagaratnam, Imperial College Healthcare NHS Trust, Du Cane Road, London, W12 0NN, UK. E: p.kanagaratnam@imperial.ac.uk

The discovery of focal ectopy in the pulmonary veins (PVs) initiating AF1 has resulted in electrical isolation of the PVs forming the mainstay of current treatment strategies. Success rates from PV isolation (PVI) for patients with paroxysmal AF (PAF) are approximately 70–75 %. However, PVI is significantly less effective for those with persistent AF, in whom many studies quote single-procedure success rates of about 50 %. The suboptimal outcomes from catheter ablation have resulted in significant research efforts to identify the underlying mechanisms driving AF in the hope of identifying targets for catheter ablation therapy.

Re-entry as a Mechanism Underlying AF While watching the exposed fibrillating atrium of an animal heart, in 1914, Garrey described chaotic activity, with contractions that did not appear to be independent of one another. He was also able to induce circus movement with a single stimulus in ring preparations. From these observations, he cut fibrillating tissue into four equal parts and found that fibrillation continued, providing evidence against a focal source, as “only one of the pieces can contain the original hypothetical tachysystolic pacemaker”. By cutting tissue into smaller pieces, he also concluded that a critical mass was required to sustain fibrillation.2,3 In 1921, Lewis et al. hypothesised that re-entry around anatomical structures, or functional re-entry around an unexcitable core due to functional block, could be potential drivers of AF.4 This model was based on a meandering central or mother wave moving in multiple directions and giving rise to daughter waves. While AF could be induced with high-rate pacing in animal models, these episodes would not persist beyond a few seconds. Moe and Abildskov, therefore, developed a canine model of AF, which enabled AF to be sustained for much longer periods of time.5 During AF, the appendage was excluded with a clamp. Upon discontinuation of atrial appendage pacing, the appendage was no longer in AF, however the rest of the

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atrium continued to fibrillate, suggesting the original focus was not required to sustain AF. The authors concluded that re-entry was the most likely mechanism for AF, with grossly irregular wavefronts becoming fractionated and producing independent, randomly wandering daughter wavelets as offspring (the multiple wavelet hypothesis). To further challenge this potential mechanism, Moe et al. undertook computational modelling.6 An estimate of 23 to 40 electrical wavelets re-entering random regions of the substrate was determined to be required to sustain fibrillation. This model also illustrated that re-entrant circuits could be generated without an anatomical obstacle, adding support for the multiple wavelet hypothesis. Interestingly, Lee et al. restudied Moe’s canine vagal nerve stimulation model of AF some 50 years later, proposing that multiple foci are responsible for driving AF, rejecting the multiple wavelet hypothesis.7 With the advent of mapping technology, Allessie et al. corroborated Moe’s findings in a series of elegant studies by placing microelectrodes on rabbit atria, and demonstrated that re-entrant circuits could be independent of an anatomical substrate.8–11 From this, the ‘leading-circle’ concept of re-entry was proposed, in which functional circuits could operate anywhere in the heart under the right local conditions. Initiation of re-entry was found to be dependent on the inhomogeneity of refractoriness of atrial fibres in close proximity to one another, and the activation wavefront continually emitting wavefronts centrally to produce and sustain a refractory core. Subsequent detailed studies by Allessie et al. were conducted on Langendorff-perfused canine hearts using epicardial multi-electrode arrays.12 Continuous beat-to-beat variations in activation pattern, including functional turning, collision, fractionation and extinction, in functional lines of block were described. Rather than the 23 to 40 wavelets required to maintain AF as proposed by Moe et al.,6 the critical number of wavelets suggested by Allessie et al. was just three to six.12

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Clinical Arrhythmias The potential benefit of multi-electrode mapping during cardiac surgery in humans was first described by Canavan et al.13 Atrial activation patterns were recorded from 156 epicardial electrodes during sinus rhythm, atrial pacing and reciprocating tachycardia. This group went on to study electrically induced AF in patients undergoing surgery for Wolf–Parkinson–White syndrome.14 Although re-entrant circuits involving anatomical obstacles were present, there was further confirmation of circuits existing in the absence of structural obstacles. Further work in a similar patient population by Konings et al. showed different degrees of disorganised activation patterns, ranging from predominantly planar activation to those with completely disorganised activation.15 In addition, the authors described a small number of new wavelets appearing to originate from the free wall of the right atrium. These focal activations were thought to be the result of epicardial breakthrough due to the frequent presence of a small R wave on the unipolar signal at the earliest site of activation, rather than a true focal source. These events were infrequent, and the dominant mechanism for sustaining AF was concluded to be multiple re-entry wavelets.

underwent limited focal radiofrequency ablation with elimination of the foci and subsequent non-inducibility of AF. The following year, in 1998, Haïssaguerre et al. made the important discovery of focal ectopy from PVs initiating AF.1 This has been important in both advancing our understanding of AF and identifying a treatment target, with PVI forming the mainstay of conventional ablation procedures.

Around the same time, Schuessler et al. described activation patterns in a canine model of induced AF.16 With increasing concentrations of acetylcholine, they observed a decrease in atrial refractory period, with eventual sustained fibrillation induced. Based on the multiple wavelet hypothesis, as the refractory period decreased, the number and instability of re-entrant circuits should have increased. As predicted, this was observed for non-sustained rapid repetitive responses, with activation sequence maps revealing multiple re-entrant circuits. However, with further shortening of the refractory period at higher acetylcholine concentrations, the trend did not continue. Instead, the re-entry “stabilized to a small, single, relatively stable re-entrant circuit”, independent of anatomic obstacles. The same group further challenged Moe’s hypothesis by demonstrating that re-entry is able to occur in a three-dimensional manner because of the connecting transmural muscle fibres between epi- and endocardium during epicardial electrode mapping in canine atria.17

It is important to recognise that mapping either the epicardial or endocardial surface will present two-dimensional data, ignoring the transmural conduction, which might be interpreted as focal activation. Biatrial high-density unipolar mapping of the epicardium has revealed frequent epicardial breakthrough of waves propagating in deeper layers in the so-called ‘double-layer hypothesis’. De Groot et al. describe the observation of small R waves in unipolar electrogram recordings, suggesting that this supports breakthrough rather than a true focal mechanism resulting from automatic cellular discharge.25 Although

Initiation and Maintenance of AF by Focal Drivers Rothberger and Winterberg first hypothesised that AF was the result of a single electrical focus in 1909. In a series of experiments, Scherf et al. suggested that AF was the result of an ectopic focus.18 In one study, they injected aconitine into canine atria, which led to rapid excitation with the appearance of AF. When they undertook local cooling of the area the arrhythmia terminated but restarted on discontinuation of cooling. Crucially in their observations, they stated that the wavefront interacted with islands of refractory tissue, causing the weaving and interweaving contraction characteristic of fibrillation as it entered the larger mass of auricular muscle. They concluded that AF was caused by a rapid stimulus rather than re-entry. Consequently, the re-entry waves of excitation are a concomitant feature of AF rather than its cause. While some groups have failed to demonstrate a repetitive focal activation as the mechanism driving AF,14,15 Harada et al. demonstrated regular and repetitive activation originating in the left atrium in 10 patients with chronic AF undergoing isolated mitral valve surgery.19 Interestingly, they found activation in the right atrium to be chaotic, suggesting that the left atrium was driving the AF. Jaïs et al. described a small series of nine patients with paroxysmal AF in which the surface ECG pattern of AF was the result of focal, rapidly firing activity, exhibiting a consistent and centrifugal pattern of activation.20 All patients

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While a subset of patients achieve success with PVI in treatment of AF, others remain in AF despite the veins being electrically isolated, indicating that this is not the only mechanism. As a result, the challenge of identifying targets for ablation beyond the PVs persisted. Termination of persistent AF has been demonstrated with ablation of complex fractionated atrial electrograms (CFAEs), suggesting that they contain either focal triggers or micro re-entrant circuits.21–23 The reproducibility of this technique has proven challenging. Ablation at CFAE sites does not always result in prolongation of AF cycle length or arrhythmia termination, indicating that some CFAEs may be active drivers, while others are likely passive effect of fibrillatory conduction.21,24

this alone is not proof of breakthrough, they used a number of other metrics to support the concept. A wave-mapping approach was used to identify individual fibrillation waves. This approach defines the starting point of the first fibrillation wave as the earliest activated site in the mapping area. The shortest time difference with the neighbouring eight electrodes is then calculated. If the time difference was ≤12 ms, the electrode activation was attributed to the surrounding wave. In case of a time difference >12 ms, the electrode was annotated as the starting point of a new wave. Four criteria were required for the classification of epicardial breakthrough. The epicardial breakthrough site had to be activated earlier than all surrounding electrodes, located at least two electrodes from the mapping array border and not obscured by large QRS complexes or artefacts. Lastly, a time delay of >40 ms between the site of epicardial breakthrough and the lateral border of another wave was required; otherwise, the wave was attributed to discontinuous conduction from the lateral boundary of that wave. This elegant mapping study does suggest some compelling evidence for the double-layer hypothesis. However, it remains challenging to understand how a small R wave from a unipolar electrogram can definitively be assigned to that of transmural activity. The complexities of interpreting electrogram morphology during AF means that this deflection may merely be the result of wavefront collision or far-field signal. Furthermore, the measurement of the smallest time delay between epicardial and endocardial signal may be difficult to interpret without the use of a reliable fiducial signal because of myocardial anisotropy. Lastly, a wavefront was deemed to reflect transmural conduction if it was present within a 4  mm distance and <15  ms before the origin of the focal wave based on normal atrial conduction properties. It is rare that patients with AF have normal atria, and therefore the likelihood of having normal conduction properties would seem doubtful in this patient population. Simultaneous mapping of the

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Drivers of Atrial Fibrillation endo- and epicardial surface has suggested asynchronous activation between the two layers, promoting maintenance of AF by replacing fibrillation waves that die out with breakthrough from the opposite side.26 This has important implications as limited and focal ablation is unlikely to result in termination of AF owing to the multiple potential breakthrough sites, and may explain the high recurrence rates of AF after ablation of focal and rotational drivers.

success rates.37 If focal drivers such as rotors were spatiotemporally stable, it would be expected that a focal ablation would result in successful treatment of AF. Furthermore, evidence that focal sources are stable is also challenged by the recent double-layer hypothesis demonstrating endocardial–epicardial dissociation, where multiple different breakthrough locations are possible.26 With this hypothesis, it is understandable why a focal ablative strategy would fail, and may in part contribute to the low procedural success rates.

The Rotor Revolution Despite recent popularity in this field of research, rotors are not a new concept. Seminal work by Winfree in canine ventricular myocardium demonstrated spiral waves rotating around a phase singularity.27 In 1992, with the use of optical mapping in animal myocardium, Davidenko et al. demonstrated cardiac fibrillation where spiral waves could be non-stationary, shifting the position of the phase singularity, as well as stationary by anchoring to anatomical structures.28 The idea that one or a number of localised rotors may drive AF holds important therapeutic implications as they may be targets for catheter ablation. Complex computational algorithms have been developed that afford investigators important insight in to the patterns of activation in human AF. The group led by José Jalife have published extensively on their optical mapping studies in the Langendorff-perfused ovine model of acetylcholine-induced AF.29–31 They demonstrated sustained rotors during AF, predominantly on the posterior left atrial wall, but also on the anterior wall of the left atrial appendage. Biatrial endocardial mapping using multispline basket catheters and a proprietary computational algorithm have been undertaken in focal impulse and rotor mapping (FIRM) by Narayan et al. In this approach, phase analysis has shown the presence of a small number of rotors in more or less fixed locations.32 Employing a completely different mapping modality, which applies a complex algorithm of inverse-solution-based analysis of body surface electrogram data, Haïssaguerre et al. have also identified rotors, but instead observed them to be transient and migratory with a tendency to cluster around fibrotic zones.33 Furthermore, the median rotor duration was 2.6 rotations, in contrast to minutes or hours as observed by Narayan et al.32 Their importance in arrhythmia maintenance has been suggested by limited ablation of these localised regions resulting in termination of AF. In the Conventional Ablation for AF With or Without Focal Impulse and Rotor Modulation (CONFIRM) trial, the acute efficacy endpoint of AF termination or ≥10 % consistent slowing of AF cycle length was achieved in 86 % of cases, with AF termination in 56 %, after a mean of 4.3 ± 6.3 minutes of FIRM ablation at the primary source.32 This limited ablation success was not the case in the AFACART study,34 in which the mean radiofrequency time for driver-only ablation resulting in AF termination was 46 ± 28 minutes despite a mean of only 4.9 ± 1.0 driver sites mapped per patient. It, therefore, seems surprising that radiofrequency ablation times are so long despite rotors being localised sources. One possible explanation may be that the proposed source areas are on the order of cm2, and the choice of ablation area is wider and operator dependent. The authors did, however, report AF termination in 64  % of patients undergoing ‘driver-only’ ablation. Despite this, evidence suggesting that rotors are transient and migratory does not explain why focal ablation should result in termination of AF.32,35,36 Initial high success rates were achieved with FIRM-guided catheter ablation,32 but several other groups were unable to achieve comparable

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In the largest series of focal source ablation, Miller et al. undertook FIRM-guided ablation in 170 consecutive patients, including patients with paroxysmal AF (37 %), persistent AF (31  %) and long-standing persistent AF (32 %).38 Overall, 43 % of these patients had undergone at least one prior ablation for AF. In combination with PVI, a single FIRM procedure achieved freedom from AF at 1 year in 87 % of participants. The authors concluded that higher rates of procedural success could be obtained with FIRM-guided ablation than with PVI alone, supporting localised sources as a mechanism for AF, and corroborating the findings of CONFIRM. If the maintenance of AF is related to a hierarchical (focal sources) rather than non-hierarchical (multiple wavelet) mechanism, it may be possible to explain why persistent AF has been terminated with relatively localised ablation. Narayan’s group has undertaken computational modelling, suggesting a possible explanation.36 They simulated spiral wave re-entry in monodomain two-dimensional myocyte sheets. Ablation lesions were applied, with models confirming that localised ablation may anchor re-entry, resulting in organised tachycardias. The ablation results in an excitable gap, which can be invaded by fibrillatory waves, which collide and rapidly terminate spiral re-entry. Targeted ablation may also terminate spiral waves by connecting lesions to large, non-conducting obstacles, such as large areas of scar or an anatomic orifice. There is disagreement as to whether rotors are stable or migratory. If rotors primarily localise at borders of fibrotic regions, it may be more appropriate to target these regions of scar rather than the rotors themselves. However, the extent of delayed-enhancement MRI abnormalities has been frequently shown to far exceed driver domains, and the microfibrosis that anchored drivers in optical studies was beyond the resolution of clinical scanners.39 Distinction between ‘culprit’ and ‘bystander’ regions would likely be required if this approach was to be successful.

Autonomic Function Initiating AF Animal models have often needed autonomic stimulation to maintain induced AF. In patients, the role for the autonomic nervous system has been assumed to occur on this background. The description of vagal symptoms and changes in heart rate variability prior to AF initiation has been presented as circumstantial evidence. Richly innervated areas on the epicardial surface of the left atrium have been identified around the PVs, known as ganglionated plexi (GP). The GP sites are located at the four PV atrial junctions and are highly innervated with both adrenergic and cholinergic nerve fibres. These sites form part of the epicardial neural network, which compromises multiple ganglia with interconnecting neurons and axons, including sensory fibres and sympathetic and parasympathetic efferents.40 During the delivery of radiofrequency energy at catheter ablation for AF, an increase in dispersion of AF cycle length has been observed with vagal responses.41 The increase in dispersion may promote wavefront

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Clinical Arrhythmias fragmentation into multiple, smaller wavelets – a potential mechanism that sustains AF.5 Direct stimulation of GP sites has been shown to initiate PV ectopy and induce AF.42 Canine studies of PV sleeve preparations have shown action potential shortening and triggered firing in the adjacent PVs, but not the atrial myocardium, in response to GP stimulation.43 This indicates that PVs appear to be the main effectors of GP stimulation. A well-described method of functionally locating GP sites is to stimulate the left atrium with high-frequency stimulation (HFS) over a presumed GP.44 If there is direct contact, a bradycardic atrioventricular (AV) nodal response can be elicited. Our group has used this technique to show autonomic modification of the AF substrate by demonstrating changes in atrial and PV AF cycle lengths both near and distant from the site of stimulation.42 With evidence of PV ectopy being triggered by stimulation of GP sites, Katritsis et al. investigated the effect of anatomically guided ablation of GP sites in addition to PVI, and found outcomes to be superior to those of PVI alone.45 The same group went on to investigate the effect of GP ablation alone on AF, although they found this strategy to be less effective than either PVI alone or PVI in combination with GP ablation.46 However, formal evidence of autonomic modification was not presented, as the study did not use a functional method to confirm GP sites or a change after ablation. There are methods described for locating GP sites that include continuous HFS, which locates GP sites with AV nodal effects, and stimulation delivered within the local refractory period (synchronised HFS), which identifies sites that trigger AF.42 There are studies that have used these techniques in a limited capacity to demonstrate the autonomic network in the human left atrium and the feasibility to ablate these effects from the endocardium. 40 Most studies have inferred a role for GP sites based on presumed anatomical colocalisation, with little direct evidence.47 In arrhythmias where there is a clear anatomical circuit, there is no need to target the autonomic stimuli, as there is a clear substrate to ablate. In AF, the stimuli and substrate appear to span a large part of the left atrial anatomy, and therefore the autonomic stimuli may actually represent a more targeted approach.

Left Atrial Substrate in AF Fibrosis has been attributed with mechanistic importance in AF. Whether cause or effect, it has frequently been observed in this patient group. Lategadolinium-enhanced cardiac MRI (LGE-CMRI) has been utilised by several groups for the quantification of atrial fibrosis. Although a technically challenging technique, it has shown that the degree of atrial fibrosis is higher with AF persistence and the presence of more AF risk factors.48 Furthermore, atrial fibrosis demonstrated by LGE-CMRI has been independently associated with AF recurrence in patients undergoing catheter ablation for AF.49 The electrical manifestations of fibrosis are sometimes, but not exclusively, seen during catheter ablation as regions of low voltage and slowed conduction. There are challenges when using voltage as a surrogate marker for fibrosis. While some areas are low -voltage during AF, they have been demonstrated to have increased voltage at the same site during sinus or paced rhythm.50,51 This is important as areas of low voltage measured during AF may not truly identify regions of abnormal atrial substrate.

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High-resolution contrast-enhanced MRI has been integrated with transmural optical mapping.39 Conduction was found to occur in preferential microanatomic tracks via fibrotically insulated pectinate muscles and intramural myocardial bundles, such that re-entry was established. Radiofrequency ablation at primary re-entrant driver regions resulted in either termination of AF, continuation of AF with a new re-entrant driver established in a different location or macrore-entry around the ablation lesion. This suggested the importance of the atrial microarchitecture in the maintenance of AF. The same group of investigators went on to hypothesise that human AF is maintained by a limited number of spatially stable, but temporally competing, microanatomic re-entrant sources.52 Haïssaguerre et al. reported a tendency for rotors to cluster around fibrotic zones.33 Some authors have raised the question of whether homogenisation of low-voltage regions from sinus rhythm maps to eradicate all potential channels and drivers supporting the arrhythmia is warranted.53 However, this risks damage to significant regions of atrial myocardium that may not even be implicated in arrhythmia maintenance.

Insights From Ablation Studies CFAE ablation was based on the assumption that areas of myocardium with such electrical activity may be acting as drivers of persistent AF. Identifying which were true drivers of AF was challenging. Ablation of some CFAEs resulted in prolongation of the AF cycle length, indicating their importance in contributing as a driver, while others had no effect on cycle length at all. Early studies by Konings et al. showed that CFAEs observed during intraoperative mapping in human AF were mainly in areas of slow conduction and/or regions of functional block where wavelets pivot.54 They were thought to represent either continuous re-entry of fibrillation or areas where multiple different wavelets enter the same area. In 121 patients, Nademanee et al. used electroanatomical mapping to tag and ablate CFAEs.55 They identified specific regions that were more likely to contain CFAEs, successfully ablating 115 of the 121 patients to sinus rhythm, without the need for external cardioversion. However, other investigators have not been able to replicate these encouraging results. Oral et al. undertook solely CFAE ablation in 100 patients with persistent AF, reporting that only 33 % of patients maintained sinus rhythm off medical therapy at a mean follow-up time of 14 months.56 Furthermore, the Benefit of Complex Ablation (BOCA) study showed that not only did adjunctive CFAE ablation confer no additional benefit in maintaining sinus rhythm, but it also significantly increased the incidence of both organised atrial tachycardia and gap-related macro-re-entrant flutter.57 Most recently, the Substrate and Trigger Ablation for Reduction of AF II (STAR-AF II) trial reported no additional benefit of CFAE ablation in addition to PVI for patients with persistent AF.24 The variability in definition of CFAE may in part be responsible for the large disparity in results from catheter ablation, or the variability of operator experience with CFAE ablation. While some have defined CFAEs based on only simple visual descriptions,55 others have produced a more comprehensive visual classification system,58 or characterisation using automated algorithms.59 There are certainly observations that support CFAE ablation resulting in acute organisation of AF, and in some cases termination. However, there are no consistently reproducible data that prove long-term adjunctive benefit. A recent meta-analysis of the efficacy of driver-guided catheter ablation for AF has demonstrated mixed results. A variety of

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Drivers of Atrial Fibrillation different strategies were used, including CFAE, FIRM and highfrequency source ablation. Four studies within the meta-analysis suggested increased single-procedure freedom from AF/atrial tachyarrhythmia (AT) at ≥1 year (RR 1.34, 95 % CI [1.05–1.70], p=0.02).32,60–62 However, after excluding cases of driver-guided ablation without PVI, this was no longer significant (RR 1.41, 95  % CI [0.96–2.08], p=0.08). Four studies also reported a higher proportion of acute AF termination with driver-guided ablation compared with controls (pooled RR 2.08, 95  % CI [1.43–3.05], p<0.001).32,60,62,63 This increased to an RR of 2.90 (95  % CI [1.15–5.55], p=0.001) after excluding patients undergoing driver-guided ablation without concomitant PVI.32,60,63 Although this is promising, the meta-analysis included primarily non-randomised studies of moderate quality, making results difficult to interpret. Interestingly, the only two fully randomised controlled trials in the

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 aïssaguerre M, Jaïs P, Shah DC, et al. Spontaneous initiation H of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med 1998;339:659–66. DOI: 10.1056/ NEJM199809033391003; PMID: 9725923. Garrey WE. Auricular fibrillation. Physiological Reviews 1924;4:215–50. DOI: 10.1152/physrev.1924.4.2.215 Garrey WE. The nature of fibrillary contraction of the heart – its relation to tissue mass and form. Am J Physiol 1914;33:397– 414. DOI: 10.1152/ajplegacy.1914.33.3.397. Lewis T, Drury AN, Iliescu CC. Further observations upon the state of rapid re-excitation of the auricles. Heart 1921;8:311–40. Moe GK, Abildskov JA. Atrial fibrillation as a self-sustaining arrhythmia independent of focal discharge. Am Heart J 1959;58:59–70. DOI: 10.1016/0002-8703(59)90274-1. Moe GK, Rheinboldt WC, Abildskov JA. A computer model of atrial fibrillation. Am Heart J 1964;67:200–20. DOI: 10.1016/00028703(64)90371-0. Lee S, Sahadevan J, Khrestian CM, et al. High density mapping of atrial fibrillation during vagal nerve stimulation in the canine heart: restudying the Moe hypothesis. J Cardiovasc Electrophysiol 2013;24:328–35. DOI: 10.1111/jce.12032; PMID: 23210508. Allessie MA, Bonke FI, Schopman FJ. Circus movement in atrial muscle as a mechanism of supraventricular tachycardia. J Physiol (Paris) 1972;65(Suppl):324A. Allessie MA, Bonke FI, Schopman FJ. The mechanism of supraventricular tachycardia induced by a single premature beat in the isolated left atrium of the rabbit. I. Circus movement as a consequence of unidirectional block of the premature impulse. Recent Adv Stud Cardiac Struct Metab 1975;5:303–8. PMID: 1188162. Allessie MA, Bonke FI, Schopman FJ. Circus movement in rabbit atrial muscle as a mechanism of tachycardia. II. The role of nonuniform recovery of excitability in the occurrence of unidirectional block, as studied with multiple microelectrodes. Circ Res 1976;39:168–77. DOI: 10.1161/01. RES.39.2.168; PMID: 939001. Allessie MA, Bonke FI, Schopman FJ. Circus movement in rabbit atrial muscle as a mechanism of tachycardia. III. The ‘leading circle’ concept: a new model of circus movement in cardiac tissue without the involvement of an anatomical obstacle. Circ Res 1977;41:9–18. DOI: 10.1161/01.RES.41.1.9; PMID: 862147. Allessie MA, Lammers WJ, Bonke FI, Hollen J. Experimental evaluation of Moe’s multiple wavelet hypothesis of atrial fibrillation. In: Zipes DP, Jalife J, Moe GK (eds). Cardiac Electrophysiology and Arrhythmias. Orlando, FL: Grune & Stratton, 1985:265–76. Canavan TE, Schuessler RB, Boineau JP, et al. Computerized global electrophysiological mapping of the atrium in patients with Wolff–Parkinson–White syndrome. Ann Thorac Surg 1988;46:223–31. DOI: 10.1016/S0003-4975(10)65904-8. Cox JL, Canavan TE, Schuessler RB, et al. The surgical treatment of atrial fibrillation. II. Intraoperative electrophysiologic mapping and description of the electrophysiologic basis of atrial flutter and atrial fibrillation. J Thorac Cardiovasc Surg 1991;101:406–26. PMID:1999934. Konings KT, Kirchhof CJ, Smeets JR, et al. High-density mapping of electrically induced atrial fibrillation in humans. Circulation 1994;89:1665–80. DOI: 10.1161/01.CIR.89.4.1665; PMID: 8149534. Schuessler RB, Grayson TM, Bromberg BI, et al. Cholinergically mediated tachyarrhythmias induced by a single extrastimulus in the isolated canine right atrium. Circ Res 1992;71:1254–67. DOI: 10.1161/01.RES.71.5.1254; PMID: 1394883. Schuessler RB, Kawamoto T, Hand DE, et al. Simultaneous epicardial and endocardial activation sequence mapping in the isolated canine right atrium. Circulation 1993;88:250–63. DOI: 10.1161/01.CIR.88.1.250; PMID: 8319340.

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meta-analysis did show greater acute AF termination with driverguided ablation.60,63 Atienza et al.60 found that driver-guided ablation was non-inferior to PVI in achieving freedom from AF/AT at 12 months in patients with paroxysmal AF; however, there was no benefit when combined with PVI in patients with persistent AF. In contrast, Lin et al. reported greater freedom from AF/AT at 17.7 ± 8.2 months in patients who had undergone PVI with driver-guided ablation rather than PVI with CFAE ablation.63

Conclusion The demonstration of PV ectopy triggering AF led to 20 years of technological development to optimise PVI techniques. It has become clear that a purely PV-based approach can resolve AF in 50–70 % of patients, implying the other drivers of AF have yet to be determined. At present there are many candidates for this role, yet conclusive proof of an alternative driver has remained elusive. n

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ablation: the AFACART study. Europace 2017;19:1302–9. DOI: 10.1093/europace/euw168; PMID: 28204452. 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. Rappel WJ, Zaman JA, Narayan SM. Mechanisms for the termination of atrial fibrillation by localized ablation: computational and clinical studies. Circ Arrhythm Electrophysiol 2015;8:1325–33. DOI: 10.1161/CIRCEP.115.002956. Steinberg JS, Shah Y, Bhatt A, et al. Focal impulse and rotor modulation: Acute procedural observations and extended clinical follow-up. Heart Rhythm 2017;14:192–7. DOI: 10.1016/j. hrthm.2016.11.008; PMID: 27826130. Miller JM, Kalra V, Das MK, et al. Clinical benefit of ablating localized sources for human atrial fibrillation: the Indiana University FIRM registry. J Am Coll Cardiol 2017;69:1247–56. DOI: 10.1016/j.jacc.2016.11.079; PMID: 28279291. 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. Armour JA, Murphy DA, Yuan BX, et al. Gross and microscopic anatomy of the human intrinsic cardiac nervous system. Anat Rec 1997;247:289–98. DOI: 10.1002/(SICI)10970185(199702)247:2<289::AID-AR15>3.0.CO;2-L. Takahashi Y, Jaïs P, Hocini M, et al. Shortening of fibrillatory cycle length in the pulmonary vein during vagal excitation. J Am Coll Cardiol 2006;47:774–80. DOI: 10.1016/j. jacc.2005.10.043; PMID: 16487844. Lim PB, Malcolme-Lawes LC, Stuber T, et al. Stimulation of the intrinsic cardiac autonomic nervous system results in a gradient of fibrillatory cycle length shortening across the atria during atrial fibrillation in humans. J Cardiovasc Electrophysiol 2011;22:1224–31. DOI: 10.1111/j.1540-8167.2011.02097.x; PMID: 21615814. Patterson E, Po SS, Scherlag BJ, Lazzara R. Triggered firing in pulmonary veins initiated by in vitro autonomic nerve stimulation. Heart Rhythm 2005;2:624–31. DOI: 10.1016/j. hrthm.2005.02.012; PMID: 15922271. Schauerte P, Scherlag BJ, Pitha J, et al. Catheter ablation of cardiac autonomic nerves for prevention of vagal atrial fibrillation. Circulation 2000;102:2774–80. DOI: 10.1161/01. CIR.102.22.2774; PMID: 11094046. 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. Baykaner T, Zografos TA, Zaman JAB, et al. Spatial relationship of organized rotational and focal sources in human atrial fibrillation to autonomic ganglionated plexi. Int J Cardiol 2017;240:234–9. DOI: 10.1016/j.ijcard.2017.02.152; PMID: 28433558. Daccarett M, Badger TJ, Akoum N, et al. Association of left atrial fibrosis detected by delayed-enhancement magnetic resonance imaging and the risk of stroke in patients with atrial fibrillation. J Am Coll Cardiol 2011;57:831–8. DOI: 10.1016/ j.jacc.2010.09.049; PMID: 21310320. 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. Chang CJ, Lin YJ, Higa S, et al. The disparities in the

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Clinical Arrhythmias

51.

52.

53.

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electrogram voltage measurement during atrial fibrillation and sinus rhythm. J Cardiovasc Electrophysiol 2010;21:393–8. DOI: 10.1111/j.1540-8167.2009.01637.x; PMID: 19909388. Teh AW, Kistler PM, Lee G, et al. The relationship between complex fractionated electrograms and atrial lowvoltage zones during atrial fibrillation and paced rhythm. Europace 2011;13:1709–16. DOI: 10.1093/europace/eur197; PMID: 21712259. Hansen BJ, Csepe TA, Zhao J, et al. Maintenance of atrial fibrillation: are reentrant drivers with spatial stability the key? Circ Arrhythm Electrophysiol 2016;9:e004398. DOI: 10.1161/ CIRCEP.116.004398; PMID: 27729340. Rolf S, Kircher S, Arya A, et al. Tailored atrial substrate modification based on low-voltage areas in catheter ablation of atrial fibrillation. Circ Arrhythm Electrophysiol 2014;7:825–33. DOI: 10.1161/CIRCEP.113.001251; PMID: 25151631. Konings KT, Smeets JL, Penn OC, et al. Configuration of unipolar atrial electrograms during electrically induced atrial fibrillation in humans. Circulation 1997;95:1231–41. DOI: 10.1161/01.CIR.95.5.1231; PMID: 9054854. Nademanee K, McKenzie J, Kosar E, et al. A new approach for catheter ablation of atrial fibrillation: mapping of the

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electrophysiologic substrate. J Am Coll Cardiol 2004;43:2044–53. DOI: 10.1016/j.jacc.2003.12.054; PMID: 15172410. 56. O  ral H, Chugh A, Good E, et al. Radiofrequency catheter ablation of chronic atrial fibrillation guided by complex electrograms. Circulation 2007;115:2606–12. DOI: 10.1161/ CIRCULATIONAHA.107.691386; PMID: 17502567. 57. Wong KC, Paisey JR, Sopher M, et al. No benefit of complex fractionated atrial electrogram ablation in addition to circumferential pulmonary vein ablation and linear ablation: Benefit of Complex Ablation study. Circ Arrhythm Electrophysiol 2015;8:1316–24. PMID:26283145. 58. Hunter RJ, Diab I, Tayebjee M, et al. Characterization of fractionated atrial electrograms critical for maintenance of atrial fibrillation: a randomized, controlled trial of ablation strategies (the CFAE AF trial). Circ Arrhythm Electrophysiol 2011;4:622–9. DOI: 10.1161/CIRCEP.111.962928; PMID: 21844156. 59. Stiles MK, Brooks AG, John B, et al. The effect of electrogram duration on quantification of complex fractionated atrial electrograms and dominant frequency. J Cardiovasc Electrophysiol 2008;19:252–8. DOI: 10.1111/j.1540-8167.2007.01034.x; PMID: 18302697.

60. A  tienza F, Almendral J, Ormaetxe JM, et al. Comparison of radiofrequency catheter ablation of drivers and circumferential pulmonary vein isolation in atrial fibrillation: a noninferiority randomized multicenter RADAR-AF trial. J Am Coll Cardiol 2014;64:2455–67. DOI: 10.1016/j. jacc.2014.09.053; PMID: 25500229. 61. Jadidi AS, Lehrmann H, Keyl C, et al. Ablation of persistent atrial fibrillation targeting low-voltage areas with selective activation characteristics. Circ Arrhythm Electrophysiol 2016;9:e002962. DOI: 10.1161/CIRCEP.115.002962; PMID: 26966286. 62. Seitz J, Bars C, Théodore G, et al. AF ablation guided by spatiotemporal electrogram dispersion without pulmonary vein isolation: a wholly patient-tailored approach. J Am Coll Cardiol 2017;69:303–21. DOI: 10.1016/j.jacc.2016.10.065; PMID: 28104073. 63. Lin YJ, Lo MT, Chang SL, et al. Benefits of atrial substrate modification guided by electrogram similarity and phase mapping techniques to eliminate rotors and focal sources versus conventional defragmentation in persistent atrial fibrillation. JACC Clin Electrophysiol 2016;2:667–78. DOI: 10.1016/ j.jacep.2016.08.005.

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Drugs and Devices

The Significance of Drug–Drug and Drug–Food Interactions of Oral Anticoagulation Pascal Vranckx, 1 Marco Valgimigli 2 and Hein Heidbuchel 3 1. Hartcentrum Hasselt, Faculty of Medicine and Life Sciences, Hasselt University, Hasselt, Belgium; 2. Swiss Cardiovascular Center Bern, Bern University Hospital, Bern, Switzerland; 3. Antwerp University and Antwerp University Hospital, Antwerp, Belgium

Abstract Vitamin K antagonists (VKAs) such as warfarin are the most commonly prescribed oral anticoagulants worldwide. However, factors affecting the pharmacokinetics of VKAs, such as food and drugs, can cause deviations from their narrow therapeutic window, increasing the bleeding or thrombosis risk and complicating their long-term use. The use of direct oral anticoagulants (DOACs) offers a safer and more convenient alternative to VKAs. However, it is important to be aware that plasma levels of DOACs are affected by drugs that alter the cell efflux transporter P-glycoprotein and/or cytochrome P450. In addition to these pharmacokinetic-based interactions, DOACs have the potential for pharmacodynamic interaction with antiplatelet agents and non-steroidal anti-inflammatory drugs. This is an important consideration in patient groups already at high risk of bleeding, such as patients with renal impairment.

Keywords Apixaban, dabigatran, direct oral anticoagulants, drug–drug interactions, edoxaban, rivaroxaban, vitamin K antagonists, warfarin Disclosure: The authors have no conflicts of interest to declare. Acknowledgement: The authors are grateful to the technical editing support provided by Katrina Mountfort of Medical Media Communications (Scientific) Ltd, which was funded by Daiichi Sankyo. Received: 6 November 2017 Accepted: 22 December 2017 Citation: Arrhythmia & Electrophysiology Review 2018;7(1):55–61. DOI: 10.15420/aer.2017.50.1 Correspondence: Pascal Vranckx, Hartcentrum Hasselt, Faculty of Medicine and Life Sciences Hasselt University, Hasselt, Belgium. E: pascal.vranckx@iccuhasselt.be

Anticoagulation with vitamin K antagonists (VKAs) has been used for the long-term treatment and prevention of thromboembolic diseases and for stroke prevention in atrial fibrillation (AF) for the past half century. Until the last decade, VKAs were the only oral anticoagulant (OAC) agents available, and warfarin remains the most commonly prescribed OAC worldwide.1 Direct oral anticoagulants (DOACs), which selectively block key factors in the coagulation cascade, provide an effective and safe alternative to VKAs for the long-term treatment and prevention of thromboembolic diseases and for stroke prevention in AF. One of the greatest advantages of DOACs in long-term treatment is the lack of need for routine monitoring of coagulation.

Vitamin K Antagonists

However, in order to balance the imminent risk of recurrent ischaemic events against the bleeding risk, factors that impact pharmacokinetics and dynamics should be taken into account in the management of OAC therapy. Given the long-term use of DOACs, the frequent use of overthe-counter medications and the need for multiple drug treatments in patients with comorbidities, the evaluation of drug–drug interactions (DDIs) with DOACs is essential.

Although effective under optimal conditions, given the narrow therapeutic window, numerous environmental (e.g. food and drug) and genetic interactions, e.g. cytochrome P450 family 2 subfamily C member 9 (CYP2C9) or vitamin K epOxide reductase complex (VKORC)1, complicate the long-term use of these drugs and render treatment with these agents complicated.7–13

The aim of this article is to present information about factors that influence the activity of OACs, and interactions between OACs and genetic and other factors, such as medicines, food, diseases and preexisting conditions. While clinical trial data for most alleged interactions are lacking, clinicians (and patients) should be aware of potential DDIs and drug–food interactions.

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By targeting vitamin K epoxide reductase, the post-translational modification of the vitamin K-dependent blood-coagulation proteins is impaired, see Figure 1.2 A reduced functional level of factor IX, factor VII, factor X and prothrombin leads to delayed blood coagulation. This inhibition is monitored in the clinical laboratory with the use of prothrombin time and is corrected for variable potencies of tissue factor used in the assay by means of a calibration factor, yielding the international normalised ratio (INR).3 The goal of therapy is to keep the INR within the therapeutic range.4,5 Patients with an average individual time >70 % are within the therapeutic range and are considered to be at a low risk of a major haemorrhagic or thrombotic event.6

Warfarin binds to albumin, and only about 3 % is free and pharmacologically active. A number of medications (e.g. ibuprofen, losartan, valsartan, amlodipine and quinidine) can displace warfarin binding, leading to its increased activity and subsequent increased rate of degradation.14 DDIs affecting the pharmacokinetics of warfarin mainly involve inhibition of the expression and/or activity of cytochrome P450 (CYP) isoenzymes

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Drugs and Devices Figure 1: The Vitamin K Cycle and Anticoagulation CH2 Prozymogen Glutamate CH2 residue COO–

CO2

CH2

Carboxylated Prozymogen

CH2 –COO

Carboxylase OH CH3

γ − carboxyglutamate residue

COO–

O

O2

CH3 O

R OH Vitamin KH2 (Hydroquinone) Vitamin K reductase

O Vitamin KO (Epoxide)

R

Vitamin K epoxide reductase

O CH3 R O Vitamin K (Quinone)

The vitamin K quinone is reduced to hydroquinone, which is a cofactor required for the conversion of specific glutamic-acid residues on vitamin K-dependent proteins to γ-carboxyglutamic acid by vitamin K-dependent carboxylase. Epoxide, a product of this reaction, is converted back to quinone by epoxide reductase, otherwise known as VKOR. The vitamin K cycle can be broken, and a state of vitamin K deficiency at the carboxylase level effected by the inhibition of VKOR by vitamin K antagonists, including warfarin.

involved in warfarin metabolism (CYP3A4 for the R-enantiomer and CYP2C9 for the three- to five-times more potent S-enantiomer of warfarin).15 The concomitant use of medications that induce CYP2C9 results in increased clearance of warfarin and less anticoagulation, see Table 1. The most pertinent DDIs are with azole antifungals, macrolides, quinolones, non-steroidal anti-inflammatory drugs (including selective cyclooxygenase-2 inhibitors), selective serotonin reuptake inhibitors, omeprazole, statins, amiodarone and fluorouracil.14 In the Apixaban for Reduction In Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial, patients on warfarin and amiodarone had lower times within the therapeutic range than patients not on amiodarone (56.5 % versus 63.0  %; p<0.0001) and a significantly increased risk of stroke and systemic embolism.16 In the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation – Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) trial, patients randomised to 30 mg (or dose-adjusted to 15 mg) of edoxaban treated with amiodarone at the time of randomisation demonstrated a significant reduction in ischaemic events versus warfarin when compared with those not on amiodarone, while preserving a favourable bleeding profile.17 In contrast, amiodarone had no effect on the relative efficacy and safety of high-dose edoxaban.17 Intake of foods – particularly vegetables containing vitamin K, such as spinach, kale and avocado – and herbal supplements can offset the effect of the daily dose of VKA.18,19 Components of grapefruit and grapefruit juice, such as furanocoumarins, inhibit CYP3A4 activity and can therefore increase plasma levels of VKAs.20,21

Direct Oral Anticoagulants The four currently-available DOACs are dabigatran, rivaroxaban, apixaban and edoxaban. DOACs are used in a number of clinical settings, including the prevention and treatment of venous thromboembolism and stroke prophylaxis in non-valvular AF. In this review we focus on the latter indication. In clinical studies, these drugs show similar efficacy and safety to warfarin, but are more convenient and do not require meticulous dose adjustment and monitoring to achieve optimal treatment.22–26 To date, no interactions with genetic factors have been

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reported. However, it is important for physicians to be mindful of any interactions that may alter plasma concentrations of DOACs (Table 1).

Effect of Drugs on the Pharmacokinetics of DOACs Drugs that induce cell efflux transporter P-glycoprotein (P-gp) and/or CYP450 may decrease DOAC plasma concentrations and increase the risk for thromboembolic events, while drugs that inhibit P-gp and/or CYP3A4 may increase DOAC concentrations and therefore increase bleeding risk. Since dabigatran etexilate is not metabolised by CYP P450 enzymes, it has a low potential for clinically-relevant interactions with drugs metabolised by CYP P450, see Figure 2.25,27 By contrast, this drug is a substrate for P-gp transporters.28 P-gp transporters are efflux transporters that are primarily expressed in the apical/luminal membrane of epithelia of the small intestine, hepatocytes, renal proximal tubules and other sites. P-gp has low substrate specificity and high transport capacity.29 In vitro studies found DDIs between dabigatran and P-gp inhibitors, including amiodarone, clarithromycin, cyclosporin A, itraconazole, ketoconazole, nelfinavir, quinidine, ritonavir and tacrolimus, but no interaction with digoxin.30–32 Co-administration with strong P-gp inhibitors, e.g. ketoconazole, should be avoided.33–35 No dose adjustment is needed with the use of amiodarone, whereas the standard dose of 150 mg twice daily should be reduced to 110 mg twice daily in patients receiving verapamil.36 It has been suggested that the interaction can be minimised if dabigatran is administered 2 hours prior to co-administering any P-gp inhibitor.33 Dabigatran absorption is reduced by the co-administration of anti-acid drugs such as proton-pump inhibitors, although this effect is rarely of clinical relevance.37 Dabigatran bioavailability increases with the concomitant use of ketoconazole or quinidine and decreases with rifampicin,22,38 hence their co-administration should be avoided. Apixaban and rivaroxaban are all substrates for CYP450, such as CYP3A4, and for P-gp breast cancer resistance protein (Bcrp (ABCG2)) transporters, see Figure 2.36,39 Cytochrome P450 isoenzyme CYP3A4 is a major source of variability in drug pharmacokinetics and response. There are 57 functional human CYPs, but around 10 enzymes belonging to the CYP1, 2 and 3 families are responsible for the biotransformation of most foreign substances, including 70–80 % of all drugs in clinical use; 248 drug metabolism pathways involve CYP.40 Cytochrome P450 (CYP3A4) is involved in the hepatic clearance of rivaroxaban and apixaban to different extents (33  % and 25  %, respectively).39,41 Dabigatran is not a CYP3A4 substrate, and less than 4 % of edoxaban is metabolised via CYP3A4. Apixaban and rivaroxaban plasma concentrations have been shown to increase to a clinically relevant degree in the presence of ketoconazole and ritonavir (a strong dual inhibitor of CYP3A4 and P-glycoprotein [P-gp]), while erythromycin (a moderate inhibitor CYP3A4 and weak inhibitor of P-gp), clarithromycin (a strong inhibitor CYP3A4 and weak-to-moderate inhibitor P-gp) and fluconazole (a moderate inhibitor CYP3A4, and potentially Bcrp) result in a moderate but not clinicallyrelevant increase in exposure.32,39,42–44 Co-administration of diltiazem leads to small increases in mean apixaban area under the curve (AUC) and Cmax45, but not rivaroxaban. Co-administration of ketoconazole or ritonavir leads to 2.6- or 2.5-fold increases in mean rivaroxaban AUC, respectively, and 1.7- or 1.6-fold increases in rivaroxaban Cmax, respectively, and is associated with increased bleeding risk.39,46 Ketoconazole 400 mg leads to approximately 70 % mean

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Drug–Drug and Drug–Food Interactions of Oral Anticoagulation Table 1: The Effect of Drug–Drug Interactions on Direct Oral Anticoagulant Plasma Levels

Mechanism

Warfarin* Dabigatran

Apixaban Edoxaban Rivaroxaban

Amiodarone (and its metabolite desethylamiodarone)

Inhibitor of CYP3A4, CYP1A2, CYP2C9, CYP2D6 and P-gp

Not known

↑ (minor)

Diltiazem

Inhibitor of CYP3A4

No effect

Not known

↑ (minor)

Dronedarone

Moderate inhibitor of CYP3A4; inhibitor of P-gp

Not known

Propafenone

Inhibitor of CYP3A4

Not known

Not known

Not known

Not known

Propranolol

Inhibitor of CYP1A2

Not known

Not known

Not known

Not known

Quinidine

Inhibitor of CYP3A4 and P-gp

Not known

↑ (minor)

Telmisartan

Inhibitor of CYP3A4

Verapamil

Weak inhibitor of CYP3A4; P-gp competition

Not known

↑ (minor)

Inhibitor of CYP3A4

Not known

No effect

No effect

Clarithromycin and erythromycin

Moderate inhibitor of CYP3A4; P-gp competition

Not known

Isoniazid

Inhibitor of CYP2C9

Not known

Not known

Not known

Not known

Metronidazole

Inhibitor of CYP1A2 and CYP2C9

Not known

Not known

Not known

Not known

Quinolones (e.g. ciprofloxacin)

Strong inhibitor of CYP1A2

Not known

Not known

Not known

Not known

Rifampicin

Inducer of CYP3A4 and CYP2C9

Trimethoprim/sulfametaoxasole

Inhibitor of CYP3A4

Not known

Not known

Not known

Not known

Inhibitor of CYP3A4; P-gp/Bcrp competition

Not known

Not known

Fluconazole

Moderate inhibitor of CYP3A4, CYP1A2 and CYP2C9

Not known

Not known

Not known

Itraconazole, ketoconazole, posaconazole and voriconazole

Strong inhibitor of CYP3A4, CYP1A2 and CYP2C9; P-gp competition

P-gp competition

Not recommended

Not known

Inhibitor of CYP2C9; competition for protein-binding sites

Not known

No effect

Not known

Gastrointestinal absorption

No effect

No effect

No effect

Barbiturates (e.g. phenobarbital)*

Inducer of CYP3A4, CYP2J and P-gp/BCRP

Carbamazepine*

Inducer of CYP3A4, CYP2J and P-gp/BCRP

Phenytoin*

Inducer of CYP3A4, CYP2J and P-gp/BCRP

Antiarrhythmic drugs

Other cardiovascular drugs Statins (atorvastatin, lovastatin, rosuvastatin and simvastatin) Antibiotics

Antiviral drugs HIV protease inhibitors (e.g. ritonavir) Fungostatics

Immunosuppressants Cyclosporin and tacrolimus Antiphlogistics Non-steroidal anti-inflammatory drugs Antacids Cimetidine and proton-pump inhibitors Others

*Based on theoretical assumptions. Adapted from Heidbuchel, et al., 2015.

24

inhibition of non-renal (metabolic) clearance of rivaroxaban and 44 % mean inhibition of active renal secretion, whereas ritonavir leads to a reduction in metabolic clearance of approximately 50 % and reduction in active renal secretion of >80  %.39 No significant interactions have been reported following co-administration of rivaroxaban and the CYP3A4 substrates midazolam  and atorvastatin.39,47,48 Co-administration of apixaban and rivaroxaban with strong CYP3A4 or P-gp inhibitors, such

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as ketoconazole or ritonavir, should be avoided.40 There is no need for dose adjustment when co-administered with weak CYP3A4 and or P-gp. Edoxaban elimination is only slightly dependent on CYP3A4 mechanisms.49,50 Edoxaban exposure is affected by P-gp inhibitors and inducers. Co-administration of amiodarone, quinidine and ketoconazole has been reported to increase exposure to edoxaban.50–52 Erythromycin

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Drugs and Devices Figure 2: Absorption and Metabolism of Direct Oral Anticoagulants Dabigatran

Rivaroxaban*

P-gp

no CYP450

~65 %

~20 %

esterase-mediated hydrolisis

Gut

Gut CYP3A4 CYP212

no CYP450

P-gp

Dabigatran

Rivaroxaban

Dabigatran

Rivaroxaban

Bio-availability 3–7 %

Bio-availability: 66 % (without food) ≈100 % (with food)

~80 %

Apixaban

Gut

~35 %

~50 % (~4 % CYP344) Gut

CYP3A4

Apixaban

P-gp/ Bcrp

Edoxaban ~73 %

P-gp

t1/2 = 5–9h (young) 11–13h (eldery)

t1/2 = 12–17h

t1/2 = 12h

CYP3A4

P-gp

Edoxaban

t1/2 = 10–14h

Edoxaban

Apixaban

Bio-availability 50 %

Bio-availability 62 % ~27 %

~50 %

* these rivaroxaban figures are valid only for doses exceeding 20 mg. Adapted from: Heidbuchel, et al., 2015.24

and cyclosporin also increase edoxaban exposure.52 The amount of edoxaban should be halved when co-administered with P-gp inhibitors that increase edoxaban exposure by ≥1.5 fold (e.g. dronedarone increases exposure by 84.5 %, quinidine by 76.7  % and verapamil by 52.7  %).50 No dose adjustment is needed with amiodarone as it only increases edoxaban exposure by 40 %.53 Digoxin is widely used for ventricular rate control in patients with AF. It is a P-gp substrate but, despite this, no interactions have been reported following co-administration with dabigatran, rivaroxaban and edoxaban.47,48,54 However, in the Rivaroxaban – Once Daily, Oral, Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKETAF) study, digoxin treatment in patients with AF taking rivaroxaban or warfarin was associated with a significant increase in all-cause mortality, vascular death and sudden death.55 Similar data were reported for edoxaban in the ENGAGE-AF TIMI 48 trial.56 Concomitant use of strong CYP3A4 inducers, such as rifampicin, phenytoin, carbamazepine or phenobarbital, can significantly lower DOAC plasma concentrations and significantly reduce the AUC for rivaroxaban, which is thought to cause a parallel decrease in pharmacodynamic effect. Co-administration of rifampicin leads to a decrease of approximately 50 % in the mean AUC of rivaroxaban.36,57,58 Rifampicin has been reported to increase the apparent oral clearance of edoxaban by 33  % and decrease its half-life by 50  %, primarily due to its effect on P-gp, since edoxaban is minimally dependent on CYP3A4.59 Administration of the P-gp inducer rifampicin (which is also a CYP3A4 inducer) for 7 days resulted in a significant reduction in the bioavailability of dabigatran, which returned almost to baseline after 7 days’ washout.59 A reduction in the bioavailability of apixaban has also been reported.60 Anti-epileptic drugs such as carbamazepine, levetiracetam, phenobarbital, phenytoin

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and valproic acid might also decrease the effect of DOACs by inducing P-gp, but further studies are required to confirm this.31

Effect of Drugs on the Pharmacodynamics of DOACs Particular caution is needed in patients in whom DOACs are co-administered with antiplatelet agents (e.g. aspirin, P2Y12 inhibitors) and non-steroidal inflammatory drugs, owning to these agents’ influence on haemostasis and increased bleeding risk.60 The co-administration of DOACs should be avoided and/or limited in time, unless specifically recommended.61 Clinical data demonstrating increased bleeding risk when individual DOACs are co-administered with antiplatelet agents are presented below. In a pooled analysis from the four large randomised controlled trials of DOACs that included 42,411 patients – 33.4 % of which, i.e. 14,148 patients, were also on aspirin or another antiplatelet drug, there was no additional benefitin those taking anticoagulation and antiplatelet therapy for stroke prevention when compared with anticoagulation alone.62 There was, however, an increased risk of bleeding.63,64 Co-administration of aspirin and dabigatran, and of aspirin and apixaban, showed an increased rate of bleeding events. Other studies found that co-administration of a single antiplatelet therapy and edoxaban resulted in higher bleeding rates than in those not receiving single antiplatelet therapy, while co-administration of aspirin and edoxaban showed a two-fold increase in bleeding time.64–68 A similar impact on bleeding events can be expected for rivaroxaban, however there are as yet no published data from the ROCKET-AF trials. Co-administration of rivaroxaban and clopidogrel increased the bleeding time in healthy subjects, but did not affect the pharmacokinetic or pharmacodynamic parameters of either drug.66 Following acute coronary syndrome, apixaban combined with standard antiplatelet therapy (21 % dual antiplatelet therapy) showed

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Drug–Drug and Drug–Food Interactions of Oral Anticoagulation Table 2: Labelling Recommendations for Direct Oral Anticoagulants Dabigatran Apixaban Edoxaban CYP3A4 and US label recommends dose Not recommended with Recommended dose P-gp inhibitors reduction to 150 mg once daily concomitant use of strong reduction to 30 mg if concomitant use of amiodarone, inhibitors of both CYP3A4 once daily if concomitant quinidine or verapamil. In moderate and P-gp, such as use with cyclosporin, impairment and co-administration ketoconazole, itraconazole, Concomitant use with quinidine, with verapamil, a dose reduction to voriconazole and posaconazole) verapamil or amiodarone 75 mg daily should be considered. and HIV protease inhibitors does not require dose reduction. However, the 75 mg dosage (e.g. ritonavir) Use with caution when is not approved in the EU. co-administered with Contraindicated with systemic P-gp inducers ketoconazole, cyclosporin and itraconazole

Rivaroxaban Not recommended in patients receiving concomitant systemic treatment with renal such as ketoconazole, itraconazole, voriconazole and posaconazole, or HIV protease inhibitors

NSAIDs Use of NSAIDs can Care is to be taken increase the risk of if patients are treated gastrointestinal bleeding. concomitantly with The administration of a NSAIDs including aspirin PPI may be considered

Care is recommended if patients are treated concomitantly with NSAIDs (including aspirin)

The concomitant chronic use of high-dose aspirin (325 mg) with edoxaban is not recommended. Concomitant administration of doses higher than 100 mg aspirin should only be performed under medical supervision

Anti-arrhythmic Contraindicated with No recommendation Recommended dose agents concomitant dronedarone reduction to 30 mg once daily if concomitant use of dronedarone

Given the limited clinical data available with dronedarone, co-administration with rivaroxaban should be avoided

CYP 3A4 = cytochrome P450; NSAID = non-steroidal anti-inflammatory drug; P-gp = P-glycoprotein; PPI = protein-pump inhibitor. Source: electronic Medicines Compendium summaries of product characteristics.

a dose-related increase in bleeding events without a significant reduction in recurrent ischaemic events.69,70 A dose-related increase in bleeding events was also reported with rivaroxaban in combination with standard antiplatelet therapy (92 % on dual antiplatelet therapy) in the Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome – Thrombolysis in Myocardial Infarction 52 (ATLAS ACS2-TIMI 52) study.71 The Study Exploring Two Treatment Strategies of Rivaroxaban and a Dose-Adjusted Oral Vitamin K Antagonist Treatment Strategy in Subjects with Atrial Fibrillation who Undergo Percutaneous Coronary Intervention (PIONEER-AF PCI) trial was the first to study the use of a DOAC as an alternative to VKA for patients with non-valvular AF requiring stent implantation.68 Rivaroxaban 15 mg once daily (plus P2Y12 inhibitor) and rivaroxaban 2.5 mg twice daily (plus P2Y12 inhibitor and aspirin 75 mg or 100 mg once daily) were associated with lower risks of clinically-significant bleeding than standard triple therapy (16.8  % and 18.0 % [HR 0.59, 95 % confidence interval [CI] 0.47–0.76, p<0.001], versus 26.7 % [HR 0.63, 95 % CI 0.50–0.80, p<0.001]). However, the trial lacked formal testing of the non-inferiority of the rivaroxaban regimens compared with the warfarin-based triple therapy. The Evaluation of Dual Therapy with Dabigatran versus Triple Therapy with Warfarin in Patients with AF that Undergo a PCI with Stenting (RE-DUAL) clinical study (n=2,725) showed that, among patients with AF who had undergone PCI, the risk of bleeding was lower in those who received dual therapy with dabigatran and a P2Y12 inhibitor than in those who received triple therapy with warfarin, a P2Y12 inhibitor and aspirin (HR 0.52; 95  % CI 0.42–0.63, p<0.001 for non-inferiority, p<0.001 for superiority). Dual therapy was non-inferior to triple therapy in terms of risk of thromboembolic events.72 The use of DOACs in patients with AF that undergo a PCI with stenting is being tested further in two other randomised trials: the Trial to Evaluate Safety of Eliquis

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(Apixaban) in Nonvalvular Atrial Fibrillation Patients with a Recent Acute Coronary Syndrome or Undergoing Percutaneous Coronary Intervention (AUGUSTUS) and the Edoxaban Treatment versus Vitamin K Antagonist in Patients with Atrial Fibrillation Undergoing Percutaneous Coronary Intervention (ENTRUST-AF PCI). In the absence of safety data from randomised clinical trials (only 6 % of patients were treated at baseline with ticagrelor or prasugrel in the PIONEER AF-PCI trial) and worrisome bleeding signals in registries, the use of these drugs should be avoided as part of triple therapy (and even double therapy) at this stage.68,69 Patients may need to switch from DOACs to VKA and vice versa. Transition from warfarin to rivaroxaban was found to enhance the prolongation of prothrombin time/INR activity due to a supra-additive effect during the initial transition period; however, there was no effect on anti-factor Xa activity.73 Dabigatran, rivaroxaban, apixaban and edoxaban can be administered safely after enoxaparin.74–76 However, because of their additive effect, co-administration of DOACs with other anticoagulants (e.g. low-molecular-weight heparin) is discouraged. Labelling recommendations for the concomitant use of DOACs with other drugs are given in Table 2.

Effect of Food on the Pharmacokinetics or Pharmacodynamics of DOACs Although, in theory, food or herbal inhibitors/inducers of CYP3A4 or P-gp might interfere with the pharmacokinetics of DOACs, no direct evidence of such interactions exist. St John’s wort, a potent inducer of P-gp and CYP3A4, is expected to lower plasma concentrations of dabigatran (a substrate of P-gp), rivaroxaban and apixaban (substrates of P-gp and CYP3A4). Co-administration should

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Drugs and Devices be made with caution with dabigatran and avoided with apixaban and rivaroxaban. Rivaroxaban shows increased bioavailability when taken with food, but there is no interaction for the other DOACs;73,77 therefore rivaroxaban should be taken with food, but this is not necessary for the other DOACs. It has been suggested that grapefruit affects the bioavailability of rivaroxaban but this has not been confirmed in clinical studies.78 No information is available regarding the potential pharmacodynamic interactions of DOACs with foods or herbal medicines.

High-risk Patient Groups Since each of the DOACs undergoes renal elimination to some extent (dabigatran 80 %, rivaroxaban 33 %, apixaban 25 % and edoxaban 50 %), patients with renal impairment or >75 years may be at a higher risk of bleeding complications, especially if they also have potential DDIs. Patients with cancer and AF may be at increased risk of thromboembolic events, and also for bleeding complications. The net clinical benefit of DOACs in this patient population is unstudied. DOAC treatment in cancer patients should therefore take into account frailty, platelet count and anaemia, as well as anticipated therapy-induced changes in organ function (especially liver and renal function). Some classes of chemotherapy appear to universally interact with CYP3A4, P-pg or both. These include the antimitotic microtubule inhibitors (e.g. vinca alkaloids and taxanes), tyrosine kinase inhibitors (but not erlotinib, gefitinib and sorafenib), and immune-modulating agents, including glucocorticoids and mammalian target of rapamycin inhibitors (but not everolimus). Conversely, none of the frequently-used antimetabolites, platinum-based agents, intercalating agents or monoclonal antibodies has significant inhibitory or inducing effects on CYP3A4 or P-pg. No clear class effect is seen among the topoisomerase inhibitors, anthracyclines, alkylating agents or anticancer hormonal agents; there is significant heterogeneity in drug interaction potential within each of these medication classes. Chemotherapeutic agents are often used in combination, and the clinical relevance of these combined weak or moderate interactions remain mostly unknown. Potential disruption in absorption due to short gut or malnutrition, which are common issues in the cancer population, are of concern.

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HIV-positive patients often require anticoagulation therapy because they are at increased risk of venous thromboembolism or cardiovascular disease.79,80 However, many anti-retroviral agents used to treat HIV, such as nevirapine, efavirenz, saquinavir and ritonavir, are inhibitors/ inducers of CYP enzymes and/or P-gp. An increased likelihood of adverse reactions or decreased efficacy of DOAC therapy is therefore an important consideration in this patient population.24,75 Bariatric surgical procedures are a well-established approach to the treatment of morbid obesity, offering sustainable weight loss and a reduction in the risk of conditions related to obesity. RouxEn-Y gastric bypass is one of the most common bariatric surgical treatments. The consequences of this procedure are a 95 % reduction in gastric capacity as well as a reduction in the functional length of the gastrointestinal tract from bypassing the duodenum and proximal jejunum. These changes potentially augment the effect of P-gp induction on limiting drug absorption. Bariatric surgery has been linked to nutritional deficiencies but has not been extensively studied for its effects on DOAC drug absorption and activity.81

Summary Numerous pharmacokinetic and pharmacodynamic interactions with drugs and food can influence the efficacy and safety of both VKAs and DOACs. Despite fewer food and drug interactions compared with warfarin, physicians should still consider DDIs when prescribing DOACs. Pharmacokinetic DDIs that may occur in association with DOACs are largely mediated by the P-gp efflux transporter protein alone or in combination with CYP3A4 enzymes. In addition to managing pharmacokinetic-based interactions, clinicians should avoid unnecessary pharmacodynamic interactions between DOACs and antiplatelet agents and non-steroidal anti-inflammatory drugs. Due to the extensive renal elimination of some DOACs (particularly dabigatran), DDIs are more significant in patients with renal impairment. It should be noted that, for many potential interactions with medications often used in AF patients for other comorbidities, no data are available. There is a need for further clinical studies and realworld evidence to provide more information about the potential DDIs of DOACs to further optimise their safety profile. n

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45. F  rost CE, Byon W, Song Y, et al. Effect of ketoconazole and diltiazem on the pharmacokinetics of apixaban, an oral direct factor Xa inhibitor. Br J Clin Pharmacol 2015;79:838–46. DOI: 10.1111/bcp.12541; PMID: 25377242. 46. Rathbun RC, Liedtke MD. Antiretroviral drug interactions: overview of interactions involving new and investigational agents and the role of therapeutic drug monitoring for management. Pharmaceutics 2011;3:745–81. DOI: 10.3390/ pharmaceutics3040745; PMID: 24309307 47. Kubitza D, Becka M, Roth A, Mueck W. Absence of clinically relevant interactions between rivaroxaban – an oral, direct Factor Xa inhibitor – and digoxin or atorvastatin in healthy subjects. J Int Med Res 2012;40:1688–707. DOI: 10.1177/030006051204000508; PMID: 23206451. 48. Stangier J, Stahle H, Rathgen K, et al. Pharmacokinetics and pharmacodynamics of dabigatran etexilate, an oral direct thrombin inhibitor, with coadministration of digoxin. J Clin Pharmacol 2012;52:243–50. DOI: 10.1177/0091270010393342; PMID: 21868715. 49. Lip GY, Agnelli G. Edoxaban: a focused review of its clinical pharmacology. Eur Heart J 2014;35:1844–55. DOI: 10.1093/ eurheartj/ehu181; PMID: 24810388. 50. Mendell J, Zahir H, Matsushima N, et al. Drug–drug interaction studies of cardiovascular drugs involving P-glycoprotein, an efflux transporter, on the pharmacokinetics of edoxaban, an oral factor Xa inhibitor. Am J Cardiovasc Drugs 2013;13:331–42. DOI: 10.1007/s40256-013-0029-0; PMID: 23784266. 51. Matsushima N, Lee F, Sato T, et al. Bioavailability and safety of the factor Xa inhibitor edoxaban and the effects of quinidine in healthy subjects. Clin Pharmacol Drug Dev 2013;2:358–66. DOI: 10.1002/cpdd.53; PMID: 27121940. 52. Parasrampuria DA, Mendell J, Shi M, et al. Edoxaban drug– drug interactions with ketoconazole, erythromycin, and cyclosporine. Br J Clin Pharmacol 2016;82:1591–600. DOI: 10.1111/bcp.13092; PMID: 27530188. 53. Bathala MS, Masumoto H, Oguma T, et al. Pharmacokinetics, biotransformation, and mass balance of edoxaban, a selective, direct factor Xa inhibitor, in humans. Drug Metab Dispos 2012;40:2250–5. DOI: 10.1124/dmd.112.046888; PMID: 22936313. 54. Mendell J, Noveck RJ, Shi M. Pharmacokinetics of the direct factor Xa inhibitor edoxaban and digoxin administered alone and in combination. J Cardiovasc Pharmacol 2012;60:335–41. DOI: 10.1097/FJC.0b013e31826265b6; PMID: 23064240. 55. Washam JB, Stevens SR, Lokhnygina Y, et al. ROCKET AF Steering Committee and Investigators. Digoxin use in patients with atrial fibrillation and adverse cardiovascular outcomes: a retrospective analysis of the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF). Lancet 2015;385:2363–70. DOI: 10.1016/S0140-6736(14)61836-5; PMID: 25749644. 56. Eisen A, Ruff CT, Braunwald E, et al. Digoxin use and subsequent clinical outcomes in patients with atrial fibrillation with or without heart failure in the ENGAGE AF-TIMI 48 trial. J Am Heart Assoc 2017;6:e006035. DOI: 10.1161/JAHA.117.006035; PMID: 28666993. 57. Altena R, van Roon E, Folkeringa R, et al. Clinical challenges related to novel oral anticoagulants: drug–drug interactions and monitoring. Haematologica 2014;99:e26–7. doi: 10.3324/ haematol.2013.097287; PMID: 24497568. 58. Kubitza D, Becka M, Zuehlsdorf M, Mueck W. Effect of food, an antacid, and the H2 antagonist ranitidine on the absorption of BAY 59-7939 (rivaroxaban), an oral, direct factor Xa inhibitor, in healthy subjects. J Clin Pharmacol 2006;46:549–58. DOI: 10.1177/0091270006286904; PMID: 16638738. 59. Mendell J, Chen S, He L, et al. The effect of rifampin on the pharmacokinetics of edoxaban in healthy adults. Clin Drug Investig 2015;35:447–53. DOI: 10.1007/s40261-015-0298-2; PMID: 26068927. 60. Kubitza D, Becka M, Mueck W, Zuehlsdorf M. Rivaroxaban (BAY 59-7939) – an oral, direct factor Xa inhibitor – has no clinically relevant interaction with naproxen. Br J Clin Pharmacol 2007;63:469–76. DOI: 10.1111/j.1365-2125.2006.02776.x; PMID: 17100983 61. Camm AJ, Lip GY, De Caterina R, et al. ESC Committee for Practice Guidelines. 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. 62. Kumar S, Danik SB, Altman RK, et al. Non-vitamin K antagonist oral anticoagulants and antiplatelet therapy for stroke prevention in patients with atrial fibrillation: a meta-analysis of randomized controlled trials. Cardiol Rev 2016;24:218–23.

DOI: 10.1097/CRD.0000000000000088; PMID: 26274538. 63. D  ans AL, Connolly SJ, Wallentin L, et al. Concomitant use of antiplatelet therapy with dabigatran or warfarin in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial. Circulation 2013;127:634–40. DOI: 10.1161/ CIRCULATIONAHA.112.115386; PMID: 23271794. 64. Alexander JH, Lopes RD, Thomas L, et al. Apixaban vs. warfarin with concomitant aspirin in patients with atrial fibrillation: insights from the ARISTOTLE trial. Eur Heart J 2014;35:224–32. DOI: 10.1093/eurheartj/eht445; PMID: 24144788. 65. Xu H, Ruff CT, Giugliano RP, et al. Concomitant use of single antiplatelet therapy with edoxaban or warfarin in patients with atrial fibrillation: analysis from the ENGAGE AF-TIMI48 trial. J Am Heart Assoc 2016;5:e002587. DOI: 10.1161/ JAHA.115.002587; PMID: 26908401. 66. Ezekowitz MD, Reilly PA, Nehmiz G, et al. Dabigatran with or without concomitant aspirin compared with warfarin alone in patients with nonvalvular atrial fibrillation (PETRO Study). Am J Cardiol 2007;100:1419–26. DOI: 10.1016/j.amjcard.2007.06.034; PMID: 17950801. 67. Kubitza D, Becka M, Mueck W, Zuehlsdorf M. Safety, tolerability, pharmacodynamics, and pharmacokinetics of rivaroxaban – an oral, direct factor Xa inhibitor – are not affected by aspirin. J Clin Pharmacol 2006;46:981–90. DOI: 10.1177/0091270006292127; PMID: 16920892. 68. Mendell J, Lee F, Chen S, et al. The effects of the antiplatelet agents, aspirin and naproxen, on pharmacokinetics and pharmacodynamics of the anticoagulant edoxaban, a direct factor Xa inhibitor. J Cardiovasc Pharmacol 2013;62:212–21. DOI: 10.1097/FJC.0b013e3182970991; PMID: 23615159. 69. Alexander JH, Lopes RD, James S, et al. APPRAISE-2 Investigators. Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med 2011;365:699–708. DOI: 10.1056/NEJMoa1105819; PMID: 21780946. 70. Oldgren J, Budaj A, Granger CB, et al. Dabigatran vs. placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, double-blind, phase II trial. Eur Heart J 2011;32:2781–9. DOI: 10.1093/eurheartj/ehr113; PMID: :21551462. 71. Mega JL, Braunwald E, Wiviott SD, et al. ATLAS ACS 2 – TIMI 51 Investigators. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 2012;366:9–19. DOI: 10.1056/ NEJMoa1112277; PMID: 22077192. 72. Cannon CP, Bhatt DL, Oldgren J, et al. Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation. N Engl J Med 2017;377:1513–24. DOI: 10.1056/NEJMoa1708454; PMID: 28844193. 73. Kubitza D, Becka M, Muck W, Kratzschmar J. Pharmacodynamics and pharmacokinetics during the transition from warfarin to rivaroxaban: a randomized study in healthy subjects. Br J Clin Pharmacol 2014;78:353–63. DOI: 10.1111/bcp.12349; PMID: 24528331. 74. Barrett YC, Wang J, Song Y, et al. A randomised assessment of the pharmacokinetic, pharmacodynamic and safety interaction between apixaban and enoxaparin in healthy subjects. Thromb Haemost 2012;107:916–24. DOI: 10.1160/TH1109-0634; PMID: 22398784. 75. Kubitza D, Becka M, Schwers S, Voith B. Investigation of pharmacodynamic and pharmacokinetic interactions between rivaroxaban and enoxaparin in healthy male subjects. Clin Pharmacol Drug Dev 2013;2:270–7. DOI: 10.1002/cpdd.26; PMID: 27121789. 76. Zahir H, Matsushima N, Halim AB, et al. Edoxaban administration following enoxaparin: a pharmacodynamic, pharmacokinetic, and tolerability assessment in human subjects. Thromb Haemost 2012;108:166–75. DOI: 10.1160/TH1109-0676; PMID: 22628060. 77. Stampfuss J, Kubitza D, Becka M, Mueck W. The effect of food on the absorption and pharmacokinetics of rivaroxaban. Int J Clin Pharmacol Ther 2013;51:549–61. DOI: 10.5414/CP201812; PMID: 23458226. 78. Bailey DG, Dresser G, Arnold JM. Grapefruit–medication interactions: forbidden fruit or avoidable consequences? CMAJ 2013;185:309–16. DOI: 10.1503/cmaj.120951; PMID: 23184849. 79. Bibas M, Biava G, Antinori A. HIV-associated venous thromboembolism. Mediterr J Hematol Infect Dis 2011;3:e2011030. DOI: 10.4084/MJHID.2011.030; PMID: 21869916 80. Dau B, Holodniy M. The relationship between HIV infection and cardiovascular disease. Curr Cardiol Rev 2008;4:203–18. DOI: 10.2174/157340308785160589. 81. Kroll D, Stirnimann G, Vogt A, et al. Pharmacokinetics and pharmacodynamics of single doses of rivaroxaban in obese patients prior to and after bariatric surgery. Br J Clin Pharmacol 2017;83:1466–75. DOI: 10.1111/bcp.13243; PMID: 28121368.

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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 for free online access to the journal, please visit:

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Letters

Unravelling the Mysteries of the Human AV Node

Citation: Arrhythmia & Electrophysiology Review 2018;7(1):63–4. DOI 10.15420/aer.2018.7.1.L1 Author: Maria Kokladi, Athens Euroclinic, Athens, Greece

Dear Sir, I read with great interest the elegant review written by Dr Efimov and colleagues on the structure and properties of the atrioventricular (AV) node in the last issue of this journal (AER 6(4):179–85).1 However, there are several points that need further clarification. The authors state that total protein and mRNA levels of Cx40, Cx43 and/or Cx45 can be assessed qualitatively and quantitatively. However, representative immunolabelled sections are shown only for Cx43. From this, as well as other publications by the same team,2,3 I am left with the impression that genotyping data have only been presented for Cx43. However, Cx43 is one of four connexins that have been described to date (Cx40, Cx43, Cx45 and Cx30). Why do no data exist for them, and what is the impact of this lack of information on the characterisation of AV nodal properties? Is it just technically not feasible to obtain this information or is it just a matter of conventional priorities? I do believe that such genotyping is important for the full characterisation of the properties of the AV node and, perhaps, the unravelling of the mysteries of the circuit of AV nodal re-entrant tachycardia.4,5 Maria Kokladi, Department of Cardiology, Athens Euroclinic, Greece

1. 2. 3. 4. 5.

George SA, Faye NR, Murillo-Berlioz A, et al. At the atrioventricular crossroads: dual pathway electrophysiology in the atrioventricular node and its underlying heterogeneities. Arrhythm Electrophysiol Rev 2017;6(4):179–85. DOI: 10.15420/aer.2017.30.1; PMID: 29326832. Hucker WJ, McCain ML, Laughner JI, et al. Connexin 43 expression delineates two discrete pathways in the human atrioventricular junction. Anat Rec (Hoboken) 2008;291:204–15. DOI: 10.1002/ar.20631; PMID: 18085635. Hucker WJ, Sharma V, Nikolski VP, Efimov IR. Atrioventricular conduction with and without AV nodal delay: two pathways to the bundle of His in the rabbit heart. Am J Physiol Heart Circ Physiol 2007;293:H1122–30. DOI: 10.1152/ajpheart.00115.2007; PMID: 17496219. Katritsis DG, Marine JE, Latchamsetty R, et al. Coexistent types of atrioventricular nodal re-entrant tachycardia: implications for the tachycardia circuit. Circ Arrhythm Electrophysiol 2015;8:1189–93. DOI: 10.1161/CIRCEP.115.002971; PMID: 26155802. Katritsis DG, Marine JE, Contreras FM, et al. Catheter ablation of atypical atrioventricular nodal reentrant tachycardia. Circulation 2016;134:1655–63. DOI: 10.1161/ CIRCULATIONAHA.116.024471; PMID: 27754882.

Authors’ Reply Citation: Arrhythmia & Electrophysiology Review 2018;7(1):63–4. DOI 10.15420/aer.2018.7.1.L1.R1 Authors: Igor R Efimov & Sharon George, George Washington University, Washington, DC, USA

Dear Sir, Thank you for the opportunity to address the reader’s very important question regarding the roles of various connexin isoforms in the complex function of the human AV node.1 These isoforms can serve as a rate-dependent AV conduction axis during normal sinus rhythm or a lifesaving filter of high-frequency excitation produced by atrial tachyarrhythmias or as a backup junctional pacemaker. Cx43, Cx40 and Cx45 are the major connexin isoforms expressed in the human AV junction. Cx43 is the most well characterised and anatomically-mapped isoform, especially in humans.2 Several important studies3–5 have reported the mRNA and protein expression of Cx40 and Cx45 in different regions of the AV junction, which appear to play an important role in the complex function of the human AV node. Cx31.9 remains controversial: its mRNA was reported to be present in the human AV node but its protein expression was undetectable in humans, unlike evidence of its ortholog Cx302 in the mouse sinoatrial and AV nodes.6 This is a good example of how mRNA expression data do not necessarily correlate with protein expression and function.

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Letters Though the mRNA and protein expression data are robust and clearly address important questions, to investigate this particular issue it would be necessary to immunolable serial sections of the human AV junction, as was done with Cx43 in Hucker et al.2 This method is more advantageous as it allows us to directly compare histological data with protein expression in the region of interest. The availability of histological data confirms the location and boundaries of the various regions of the AV junction (which have morphological differences) that are otherwise not easy to define. The serial sectioning protocol is technically challenging and strongly dependent on the quality of antibodies. For more than a decade we have tried to anatomically map Cx45 and Cx40 protein expression using immunofluorescence microscopy. Unfortunately only Cx43 mapping was possible due to the low quality of antibodies available on the market and those produced by our collaborators and us. Despite numerous attempts to immunolable serial sections of the human AV and sinoatrial nodes, we have been unable to obtain the consistent high-quality signals from either Cx40 or Cx45 antibodies that are necessary for 3D reconstruction of their distribution in the AV junction. Over the past few years, we have tested and validated several new antibodies that might work well for this purpose, especially with the advent of the novel CLARITY method, which allows protein mapping in 3D anatomical structures without the need for tissue sectioning.7 This topic is an on-going collaborative project in our laboratory and we hope to have data that directly answer this question in the near future. Igor R Efimov, George Washington University, Washington, DC, USA Sharon George, George Washington University, Washington, DC, USA

1. 2. 3. 4. 5. 6. 7.

George SA, Faye NR, Murillo-Berlioz A, et al. At the atrioventricular crossroads: dual pathway electrophysiology in the atrioventricular node and its underlying heterogeneities. Arrhythm Electrophysiol Rev 2017;6(4):179–85. DOI: 10.15420/aer.2017.30.1; PMID: 29326832. Hucker WJ, McCain ML, Laughner JI, et al. Connexin 43 expression delineates two discrete pathways in the human atrioventricular junction. Anat Rec 2008;291:204–15. DOI: 10.1002/ ar20631; PMID: 18085635. Dobrzynski H, Anderson RH, Atkinson A, et al. Structure, function and clinical relevance of the cardiac conduction system, including the atrioventricular ring and outflow tract tissues. Pharmacol Ther 2013;139:260–88. DOI: 10.1016/j.pharmthera.2013.04.010; PMID: 23612425. Dobrzynski H, Atkinson A, Borbas Z, et al. Molecular investigation into the human atrioventricular node in heart failure. Anat Physiol 2015;5:164. DOI: 10.4172/2161-0940.1000164. Greener ID, Monfredi O, Inada S. Molecular architecture of the human specialised atrioventricular conduction axis. J Mol Cell Cardiol 2011;50:642–51. DOI: 10.1016/j.yjmcc.2010.12.017; PMID: 21256850. Kreuzberg MM, Liebermann M, Segschneider S, et al. Human connexin31.9, unlike its orthologous protein connexin30.2 in the mouse, is not detectable in the human cardiac conduction system. J Mol Cell Cardiol 2009;46:553–9. DOI: 10.1016/j.yjmcc.2008.12.007; PMID: 19168070. Hsueh B, Burns VM, Pauerstein P, et al. Pathways to clinical CLARITY: volumetric analysis of irregular, soft, and heterogeneous tissues in development and disease. Sci Rep 2017;7:5899. DOI: 10.1038/s41598-017-05614-4; PMID: 28724969.

The Risks of Electric Currents at Home

Citation: Arrhythmia & Electrophysiology Review 2018;7(1):64. DOI: 10.15420/aer.2017.7.1.L2 Author: Boghos L Artinian, MD, Private Practice, Salam Building, Beirut, Lebanon

Dear Sir, I read with interest the article on the cardiac effects of lightening strikes, published in AER last year.1 ‘Never bathe or take a shower during a thunderstorm,’ as the saying goes. Sudden cardiac death, which is more common in the bathtub or under the shower, in some cases may be due to non-electrocuting, mild stray electric currents not felt by the victim or noticed by the family, nor diagnosed at autopsy. Boghos L Artinian, Private Practice, Beirut, Lebanon

1.

Christophides T, Khan S, Ahmad M, et al. Cardiac effects of lightning strikes. Arrhythm Electrophysiol Rev 2017;6:114–7. DOI: 10.15420/aer.2017:7:3; PMID: 29018518.

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Letters

Hybrid Approach for Atrial Fibrillation Ablation: the Jury is Still Out

Citation: Arrhythmia & Electrophysiology Review 2018;7(1):65–6. DOI: 10.15420/aer.2017.7.1.L3 Author: Georgios Giannopoulos & Spyridon Deftereos, Yale School of Medicine, New Haven, CT, USA

Dear Sir, We read with great interest the meta-analysis by Pearman et al.1 on the comparison between epicardial ablation for atrial fibrillation and the hybrid approach. The authors should be commended on the way they handled the data. The imbalance between the two meta-analytic cohorts – in terms of the type of atrial fibrillation and left atrial diameter – may have worked to the detriment of the hybrid arm, but the sensitivity analysis shows quite convincingly, at least from a statistical point of view, that this is probably not the case. However, one cannot fail to note that statistics can only go so far as the quality of available data allows. An all-encompassing meta-analysis that includes not only randomised data but also small series of patients from observational and/or retrospective studies may dilute the true signals of difference between the two strategies studied. Therefore, it would be interesting to report results only from studies with a prospective design. Furthermore, considering that clear definitions of the parameters studied are the basis of any sound analysis, one may wonder what exactly is meant as a ‘hybrid’ technique. Is it merely a combination of epicardial and endocardial ablation? Do epi- and endocardial ablation happen at the same time or in a staged manner and, when performed simultaneously, is the confirmation of electrical isolation reliable? Aggregating different approaches – all termed ‘hybrid’ – in the same analysis may cloud the picture. Finally, another point of concern would be the method of follow up. Considering that the minimally-invasive epicardial technique antecedes the hybrid approach, it is conceivable that in a number of the earlier studies (thus more frequently in studies of epicardial technique) follow-up was merely clinical/electrocardiographic, while in later studies (thus more frequently in studies of hybrid technique) higher-yield techniques of patient monitoring may have been used. This would result in a lower detection rate of arrhythmia recurrence in less intensively followed patients, i.e. artificially higher ‘success’ rates. Are there any data regarding these aspects of follow-up for the two patient groups? Georgios Giannopoulos, Yale School of Medicine, New Haven, CT, USA Spyridon Deftereos, Yale School of Medicine, New Haven, CT, USA

1.

Pearman CM, Poon SS, Bonnett LJ, et al. Minimally invasive epicardial surgical ablation alone versus hybrid ablation for atrial fibrillation: a systematic review and meta-analysis. Arrhythm Electrophysiol Rev 2017;6(4):202–9. DOI: 10.15420/aer/2017.29.2; PMID: 29326836.

Authors’ Reply Citation: Arrhythmia & Electrophysiology Review 2018;7(1):65–6. DOI: 10.15420/aer.2017.7.1.L3.R3 Authors: Charles M Pearman, Liverpool Heart and Chest Hospital, Liverpool and Manchester Academic Health Science Centre, University of Manchester, Manchester, UK; Dhiraj Gupta, Liverpool Heart and Chest Hospital, Liverpool, UK

Dear Sir, We thank Drs Giannopoulos and Deftereos for showing interest in our work.1 They wonder whether a true difference might exist between hybrid and epicardial ablation alone that may have been masked by our combining the results from retrospective observational studies with those from randomised trials. A fine balance needs to be struck for this type of analysis. On one hand, adopting narrow inclusion criteria will ensure that

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Letters the studies within each group share very similar designs, interventions and populations, minimising the chance of dilution of a genuine difference between groups. On the other hand, using broad inclusion criteria will increase statistical power by including a larger number of studies. Previous work exploring outcomes following atrial fibrillation ablation has shown that results from observational studies match those from randomised trials and can strengthen the power of a meta-analysis.2 We have tried to reconcile this dilemma by presenting our primary outcome first using a broad inclusion strategy and subsequently by verifying this in sensitivity analyses designed to reduce heterogeneity. Each sensitivity analysis that was performed confirmed the initial conclusion that there was no detectable advantage associated with routine hybrid ablation. Seven randomised trials of epicardial ablation alone were included, and the pooled estimate of 12-month survival free from atrial arrhythmias without antiarrhythmic drugs in these studies was 70.7 %, similar to the result (71.5 %) when all studies were included. However, it is notable that major complications were reported to occur in 31 of the 602 (5.1 %) patients included in randomised trials, considerably more than the pooled estimate of 2.9 % when all studies were included, suggesting that under-reporting of complications may have been present among non-randomised studies. We were unable to compare epicardial-alone with hybrid ablation in this sensitivity analysis as no randomised trials of hybrid ablation could be found that met our inclusion criteria. Giannopoulos and Deftereos enquire about the definition used for hybrid ablation. We used the term to include all studies in which a combination of epicardial and endocardial ablation was used routinely, either simultaneously or as a staged procedure. Studies in which supplementary endocardial ablation was used only in cases of recurrent arrhythmia were not included in this group. Despite theoretical concerns that simultaneous hybrid ablation may be less effective, the single study we are aware of that has compared staged with simultaneous hybrid ablation showed no difference in success rates between these strategies.3 We agree that the confirmation of electrical isolation could potentially be less reliable using a simultaneous hybrid approach. Interestingly, although some studies reported performing epicardial ablation without verification of conduction block, metaregression did not identify this as a significant predictor of arrhythmia recurrence. The readers’ third point addresses the usage of ambulatory monitoring to detect recurrent arrhythmias. We fully appreciate that a higher prevalence of extended ambulatory monitoring is more likely to correctly identify treatment failure. In view of this, we performed a sensitivity analysis including only studies in which patients underwent at least 1 week of ambulatory monitoring in total over the follow-up period. Seventy-five per cent of patients in the epicardial-alone group remained free from atrial arrhythmias at 12 months compared to 61 % of patients in the hybrid group, once again failing to find a benefit for routine hybrid ablation. In summary, multiple sensitivity analyses aimed at decreasing heterogeneity within the treatment groups supported our initial results, leading us to conclude that evidence supporting a role for routine hybrid ablation is lacking. Charles M Pearman, Liverpool Heart and Chest Hospital, Liverpool and Manchester Academic Health Science Centre, University of Manchester, Manchester, UK Dhiraj Gupta, Liverpool Heart and Chest Hospital, Liverpool, UK

1. 2. 3.

Pearman CM, Poon SS, Bonnett LJ, et al. Minimally invasive epicardial surgical ablation alone versus hybrid ablation for atrial fibrillation: a systematic review and meta-analysis. Arrhythm Electrophysiol Rev 2017;6(4):202–9. DOI: 10.15420/aer/2017.29.2; PMID: 29326836. Chambers D, Rodgers M, Woolacott N. Not only randomized controlled trials, but also case series should be considered in systematic reviews of rapidly developing technologies. J Clin Epidemiol Dec 2009;62:1253–60.e1254. DOI: 10.1016/j.jclinepi.2008.12.010; PMID: 19349144. Richardson TD, Shoemaker MB, Whalen SP, et al. Staged versus simultaneous thoracoscopic hybrid ablation for persistent atrial fibrillation does not affect time to recurrence of atrial arrhythmia. J Cardiovasc Electrophysiol 2016;27:428–34. DOI: 10.1111/jce.12906; PMID: 26725742.

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Volume 12 • Issue 1 • Spring 2018

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Volume 12 • Issue 1 • Spring 2018

Recognition, Diagnosis, and Management of Heart Failure with Preserved Ejection Fraction Meshal Soni, MD and Edo Y Birati, MD

Fulminant Myocarditis: A Review of the Current Literature Emily Seif, MD, Leway Chen, MD, MPH, and Bruce Goldman, MD

Interventional Echocardiography: Field of Advanced Imaging to Support Structural Heart Interventions Roy Arjoon, MD, Ashley Brogan, MD, and Lissa Sugeng, MD, MPH

Catheter Ablation for Ventricular Tachycardia in Patients with Structural Heart Disease Timothy M Markman, MD Daniel A McBride, MD and Jackson J Liang, DO

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*Based on head-to-head bench testing in parallel orientation.

indications, contraindications, warnings, precautions, potential adverse events and directions for use.

** Most studied contact force ablation catheter and unmatched clinical evidence claims based on number of completed prospective, protocol driven, industry sponsored, registered studies on Contact Force technology. Note that the TactiCath Quartz catheter is an evolution of the previous generation TactiCath catheter. TactiCath Quartz catheter uses the same contact force sensing technology (i.e. optical technology) as TactiCath catheter. TOCCASTAR clinical data from the TactiCath catheter are applicable to the TactiCath Quartz catheter as the design modifications made to the TactiCath catheter are fully verifiable in bench testing.

TactiCath™ Quartz Contact Force Ablation Catheter US: The TactiCath Quartz Contact Force Ablation Catheter is indicated for use in cardiac electrophysiological mapping and for the treatment of drug refractory recurrent symptomatic paroxysmal atrial fibrillation, when used in conjunction with a compatible RF generator and three-dimensional mapping system. ID: The TactiCath™ Quartz Contact Force Ablation Catheter is indicated for use in cardiac electrophysiological mapping (stimulation and recording) and, when used in conjunction with a radiofrequency generator, for cardiac ablation of supraventricular arrhythmias in right and left atrium, including atrial fibrillation. Contraindications: Do not use for any of the following conditions: certain recent heart surgery; prosthetic valves; active systemic infection; use in coronary vasculature; myxoma or intracardiac thrombus, or an interatrial baffle or patch; retrograde trans-aortic approach in patients with aortic valve replacement. Warnings: It is important to carefully titrate RF power; too high RF power during ablation may lead to perforation caused by steam pop. Contact force in excess of 70 g may not improve the characteristics of lesion formation and may increase the risk for perforation during manipulation of the catheter. Patients undergoing septal accessory pathway ablation are at risk for complete AV block which requires the implantation of a permanent pacemaker. Implantable pacemakers and implantable cardioverter/defibrillator may be adversely affected by RF current. Always verify the tubing and catheter have been properly cleared of air prior to inserting the catheter into the vasculature since entrapped air can cause potential injury or

1. Bourier F, Deisenofer I, Hessling G, et al. Contactforce sensing electrophysiological catheters: How accurate is the technology? [Abstract PO03-170]. Presentation at HRS 2016, San Francisco, CA, May 4 -7,2016. Heart Rhythm. 2016;13(5 Suppl 1):S318-S319. 2. Bourier F, Gianni C, Dare M, et al. Fiberoptic Contact-Force Sensing Electrophysiological Catheters: wHow Precise Is the Technology? J Cardiovasc Electrophysiol. 2017 Jan;28(1):109-114. Abbott One St. Jude Medical Dr., St. Paul, MN 55117 USA Tel: 1 651 756 2000 SJM.com St. Jude Medical is now Abbott. Rx Only Brief Summary: Prior to using these devices, please review the Instructions for Use for a complete listing of

Abbott_.indd 1

fatality. The temperature data transmitted by the sensor in this catheter is representative of the irrigated electrode only and does not provide tissue temperature data. Precautions: The long-term risks of protracted fluoroscopy and creation of RF induced lesions have not been established; careful consideration must be given for the use of the device in prepubescent children. When using the catheter with conventional EP lab system or with a 3D navigational system, careful catheter manipulation must be performed, in order to avoid cardiac damage, perforation, or tamponade. Always maintain a constant saline irrigation flow to prevent coagulation within the lumen of the catheter. Access the left side of the heart via a transseptal puncture. Care should be taken when ablating near structures such as the sino-atrial and AV nodes. Potential Adverse Events: Potential adverse events include, but are not limited to, cardiovascular related complications, including groin hematoma, pericardial effusion and infection. More serious complications are rare, which can include damage to the heart or blood vessels; blood clots (which may lead to stroke); tamponade; severe pulmonary vein stenosis; heart attack; esophageal fistula, or death. Please refer to the Instructions for Use for a complete list. ™ Indicates a trademark of the Abbott group of companies. ‡ Indicates a third party trademark, which is property of its respective owner. © 2018 Abbott. All Rights Reserved. 26624-SJM-TCC-0218-0077 Item approved for global use.

07/03/2018 13:30

AER 7.1  

Arrhythmia & Electrophysiology Review Volume 7 Issue 1 Spring 2018

AER 7.1  

Arrhythmia & Electrophysiology Review Volume 7 Issue 1 Spring 2018