AER 4.1 by Radcliffe Cardiology

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

www.AERjournal.com

Volume 4 • Issue 1 • Spring 2015

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

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

Role of Rotors in the Ablative Therapy of Persistent Atrial Fibrillation Amir A Schricker, Junaid Zaman and Sanjiv M Narayan

Computer Modelling for Better Diagnosis and Therapy of Patients by Cardiac Resynchronisation Therapy Marieke Pluijmert, Joost Lumens, Mark Potse, Tammo Delhaas, Angelo Auricchio and Frits W Prinzen

Phase +π 2 t=813 ms

t=840 ms

t=939 ms

t=964 ms

t=897 ms

0 -2 -π

ISSN - 2050-3369

Voltage Map of the Left Atrium During Atrial Fibrillation Ablation

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

t=1,029 ms

Simulated Activation Times on the Endocardia of Both Ventricles

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Fast All Around Accelerate RF ablation in Paroxysmal Atrial Fibrillation with the nMARQ™ Circular Catheter.

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Biosense Webster A Division of Johnson & Johnson Medical NV/SA Leonardo Da Vincilaan 15 - 1831 Diegem, Belgium Tel: +32-2-7463-401 - Fax: +32-2-7463-403 *Based on reported mean total procedure time of the nMARQ™ Catheter as demonstrated in the REVOLUTION Study compared with mean total procedure time of the THERMOCOOL® Catheter, as reported by Wilber et al.1,2 1. Shin DI, Kirmanoglou K, Eickholt C, et al. Initial results of using a novel irrigated multielectrode mapping and ablation catheter for pulmonary vein isolation. Heart Rhythm. 2014;11(3):375-383. 2. Wilber DJ, Pappone C, Neuzil P, et al. Comparison of antiarrhythmic drug therapy and radiofrequency catheter ablation in patients with paroxysmal atrial fibrillation: a randomized controlled trial. JAMA. 2010;303(4):333-340. Please refer to the Instructions for Use accompanying each device before use. For healthcare professionals only. nMARQTM Catheters and generator are approved for sale only in countries which accept the CE mark. Please check with your local Biosense Webster representative for product status in your country. © Johnson & Johnson NV/SA 2015. All rights reserved. 024593-141105

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Volume 4 • Issue 1 • Spring 2015

Editor-in-Chief Demosthenes Katritsis Athens Euroclinic, Athens Greece; Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA

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

Etienne Aliot

Warren Jackman

Christopher Piorkowski

University Hospital of Nancy, France

University of Oklahoma Health Sciences Center, Oklahoma City, US

University of Dresden, Germany

Carina Blomström-Lundqvist

Antonio Raviele

University Hospital Uppsal, Sweden

Mark Josephson

Johannes Brachmann

Beth Israel Deaconess Medical Center, Boston, US

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

Klinikum Coburg, II Med Klinik, Germany

Josef Kautzner

Pedro Brugada

Institute for Clinical and Experimental Medicine, Prague, Czech Republic

Frédéric Sacher

University of Brussels, UZ-Brussel-VUB, Belgium

Samuel Lévy

Hugh Calkins Johns Hopkins Medical Institutions, Baltimore, US

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

Riccardo Cappato IRCCS Policlinico San Donato, Milan, Italy

Ken Ellenbogen Virginia Commonwealth University School of Medicine, US

Sabine Ernst Royal Brompton and Harefield NHS Foundation Trust, UK

Aix-Marseille Université, France

William Stevenson

Cecilia Linde

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

Karolinska University, Stockholm, Sweden

Gregory YH Lip

Richard Sutton

University of Birmingham Centre for Cardiovascular Sciences, UK

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

Francis Marchlinski

Juan Luis Tamargo

University of Pennsylvania Health System, Philadelphia, US

Jose Merino Hospital Universitario La Paz, Spain

Fred Morady

Andreas Götte

Bordeaux University Hospital, LIRYC Institute, France

University Complutense, Madrid, Spain

Sotirios Tsimikas University of California San Diego, US

Panos Vardas

St Vincenz-Hospital Paderborn and University Hospital Magdeburg, Germany

Cardiovascular Center, University of Michigan, US

Heraklion University Hospital, Greece

Sanjiv M Narayan

Marc A Vos

Hein Heidbuchel

Stanford University Medical Center, US

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

Mark O’Neill

Gerhard Hindricks University of Leipzig, Germany

Carsten W Israel JW Goethe University, Germany

University Medical Center Utrecht, The Netherlands

King’s College, London, UK

Katja Zeppenfeld

Carlo Pappone Maria Cecilia Hospital, Italy

Leiden University Medical Center, The Netherlands

Sunny Po

Douglas P Zipes

Heart Rhythm Institute, University of Oklahoma Health Sciences Center, US

Krannert Institute of Cardiology, Indianapolis, US

Managing Editor Becki Davies • Design Manager Tatiana Losinska Managing Director David Ramsey • Publishing Director Liam O’Neill Publication Manager Michael Schmool •

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In partnership with

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Editorial Contact Becki Davies | managingeditor@radcliffecardiology.com Circulation Contact David Ramsey | david.ramsey@radcliffecardiology.com Commercial Contact Michael Schmool | michael.schmool@radcliffecardiology.com Cover images | shutterstock.com • Cover design Tatiana Losinska Lifelong Learning for Cardiovascular Professionals

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Published by Radcliffe Cardiology. All information obtained by Radcliffe Cardiology and each of the contributors from various sources is as current and accurate as possible. However, due to human or mechanical errors, Radcliffe Cardiology and the contributors cannot guarantee the accuracy, adequacy or completeness of any information, and cannot be held responsible for any errors or omissions, or for the results obtained from the use there of. Where opinion is expressed, it is that of the authors and does not necessarily coincide with the editorial views of Radcliffe Cardiology. Statistical and financial data in this publication have been compiled on the basis of factual information and do not constitute any investment advertisement or investment advice. Radcliffe Cardiology, 7/8 Woodlands Farm, Cookham Dean, Berks, SL6 9PN. © 2015 All rights reserved © RADCLIFFE CARDIOLOGY 2015

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Established: October 2012

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

Structure and Format

Frequency: Tri-annual

Current Issue: Spring 2015

• 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

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

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

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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 tri-annually through controlled circulation to general and specialist senior cardiovascular professionals in Europe. All manuscripts published in the journal are free-to-access online at www.AERjournal.com and www.radcliffecardiology.com

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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 Faiilure Review and European Cardiology Review. n

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Contents

Foreword

Arrhythmia & Electrophysiology Review – A New Era for NOAC Antidotes Demosthenes Katritsis, Editor-in-Chief

Athens Euroclinic, Athens Greece; Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA

Arrhythmia Mechanisms

HCN4, Sinus Bradycardia and Atrial Fibrillation

Dario DiFrancesco

PaceLab, University of Milan and Centro Interuniversitario di Medicina Molecolare e Biofisica Applicata (CIMMBA), Milan, Italy

Obstructive Sleep Apnoea and Atrial Fibrillation

Ling Zhang, 1 Yuemei Hou 2 and Sunny S Po 3

1. Cardiovascular Centre, First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China; 2. Sixth People’s Hospital Affiliated to Shanghai Jiaotong University, Shanghai, China; 3. Heart Rhythm Institute, University of Oklahoma Health Sciences Center, Oklahoma, US

Contemporary Mapping Techniques of Complex Cardiac Arrhythmias – Identifying and Modifying the Arrhythmogenic Substrate

Emmanuel Koutalas, Sascha Rolf, Borislav Dinov, Sergio Richter, Arash Arya, Andreas Bollmann, Gerhard Hindricks and Philipp Sommer

Leipzig Heart Center, University of Leipzig, Leipzig, Germany

Biology of the Sinus Node and its Disease

Moinuddin Choudhury, Mark R Boyett and Gwilym M Morris

Institute of Cardiovascular Sciences, University of Manchester, Manchester, UK

What is a Ca 2+ wave? Is it like an Electrical Wave?

Penelope A Boyden, 1 Wen Dun 1 and Bruno D Stuyvers 2

1. Columbia University, New York; 2. Faculty of Medicine, Division of Biomedical Sciences, Memorial University of Newfoundland, St. John’s, NL, Canada

Science Linking Pulmonary Veins and Atrial Fibrillation

Saagar Mahida, Frederic Sacher, Nicolas Derval, Benjamin Berte, Seigo Yamashita, Darren Hooks, Arnaud Denis, Sana Amraoui, Meleze Hocini, Michel Haissaguerre and Pierre Jais

Hôpital Cardiologique du Haut-Lévêque and Université Victor Segalen Bordeaux II, Bordeaux, France

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Contents

Diagnostic Electrophysiology & Ablation

Optimal Anticoagulation Strategy for Cardioversion in Atrial Fibrillation Philipp Bushoven, Sven Linzbach, Mate Vamos and Stefan H Hohnloser JW Goethe University, Frankfurt, Germany

Role of Rotors in the Ablative Therapy of Persistent Atrial Fibrillation

Amir A Schricker, 1 Junaid Zaman 2 and Sanjiv M Narayan 2

1. University of California San Diego Medical Center, San Diego, US; 2. Stanford Medicine, Stanford, California, US

Device Therapy 53

Management of Cardiovascular Implantable Electronic Devices Infections in High-Risk Patients

Charles Kennergren

Sahlgrenska University Hospital, Gothenburg, Sweden

Balloon Devices for Atrial Fibrillation Therapy

Andreas Metzner, Erik Wissner, Tina Lin, Feifan Ouyang and Karl-Heinz Kuck

Asklepios Klinik St. Georg, Hamburg, Germany

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

Marieke Pluijmert, 1 Joost Lumens, 1 Mark Potse, 2 Tammo Delhaas, 1 Angelo Auricchio 2,3

and Frits W Prinzen 4

1. Cardiovascular Research Institute, Maastricht, The Netherlands; 2. Centre for Computational Medicine in Cardiology, Universita della Svizzera Intaliana, Lugano, Switzerland; 3. Fondazione Cardiocentro Ticino, Lugano, Switzerland; 4. Cardiovascular Research Institute, Maastricht, The Netherlands

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ÂŠ RADCLIFFE CARDIOLOGY 2015

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Foreword

Arrhythmia & Electrophysiology Review – A New Era for NOAC Antidotes

eviewing recent literature of advances in arrhythmia therapy, I have found most interesting the emergence of antidotes, both general and specific, for the non-vitamin K antagonist oral anticoagulants

(NOACs). NOACs offer a relative 50 % reduction in the risk of intracranial haemorrhage and haemorrhagic stroke compared with warfarin that is also maintained in the elderly. There are no clear interactions with food, and no need for frequent laboratory monitoring and dose adjustments.1–3 Their main problems so far have been the lack of antidotes and specific assays to measure anticoagulant effect, and considerably higher cost than warfarin.4 It is, therefore, of major clinical importance to see specific antidotes emerging in phase 1 and 2 trials. Non-specific procoagulant agents such as 3- or 4-factor prothrombin complex concentrates (PCCs) and activated factor VIIa can be used as antidotes for dabigatran.5–7 Specific antidotes are also under study. Idarucizumab, a fully humanised antibody fragment, or Fab, is investigated as a specific antidote of dabigatran, and also reversed its effects and, unlike PCCs, was not associated with over-correction of thrombin generation.7 Four-factor PCCs are also general antidotes for Xa inhibitors such as apixaban, rivaroxaban and endoxaban.6 Specific antidotes such as aripazine (PER977, 100–200 mg), a synthetic molecule that binds specifically to unfractionated heparin and low-molecular-weight heparin, and the recombinant factor Xa andexanet have been successfully used for edoxaban and rivaroxaban. Aripazine also binds in a similar way to dabigatran, but further clinical experience is needed in this setting. Clinical experience with the NOACs compared with warfarin is too limited to unequivocally pronounce dead this useful old drug. Nevertheless, a new era has begun, and the results of clinical trials and ‘real-life’ registries are eagerly awaited in this respect. Dr Demosthenes Katritsis, Editor-in-Chief Athens Euroclinic, Greece and Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, US

De Caterina R, Husted S, Wallentin L, et al. New oral anticoagulants in atrial fibrillation and acute coronary syndromes: Esc working group on thrombosis-task force on anticoagulants in heart disease position paper. J Am Coll Cardiol 2012;59:1413–25 Dentali F, Riva N, Crowther M, et al. Efficacy and safety of the novel oral anticoagulants in atrial fibrillation: A systematic review and meta-analysis of the literature. Circulation 2012;126:2381–91.

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Ruff CT GR, Braunwald E, Hoffman EB, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: A meta-analysis of randomised trials. Lancet 2014;383:955–62. Canestaro WJ PA, Avorn J, Ito K, et al. Cost-effectiveness of oral anticoagulants for treatment of atrial fibrillation. Circ Cardiovasc Qual Outcomes 2013;6:724–31. Eerenberg ES KP, Sijpkens MK, Meijers JC, et al. Reversal of rivaroxaban and dabigatran by prothrombin complex

concentrate: A randomized, placebo-controlled, crossover study in healthy subjects. Circulation 2011;124:1573–9. Gómez-Outes A, Suarez-Gea ML, Lecumberri R, et al. Specific antidotes in development for reversal of novel anticoagulants: A review. Recent Pat Cardiovasc Drug Discov 2014;9:2–10. Honickel M TS, van Ryn J, Tillmann S, et al. Reversal of dabigatran anticoagulation ex vivo: Porcine study comparing prothrombin complex concentrates and idarucizumab. Thromb Haemost 2015;113:728–40.

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Arrhythmia Mechanisms

HCN4, Sinus Bradycardia and Atrial Fibrillation D a r i o D i Fra n c e s c o PaceLab, University of Milan and Centro Interuniversitario di Medicina Molecolare e Biofisica Applicata (CIMMBA), Milan, Italy

Abstract Based on their established role in the generation of spontaneous activity in pacemaker cells and control of cardiac rate, funny/ hyperpolarisation-activated, cyclic nucleotide gated 4 (HCN4) channels are natural candidates in the search for causes of sinus arrhythmias. Investigation of funny current-related inheritable arrhythmias has led to the identification of several mutations of the HCN4 gene associated with bradycardia and/or more complex arrhythmias. More recently, the search has been extended to include auxiliary proteins such as the minK-related peptide 1 (MiRP1) β-subunit. All mutations described so far are loss-of-function and in agreement with the role of funny channels, the predominant type of arrhythmia found is bradycardia. Funny channel-linked arrhythmias, however, also include atrioventricular (AV) block and atrial fibrillation, in agreement with an emerging new concept according to which defective funny channels have a still unexplored role in impairing AV conduction and triggering atrial fibrillation. Also, importantly, recent work shows that HCN4 mutations can be associated with cardiac structural abnormalities. In this short review I briefly address the current knowledge of funny/HCN4 channel mutations and associated sinus and more complex arrhythmias.

Keywords HCN4 channels, funny current, arrhythmias, atrial fibrillation, AV block, bradycardia Disclosure: The author has no conflicts of interest to declare. Acknowledgments: This work was partly supported by a grant from the Ministero dell’Istruzione, dell’Università e della Ricerca (PRIN 2010BWY8E9). Received: 3 September 2014 Accepted: 29 January 2015 Citation: Arrhythmia & Electrophysiology Review 2015;4(1):9–13 Access at: www.AERjournal.com Correspondence: Dario DiFrancesco, Professor of Physiology, Department of Biosciences, The PaceLab, University of Milano, via Celoria 26, 20133 Milano, Italy. E: dario.difrancesco@unimi.it

HCN4 (hyperpolarisation-activated, cyclic nucleotide gated 4) channels, the pore-forming α–subunits of ‘funny’ channels originally described in pacemaker cells of the sinoatrial node (SAN),1 are responsible for the early phase of diastolic depolarisation in these cells and are key determinants of pacemaker generation and control of heart rate.2–5 HCN4 channels are selectively expressed in the SAN and in the conduction system, and their expression correlates tightly with the presence of spontaneous activity in adult tissue and during development; the degree of correlation is such that the HCN4 channel gene is commonly considered as a genetic marker of pacemaker tissue.6–9

therapeutic tool against chronic stable angina and heart failure,15,16 and off-label use in tachycardia syndromes is proving efficient.17–21

The function of funny channels, and more recently of HCN4 channels, in pacemaker activity has been amply discussed in a variety of conditions.5,10 Originally described and regarded as a conceptual achievement in the understanding of the physiological basis of spontaneous activity, funny channel-based pacemaking has more recently developed into a practical notion useful in clinically relevant applications.3,11 For example, an important practical application has been the development of a family of drugs that act by specifically blocking HCN4 channels.12–14

A further important clinically relevant application of the concept of funny channel-based pacemaking relates to the genetic basis of arrhythmias. It is to be expected that functional defects of funny channels caused by mutations of α-subunits (HCN4) channels and/ or ancillary proteins are involved in inheritable forms of cardiac arrhythmias. Genetic screening has shown that several mutations of HCN4, and more recently also of subsidiary proteins, are associated with sinus bradycardia and/or more complex rhythm disturbances.

Given the role of the funny (If) current in generation and control of rate, it is not surprising that the specific effect of these drugs is to slow the diastolic depolarisation of pacemaker cells, hence cardiac rate, with limited adverse cardiovascular side-effects. Selective and quantitatively controlled slowing of heart rate provides an important therapeutic advantage in a variety of cardiac conditions. The only ‘pure’ heart rate slowing agent presently approved, ivabradine, is used as a

This short review partly extends and updates material covered by previous review publications.24-26

DiFrancesco_FINAL.indd 9

The functional properties of HCN4 channels are also the basis for the development of ‘biological’ pacemakers; the basic idea here is to induce silent or defective cardiac muscle to pace by means of gene- or cell-based in situ delivery of HCN channels. While the technology developed so far is insufficient to allow safe clinical application and replacement of electronic devices, several studies have shown that the proof-of-principle approach is feasible.22,23

HCN4 Channel Gene Mutations Associated with Sinus Arrhythmias and More Complex Rhythm Disorders Data from genetic screening gathered in the last decade have provided substantial evidence that mutations in HCN4 are associated with rhythm

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Arrhythmia Mechanisms Table 1: Features of Arrhythmia-linked Mutations in HCN4 and MiRP1 Reported in the Literature Mutation Bradycardia Syncope AF L573X

symptomatic

malignant

bouts

Other Shift Act If Density Arrhythmias Curve

cAMP Dependence

Notes

Reference

lost;

single patient

chronotropic

incompetence

D553N

symptomatic

recurrent

LQT; torsades

lower;

de pointes

asymptomatic

negative shift

G480R

asymptomatic

negative shift

maintained

lower;

trafficking

defective

A485V

lower;

presyncopal

cardiac arrest

negative shift

episodes

E695X

asymptomatic

K530N

symptomatic

ventricular

GYG triplet

signature

3 families

trafficking

Moroccan

defective

Jews

lost; no chronotropic

premature beats

incompetence

negative shift

K+ channel

paroxysmal tachy-brady

defective

S672R

symptomatic

single patient

trafficking

no effects

syndrome

69 70

homomeric

mutants

P257S

haplo-

early-onset

lower;

trafficking

G1097W

recurrent

complete

AV block

Y481H

LVCM

symptomatic

insufficiency

defective

negative shift

maintained

negative shift

G482R

single patient

structural

disease

A414G G482R

symptomatic

SND NCCM

lower (G482R)

structural

E695X

disease

P883R M54T (MiRP1) asymptomatic

LQT6

lower

Eleven publications reporting HCN4 mutations are listed in order of publication date. The M54T mutation of the MiRP1 β-subunit is listed in the last (12th) row. Only major symptoms are indicated. AF = atrial fibrillation; AV = atrioventricular; cAMP = cyclic adenosine monophosphate; GYG = amino acid triplet signature of K-permeable channels; LQT = long QT syndrome; LVCM = left ventricular non-compaction cardiomyopathy; SND = sinus node disease; SND NCCM = Isolated non-compaction cardiomyopathy; NCCM = non-compaction cardiomyopathy. Further explanation in text.

disorders. A list of 11 reports, ordered according to publication date and describing HCN4 mutations in patients with sinus arrhythmias or more complex disorders is shown in Table 1. The last (12th) row of Table 1 refers to a mutation in the minK-related peptide 1 (MiRP1) protein. Other potentially harmful mutations reported in the literature for individual patients without specific investigation of genotype-phenotype association are not listed here. Some general observations highlight a few noteworthy aspects: • All mutations are heterozygous. • All mutations are dominant-negative, with various degrees of penetrance, except one (P257S), proposed to be dysfunctional because of haploinsufficiency. • All are loss-of-function mutations – functional loss is caused either by a negative shift of the activation curve or by lower density of membrane expression of channels and consequent reduction of current density, typically attributable to trafficking defects or both. • Several mutations, involving either single amino acid substitutions or truncations, are localised in the C-terminus, and three of them are in the C-linker, the region joining the sixth transmembrane domain to the cyclic nucleotide binding domain (CNBD), known to be involved in linking structural rearrangements of the CNBD to gating.27,28

DiFrancesco_FINAL.indd 10

• R ecently reported loss-of-function mutations29,30 have been proposed to cause a symptom complex comprising bradycardia and ventricular structural abnormalities (non-compaction cardiomyopathy). In all but two of the reported mutations, patients manifested various degrees of symptomatic or asymptomatic bradycardia. This is in accordance with the fact that mutations are loss-of-function, given the known function of the funny current in driving pacemaker activity and controlling cardiac rate. According to this concept, the size of the If current flowing during diastolic depolarisation directly determines the steepness of diastolic depolarisation itself, hence cardiac rate.31,32 For example, in the largest single family investigated so far (27 members33), the single-point mutation S672R caused, relative to wild-type channels, a negative shift of the activation curve of the If current of about 5 mV in heterozygous wild-type/mutant channels. It is interesting to note that a negative shift of the activation curve is a cholinergic-type of effect, since it mimics the inhibitory action of parasympathetic stimulation on the funny current, known to mediate vagal-induced slowing of the heart rate.2,34 Thus, the pacemaker current in patients carrying the heterozygous S672R mutation in HCN4 behaves as if in a permanent state of higher than normal vagal tone. The mutation-induced shift of the activation curve can be shown to be quantitatively adequate to slow heart rate by the amount observed within the family investigated (about 29 %).5

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HCN4, Sinus Bradycardia and Atrial Fibrillation

As well as bradycardia, other more complex arrhythmic disorders have been linked to HCN4 mutations, including ventricular premature beats, tachycardia–bradycardia syndrome and atrial fibrillation (AF), complete atrioventricular (AV) block, long QT syndrome (LQTS) and torsades de pointes. In most cases these disorders appear in addition to bradycardia, except with P257S, associated with early onset AF,35 and G1097W, associated with complete AV block.36 It is interesting to note that two recent reports29,30 provide evidence that dysfunctional HCN4 channel mutations can also be linked to cardiac structural abnormalities and specifically to non-compaction cardiomyopathy (NCCM), a disease characterised by non-compacted ventricular myocardial layer with excessive trabeculations, often associated with heart failure, arrhythmias and systemic embolic events. These studies identify two novel loss-of-function mutations in the pore loop of the channel (Y481H and G482R) and a loss-of-function mutation in the S4–S5 linker (A414G) in patients presenting a symptom complex comprising sinus node disease and NCCM. The same combined phenotype is also reported in a family, previously investigated by the same group, carrying the HCN4-695X mutation, and in a single patient with a mutation in the terminal part of the C-terminus (P883R), though in this case no functional study is provided.30 These findings confirm the notion that, as well as controlling pacemaker activity, HCN4 channels contribute to normal cardiac development.37 Since HCN4 is expressed in cardiac progenitor cells, as a potential underlying mechanism, the authors suggest the possibility that dysfunctional HCN4 mutations directly disrupt the normal ventricular compaction process during development.29,30 The G482R mutation was found in combination with a common variant (CSRP3-W4R) in one study30 but not in another,29 suggesting that the variant is not essential, though it can act as a predisposing condition. Expression of heterozygous wild-type/G482R mutated channels generated apparently contrasting results in the two studies: a strong negative shift of the activation curve in one study29 and a reduced membrane expression with no shift of the activation curve in the other.30 In both cases, however, the changes lead to loss of function and are compatible with the bradycardic phenotype. While, as discussed above, it is expected that a loss-of-function modification of HCN4 causes sinus bradycardia, it is less immediately obvious how an HCN4-reduced contribution to activity can correlate with AV block or AF. Interestingly, however, as discussed below, several data indicate the potential involvement of a dysfunctional funny current in AV block and AF. It is known from early studies that funny channels are expressed in the AV node, where they contribute to spontaneous activity.38,39 Other more recent studies have identified pacing cells in the sleeves of pulmonary veins (PV), which express funny channels.40,41 Such PV cells can contribute to ectopic beat generation and thus represent important focal sources potentially able to initiate AF.42,43 A correlation between AF and expression of funny channels in the SAN has already been proposed in a study that investigated the SAN dysfunction associated with AF, normally apparent after AF termination (tachycardia–bradycardia syndrome).44 This study showed that the SAN dysfunction has a reversible component, related to the SAN remodelling caused by rapid atrial tachyarrhythmias, which

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involves If downregulation. Furthermore, HCN4 was identified more recently as a candidate AF-linked gene in a large-scale meta-analysis of genome-wide association studies (GWAS) conducted to detect new AF susceptibility loci.45 In the study of Macri et al.35 the authors did not investigate specific families but rather collected early onset AF patients from the Massachusetts General Hospital (MGH) AF study and compared them with controls from the Framingham Heart Study (FHS). Sequencing for HCN4 variants led to the identification of several single nucleotide polymorphisms (SNPs) with a higher rate of expression in AF patients. Only one of these variants, P257S, was functionally different from wild-type, and expression in Chinese hamster ovary (CHO) cells of mutated HCN4 channels resulted in no current, indicating that P257S channels did not traffic to the cell membrane. This is consistent with the idea that the N-terminal region of HCN4 channels is involved in membrane insertion of the protein.46 Curiously, however, the loss-offunction property was lost when the mutated protein was expressed in heterozygous conditions, excluding a dominant-negative effect of the mutation. The authors interpreted these data to indicate that early-onset AF in P257S carriers is due to haploinsufficiency, i.e. only wild-type proteins contributing to functional channels. It should be noted in the context that the P257 residue is part of the caveolinbinding sequence present in the N-terminus of HCN4 channels47 and that a mutation-induced disruption of the channel binding to caveolin is expected to cause reduced membrane expression. In relation to AV block, indication of a potential contribution of defective HCN4 is apparent, for example from HCN4 knockout studies. In a study investigating inducible, cardiac specific knockout of HCN4 channels, Baruscotti et al.48 found that HCN4 knockout causes, as expected, progressive slowing of sinus rate. This process was, however, accompanied by a progressive prolongation of the PQ interval that evolved into second-degree block and eventually complete AV block and heart arrest in knockout animals, suggesting a role of HCN4 channels in AV node (AVN) conduction. Interestingly, a similar conclusion was suggested by experiments showing that block of the funny current generates a larger response in AVN than in SAN myocytes.39 In the study of Zhou et al.,36 a single patient with complete AV block, but no sinus node dysfunction, who had undergone pacemaker implantation, was found to carry the HCN4 mutation G1097W. This was shown to be a loss-of-function mutation associated with a negative shift of the activation curve and a lower membrane expression level. It is worth noting that before pacemaker implantation the patient had a 4:1 conduction ratio, with a sinus rate of 132 and a ventricular rate of 33 bpm, suggesting the presence of a reflex sinus tachycardia compensating for the ventricular slow rate. This is interesting since it suggests that a basal sinus bradycardia, hidden by a reflex sinus tachycardia, cannot be excluded.

Screening of Defective HCN4 Auxiliary Subunits – MiRP1 The results discussed above indicate that several types of arrhythmias, some of which complex, are found in patients with HCN4 mutations, yet all mutations are loss-of-function and only affect either channel kinetics (by shifting the activation range of the current to more negative voltages), or membrane expression (by decreasing it), or both. Clearly, changes in the HCN4 channel only cannot explain the whole variety of rhythm disorders found, and other factors are likely to contribute.

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Arrhythmia Mechanisms In line with this consideration, it should be taken into account that HCN4 channels represent only one of the components of funny channels (i.e. the α-subunits), and that disturbances of the pacemaker process can also derive from alterations of auxiliary subunits or interfering proteins (such as for example MiRP149,50 or caveolin-347,51,52) or other proteins such as KCR1 and SAP97.53 Screening of these proteins in arrhythmia patients can thus provide useful insight into new potentially causative mutations. One published example is mutation M54T of the MiRP1 β-subunit (KCNE2 gene). MiRP1 is a hERG potassium channel β-subunit,54 which also interacts with HCN channels.50 Mutations of MiRP1 that reduce delayed potassium currents have been reported in LQTS patients, and are thought to be responsible for QT prolongation and delayed repolarisation.54–56 Sinus node dysfunction and bradycardia are sometimes observed in LQTS patients, and to investigate if the bradycardia associated with LQTS involves changes in the funny current, Nawathe et al.56 analysed the effects on HCN channels of the MiRP1 M54T mutation found in a patient from an LQTS6 registry with bradycardia (see last row in Table 1). Functional studies performed by co-expressing wild-type or mutated MiRP1 subunits with HCN4 showed that the M54T mutation strongly decreases the HCN4 current contribution to activity. Numerical reconstruction obtained by combining changes induced in HCN4 and hERG potassium channels by the M54T MiRP1 mutation was able to mimic bradycardia. These data represent the first evidence that the contribution of funny channels to activity can be altered and become arrhythmogenic in the presence of dysfunctional auxiliary subunits.

Conclusions and Future Perspectives A direct way to appreciate the relevance of funny/HCN4 channels to pacemaking is to look at the consequences of their modifications on rhythmic activity. There are several ways by which the normal contribution of the If current to activity can be altered. Alteration of normal function is primarily caused by gene mutations, which, as discussed above, can occur in the channel α-subunits as well as in auxiliary subunits like MiRP1, caveolin-3 and other elements known to interact with funny channels.53 Clearly, in this latter case other channels may also undergo modifications since auxiliary subunits often regulate multiple targets. HCN4 mutations found so far are all loss-of-function, and it will be interesting to see if

Brown HF, DiFrancesco D, Noble SJ. How does adrenaline accelerate the heart? Nature 1979;280(5719):235–6. DiFrancesco D. Pacemaker mechanisms in cardiac tissue. Annu Rev Physiol 1993;55:455–72. 3. DiFrancesco D, Borer JS. The funny current: cellular basis for the control of heart rate. Drugs 2007;67 Suppl 2:15–24. 4. Barbuti A, Baruscotti M, DiFrancesco D. The pacemaker current: from basics to the clinics. J Cardiovasc Electrophysiol 2007;18(3):342–7. 5. DiFrancesco D. The role of the funny current in pacemaker activity. Circ Res 2010;106(3):434–46. 6. Liu J, Dobrzynski H, Yanni J, et al. Organisation of the mouse sinoatrial node: structure and expression of HCN channels. Cardiovasc Res 2007;73(4):729–38. 7. Mommersteeg MT, Hoogaars WM, Prall OW, et al. Molecular pathway for the localized formation of the sinoatrial node. Circ Res 2007;100(3):354–62. 8. Wiese C, Grieskamp T, Airik R, et al. Formation of the sinus node head and differentiation of sinus node myocardium are independently regulated by Tbx18 and Tbx3. Circ Res 2009;104(3):388–97. 9. Brioschi C, Micheloni S, Tellez JO, et al. Distribution of the pacemaker HCN4 channel mRNA and protein in the rabbit sinoatrial node. J Mol Cell Cardiol 2009;47(2):221–7. 10. Lakatta EG, DiFrancesco D. What keeps us ticking: a funny current, a calcium clock, or both? J Mol Cell Cardiol 2.

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gain-of-function mutations also occur. Based on the established role of the funny current, it is to be expected that these mutations are associated with tachyarrhythmias. Finally, another way by which the channels normal function can be altered is remodelling. In general, remodelling can be viewed as the set of processes by which channel activity is regulated, via turnover of membrane expression, by DNA transcriptional control. While this mechanism is normally physiological, it can be modified by non-physiological conditions and under specific circumstances lead to abnormal contribution of ion channels to activity. Funny channels undergo remodelling and altered contribution in various cardiac diseases. It is known for example that funny channels are overexpressed in the ventricular muscle of human failing hearts in dilated cardiomyopathy, and that this mechanism is potentially pro-arrhythmogenic.57,58 As mentioned above, downregulation of HCN channels has been reported in tachycardia-induced SAN remodeling.44 Also, remodelling of the peripheral cardiac conduction system in response to pressure overload causes hypertrophy and a four-fold increase in the expression of HCN4.59 A more recent study has investigated the effects of training on cardiac ion channel remodelling. It is generally assumed that exercise training-induced bradycardia is caused by an increased parasympathetic drive.60,61 This view has been recently challenged by a novel, radically different interpretation. A collaborative study by D’Souza et al.62 has shown that slowing of heart rate induced by exercise training in rodents is actually caused by downregulation of HCN4, rather than to increased parasympathetic activity. HCN4 channel downregulation has a major role in determining heart rate, but it occurs in the framework of a widespread remodelling involving ion channels, transporters, transcriptional factors and other molecules. This finding may explain why endurance athletes are often subject to bradycardia associated with a higher incidence of sinus node disease and require electronic pacemaker implantation more frequently than sedentary patients.63,64 It is likely that more mechanisms involving modification of funny channel contribution to pacemaking, including gene mutations of α or ancillary subunits, changes of channel modulation processes, interacting proteins, remodelling of ion channels and related proteins, will need to be added in the near future to those listed here. n

2009;47(2):157–70. 11. DiFrancesco D, Camm JA. Heart rate lowering by specific and selective If current inhibition with ivabradine: a new therapeutic perspective in cardiovascular disease. Drugs 2004;64(16):1757–65. 12. Bucchi A, Baruscotti M, DiFrancesco D. Current-dependent block of rabbit sino-atrial node I(f) channels by ivabradine. J Gen Physiol 2002;120(1):1–13. 13. DiFrancesco D. If inhibition: a novel mechanism of action. Eur Heart J 2003;5(suppl G):G19–25. 14. Bucchi A, Tognati A, Milanesi R, et al. Properties of ivabradine-induced block of HCN1 and HCN4 pacemaker channels. J Physiol 2006;572(Pt 2):335–46. 15. Borer JS, Fox K, Jaillon P, Lerebours G. Antianginal and antiischemic effects of ivabradine, an I(f) inhibitor, in stable angina: a randomized, double-blind, multicentered, placebo-controlled trial. Circulation 2003;107(6):817–23. 16. Camm AJ, Lau CP. Electrophysiological effects of a single intravenous administration of ivabradine (S 16257) in adult patients with normal baseline electrophysiology. Drugs R D 2003;4(2):83–9. 17. Calò L, Rebecchi M, Sette A, et al. Efficacy of ivabradine administration in patients affected by inappropriate sinus tachycardia. Heart Rhythm 2010;7(9):1318–23. 18. Kumar S, Vohra J. Ivabradine: appropriate treatment for inappropriate sinus tachycardia. Heart Rhythm 2010;7(9):1324–5.

19. Zellerhoff S, Hinterseer M, Felix Krull B, et al. Ivabradine in patients with inappropriate sinus tachycardia. Naunyn Schmiedebergs Arch Pharmacol 2010;382(5–6):483–6. 20. Weyn T, Stockman D, Degreef Y. The use of ivabradine for inappropriate sinus tachycardia. Acta Cardiol 2011;66(2):259–62. 21. Femenía F, Baranchuk A, Morillo CA. Inappropriate sinus tachycardia: current therapeutic options. Cardiol Rev 2012;20(1):8–14. 22. Rosen MR, Brink PR, Cohen IS, Robinson RB. Genes, stem cells and biological pacemakers. Cardiovasc Res 2004;64(1):12–23. 23. Rosen MR, Robinson RB, Brink PR, Cohen IS. The road to biological pacing. Nat Rev Cardiol 2011;8(11):656–66. 24. Baruscotti M, Bottelli G, Milanesi R, et al. HCN-related channelopathies. Pflugers Arch 2010;460(2):405–15. 25. DiFrancesco D. Funny channel gene mutations associated with arrhythmias. J Physiol 2013;591(Pt 17):4117–24. 26. Verkerk AO, Wilders R. Pacemaker activity of the human sinoatrial node: effects of HCN4 mutations on the hyperpolarization-activated current. Europace 2014;16(3):384–95. 27. Zagotta WN, Olivier NB, Black KD, et al. Structural basis for modulation and agonist specificity of HCN pacemaker channels. Nature 2003;425(6954):200–5. 28. Decher N, Chen J, Sanguinetti MC. Voltage-dependent gating of hyperpolarization-activated, cyclic nucleotide-gated

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pacemaker channels: molecular coupling between the S4-S5 and C-linkers. J Biol Chem 2004;279(14):13859–65. 29. Milano A, Vermeer AM, Lodder EM, et al. HCN4 mutations in multiple families with bradycardia and left ventricular noncompaction cardiomyopathy. J Am Coll Cardiol 2014;64(8):745–56. 30. Schweizer PA, Schröter J Greiner S, et al. The symptom complex of familial sinus node dysfunction and myocardial noncompaction is associated with mutations in the HCN4 channel. J Am Coll Cardiol 2014;64(8):757–67. 31. Bucchi A, Baruscotti M, Robinson RB, DiFrancesco D. Modulation of rate by autonomic agonists in SAN cells involves changes in diastolic depolarization and the pacemaker current. J Mol Cell Cardiol 2007;43(1):39–48. 32. DiFrancesco D. Considerations on the size of currents required for pacemaking. J Mol Cell Cardiol 2010;48(4):802–3. 33. Milanesi R, Baruscotti M, Gnecchi-Ruscone T, DiFrancesco D. Familial sinus bradycardia associated with a mutation in the cardiac pacemaker channel. N Engl J Med 2006;354(2):151–7. 34. DiFrancesco D, Ducouret P, Robinson RB. Muscarinic modulation of cardiac rate at low acetylcholine concentrations. Science 1989;243(4891):669–71. 35. Macri V, Mahida SN, Zhang ML, et al. A novel traffickingdefective HCN4 mutation is associated with early-onset atrial fibrillation. Heart Rhythm 2014;11(6):1055–62. 36. Zhou J, Ding WG, Makiyama T, et al. A novel HCN4 mutation, G1097W, is associated with atrioventricular block. Circ J 2014;78(4):938–42. 37. Stieber J, Herrmann S, Feil S, et al. The hyperpolarizationactivated channel HCN4 is required for the generation of pacemaker action potentials in the embryonic heart. Proc Natl Acad Sci U S A 2003;100(25):15235–40. 38. Kokubun S, Nishimura M, Noma A, Irisawa H. Membrane currents in the rabbit atrioventricular node cell. Pflugers Arch 1982;393:15–22. 39. Liu J, Noble PJ, Xiao G, et al. Role of pacemaking current in cardiac nodes: insights from a comparative study of sinoatrial node and atrioventricular node. Prog Biophys Mol Biol 2008;96(1–3):294–304. 40. Chen YC, Pan NH, Cheng CC, et al. Heterogeneous expression of potassium currents and pacemaker currents potentially regulates arrhythmogenesis of pulmonary vein cardiomyocytes. J Cardiovasc Electrophysiol 2009;20(9):1039–45. 41. Suenari K, Cheng CC, Chen YC, et al. Effects of ivabradine on the pulmonary vein electrical activity and modulation of pacemaker currents and calcium homeostasis. J Cardiovasc Electrophysiol 2012;23(2):200–6. 42. Haïssaguerre M, Jaïs P, Shah DC, et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med 1998;339(10):659–66.

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43. Chen SA, Hsieh MH, Tai CT, et al. Initiation of atrial fibrillation by ectopic beats originating from the pulmonary veins: electrophysiological characteristics, pharmacological responses, and effects of radiofrequency ablation. Circulation 1999;100(18):1879–86. 44. Yeh YH, Burstein B, Qi XY, et al. Funny current downregulation and sinus node dysfunction associated with atrial tachyarrhythmia: a molecular basis for tachycardiabradycardia syndrome. Circulation 2009;119(12):1576–85. 45. Ellinor PT, Lunetta KL, Albert CM, et al. Meta-analysis identifies six new susceptibility loci for atrial fibrillation. Nat Genet 2012;44(6):670–5. 46. Tran N, Proenza C, Macri V, et al. A conserved domain in the NH2 terminus important for assembly and functional expression of pacemaker channels. J Biol Chem 2002;277(46):43588–92. 47. Barbuti A, Scavone A, Mazzocchi N, et al. A caveolin-binding domain in the HCN4 channels mediates functional interaction with caveolin proteins. J Mol Cell Cardiol 2012;53(2):187–95. 48. Baruscotti M, Bucchi A, Viscomi C, et al. Deep bradycardia and heart block caused by inducible cardiac-specific knockout of the pacemaker channel gene Hcn4. Proc Natl Acad Sci U S A 2011;108(4):1705–10. 49. Yu H, Wu J, Potapova I, et al. MinK-related peptide 1: A beta subunit for the HCN ion channel subunit family enhances expression and speeds activation. Circ Res 2001;88(12):E84–7. 50. Qu J, Kryukova Y, Potapova IA, et al. MiRP1 modulates HCN2 channel expression and gating in cardiac myocytes. J Biol Chem 2004;279(42):43497–502. 51. Barbuti A, Gravante B, Riolfo M, et al. Localization of pacemaker channels in lipid rafts regulates channel kinetics. Circ Res 2004;94(10):1325–31. 52. Barbuti A, Terragni B, Brioschi C, DiFrancesco D. Localization of f-channels to caveolae mediates specific β2-adrenergic receptor modulation of rate in sinoatrial myocytes. J Mol Cell Cardiol 2007;42(1):71–8. 53. Barbuti A, Bucchi A, Milanesi R, et al. The “funny” pacemaker current. In: Tripathi ON, Ravens U, Sanguinetti MC (eds). Heart Rate and Rhythm: Molecular Basis, Pharmacological Modulation and Clinical Implications. Heidelberg, Germany: Springer Berlin, 2011;59–81. 54. Abbott GW, Sesti F, Splawski I, et al. MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia. Cell 1999;97(2):175–87. 55. Splawski I, Tristani-Firouzi M, Lehmann MH, et al. Mutations in the hminK gene cause long QT syndrome and suppress IKs function. Nat Genet 1997;17(3):338–40. 56. Nawathe PA, Kryukova Y, Oren RV, et al. An LQTS6 MiRP1 Mutation Suppresses Pacemaker Current and is Associated with Sinus Bradycardia. J Cardiovasc Electrophysiol

2013;24(9):1021–7. 57. Cerbai E, Sartiani L, DePaoli P, et al. The properties of the pacemaker current If in human ventricular myocytes are modulated by cardiac disease. J Mol Cell Cardiol 2001;33(3):441–8. 58. Stillitano F, Lonardo G, Zicha S, et al. Molecular basis of funny current (If) in normal and failing human heart. J Mol Cell Cardiol 2008;45(2):289–99. 59. Harris BS, Baicu CF, Haghshenas N, et al. Remodeling of the peripheral cardiac conduction system in response to pressure overload. Am J Physiol Heart Circ Physiol 2012;302(8):H1712–25. 60. al-Ani M, Munir SM, White M, et al. Changes in R-R variability before and after endurance training measured by power spectral analysis and by the effect of isometric muscle contraction. Eur J Appl Physiol Occup Physiol 1996;74(5):397–403. 61. Maron BJ, Pelliccia A. The heart of trained athletes: cardiac remodeling and the risks of sports, including sudden death. Circulation 2006;114(15):1633–44. 62. D’Souza A, Bucchi A, Johnsen AB, et al. Exercise training reduces resting heart rate via downregulation of the funny channel HCN4. Nature Comm 2014;5:3775. 63. Baldesberger S, Bauersfeld U, Candinas R, et al. Sinus node disease and arrhythmias in the long-term follow-up of former professional cyclists. Eur Heart J 2008;29(1):71–8. 64. O’Keefe JH, Patil HR, Lavie CJ, et al. Potential adverse cardiovascular effects from excessive endurance exercise. Mayo Clin Proc 2012;87(6):587–95. 65. Schulze-Bahr E, Neu A, Friederich P, et al. Pacemaker channel dysfunction in a patient with sinus node disease. J Clin Invest 2003;111(10):1537–45. 66. Ueda K, Nakamura K, Hayashi T, et al. Functional characterization of a trafficking-defective HCN4 mutation, D553N, associated with cardiac arrhythmia. J Biol Chem 2004;279(26):27194–8. 67. Nof E, Luria D, Brass D, et al. Point mutation in the HCN4 cardiac ion channel pore affecting synthesis, trafficking, and functional expression is associated with familial asymptomatic sinus bradycardia. Circulation 2007;116(5):463–70. 68. Laish-Farkash A, Glikson M, Brass D, et al. A novel mutation in the HCN4 gene causes symptomatic sinus bradycardia in Moroccan Jews. J Cardiovasc Electrophysiol 2010;21(12):1365–72. 69. Schweizer PA, Duhme N, Thomas D, et al. cAMP sensitivity of HCN pacemaker channels determines basal heart rate but is not critical for autonomic rate control. Circ Arrhithm Electrophysiol 2010;3(5):542–52. 70. Duhme N, Schweizer PA, Thomas D, et al. Altered HCN4 channel C-linker interaction is associated with familial tachycardia-bradycardia syndrome and atrial fibrillation. Eur Heart J 2013;34(35):2768–75.

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Arrhythmia Mechanisms

Obstructive Sleep Apnoea and Atrial Fibrillation Ling Z h a n g , 1 Yu e m e i H o u 2 a n d S u n n y S P o 3 1. Cardiovascular Centre, First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China; 2. Department of Cardiovascular Diseases, Sixth People’s Hospital Affiliated to Shanghai Jiaotong University, Shanghai, China; 3. Heart Rhythm Institute, University of Oklahoma Health Sciences Center, Oklahoma, US

Abstract Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia and is associated with significant morbidity and mortality. Obstructive sleep apnoea (OSA) is common among patients with AF. Growing evidence suggests that OSA is associated with the initiation and maintenance of AF. This association is independent of obesity, body mass index and hypertension. OSA not only promotes initiation of AF but also has a significant negative impact on the treatment of AF. Patients with untreated OSA have a higher AF recurrence rate with drug therapy, electrical cardioversion and catheter ablation. Treatment with continuous positive airway pressure (CPAP) has been shown to improve AF control in patients with OSA. In this article, we will review and discuss the pathophysiological mechanisms of OSA that may predispose OSA patients to AF as well as the standard and emerging therapies for patients with both OSA and AF.

Keywords Atrial fibrillation, obstructive sleep apnoea, autonomic nervous system, apnoea–hypopnea index, continuous positive airway pressure Disclosure: The authors have no conflicts of interest to declare. Received: 22 September 2014 Accepted: 29 January 2015 Citation: Arrhythmia & Electrophysiology Review 2015;4(1):14–8 Access at: www.AERjournal.com Correspondence: Sunny S Po, Heart Rhythm Institute, University of Oklahoma Health Sciences Center, 1200 Everett Dr (6E103), Oklahoma City, OK, US. E: sunny-po@ouhsc.edu

Atrial fibrillation (AF) is the most frequently encountered arrhythmia in clinical practice and has become an emerging epidemic. AF is associated with increased cardiovascular mortality and morbidy such as stroke.1–3 Over 2.3 million people in the US are affected by AF: it is estimated that AF will affect more than 15 million Americans by 2050.3 The traditional risk factors implicated in the pathogenesis of AF include age, hypertension, diabetes, obesity, coronary artery disease (CAD) and congestive heart failure.4,5 Recent studies revealed that the prevalence of obstructive sleep apnoea (OSA) is substantially higher among patients with AF (ranging from 32 to 49 %), strongly indicating that OSA may be contributing to the initiation and progression of AF.6,7 Sleep apnoea, a severe form of sleep-disordered breathing, is broadly divided into two categories: central sleep apnoea (CSA) and OSA.8 CSA is caused by abnormal responses in the brain stem that controls the respiration drive, leading to the Cheyenne-Stokes pattern of respiration. CSA is one of the most common comorbidities in patients with heart failure. Cheyenne-Stokes respiration, commonly observed in CSA patients, is caused by a complex interaction among increased pulmonary capillary/venous pressure, fluctuation of blood oxygen and CO2 level, and chemoreceptor function. The incidence of CSA in heart failure patients ranged from 21 to 82 %, depending on the severity of heart failure and the cut-off value of the apnoea–hypopnoea index (AHI) adopted in different studies.9 The severity of CSA also correlates with the incidence of arrhythmias such as AF. OSA is caused by obstruction of the upper airway despite increased efforts of breathing exerted by the thoracic and abdominal respiratory

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muscles. OSA affects approximately 24 % of men and 9 % of women, between 30 and 60 years of age.8,10,11 It is estimated that approximately one in 15 adults has at least moderate OSA and most cases remain undiagnosed.8,10,11 The incidence of OSA has increased progressively among people of different ages. OSA induces intermittent hypoxia, hypercapnia, intrathoracic pressure shifts, hyperactivity of the autonomic nervous system and abrupt surges in arterial pressure and inflammation, leading to hypertension, diastolic dysfunction, left atrial enlargement and atrial fibrosis. All of these diseases are established risk factors or contributing factors to AF.5–8

Definition and Diagnosis of Central Sleep Apnoea and Obstructive Sleep Apnoea Based on the high prevalence of sleep apnoea, particularly CSA, in the heart failure patients, it is advisable to ask the patient’s spouse or partner about any abnormal respiratory pattern during sleep. When a new arrhythmia such as AF is diagnosed in a heart failure patient, screening for sleep apnoea is worthwhile. OSA can be implicated on the basis of medical history (e.g. snoring, witnessed apnoeas, waking up with a choking sensation, and excessive daytime sleepiness) and physical examination (e.g. short neck, increased neck circumference).12 The gold standard of diagnosing sleep apnoea is overnight polysomnography, which measures the air flow, respiratory muscle activity, electroencephalography, electrocardiogram (ECG) and blood pressure (BP). CSA can be distinguished from OSA by the absence of abdominal or thoracic respiratory muscle efforts during the apnoeic episode. Apnoea is defined as airflow reduced to less than 10 % of baseline for more than 10 seconds. Hypopnea is defined as a reduction

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Obstructive Sleep Apnoea and Atrial Fibrillation

of airflow to less than 50 % of baseline for more than 10 seconds, in association with a ≥3 % oxygen desaturation or arousal from sleep. Severity of sleep apnoea is measured by the AHI and the frequency of apnoeas and hypopnoeas per hour of sleep. An AHI of 5–15 is considered mild, while severe sleep apnoea is defined as AHI ≥30.12–16 The growing awareness of sleep apnoea among physicians inevitably leads to a long waiting period for an overnight polysomnograpy study. Unattended portable monitoring, with a cost only 10–20 % of an overnight polysomnography study, has emerged as a screening tool for OSA. These portable devices are capable of recording respiratory movement, airflow and blood oxygenation. More advanced devices also provide an ECG/heart rate channel for heart rhythm monitoring.17 While portable monitoring tends to underestimate the AHI score in patients with heart failure and chronic obstructive pulmonary disease, portable monitoring may to evolve to a diagnostic tool for patients with high clinical suspicion of OSA in which a positive test essentially verifies the diagnosis of OSA without the need for an overnight polysomnography study.

Association between Atrial Fibrillation and Obstructive Sleep Apnoea Multiple studies have demonstrated that AF is substantially more prevalent in patients with OSA than those without OSA.18–21 The frequency of arrhythmias increases with the severity of the OSA. Table 1 summarises the studies showing an increased risk for AF in OSA patients. One of the early studies that analysed the prevalence of cardiac arrhythmias and conduction disturbance in 400 OSA patients was performed using 24-hour Holter monitoring. Guilleminault et al.22 found a slight nonstatistically significant increase in the prevalence of paroxysmal AF in this group of patients. However, most studies identified a much higher prevalence of AF in OSA patients. For example, in a prospective sleep study, Hoffstein et al.23 followed 458 subjects with suspected OSA undergoing polysomnography. The authors reported a 58 % prevalence of arrhythmias in those with OSA (AHI >10) and 42 % in the controls without OSA (AHI ≤10; p<0.001). In addition, the author also found that the rate of cardiac arrhythmias increased with AHI, with 70 % of individuals (AHI ≥40) having arrhythmias versus 42 % of individuals with an AHI ≤10 (p=0.002). In two groups of patients sampled from the study population of the Sleep Heart Health Study, 228 patients with a high sleep-disordered breathing index (respiratory disturbance index [RDI] ≥30) and 338 subjects with a low index (RDI <5), Mehra et al.,24 discovered that the risk for AF in patients with severe OSA is about four times higher than those without OSA (adjusted odds ratio [OR]=4.02, 95 % confidence interval [CI] 1.03–15.74). Gami et al.25 conducted a retrospective cohort study of 3,542 Olmsted County adults with OSA diagnosed by polysomnogram. New-onset AF was confirmed by electrocardiography during a mean follow-up of 4.7 years. The authors discovered that AF occurred in 133 subjects (cumulative probability 14 %). Univariate predictors of AF include age, male gender, hypertension, CAD, heart failure, smoking, body mass index, OSA (hazard ratio [HR] 2.18), and the severity of OSA. While OSA patients have a higher incidence of AF, it has also been shown that OSA is substantially more prevalent in AF patients as well. Except for a few studies showing the lack of increased incidence of OSA in AF patients, the majority of studies demonstrated otherwise.26,27 For example, Gami et al. prospectively studied consecutive patients undergoing electrocardioversion for AF (n=151) and consecutive

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Table 1. Risk for AF in Obstructive Sleep Apnoea Patients Investigator

Methods of Diagnosis for OSA

Results

Mooe et al.72 (1996) PSG

Risk for AF after CABG in OSA

(n=121)

patients (OR 2.8 [95% CI 1.2–6.8])

Gami et al.7 (2004) Berlin questionnaire

The proportion of patients with

(n=463)

OSA was significantly higher in the AF group than in the general cardiology group (49% versus 32%; p=0.0004); association between AF and OSA (OR 2.19 [95% CI 1.40–3.42])

Mehra et al.24(2006) PSG

Risk for AF in OSA patients

(n=566)

(adjusted OR 4.02 [CI 1.03–15.74])

Tanigawa et al.73

Pulse oximeter

Risk for AF for severe OSA

(2006) (n=1763)

(adjusted OR 5.66 [CI 1.75–18.34])

Gami et al.25 (2007) PSG

Incident AF in OSA for patients

(n=3542)

aged <65 (HR 3.29 [CI 1.35-8.04])

Monahan et al.20

PSG

(2009) (n=2816)

Risk for AF after a respiratory disturbance compared with normal breathing (OR 17.9 [CI 2.2–114.2])

Mehra et al.8 (2009) PSG

Increasing OSA quartile associated

(n=2911)

with CVE (p=0.01) but not AF

Valenza et al.44 (2014) (n=1210)

PSG

Compared with patients with an AHI <5, patients with an AHI >30 were older and had a higher BMI, a higher rate of hypertension and a higher CHADS2 score than those with AHI <5

AF = atrial fibrillation; AHI = apnoea–hypopnoea index; BMI = body mass index; CABG = coronary artery bypass graft; CHADS2 = congestive heart failure, hypertension, age, diabetes and prior stroke; CVE = complex ventricular ectopy; HR = hazard ratio; ODI = oxygen desaturation index; OSA = obstructive sleep apnoea; OR = odds ratio; PSG = polysomnogram. Modified from Latina JM et al.21

312 patients referred to a general cardiology practice without a past or current history of AF (n=312).7 They showed the proportion of patients with OSA was significantly higher in the AF group than in the general cardiology group (49 % versus 32 %; p=0.0004). The adjusted OR for the association between AF and OSA was 2.19 (95 % CI 1.40–3.42; p=0.0006). Stevenson et al. also demonstrated similar results in 90 patients with paroxysmal or persistent AF and 45 controls.28 They found that AHI in AF patients was higher than in controls (23.19±19.26 versus 14.66±12.43; p=0.01). The OR for the association between AF and sleep disordered breathing (SDB) (AHI >15) was 3.04. Bitter et al. reported similar findings in which sleep apnoea was documented in 74 % of all patients with AF (43 % had OSA and 31 % had CSA).29

Mechanisms Underlying Atrial Fibrillation in Obstructive Sleep Apnoea OSA is characterised by sleep-related periodic breathing and repetitive collapse of the upper airway, resulting in hypoxia, hypercapnia, sleep arousals, shifts in intrathoracic pressure, and hyperactivity of the autonomic nervous system.30–32 AF and OSA share some common risk factors, such as advanced age, obesity, male gender, hypertension and CAD.30–33 It seems that several pathophysiological mechanisms may account for both OSA and AF; therefore, the presence of one may promote the other. Studies also demonstrated that OSA may promote cardiac remodelling and systemic inflammation.31–35 Figure 1 summarises potential mechanisms that may be responsible for the initiation and maintenance of AF in OSA patients.

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Arrhythmia Mechanisms Figure 1: Schematic Illustration of Putative Pathophysiological Mechanisms Contributing to Atrial Fibrillation in Obstructive Sleep Apnoea OSA Negative Intrathoracic Pressure

Afterload Increase ↑

Vagal Activity ↑

Atrial Stretch

Sympathetic Activity ↑

CO2 ↑ O2 ↓

Shortening APD, ERP Systematic Inflammation ↑ Oxidative Stress ↑

LVH

Atrial Remodelling

Obesity

Atrial Enlargement

AF Initiation ↑ AF Manifest ↑

AF = atrial fibrillation; APD = action potential duration; ERP = effective refractory period; LVH = left ventricular hypertrophy; OSA = obstructive sleep apnoea.

Hypoxia, Oxidative Stress and Inflammation OSA induces repeated episodes of hypoxia and hypercapnia that trigger chemoreflex and enhance the sympathetic nerve activity, leading to tachycardia and BP surges, especially at the end of the apnoeic episodes.22,35 Tachycardia and hypertension increases myocardial oxygen demand while myocardial oxygen supply is at its lowest level due to hypoxia. This results in repeated myocardial ischaemia during sleep, promotes atrial and ventricular fibrosis and subsequently induces atrial and ventricular arrhythmias as well as sudden cardiac death during sleep.34,35

In addition, overly negative intrathoracic pressure is transmitted to the thin-walled atria and leads to atrial stretch. Repeated stretch may result in atrial chamber enlargement and fibrosis, both of which are known to predispose atria to AF.41–44 It has been suggested that negative tracheal pressure during obstructive apnoea is a strong trigger for AF, which was mediated by shortening the atrial effective refractory period (ERP) and increasing susceptibility to AF mainly by enhanced vagal nerve activity.41,42

Obstructive Sleep Apnoea and Atrial Remodelling Atrial structural remodelling and electrical remodelling are well known to be critical elements in the pathogenesis of AF. Importantly, several studies have demonstrated that OSA may increase left atrial size independently, leading to atrial conduction abnormalities, and longer sinus node recovery time (SNRT) in both animal and human studies.45–48 Animal studies demonstrated that AF induced by OSA is related to shortening of the ERP.42,47,49 Using electroanatomical mapping, patients with OSA showed significant atrial remodelling including atrial enlargement, voltage decrease, conduction abnormalities and longer SNRT.34 In a consecutive group of 720 AF patients undergoing cardiac magnetic resonance imaging before AF ablation, Neilan et al. reported that patients with OSA have an increased BP, right ventricular volume, left atrial size and LV mass.50 All these studies suggest that OSA is associated with atrial structural and electrical remodelling characterised by atrial enlargement and reduction in voltage, as well as conduction abnormalities. Treatment with CPAP is associated with lower BP, decreased atrial size, and ventricular mass, and a lower risk for AF recurrence after pulmonary vein isolation (PVI).50

Hyperactivity of the Cardiac Autonomic Nervous System Intermittent hypoxia and post-apnoeic re-oxygenation lead to excessive oxidative stress, which also plays a major role in inflammation.35–40 Repetitive oxidative stress on the myocardium may result in adverse myocardial remodelling and inflammation, thereby producing a substrate for AF. Shamsuzzaman et al. reported significantly higher levels of plasma C-reactive protein (CRP) in patients with OSA than in control subjects (0.33 versus 0.09 mg/dl) and CRP levels were independently associated with the OSA severity as well.36 In addition, systemic oxidative stress was markedly elevated in patients with OSA than the controls.37,38 Treating OSA with continuous positive airway pressure (CPAP) significantly attenuated the effect of OSA on CRP and interleukin (IL)-6 levels.39 Inflammation and oxidative stress also leads to vascular endothelial dysfunction, predisposing OSA patients to atherosclerosis.40

Substantially Negative Intrathoracic Pressure OSA is characterised by repetitive forced inspiration against an obstructed upper airway that generates a substantially negative intrathoracic pressure (e.g. -65 mmHg) with a subsequent increase in the left ventricular (LV) transmural pressure (afterload).41,42 Increased afterload can lead to LV hypertrophy. Orban and colleagues performed the Mueller manoeuvre to simulate OSA in 24 healthy young adults.43 The Mueller manoeuvre involves a forced inspiration against a closed mouth and nose in order to make a substantially negative pressure in the chest. They found that left atrial volume markedly decreased and LV end-systolic dimension increased with a decreased LV ejection fraction during the manoeuvre. After releasing the manoeuvre, there was a compensatory increase in blood flow, stroke volume, ejection fraction and cardiac output exceeding baseline. They proposed that repetitive swings in afterload burden and chamber volumes may have implications for future development of AF and heart failure.

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Normal sleep is often divided into nonrapid eye movement (NREM) sleep and rapid eye movement (REM) sleep. When a person falls asleep, the NREM sleep progresses from stage 1 to stage 4 before entering the REM stage. The cycles of NREM and REM sleep repeat themselves throughout the period of sleep.11,51–53 During NREM sleep, there is a progressive increase in the parasympathetic tone and withdrawal of sympathetic tone, manifesting as slowing of the heart rate, reduction of BP and a decrease in the sympathetic nerve activity.53 When the REM sleep begins, there is a surge of the sympathetic nerve activity, BP and heart rate.53–55 This pattern of natural variations in the sympathetic/parasympathetic balance is disturbed in patients with OSA. For instance, the timing of sudden death in the general population is known to be highest between 06:00 and noon when the sympathetic tone is high. In patients with OSA, the highest incidence of sudden death occurred between midnight and 06:00 when the victims were in sleep.56 In addition, in patients with OSA, because of the nightly struggle with respiration, the baseline sympathetic activity is significantly higher than those without OSA, leading to increased risks for cardiovascular diseases and metabolic disorders.15,57 Moreover, repetitive hypoxia and hypercapnia stimulate the central and peripheral chemoreceptors that augment sympathetic nervous activity.58 At the same time, baroreflex in OSA patients is attenuated, leading to unopposed sympathetic activation, resulting in marked vasoconstriction and hypertension. Previous experimental studies have shown a close mechanistic association between the autonomic nervous system and AF induced by OSA.41,42,47,49 In a canine model of OSA, direct neural recording from a ganglionated plexi (Ao-SVC GP), located at the junction of the aorta, superior vena cava and right pulmonary artery, revealed markedly

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increased neural activity preceding the initiation of AF. Ablation of the Ao-SVC GP, which was proposed to be the gateway for vagal innervation to the heart, markedly suppressed AF inducibility in this canine model of OSA. Linz et al. reported that in a pig model of OSA, the negative intratracheal pressure generated by forced inspiration, known to activate afferent vagal fibres in the thorax, activated the parasympathetic nervous system, which in turn facilitated the initiation of AF.49,59 Airway obstruction without generating a strong negative intratracheal pressure failed to initiate AF. AF initiation was also inhibited by vagotomy. Acute atrial stretch induced by markedly increased intrathoracic pressure generated by forced inspiration as well as diastolic dysfunction in obese animals also play major roles in the genesis of AF in OSA.45,48

Initiation and Maintenance of Atrial Fibrillation in Obstructive Sleep Apnoea Patients As discussed above, surges of sympathetic and parasympathetic activity are induced by OSA.42,47 The former induces a large and extended Ca++ transient and the latter markedly shortens the action potential duration and refractory period, leading to triggered firing of the PV and atrium, thereby inducing AF.60 Atrial stretch, caused by a substantial drop of the intrathoracic pressure in order to compensate for the obstructed airway, markedly shortens the atrial and PV refractory period, similar to the electrophysiological effect of parasympathetic activation.61,62 Prolonged atrial conduction time, increased dispersion of the refractoriness and enhanced atrial fibrosis caused by repeated OSA all contribute to the maintenance of AF in OSA patients.

Treatment for Atrial Fibrillation in the Presence of Obstructive Sleep Apnoea Continuous Positive Airway Pressure The gold standard for OSA therapy is CPAP. The positive pressure keeps the pharyngeal area from collapsing and thus helps alleviate the airway obstruction. Shah et al. conducted a study on consecutive 720 AF patients and found that OSA is independently associated with adverse LV remodelling and clinical outcomes, whereas CPAP therapy is associated with a beneficial effect on LV remodelling.63 Hall et al. recently discovered that in patients with heart failure and OSA, 6–8 weeks of CPAP therapy increased hydroxyephedrine retention, indicating improved myocardial sympathetic nerve function. Cardiac efficiency may be improved by CPAP in patients with severe OSA and heart failure.64 Without appropriate CPAP therapy, AF patients with OSA respond poorly to both pharmacological and nonpharmacological therapy (cardioversion or ablation) with high rates of recurrence.65–67 Monahan et al. studied 61 patients treated with antiarrhythmic drugs for AF who were referred for a sleep study.67 Nonresponders to antiarrhythmic drugs were more likely to have severe OSA than mild OSA (52 % versus 23 %). Severe OSA patients were more likely to be nonresponders as well (70 % versus 39 %). In addition to arrhythmias,

2. 3.

ACC/AHA/ESC 2006 Guidelines for the management of patients with atrial fibrillation – executive summary. Circulation 2006;114:700–52. Basner RC. Cardiovascular morbidity and obstructive sleep apnea. N Engl J Med 2014;370:2339–341. Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA 2001;285:2370–5. Benjamin EJ, Wolf PA, D’Agostino RB, et al. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation 1998;98:946–52.

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OSA patients have an increased BP, pulmonary artery pressure, right ventricular volume, left atrial size and LV mass.50 Therapy with CPAP is associated with lower BP, decreased atrial size and ventricular mass, and a lower risk for AF recurrence after AF ablation. CPAP therapy substantially reduced the incidence of AF, premature ventricular depolarisation and sinus bradycardia in patients with severe OSA.68 This is in agreement with the study of Kanagala et al. that AF recurrence after cardioversion was 82 % in those with untreated OSA compared with 42 % in the CPAP-treated group.69 Fein et al. demonstrated that AF recurrence following AF ablation in CPAP nonuser patients was significantly higher (HR 2.4) and CPAP therapy resulted in greater AF-free survival rate (71.9 % versus 36.7 %).66 While catheter ablation remains the mainstay therapy for drug-refractory AF, screening AF patients for OSA and initiating CPAP therapy before catheter ablation is advisable.

Emerging Therapy – Autonomic Neuromodulation Although renal nerve denervation (RND) failed to deliver its promise in controlling drug-refractory hypertension, several preliminary studies indicated that RND may be a promising new therapy for arrhythmias related to hyperactivity of the sympathetic nerves. RND is likely to influence cardiac electrophysiology through alleviating the hyperactive state of the sympathetic nervous system. In fact, recent experimental studies have indicated that RDN was effective in suppressing OSAinduced AF and atrial ERP shortening and could inhibit post-apnoeic BP elevation in an animal model of OSA.49,59 It is noteworthy that Witkowski et al. studied 10 patients with refractory hypertension and OSA who underwent RDN and completed 3- and 6-month follow-up evaluations. They found a decrease in AHI at 6 months after RDN (16.3 versus 4.5), suggesting that RDN may be used to treat hypertension in OSA patients but may also serve as an adjunct therapy to treat OSA.70 A recent study from our group demonstrated that in a rabbit model of OSA, ERP shortening and AF duration induced by OSA can be suppressed by low-level vagal stimulation at voltages not slowing the sinus rate or AV conduction.71 This finding implies that low-level vagal stimulation may be used to treat AF induced by OSA. Inferences from these experimental and clinical studies must be cautiously extrapolated to clinical practice. However, neuromodulation may serve as an adjunct therapy in treating AF in OSA patients by directly modulating the hyperactivity of the autonomic nervous system that facilitates the initiation and maintenance of AF.

Conclusion OSA is an important but overlooked risk factor for AF. OSA and AF share many common risk factors; therefore, the presence of one may promote the development of the other. OSA also negatively affects the efficacy of pharmacological and ablative therapy for AF. All AF patients should be screened for OSA and therapy to alleviate OSA should be initiated as soon as it is diagnosed in patients with AF. n

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Arrhythmia Mechanisms

Contemporary Mapping Techniques of Complex Cardiac Arrhythmias – Identifying and Modifying the Arrhythmogenic Substrate Emmanuel Koutalas, Sascha Rolf, Borislav Dinov, Sergio Richter, Arash Arya, Andreas Bollmann, Gerhard Hindricks and Philipp Sommer Department of Electrophysiology, Leipzig Heart Center, University of Leipzig, Leipzig, Germany

Abstract Cardiac electrophysiology has moved a long way forward during recent decades in the comprehension and treatment of complex cardiac arrhythmias. Contemporary electroanatomical mapping systems, along with state-of-the-art technology in the manufacture of electrophysiology catheters and cardiac imaging modalities, have significantly enriched our armamentarium, enabling the implementation of various mapping strategies and techniques in electrophysiology procedures. Beyond conventional mapping strategies, ablation of complex fractionated electrograms and rotor ablation in atrial fibrillation ablation procedures, the identification and modification of the underlying arrhythmogenic substrate has emerged as a strategy that leads to improved outcomes. Arrhythmogenic substrate modification also has a major role in ventricular tachycardia ablation procedures. Optimisation of contact between tissue and catheter and image integration are a further step forward to augment our precision and effectiveness. Hybridisation of existing technologies with a reasonable cost should be our goal over the next few years.

Keywords Electroanatomical mapping systems, mapping techniques, atrial fibrillation, ventricular tachycardia, arrhythmogenic substrate, contact force, image integration Disclosure: Dr Koutalas, Dr Dinov, Dr Richter and Dr Arya have no conflicts of interest to declare; Dr Rolf reports personal fees and non-financial support from Saint Jude Medical and Biosense, outside the submitted work; Dr. Bollmann reports personal fees and non-financial support from Boston Scientific, outside the submitted work; Dr. Hindricks reports personal fees and other from Saint Jude Medical and Biosense outside the submitted work; Dr. Sommer reports personal fees and non-financial support from Saint Jude Medical and Biosense, outside the submitted work Received: 8 December 2014 Accepted: 12 January 2015 Citation: Arrhythmia & Electrophysiology Review, 2015;4(1):19–27 Access at: www.AERjournal.com Correspondence: Philipp Sommer, MD, Department of Electrophysiology, Heart Center Leipzig, Strümpellstr. 39, 04289 Leipzig, Germany. E: philipp.sommer@helios-kliniken.de

Since the introduction of electroanatomical mapping (EAM) into clinical practice in 1997, remarkable progress has been made in catheter infrastructure, signal recording and processing, catheter guidance and visualisation and simultaneous real-time depiction and processing of different types of critical information during an ablation procedure.1 The latter, along with the comprehension of the pathophysiological mechanisms of arrhythmias’ induction and perpetuation have boosted catheter-based ablation of complex arrhythmias, such as atrial fibrillation (AF) and ventricular tachyarrhythmias (VAs). In this context, identification and modification of the arrhythmogenic substrate has entered clinical practice, leading, however, to elongated procedure times and increased exposure to ionising radiation for both operator and patients. Contemporary three-dimensional (3D) EAM systems (EAMS) have significantly reduced the need for fluoroscopic visualisation of catheters.2,3 They have also created a precise and trustworthy ‘virtual environment’ capable of guiding complex mapping and ablation procedures. The latter is enhanced by integrating data from other imaging modalities, such as computed tomography (CT) and cardiac magnetic resonance (CMR). Contact-based EAM remains the standard of care in most cases, while non-contact and/or multipolar catheters enable high-density mapping of arrhythmias in as few as a single

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beat. Recently, the matter of optimal catheter–tissue contact and its effect on obtained data and ablation efficacy has been addressed by a number of studies.4,5 Modern EAM techniques have also been enriched with high-density body surface electrocardiogram (ECG) maps projected onto reconstructed images of cardiac chambers created by CT and CMR, in an attempt to map arrhythmias in a non-invasive way. In this review, the authors aim to sum up state-of-the-art EAM techniques and their impact on the acute- and long-term results of ablation of complex arrhythmias.

Clinical Perspective • E lectroanatomical mapping systems are the cornerstone of contemporary invasive cardiac electrophysiology. • Identification and modification of the underlying arrhythmogenic substrate has emerged as an ablation strategy that improves outcome in atrial fibrillation and ventricular tachycardia ablation procedures. • Implementation of contact force, image integration and hybridisation of existing electroanatomical mapping technologies are the necessary steps forward to further improve our effectiveness during mapping and ablation of complex arrhythmias.

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Arrhythmia Mechanisms Electroanatomical Mapping Systems – Architecture and Features Contact-based Electroanatomical Mapping The two most widely used contact-based EAMS worldwide are CARTO® (Biosense Webster Inc., Diamond Bar, CA, USA) and EnSite NavX Velocity® (St Jude Medical, St Paul, MN, US). The primary inherent feature of every EAMS is considered the non-fluoroscopical and precise spatiotemporal depiction of various diagnostic and therapeutic catheters and devices into a 3D shell that reenacts the cardiac chamber of interest. This 3D shell consists of ‘electrical points’ sampled by the mapping catheter through contact with the anatomical structure. Modern EAMS incorporate utilities enabling computer-automated multi-point model creation while the mapping catheter is roved around the anatomical structure (CARTO3® Fast Map Module and EnSite NavX Velocity® One-Model Module). The CARTO system is based on three active weak magnetic fields (5x10-6 to 5x10-5 Tesla), produced by a three-coil location pad placed underneath the patient’s thorax. Dedicated catheter tips incorporate a magnetic mini-sensor that continually measures the strength of the magnetic field and calculates the catheter’s exact position in space.1 Contemporary CARTO versions (CARTO3) can concurrently portray multiple catheters, due to a sophisticated current-based catheter location technology. Six electrode patches positioned at the patient’s back and chest monitor the current emitted at a unique frequency by various catheter electrodes.6,7 Visualisation of catheters is confined into a 3D virtual area called the ‘matrix’, which can be built only by a magnetic sensor-equipped manufacturer-specific catheter. Ensite NavX technology in its latest version (Velocity) uses six skin electrodes to create a high-frequency electric field (8.0 kHz) in three mutually orthogonal planes on the patient’s thorax, creating a coordination system in three X/Y/Z axes. The 3D-localisation of conventional electrophysiology catheters is based on an impedance gradient-calculation system in relation to a reference electrode placed on the patient’s body, too.8 Field scaling is a process by which through complex calculations the body’s non-linear impedance can be overcome and a more representative model of the mapped 3D anatomy can be built.7,8 NavX Velocity is an architecturally open system within which multiple catheters from different manufacturers can be visualised.9 An additional advantage of the NavX Velocity technology during ablation procedures is that it is partially insensitive to potential patient movements, as the reference electrodes and catheters are placed either on the patient’s skin or in the patient’s cardiac chambers, respectively, and therefore they move simultaneously with the patient, preventing map shifts. Recently, a novel EAMS (Rhythmia Mapping®, Rhythmia Medical, Boston Scientific Inc., Marlborough, MA, US) received regulatory approval. A major advantage of the new system is its ability to simultaneously record large numbers of electrograms (EGMs) with a very high spatial resolution. This is achieved through a specially designed mini basket bidirectional deflectable catheter (64-electrode IntellaMap Orion® High Resolution Mapping Catheter, Boston Scientific Inc.) The mapping catheter incorporates a basket electrode array (usual mapping diameter 18 mm) with eight splines. Each spline incorporates eight small, low impedance electrodes (64 electrodes in total). Electrode localisation is carried out by a magnetic sensor in the distal region of the catheter combined with impedance sensing on each of the 64 basket electrodes. Mapping in auto mode enables automatic annotation of activation times in sites of interest without

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manual interventions. The features and capabilities of this novel EAMS have been evaluated in canines by Nakagawa et al.10 A median of 4,227 EGMs with a median resolution of 2.6 mm in 6.1 minutes were obtained, enabling the rapid creation of a credible activation map.10 Clinical studies will clarify the potential value of the system in humans.

Contact Force During an electrophysiological study, bipolar EGMs are the most commonly analysed waveforms. EGM properties that are usually used to draw conclusions on cardiac tissue characteristics include signal amplitude, power spectrum and fractionation.11–13 However, the distance and the orientation of the mapping catheter bipole to the underlying tissue plays a significant role in the qualitative and quantitative characteristics of the acquired signal, which, in turn, influence the results of voltage-based substrate mapping.14 Adequate contact between catheter and tissue is considered determinant to credible characterisation of the underlying arrhythmogenic substrate.15 Furthermore, even though lesion formation during ablation is evaluated through fulfilment of certain criteria, including EGM amplitude reduction, initial impedance and impedance drop during ablation and electrode temperature, the proper contact between tissue and catheter can be guaranteed only through its direct measurement. The contact force (CF) is used to evaluate the contact between the tissue and the catheter tip. Numerous studies have demonstrated that adequate CF is crucial for radiofrequency lesion size.16–20 At the other side of the CF spectrum, it has been found that lesions placed using high power settings (45 W) and high pressures (>40 g) are correlated to char and crater formation.21 Of note, CF <100 g during ablation procedures is associated with complications, i.e. cardiac perforation.5 Three available technologies enable direct measurement of CF during ablation procedures. The TactiCath® catheter (Endosense, Geneva, Switzerland) incorporates a force sensor between the second and third electrode, consisting of a deformable body and three optical fibres (0.125 mm diameter) to measure micro-deformations that correlate with the force applied to the catheter tip. Infrared laser light is emitted through the proximal end of the three optical fibres. The change of wavelength during application of CF to the tip of the catheter is proportional to the CF applied to the tip.4 The technology used in the ThermoCool SmartTouch® ablation catheter (Biosense Webster Inc., Diamond Bar, CA, US) is based on the electromagnetic location technology used in the CARTO3 System. The catheter tip electrode is mounted on a precision spring that permits a small amount of electrode deflection. A transmitter coil that is coupled to the tip electrode, distal to the spring, emits a location reference signal. Location sensor coils placed at the proximal end of the spring detect micro-movement of the transmitter coil, representing movement of the tip electrode on the spring. The system senses the location information of the sensor and calculates the associated force based on the known spring characteristics.22 The third system, IntelliSense® (Hansen Medical Inc., Mount View, CA, US), can be used in conjunction with the use of a dedicated robot system for catheter ablation.23

Non-contact and Multi-electrode Mapping In contact-based EAMS, manual point-by-point mapping is required to build a proper activation map of the arrhythmia of interest, i.e. running tachycardia or extra-systoles. On the other hand, if the arrhythmia is not sustained or not haemodynamically tolerated, point-by-point mapping may be insufficient or even not feasible. Non-contact mapping can address this concern as it can create a full map even from a single tachycardia beat. The most widely applied non-contact mapping system

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uses the Ensite Array® (St. Jude Medical Inc., St Paul, MN, US) basketcatheter and requires a 3D Ensite NavX reconstruction created with a roving mapping catheter to project data on. The multipolar non-contact catheter uses 64 unipolar electrodes, which record virtual unipolar farfield EGMs using a mathematical inverse solution of the Laplace law and then project them (n=3,360) on an already reconstructed 3D model shell. The precision of the recorded EGMs depends on the distance from the centre of the array to the endocardial surface (R-value, displayed continuously during mapping) with distances <40 mm giving the most accurate data.24,25 Unipolar recording analysis is used after collection of data to build maps of interest.26 The specific shape of the basket catheter enables simultaneous recording of several potential sites of interest without actual catheter manipulation. During ectopic activity, virtual unipolar EGMs obtained at the earliest site of activation have a QS or rS morphology, with the intrinsic defection inscribing earlier compared with every adjacent sites.26 The variable distance and orientation of the centre of the EnSite balloon electrode to the recording sites can result in differing dV/dt of the virtual unipolar EGMs at different recording sites.26 During mapping in atria and in the right ventricle (RV), the basketcatheter remains constantly stable. However, quality of recorded signals worsens with distances exceeding 40mm from the centre of the array. In case of ventricular tachycardias (VTs) coming from the left ventricle (LV), the stability of the basket-catheter remains an important issue to be addressed. In the era of cost-effectiveness, another main drawback of non-contact mapping is the relatively high cost in comparison to conventional contact-based EAM. Use of multi-electrode catheters enables rapid high-density activationand substrate-mapping through simultaneous multiple-point acquisition. Recently, a number of multi-electrode contact-based catheters (PentaRay®, Biosense Webster, Inc., Diamond Bar, CA, US) and the Duo-decapolar® catheter (Livewire®, 2-2-2 mm spacing, St Jude Medical, St Paul, MN, US) have been introduced into clinical practice. Using the PentaRay® catheter for the mapping of local abnormal ventricular activities in 35 patients with scar-related VT, Jaïs et al. found that the PentaRay® was capable of providing high-density maps with clean electrical signals, but also enabling careful monitoring of transmural response to ablation, which is particularly helpful in the case of high-density epicardial mapping.27 Several recent studies also showed promising applications of multi-electrode catheters.28,29 Della Bella et al. performed ultra-high-density mapping using the Duo-decapolar catheter to define features of complex post-infarction scar architecture by mapping of late potentials (LPs) that were critically related to reentrant VTs.30 Pacingmapping manoeuvres were also facilitated by the presence of multiple electrode pairs for pacing. A multi-electrode mapping strategy has the potential to further shorten procedural and fluoroscopy times. Prospective large-scale studies are warranted to establish the implementation of multi-electrode mapping in VT ablation.

Non-invasive Mapping Non-invasive cardiac mapping provides information on the topography of arrhythmogenic foci pre-procedurally, in order to reduce timeconsuming mapping times. Body surface unipolar recordings are projected onto 3D reconstructed images of the heart derived from CT or CMR scans. Using complex mathematical equations, the torso potentials are related to the epicardial surface of the heart.31 Using body surface potential maps (BSPM) Lai et al. demonstrated the feasibility of this technique for approximating the site of origin of cardiac ectopic activity, propagation properties of ectopic beats and, most recently, for reporting

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Figure 1: Voltage Map of the Left Atrium During a Repeat Procedure of Atrial Fibrillation Ablation

All voltage and ablation points are projected on the segmented computed tomography (CT) model of the left atrium after fusion of the electroanatomical model with the help of OneModel® Module of the EnSite Velocity® system. Red points correspond to ablation lines. White points correspond to areas where pacing over the ablation catheter resulted in no atrium capture, helping us to avoid unnecessary ablation. Purple areas depict zones of the atrium with voltage amplitude >0.5 mV. Grey areas depict zones of voltage <0.2 mV. Other colours correspond to intermediate amplitude voltage zones. In this case, after re-isolation of the pulmonary veins, completion of an already existing box lesion at the antrum of the left atrium was conducted.

on the value of BSMP-derived ventricular endocardial reconstruction for localisation of ventricular ectopic beats.32,33 Non-invasive mapping has strengthened efforts to explain the mechanisms involved to the initiation and perpetuation of AF. Haissaguerre et al. applied non-invasive electrocardiographic mapping in patients with AF and suggested a co-existence of multiple AF mechanisms, including wave genesis from focal sources or rotors, as well as wave propagation. Regarding rotors, their presence was not confined to a certain small area as they shifted to different areas of the atrium, recurring and firing occasionally.34

Implementation of Electroanatomical Mapping Systems in Clinical Practice Ablation of Atrial Fibrillation Contact-based EAMS are ideal for visualising reentry circuits or centrifugal activation round an arrhythmogenic focus in 3D reconstruction models. As a result, EAMS are of utmost importance in AF ablation procedures and in macroreentry, focal or microreentry atrial tachycardias (ATs) outside PVs, during index or repeat procedures.11,35–38 Non-contact mapping is not consistently used for catheter ablation of AF, although it may facilitate recognition of gaps in the ablation lesions in redo procedures and localisation of arrhythmogenic extra-PV foci.26,39 Entrainment techniques can be applied during mapping of macroreentry ATs with stable cycle length. Using colour-coded 3D entrainment with the help of EAMS Esato et al. precisely portrayed the 3D location of the reentrant circuit in all 26 patients with regular macroreentry AT enrolled in the study. Lines of impulse propagation were interrupted by linear lesions, resulting in a procedural success of 100 %. Of note, 88 % of patients had no AT recurrences during follow-up.40

Substrate Modification EAMS depict voltage maps on 3D reconstruction models. In the atrium, areas with endocardial bipolar voltage amplitude of <0.5 milli-Volt (mV), ≤0.5–1.5mV≤ and >1.5 mV are considered dense scar, border-zone and healthy tissue, respectively. Low-voltage is considered a surrogate of atrial fibrosis, although cut-off scar values for scar identification were originally based on baseline noise level recorded in early EAMS (see

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Arrhythmia Mechanisms Figure 1).41 Only recently, a validation study using CMR endocardial voltage mapping and histological examination of post-ablation injuries in pigs, demonstrated a mean voltage amplitude at the centre of the ablation line of 0.6 mV immediately post-ablation, and 0.3 mV late after ablation.42 A bipolar voltage cut-off value of 0.2 mV (0.45 mV for the left pulmonary vein [PV]-left atrial appendage ridge) and 0.15 mV (0.2 mV for the left PV-left atrial appendage ridge) can identify acute and chronic inexcitable dense scar in patients undergoing first time PV isolation (PVI) and redo PVI, respectively.43 In patients undergoing AF ablation with PV antrum isolation, in whom existing low-voltage areas are not modified, the latter are independently related to AF recurrence during follow-up.44 Recently, the Delayed-Enhancement MRI Determinant of Successful Radiofrequency Catheter Ablation of Atrial Fibrillation (DECAAF) study demonstrated that increased atrial tissue fibrosis quantified by CMR with late gadolinium enhancement (LGE-CMR) was independently related to recurrence of AF following ablation procedure.45 Our group has recently demonstrated the presence of low-voltage areas by endocardial bipolar mapping in 35 % of patients with persistent AF and in 10 % of patients with paroxysmal AF. In patients without low-voltage areas no further substrate modification was performed. After a single procedure, 62 % of them remained free of atrial arrhythmias. By contrast, 23 % of patients with low-voltage areas and PVI only remained free of arrhythmia after 12 months of follow-up. In the group of patients with low-voltage areas and substrate-guided modification, a 70 % success rate of arrhythmiafree survival after one year was reported.46 Prospective randomised clinical studies evaluating the effects of ‘low-voltage areas’ ablation are warranted in order to further clarify the impact of substrate modification on post-procedural AF-free survival.

Contact Force CF mapping is another piece of the puzzle in AF ablation procedures. It enables acquisition of voltage points without the restrictions of potential lack of contact and creation of credible maps of the underlying substrate. More importantly, efficient CF has been shown to be associated with the permanence of PVI. In the TOuCh+ for CATheter Ablation (TOCCATA) study, all patients with an average CF<10 g experienced recurrences, while 80 % of the patients ablated with an average CF>20 g remained free of recurrence during 12 months follow-up.47 The Efficacy Study on Atrial Fibrillation Percutaneous Catheter Ablation With Contact Force Support (EFFICAS I) trial correlated the CF during the initial procedure and the incidence of isolation gaps at three months follow-up. Reconnection of the PVs correlated strongly with minimum CF and minimum forcetime integral (FTI, i.e. amount of contact applied over time) at the site of gap. CF and FTI were reported as higher on the right PVs. The authors recommended an optimal CF target of 20 g and a minimum FTI of 400 g x second (gs) for each point lesion.48 Patients achieving a mean CF >20 g require shorter procedural time, without significant difference in complication rate in comparison to patients in whom CF is <10 g.49 Recently, the transmurality of the ablation lesion has been correlated with CF and FTI. Squara et al. suggest that an FTI >392 gs can be used as an endpoint during radiofrequency ablation, which corresponds well to already published data.50

Complex Fractionated Atrial Electrograms Complex fractionated atrial electrograms (CFAEs) are defined as low voltage (≤0.15 mV) multi-segment signals with one or both of the following characteristics: (1) atrial EGMs composed of two deflections or more and/or perturbations of the baseline with continuous deflection of a prolonged activation complex; (2) atrial EGMs with a very short cycle length (≤120 milliseconds), with or without multiple potentials.51

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The exact role of CFAE in the pathogenesis of AF has not been yet clarified. CARTO® and NavX® integrate specific algorithms that enable acquisition of CFAEs and construction of corresponding maps. However, the number and allocation of CFAEs are rhythm dependent and in only 5 % of the patients a fractionation in both sinus rhythm (SR) and AF could be proved.52 In a recent meta-analysis, PVI alone was compared with PVI with additional CFAE ablation. The authors concluded on lower recurrence rates of atrial tachyarrhythmias after a single procedure when supplementary CFAE ablation was performed in cases of persistent and long-lasting persistent but not paroxysmal AF.53

Focal Impulse and Rotor Modulation Mapping and Ablation The mechanisms perpetuating AF after initial onset are still only partially defined, with distinct theories having been developed over the years. Recently, in an effort to further elucidate this question, Allessie et al. performed epicardial wave mapping during heart surgery in patients with long-standing persistent AF and demonstrated the presence of multiple wavelets separated by lines of longitudinal conduction block propagating through the atrial wall.54 Rotor theory, along with demonstration of focal impulses, has nowadays emerged as an equally significant major cause for AF.55–57 Narayan et al. developed a novel computational contact mapping approach that involved the use of two 64-pole catheters (Constellation, Boston Scientific, MA, US) placed simultaneously in the left and right atrium, to collect and analyse monophasic action potential data during AF. Absolute electrode locations within the atria were visualised within the NavX® or CARTO® environments.58 Spatiotemporal analysis of AF was performed primarily by directly analysing EGMs. Large numbers of AF-activation cycles were then reconstructed as movies or isochronal maps to exemplify single cycle snapshots of AF. Rotors were identified as rotational activity around a centre (using isopotential movies and isochronal activation maps). Focal beats in AF were then identified at their point of origin based on isopotential movies and isochronal maps. Sustained localised electrical rotors and repetitive focal beat sources were identified in nearly all AF patients studied.58 The subsequent Conventional Ablation for Atrial Fibrillation With or Without Focal Impulse and Rotor Modulation (CONFIRM) study included 92 patients undergoing 107 ablation procedures, in which a conventional strategy during ablation was prospectively compared with ablation at sources followed by conventional ablation.59 With the use of a novel system (RhythmView, Topera Medical, Lexington, MA, US), computational maps of AF were generated. Rotors or focal impulses were observed in the majority (97 %) of cases. During focal impulse and rotor modulation (FIRM) ablation, the ablation catheter was manipulated within the area indicated by the FIRM map as the centre of rotation (for rotors) or focal impulse origins. The authors demonstrated that ablation of drivers in human AF, in the form of small number of stable rotors or focal sources, frequently located outside the PV ostia, was able to terminate or slow AF and improve AF ablation outcomes. In a recent sub-analysis of the CONFIRM trial, it was further shown that, in patients with obesity, hypertension, obstructive sleep apnoea (OSA) and enlarged left atria (>40 mm), FIRM mapping was able to identify more coexisting AF sources, distributed more extensively in both atria compared with patients without such comorbidities. Reported freedom from AF after a single procedure was significantly higher when FIRM ablation was used (>80 % versus <50 %).60

Ripple Mapping Established EAMS necessitate manual-based annotation and/or evaluation of acquired map points because automated annotation has been so far prone to serious errors. On the other hand,

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manual point-by-point annotation can also lead to severe signal misjudgement. In an alternative assessment by Linton et al., EGM location, timing and amplitude were presented on the shell of the cardiac chamber created by CARTO XP® and EGMs were visualised as colour bars with corresponding 3D coordinates, of varying colours and dimensions according to the voltage–time relationship, time-gated to a preselected reference EGM. This gave the impression of a ‘wave-like’ movement of the propagation, without the need for any intervention to adjust the manual or automatic annotation.61 Recently, data on the feasibility of ‘ripple mapping’ for the diagnosis of atrial tachycardias were published.62

Figure 2: Pace Mapping of a Ventricular Premature Beat Utilising the PaSo ® Module of CARTO ® System A

Ablation of Ventricular Tachycardia Application of mapping strategies during VT ablation are constrained by a series of factors, including: 1) the ability to reproducibly induce the clinical tachycardia, 2) the potential induction of multiple, eventually not clinically relevant VTs, and 3) the haemodynamic tolerance of the induced tachycardia. In haemodynamically tolerant ongoing reentry or mostly focal VTs, creation of an activation map is the ‘gold standard’ method for depicting reentry circuits or foci. Mapping can be performed using unipolar or bipolar recordings, non-contact mapping or multi-electrode arrays visualised on EAMS.30,63,64 During haemodynamically stable VTs, entrainment manoeuvres demonstrating concealed fusion of QRS complexes can indicate placement of the catheter on a critical VT isthmus – it is important to know that post-pacing intervals can reliably distinguish between critical isthmuses and bystander sites.30,65 If the tachycardia of interest is not inducible, not sustained nor haemodynamically untolerated, the aforementioned mapping techniques are not easily applicable. Pacing over the ablation catheter can be performed and the resulting QRS complex is compared with that of the clinical and/or induced VT. Demonstration of a 12-lead QRS morphology resembling or optimally being identical to the VT morphology guides ablation at the pacing site of interest. de Chillou et al. assessed post-infarct critical isthmuses of reentry VTs and created colour-coded high-density 3D pace-mapping maps. The pace maps were matched to the 3D endocardial reentrant VT activation maps. The resulting paced 12-lead ECG at areas of interest was compared with that of the clinical VT and matched up to 100%. The subsequent sequences (from the best to the poorest matching sites) on the pace-mapping maps revealed figure-of-eight pictures in concordance with VT activation maps and identified critical VT isthmuses.66 Manual comparison of ECG configuration, however, can be time-consuming and subjective. Recently, a novel module of the CARTO® EAMS was introduced. The PaSo® module delivers automated template matching for targeting complex VT procedures (see Figure 2). It automatically compares pace mapping signals with arrhythmia signals to guide VT ablation.67,68 So far, however, no clinical studies have compared the PaSo® module with conventional pace mapping to evaluate procedure-, fluoroscopy- and application-time and efficacy rates.

Substrate Modification In patients with cardiomyopathies, the majority of arising VTs are caused by reentry mechanisms. The reentry circuit is almost always defined within areas of low voltage and slow conduction. In ischaemic cardiomyopathy (ICM) distinct subendocardial or even transmural scar areas corresponding to the level and distribution of underlying coronary vessel disease are identified. Around areas of dense

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A. The mapped ventricular premature beats (VPBs) have a left bundle branch block (LBBB) morphology and inferior axis, transition zone in lead V4, indicating an origin from the right ventricular outflow tract. B. During pacing over the mapping catheter at a free wall site with a cycle length of 600 milliseconds, a paced QRS morphology was produced. The latter was superimposed onto the native QRS morphology and the the PaSo® Module calculated the correlation between paced and native QRS morphology in each lead. Finally, an overall correlation percentage was demonstrated, in this case 87 %, driven mainly by the positive lead aVL on the pacing site, in contrast to the negative aVL of the native QRS. C. Pacing at a more septal and superior site produced a correlation of 0.97 %. Ablation at this site successfully terminated the VPB.

myocardial fibrosis, border zones contain irregularly arranged islets of surviving myocyte bundles that can act as pathways of slow conduction, giving rise to reentry VTs.69 In non-ischaemic dilated cardiomyopathy (NIDCM), areas of low voltage and slow conduction exist dominantly in the epicardial layers of the cardiac muscle, frequently sparing the endocardium. The distribution of fibrosis is rather unpredictable, although postero-lateral areas and regions bordering on valvular annuli are most often involved.70 Finally, in arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) areas of endocardial electroanatomical scar extend from the tricuspid or pulmonary valve to the RV free wall, while the RV apex seems to be excluded.71,72 Low-voltage epicardial areas correspond well to endocardial ones but extend further over the surface of the RV.73 The identification and modification of the arrhythmogenic substrate in the endocardium and/or the epicardium is considered as primary ablation strategy in contemporary VT ablation procedures in patients with structural cardiomyopathies.74 Bipolar mapping is the gold standard technique to characterise substrate. Endocardially, a bipolar voltage amplitude of ≥1.5 mV identifies healthy tissue and areas with voltage of 0.5 to 1.5 mV are considered border zones. It is suggested that the majority of unstable VTs have critical circuit components located in the border zone.75 In the epicardium, a bipolar voltage cut-off of ≥1 mV is considered normal and voltage amplitudes of 0.5 to 1.0 mV define the border zone. ‘Scar’ is defined as an area with bipolar signal amplitude <0.5 mV both endo- and epi-cardially (see Figure 3).76 Unipolar endocardial voltage mapping offers a larger field of view to the operator, in particular it portrays information on the degree of epicardial presence of low-voltage areas. Unipolar voltage amplitude of ≤6.52 mV has shown optimal receiver operating characteristic curves for defining scar consistent with LGE-CMR and is suggestive of epicardial low-voltage areas.76 A variety of abnormal EGMs are recorded in areas of scar/low-voltage, i.e. fractionated potentials, double potentials and LPs (discrete and separated from QRS by 40 milliseconds (ms). These voltage criteria were recently validated in a myocardial viability study using fluoro-deoxyglucose positron-emission tomography (FDG-PET).77

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Arrhythmia Mechanisms Figure 3: Pace Mapping of a Ventricular Premature Beat Utilising the PaSo ® Module of CARTO ® System A

A. Right anterior oblique (RAO) view of an electroanatomical model of the left ventricle during endocardial voltage mapping. Purple areas correspond to voltage amplitude >1.5 mV, whereas blue to yellow-coloured areas to amplitudes between 0.5 and 1.5 mV. Scar areas (<0.5 mV) are depicted in red. The electroanatomical model is superimposed onto a RAO fluoroscopical view of the same patient after registration with the CARTO UniVu®, an upgrade of the CARTO3® system that enables visualisation of electroanatomical models on pre-recorded fluoroscopy images or cine-loops of the anatomical structures of interest. In this fluoroscopical view a coronary angiography of the left coronary system is portrayed (LAD = left anterior descending artery; LCx=left circumflex artery). B. RAO view of the left ventricle during epicardial voltage mapping. C. Left anterior oblique (LAO) view of the left ventricle during endocardial voltage mapping. Underneath the model, the mapping catheter (MAP) is visualised, laying into the pericardial cavity. An epicardial steerable sheath is used to support guidance of the catheter into pericardium. D. LAO view of the left ventricle during voltage mapping epicardially. In panel A, the yellow point corresponds to His bundle position. In panels B and D colour points correspond to certain areas with potentials of interest for ablation.

A variety of methods are implemented during substrate modification, resulting in extensive or less-extensive ablation lesions according to the preset endpoints of the procedure.11,78–80 The main strategies include: i) linear ablation lesions with cross-section of the scar and border-zone, ii) scar/border-zone encircling, iii) placement of short lines after identification of the critical isthmus by entrainment or by pace mapping and additional lesions during SR, parallel to the border zone of the infarct until loss of capture during pacing at 10 milli-Ampere (mA) at 2 ms stimulus strength, iv) ablation of conducting channels and v) complete LP abolition.81 Since Marchlinski et al. demonstrated that linear lesions extending from the dense scar to the normal endocardium or anatomic boundary are effective in preventing recurrence of difficult-tomap VT, efforts have been made to limit the extent of ablation to critical parts of the reentry pathway, i.e. the reentry isthmus or transection, after identification, of conducting channels and delayed potentials.11,82,83

scar homogenisation without the need for abolition of all LPs.87 Beyond established criteria of successful VT ablation, Vergara et al. suggest LP abolition as an additional endpoint of the procedure.81 Of importance, though, is the timing of LPs in relation to the QRS as it is related to their localisation. Substrate-based mapping and ablation targeting LPs may oversee a proportion of the arrhythmogenic substrate, particularly in the septum and other early-to-activate regions.87 Prospective randomised studies should assess the relative efficacy of different ablation strategies regarding VT substrate modification. In patients with coronary artery disease (CAD) and remote myocardial infarction, the feasibility and effectiveness of catheter ablation for the treatment of malignant VAs have been established.88,89 The recently published Heart Center of Leipzig VT (HELP-VT) study demonstrated an acute complete success of the procedure (non-inducibility of any clinical and non-clinical VT) in 77.4 % of patients with ICM in comparison with 66.7 % patients with NIDCM.90 Although there was no statistically significant difference in short-term outcome between the two groups, long-term outcome differed significantly in favour of ICM, with rates of freedom from VT of 57 % and 40.5 %, respectively.90 In the largest series of NIDCM VT patients so far, acute complete success of 51 % and partial success of 29 % were reported after combined endocardial/epicardial mapping and ablation. Epicardial mapping was performed only in case of a failed endocardial approach.91 In this context, if a significant substrate endocardially is absent and electrocardiographic criteria indicate an epicardial origin of the VT, a combined concomitant endocardial/epicardial approach is suggested, in order to improve outcome.92 Even in case of no suspected epicardial VTs, subxyphoidal puncture and placement of a guidewire in the epicardial space before endocardial mapping and administration of intravenous anticoagulation should be taken into consideration.92 The extent of bipolar but not unipolar RV endocardial low-voltage area was the only independent predictor of arrhythmic outcome in a series of 69 prospectively studied patients with ARVC/D, independent of history and RV dilatation/dysfunction. A normal bipolar voltage in the RV characterises a low-risk subgroup of ARVC/D patients.93 Bai et al. compared endocardium-confined ablation versus endocardial/ epicardial substrate-based ablation and reported a rate of freedom from any VT of 52.2 % and 84.6 %, respectively.94 Recent data confirm the superiority of epicardial ablation in this population. Out of 87 patients from 80 different centres who underwent epicardial ablation, 64 % and 45 % were free from VT recurrence at 1 year and 5 years follow-up, respectively, an outcome significantly better compared with endocardial-defined ablation.95 Tschabrunn et al. favour a step-by-step approach in such patients, suggesting endocardial substrate mapping in SR in the RV and subsequent epicardial mapping if VTs are inducible after endocardial ablation.96

Image Integration The presence of LPs may correlate with a better post-ablation outcome.84 Both patients with ischaemic and non-ischaemic VT seem to profit from an ablation strategy based on LP ablation.85,86 Vergara et al. reported a success rate of 71.4 %, as defined by VT non-inducibility in patients with inducible VT before the ablation. EAMS enabled the creation of colourcoded LP maps, which were compared with LP maps post-ablation. In patients with complete LP abolition, VT was inducible only in 16 %, demonstrating that complete LP was a significant predictor of VT-free survival.81 Ablation of LPs can also alter electrical activity in regions of scar outside of the known radius of a radiofrequency lesion, accelerating

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In VT ablation procedures, additional information on the presence and distribution of myocardial substrate is needed. Scar image integration has recently been implemented in an effort to improve substrate identification and modification. Contrast-enhanced multi-detector CT images have been used in combination with electroanatomical maps to accurately identify dense scar and border-zone regions in 81.7 % of analysed segments.97 LGE-CMR is considered the gold standard in portraying and quantifying myocardial scar. Feasibility of LGECMR image integration into electroanatomical maps using different strategies of image registration has been already demonstrated.98–100

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Integrated LV images depicting scar areas significantly improve the accuracy of endocardial or epicardial substrate mapping, particularly in areas where proper and sufficient catheter contact is difficult to achieve.98 In patients with an implanted cardioverter-defibrillator (ICD), LGE-CMR has also been proved feasible and safe, offering a significant amount of additional data on scar regions and facilitating scar identification and mapping.101 In this study by Dickfeld et al., 4 % of mapping points with initial voltages of <1.5 mV were found to have been caused by suboptimal catheter contact. Voltage >1.5 mV could result from 2 mm of viable endocardium, although mapping was conducted in an area of >63 % meso-myocardial scar. LGE-CMR integration enabled portrayal of mid-myocardial scar, which was not detected by conventional endocardial mapping.101 More recently, Piers et al. made significant headway in the optimisation of voltage cut-off points in the epicardium by performing EAM in patients with NIDCM with real-time integration of CT-derived epicardial fat and LGE-CMR.100

Contact Force In a pivotal study, Mizuno et al. evaluated CF during VT ablation procedures.15 They suggested a CF cut-off value of 9, 8, and 8 g to obtain adequate systolic and diastolic contact in the RV, LV and epicardium, respectively. Application of the classic criteria to assess tissue contact led to a high number of points with poor contact, defined as absence of positive CF in diastole (50.9 %), revealing their limits on defining tissuecatheter contact. A weak CF <3 g led to low signal amplitudes. Increase of CF caused the increase of unipolar and bipolar signal amplitude followed by plateau when CF exceeded 20 g. The frequency of LPs identified in points with poor contact was significantly lower than that in points with good contact (11.9 % versus 23.2 %).15 The authors hypothesised that certain cut-offs for the various angles might be derived from analysis of the CF under intracardiac echocardiography monitoring. A potential reason for inferior CF values during the retrograde approach in comparison to transseptal one could be the requirement of two curves in the mapping catheter to reach the anterior and basal-septal walls of the LV.15 Tilz et al. recently conducted a direct comparison of antegrade versus retrograde LV-mapping approach and demonstrated that they result in different CF and suggested that a combined approach would result in better clinical outcomes after VT ablation.102

Non-contact Mapping in Ventricular Tachycardia Ablation Non-contact mapping is applicable in VT mapping.103 Nair et al. reported on endocardial mapping and ablation of VTs in patients with ARVC/D. EnSite Array® enabled endocardial unipolar activation mapping of

Gepstein L, Hayam G, Ben-Haim SA. A novel method for nonfluoroscopic catheter-based electroanatomical mapping of the heart: In vitro and in vivo accuracy results. Circulation 1997;95:1611–22. Rotter M, Takahashi Y, Sanders P, et al. Reduction of fluoroscopy exposure and procedure duration during ablation of atrial fibrillation using a novel anatomical navigation system. Eur Heart J 2005;26:1415–21. Estner HL, Deisenhofer I, Luik A, et al. Electrical isolation of pulmonary veins in patients with atrial fibrillation: reduction of fluoroscopy exposure and procedure duration by the use of a non-fluoroscopic navigation system (NavX). Europace 2006;8:583–7. Yokoyama K, Nakagawa H, Shah DC, et al. Novel contact force sensor incorporated in irrigated radiofrequency ablation catheter predicts lesion size and incidence of steam pop and thrombus. Circ Arrhythm Electrophysiol 2008;1:354–62. Shah D, Lambert H, Langenkamp A, et al. Catheter tip force required for mechanical perforation of porcine cardiac chambers. Europace 2011;13:277–83. Scaglione M, Biasco L, Caponi D, et al. Visualization of multiple catheters with electroanatomical mapping reduces X-ray exposure during atrial fibrillation ablation. Europace 2011;13:955–62.

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9. 10.

11.

12.

13.

14.

unstable VTs, even in a single beat.63 Zhang et al. reported on the feasibility of non-contact mapping in ablation of right outflow tract arrhythmias even though spatial resolution of activation and pace mapping is limited by rapid electrical propagation in the right ventricular outflow tract (RVOT). With a follow-up of 36.2±17.5 months, the success rate after a single procedure without antiarrhythmic agents was 86.8 %.104 Most recently, thorough analysis of virtual unipolar EGMs using non-contact mapping enabled the differentiation of left versus right-sided outflow tract foci while it has also the potential to guide ventricular extrasystole and/or VT ablation in this region.105 Arrhythmogenic substrate can be identified using the Dynamic Substrate Mapping® (DSM) module of the EnSite Velocity® system (St Jude Medical Inc., St Paul, MN, US).106 Voss et al. electroanatomically reconstructed LVs of sheep with a roved mapping catheter and applied DSM to define myocardial infarct size in comparison to CMR. They demonstrated a good correlation of scar to peak negative voltage amplitudes of <34 % of maximal unipolar noncontact EGMs recorded providing a static isopotential voltage map during SR.106 Visualisation of VT reentry circuit by non-contact mapping is feasible.107 Vergara et al. portrayed in vivo critical components of reentry circuit during the same beat during SR, ongoing VT and pace mapping.107 Prospective studies are cine qua non in order to define the usage spectrum of non-contact mapping in VT ablation.

Perspectives The exciting journey of invasive electrophysiology continues with significant innovations entering and shaping the clinical practice. EAMS have come a long way in improving our understanding of diverse pathophysiological mechanisms that initiate and perpetuate arrhythmias, enabling real time visualisation of data that are essential to the operator and in applying of effective therapeutic solutions even for the most complex arrhythmogenic substrates. Credible visualisation of areas of low-voltage/scar surrogating fibrosis further impels our ability to effectively modulate/eliminate arrhythmogenic substrate and change the prognosis of patients suffering from highly symptomatic complex supraventricular and ventricular arrhythmias. Real-time feedback on tissue-catheter contact and multi-electrode high-resolution mapping with reliable automatic point annotation further augment our mapping armament. In fact, what we were imagining 20 years ago is now becoming true. Our primary future goal should be to improve effectiveness of mapping with the help of EAMS through hybridisation of technologies available, along with implementing state-of-the-art technology in as many electrophysiology labs worldwide as possible with rational cost. n

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Integration of MR images with electroanatomical maps: feasibility and utility in guiding left ventricular substrate mapping. J Interv Card

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Electrophysiol 2010;29:157–66. 99. T ao Q, Milles J, van Huls van Taxis C, et al. Toward magnetic resonance-guided electroanatomical voltage mapping for catheter ablation of scar-related ventricular tachycardia: a comparison of registration methods. J Cardiovasc Electrophysiol 2012;23:74–80. 100. Piers SR, van Huls van Taxis CF, Tao Q, et al. Epicardial substrate mapping for ventricular tachycardia ablation in patients with non-ischaemic cardiomyopathy: a new algorithm to differentiate between scar and viable myocardium developed by simultaneous integration of computed tomography and contrast-enhanced magnetic resonance imaging. Eur Heart J 2013;34:586–96.

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101. Dickfeld T, Tian J, Ahmad G, et al. MRI-Guided ventricular tachycardia ablation: integration of late gadoliniumenhanced 3D scar in patients with implantable cardioverterdefibrillators. Circ Arrhythm Electrophysiol 2011;4:172–84. 102. Tilz RR, Makimoto H, Lin T, et al. In vivo left-ventricular contact force analysis: comparison of antegrade transseptal with retrograde transaortic mapping strategies and correlation of impedance and electrical amplitude with contact force. Europace 2014;16:1387–95. 103. Yao Y, Zhang S, He DS, et al. Radiofrequency ablation of the ventricular tachycardia with arrhythmogenic right ventricular cardiomyopathy using non-contact mapping. Pacing Clin Electrophysiol 2007;30:526–33. 104. Zhang F, Yang B, Chen H, Ju et al. Non-contact mapping to

guide ablation of right ventricular outflow tract arrhythmias. Heart Rhythm 2013;10:1895–902. 105. Trevisi N, Silberbauer J, Radinovic A, et al. New diagnostic criteria for identifying left-sided ventricular ectopy using noncontact mapping and virtual unipolar electrogram analysis. Europace 2015;17:108–16. 106. Voss F, Steen H, Bauer A, et al. Determination of myocardial infarct size by noncontact mapping. Heart Rhythm 2008;5:308–14. 107. Vergara P, Trevisi N, Bisceglie A, et al. Changes in the propagation pattern within the conduction channel during sinus rhythm and ventricular tachycardia demonstrated by noncontact mapping: role of late potential activity. Europace 2012;14 Suppl 2:ii3–ii6.

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Arrhythmia Mechanisms

Biology of the Sinus Node and its Disease Moinuddin Choudhury, Mark R Boyett and Gwilym M Morris Institute of Cardiovascular Sciences, University of Manchester, Manchester, UK

Abstract The sinoatrial node (SAN) is the normal pacemaker of the heart and SAN dysfunction (SND) is common, but until recently the pathophysiology was incompletely understood. It was usually attributed to idiopathic age-related fibrosis and cell atrophy or ischaemia. It is now evident that changes in the electrophysiology of the SAN, known as electrical remodelling, is an important process that has been demonstrated in SND associated with heart failure, ageing, diabetes, atrial fibrillation and endurance exercise. Furthermore, familial SND has been identified and mutations have been characterised in key pacemaker genes of the SAN. This review summarises the current evidence regarding SAN function and the pathophysiology of SND.

Keywords Sinoatrial node, pacemaking, sinus node dysfunction, sinus node disease, sick sinus syndrome, membrane clock, calcium clock, biological pacemaker, tachy-brady, atrial fibrillation Disclosure: The authors have no conflicts of interest to declare. Received: 3 November 2014 Accepted: 5 March 2015 Citation: Arrhythmia & Electrophysiology Review 2015;4(1):28–34 Access at: www.AERjournal.com Correspondence: Gwilym Morris, Institute of Cardiovascular Sciences, University of Manchester, 46 Grafton Street, Manchester, M13 9NT, UK. E: Gwilym.Morris@manchester.ac.uk

The sinoatrial or sinus node (SAN) is the heart’s natural pacemaker. Located in the superior right atrium, it automatically produces cyclical electrical activity to initiate each heartbeat in normal sinus rhythm. SAN dysfunction (SND) in humans, also known as ‘sick sinus syndrome’, can manifest as pathological bradycardia and asystolic pauses. As a result, SND can lead to symptoms of reduced cerebral perfusion such as dizziness and syncope. However, early SND may be latent and individuals may remain asymptomatic. Implantable electronic pacemakers are currently the only effective treatment. SND is the most common reason to have a pacemaker implanted, the indication for 27.5 % of all pacemakers implanted in the UK.1 The prevalence of SND in the UK is around 0.03 % affecting all ages, but it is much more common in the elderly population.2 The aetiology of SND can be intrinsic, extrinsic or often a mixture of the two. One retrospective study of 277 patients presenting to the emergency department with compromising bradycardia showed that 51 % of cases were attributable to a treatable extrinsic cause such as an adverse drug reaction, electrolyte imbalance or acute myocardial infarction. The other 49 % were assumed to be intrinsic or ‘idiopathic’.3 The pathophysiology of ‘idiopathic’ SND is still not clearly understood. Historically it is attributed to fibrosis and cell senescence and this is often still quoted today.4,5 However, contemporary evidence suggests that electrical remodelling of molecular pacemaking mechanisms such as membrane ion channels and intracellular Ca2+ cycling are important factors in SND.6 In this article we summarise the mechanisms of SAN function and review the current evidence surrounding the pathophysiology of SND.

Choudhury_FINAL.indd 28

Development of the Sinoatrial Node The SAN is the uppermost part of the cardiac conduction system (CCS), a chain of specialised tissue that directs electrical impulses through the heart and thus co-ordinates the way it contracts. The CCS is defined by a specific pattern of gene expression, differing to the surrounding ‘working myocardium’. During early embryogenesis as the heart tube forms, mesodermal cells quickly multiply and differentiate into working cardiomyocytes capable of contraction and fast conduction.7 However, the CCS is derived from primary myocardium that is instead led down a different lineage directed by specific transcription factors (Figure 1).7 Tbx3 is a T-box transcription factor found selectively within the CCS. Transgenic mice have been used to demonstrate its role in repressing working myocardial development and promoting a pacemaker programme of genes.8 These include key pacemaker genes, such as those encoding the low conductance gap junction connexin (Cx)45 and the hyperpolarisation-activated cyclic nucleotide-gated (HCN) membrane ion channel.8,9 The function of HCN channels within the SAN is discussed below. The SAN is derived from an area of the developing CCS called the sinus venosus. The sinus venosus expresses a homeobox regulatory gene named Shox2.10 Shox2 represses the activation of Nkx2–5, Nppa and Cx40 which are all genes involved with contractile working myocardium.10 Nkx2–5 normally represses Tbx3 in the working myocardium and so Shox2 is associated with Tbx3 promotion.10 Null mutation of Shox2 in mouse embryos is lethal due to atrial malformation and severe bradycardia.10 Tbx18 is another important T-box transcription factor which appears during embryogenesis in the sinus horns of the sinus venosus and

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disappears from this region prior to birth.11 It drives progenitor cells in the sinus venosus to morphologically develop into a SAN core upon which Tbx3 then exerts its pacemaker programme of membrane ion channels.12 Tbx18-deficient mice have demonstrated a failure of this core SAN tissue to develop.12

Figure 1: Embryogenesis of the Sinoatrial Node

Sinoatrial Node Structure

The SAN is a relatively small amount of tissue surrounded by a large amount of hyperpolarised atrial muscle. In order to deliver robust pacemaking it needs a way of effectively driving electrical activity into the right atrium and avoid being suppressed or becoming a source of re-entry. Transitional tissue within the SAN periphery forms a complex structure of block zones and exit pathways that allow co-ordinated delivery of stimulation to the right atrium. Recently optical mapping has demonstrated exit pathways at superior, middle and inferior levels from the SAN via which impulses are propagated into surrounding atrial muscle.17 This was correlated with histology showing insulating connective tissue and fat around the SAN except for where these exit pathways were exhibited functionally.17 Anatomically defined exit pathways are still controversial, however, since other work has failed to identify any histologically visible exit sites, suggesting a functional phenomenon.13,18 Tissue in the SAN periphery has several characteristics. Firstly, intermingling of nodal and atrial muscle cells has been seen with a gradual shift in the ratio of nodal to atrial cells (the mosaic effect).19 Interlocking ‘digits’ of SAN and working myocardial tissue have been seen.13 Additionally, the morphology of the cells themselves may gradually change between nodal and atrial cell types, with transitional cell types and intermediate features in between (the gradient effect).16,19 These features may help to gradually match SAN activity with the right atrium and promote an antegrade direction of conduction.20 The first site of activation, termed the ‘leading pacemaker’, can shift within the SAN (see Figure 3). Although this site is usually in its superior aspect, it can sometimes be more inferior or even multifocal in some cases.21,22 Spontaneous pacemaking inferiorly in the SAN has been seen to be slower, and one theory is that there is a hierarchy of cells from those that fire fastest superiorly, to slower firing cells inferiorly.23 Heart rate changes can therefore be mediated by a shift in the leading pacemaker rather than by a single pacemaker site that changes its rate. For example, sympathetic stimulation can shift the leading pacemaker site superiorly within the SAN thereby increasing heart rate.23 This mechanism may also contribute to bradycardia in SND through a caudal shift in the leading pacemaker.24

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The early heart tube is depicted (left) at day 10.5–12.5 of embryogenesis. The outer curvature of primary myocardium (black) differentiates and expands to form the heart chambers (blue). However, central primary myocardium remains and goes on to form the cardiac conduction system in the adult heart (right). The SAN forms from the sinus venosus (sv). Oft = outflow tract; pr = primary ring; lv = left ventricle; avc = atrioventricular canal; san = sinoatrial node; avn = atrioventricular node; avb = atrioventricular bundle; avj = atrioventricular junction; scv = superior caval vein; ra = right atrium; la = left atrium; rv = right ventricle; lbb = left bundle branch; rbb = right bundle branch; pvcs = peripheral ventricular conduction system. Adapted from Christoffels et al.7 Reproduced with permission from the American Heart Association, Inc.

Figure 2: 3D Computer Reconstruction of the Human Heart Sinoatrial Node from Histological and Immunohistochemical Data Demonstrating the Extent of the Sinoatrial Node and Peripheral Pacemaking Tissue

SVC Ao

RV Crista terminalis

The SAN in humans is a much more extensive and complex structure than originally described (e.g. as portrayed in Figure 1). It is located 0.1–1 mm subepicardially within the posterior wall of the right atrium, closely opposed to the crista terminalis (CT), extending from near to the insertion of the superior vena cava (SVC) towards the inferior vena cava (IVC) (see Figure 2).13 The histologically defined human SAN ranges from 8–21.5 mm in length.13 However, nodal tissue capable of supporting pacemaker activity can be detected inferiorly as far as the most inferior aspect of the CT and the Eustacian ridge.14,15 The main body is crescent-shaped with a thinner tail of tissue extending below it.13 Nodal cells are densely packed within fibrous connective tissue.13 The cells are pale, small and relatively ‘empty’ of microfilament cytoskeleton and sarcomeric components compared with those of the surrounding muscular tissue.16

IVC Red = sinoatrial node (SAN); yellow = peripheral pacemaking tissue; the leading pacemaker is shown as a white dot in the superior aspect of the SAN. Ao = aorta; SVC = superior vena cava; PA = pulmonary artery; PV = pulmonary vein; CS = coronary sinus; IVC = inferior vena cava; RA = right atrium; RV = right ventricle. Adapted from Chandler et al.84 Reproduced with permission from Wiley-Liss, Inc.

Sinoatrial Node Automaticity The SAN produces automatic electrical activity, which arises from several unique features. SAN cells have developed an interplaying combination of membrane ion channels, the ‘membrane clock’, and intracellular Ca2+ handling mechanisms, the ‘Ca2+ clock’, which lead to ‘diastolic depolarisation’ i.e. automatic depolarisation that occurs during the resting phase between beats (also termed ‘phase 4’ of an action potential). Phase 4 diastolic depolarisation serves to bring the membrane potential to the triggering threshold for the next beat and is key to SAN automaticity. Figure 4 shows phases 0 to 4 of the SAN

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Arrhythmia Mechanisms Figure 3: Leading Pacemaker Shift During Vagal Stimulation With 80 Pulses at 200 Hz in the Isolated Rabbit Right Atrium Vagal stimulation VS 0

VS 1

VS 2

VS 3

SEP

SVC

Cycle length (ms) IVC

437

1029

VS 4

VS 8

393

477 Trajectory

VS 9

Control, 9, 10 2 mm

392

581

557

The crista terminalis is shaded grey. The first seven panels show the activation sequences of the last spontaneous beat before vagal stimulation (VS0) and subsequent beats post vagal stimulation (VS1,2,3,4,8 and 9). Red circles indicate the leading pacemakers. The cycle length in milliseconds for each beat can be seen in blue. The lower right panel illustrates the beat-to-beat trajectory following vagal stimulation. RA = right atrium; SVC = superior vena cava; IVC = inferior vena cava. Adapted from Shibata et al.85 Reproduced with permission from The Physiological Society.

Figure 4: Typical Sinoatrial Node Membrane Action Potentials (Red Trace) and the Timing of Membrane Clock and Ca 2+ Clock Components Cycle length

Membrane potential

0 200 ms

3 20 mV

Membrane clock

Calcium clock

{ {

MDP

4 ICa T ICa L 2

ICa T

ICa L

INCX

LCRs

Wholecell AP-induced Ca2+ transient

action potential and summarises the timing of membrane and Ca2+ clock components as discussed below.

The Membrane Clock Three membrane ion currents are key to the membrane clock – presence of the so-called funny current (If), decay of the delayed rectifier K+ current (IK,r), and absence of the inward rectifier K+ current (IK,1). If is a mixed Na+ and K+ inward current that passes through membrane bound HCN channels. It activates early in phase 4 (diastole) when the cell is hyperpolarised and thus contributes to early diastolic depolarisation. Additional to this voltage-sensitive activity, HCN channels are also

Choudhury_FINAL.indd 30

In order for If to depolarise the cell, opposing repolarising K+ currents (which normally bring working cardiomyocytes back to a stable resting potential) need to be absent or reduced. IK,1 is responsible for maintaining a stable resting membrane potential in working myocardium but it is absent in the SAN. Without IK,1, the SAN membrane potential is labile, which is key to aiding early diastolic depolarisation.29,30 Lastly, IK,r is responsible for repolarising working myocardial cells after the initial upstroke. This current is present in SAN cells and its decay aids early diastolic depolarisation.29,31,32

SERCA Ca2+ pumping

The phases of the action potentials are labelled including phase 4, the resting phase in which diastolic depolarisation (DD) takes place, the key to automatic pacemaker activity. MDP = maximum diastolic potential; DD = diastolic depolarisation; ICa2T = T-type voltagedependent Ca2+ current; ICa2L = L-type voltage-dependent Ca2+ current; INCX = sodium-calcium exchange current; IK2 = delayed rectifier potassium current; If = funny current; SERCA = sarco-endoplasmic reticulum ATPase; LCRs = local Ca2+ releases. From Monfredi et al.37 Reproduced with permission from The American Physiological Society.

regulated by 3’-5’-cyclic adenosine monophosphate (cAMP) signalling and so are an important pathway for the regulation of heart rate by the autonomic nervous system.25,26 Hcn4 has been knocked out in transgenic mice by two groups with varied results. One group demonstrated ~50 % reduction in heart rate,27 while the other showed recurrent sinus pauses rather than profound bradycardia.28 Knocking out If does not abolish pacemaking completely, suggesting that although it is important for pacemaking, there are other mechanisms at play.

The Ca 2+ Clock Intracellular Ca2+ cycling is important in the excitation–contraction coupling of muscle cells, but in the SAN, Ca2+ contributes to pacemaking via the Ca2+ clock that is mutually entrained with the membrane clock, making an important contribution to automaticity. Within SAN cells, the sarcoplasmic reticulum (SR) is central to the Ca2+ clock. Ryanodine receptors (RYRs) on the SR membrane release Ca2+ into the cell cytosol in the form of spontaneous ‘sparks’ or local Ca2+ releases (LCRs).33,34 These LCRs are seen to increase in frequency in response to Ca2+ influx through the cell membrane, termed Ca2+induced Ca2+ release (CICR).33 Ca2+ influx occurs initially via T-type voltage-gated Ca2+ channels, which open as a result of the rising membrane potential initiated by the membrane clock.35 Thus LCRs lead to small increments in cytosolic Ca2+ concentration during phase 4. In response to rising intracellular Ca2+ levels, the Na+–Ca2+ exchanger (NCX) on the cell membrane exchanges one Ca2+ ion out for three Na+ ions into the cell leading to a net positive charge influx.36 In this way, the Ca2+ clock as a whole contributes to late diastolic depolarisation.

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Finally, once diastolic depolarisation causes the cell membrane to reach threshold potential, phase 0 is triggered and L-type voltage-gated Ca2+ channels open allowing large scale depolarisation of the cell via Ca2+ influx.34 RYRs on the SR membrane respond again with CICR, emptying the SR en masse, leading to a whole-cell Ca2+ transient sweeping across the cell and myofilament contraction.34,37 Ca2+ stores in the SR are subsequently replenished by sarcoplasmic-endoplasmic reticulum calcium adenosine triphosphatase (SERCA) on the SR membrane.38 cAMP-driven pathways also play a major role in regulation of intracellular Ca2+ cycling, and so this is another way the autonomic nervous system can control heart rate.39 This among the other common links described between the membrane clock and the Ca2+ clock allow them to couple together to produce robust, automatic and cyclical diastolic depolarisation key to SAN automaticity.37

Diseases of the Sinoatrial Node SND is normally diagnosed using the electrocardiographic features of bradycardia (<60 beats per minute) or asystolic pauses (>3 seconds) which may be due to reduced intrinsic SAN automaticity, sinus arrest or SAN exit block. Electrophysiology studies are not routinely performed in SND but may be done in equivocal cases. Two parameters, the corrected sinus node recovery time (cSNRT) and sinoatrial conduction time (SACT) in response to atrial pacing, can aid the investigation of SND. The sensitivity of both tests combined is 64 %, and the specificity if they are found to be significantly prolonged is 88 %.40 cSNRT is defined as the interval between the last paced beat and the next spontaneous beat, minus the spontaneous cycle length.41 A longer cSNRT indicates an increased tendency for suppression by ectopic activity from outside the SAN. Regardless of the underlying pathology, SND is characterised by increased cSNRT, conduction delay along the CT, a more unicentric and caudal shift to leading pacemaker activity within the SAN and areas of low voltage within the right atrium attributed to atrophy and scar formation.42 In order to account for these changes in function, multiple processes and widespread remodelling are likely to be taking place, evidence for which is discussed below and summarised in Table 1 and Figure 5.

Idiopathic Sinoatrial Node Disfunction Idiopathic SND predominantly occurs in the elderly population.43 SAN fibrosis is often quoted as the major cause. Histological studies in the 1970s of patients diagnosed with SND revealed that most cases were associated with either fibrosis or SAN atrophy.4,5 However, the same studies showed SND could also be associated with normal histology and, in some cases, severe fibrosis was associated with normal sinus rhythm.4,5 Furthermore, normal ageing of the SAN has been shown to be associated with SAN atrophy and fatty infiltration.44 It is therefore possible that at least some of the histological changes seen in SND cases were as a result of the ageing process itself. Clear causation of SND by fibrosis has not been established. There is widespread electrical remodelling of the atria with ageing, and this has also been demonstrated in the SAN. This electrical remodelling is the result of changes in the expression of key ion channels that cause dysfunction of the normal pacemaker activity in the SAN. The Na+ channel Nav1.5 is normally present at the periphery of the SAN and is important for electrical coupling to right atrial myocardium.45 In ageing rats, Nav1.5 has been shown to decrease around the SAN

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Table 1: Summary of the Genes and Electrical Remodelling Involved in Some Causes of Sinus Node Dysfunction Causes of SND Idiopathic/ageing

Ion channels and genes involved ↓Nav1.5,46 ↓Cx43,47 ↓Cav1.2,49 ↓RYR2,50 ↓HCN1,50,51

↓HCN451

Atrial tachyarrhythmia ↓HCN2,57 ↓HCN457 Inherited

HCN4,58–62 SCN5A (Nav1.5),63 RYR2,66 CASQ2,65,66

ANKB67

Exercise training

↓HCN4,70 ↓Tbx370

Heart failure

↓HCN487

The inherited genes are mutations seen in human families with sinus node dysfunction (SND), whereas in other types of SND electrical remodelling was seen in animal models. Downward arrows mean downregulation.

Figure 5: Summary of the Different Aetiologies Surrounding Sinus Node Dysfunction, Illustrating That Diverse Pathophysiology Can Lead to the Same Phenotype Idiopathic/ageing

Ischaemia

Inherited

Heart failure

Sinus node dysfunction and sick sinus syndrome

Atrial tachyarrhythmia

Exercise training Diabetes

Examples of the types of ion channel remodelling seen in each case are shown. Further to our discussion, sinus node dysfunction is also seen in heart failure and diabetes. Atrial tachyarrhythmias include atrial fibrillation and atrial flutter. Adapted from Monfredi et al.86 Reproduced with permission from Wiley Periodicals, Inc.

periphery which could potentially lead to SAN exit block.46 Furthermore, the gap junction channel Cx43 is responsible for electrical coupling between working myocardial cells and is normally absent from the centre of the SAN. Ageing has been shown to reduce levels of Cx43 in the SAN periphery in association with conduction slowing.47 The L-type Ca2+ channel Cav1.2 is involved in the phase 0 upstroke of the SAN action potential.48 A comparison of young and old guineapigs demonstrated a decline in levels of this channel with ageing, progressing from the SAN centre outwards, and this was associated with increased sensitivity to the Ca2+ blocker nifedipine as well as reduced spontaneous SAN activity.49 Another study looking at young and old rats found decreased levels of RYR2 and the pacemaker channel HCN1, in association with a decreased intrinsic heart rate, increased action potential duration and cSNRT.50 Lastly, comparison of the functional and molecular features of young and old mice revealed bradycardia, increased SACT and reduced expression of a wide number of ion channels including HCN1, HCN4 and Nav1.5, along with several K+ and Ca2+ channels.51 Ageing is therefore associated with both structural and molecular remodelling and the cause of SND in this population is likely to be complex and heterogeneous.

Sinoatrial Node Dysfunction and Atrial Tachyarrhythmias SND is often associated with intermittent episodes of atrial tachyarrhythmias such as atrial fibrillation (AF) leading to the term

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Arrhythmia Mechanisms ‘tachy-brady syndrome’. Diffuse atrial remodelling can be seen in some patients with SND including atrial enlargement, increased refractoriness and prolonged conduction times which may predispose to the development of re-entrant circuits and AF.42 This suggests SND may be a prodrome of AF. There is evidence that chronic AF causes SND by electrically remodelling the SAN. Patients undergoing electrical cardioversion for chronic AF demonstrate SND once reverted to sinus rhythm with bradycardia and increased cSNRT.52 In a canine model of atrial tachyarrhythmia using 20 Hz atrial pacing there is an increase in SNRT and a reduction of both maximal and intrinsic heart rate.53 The leading SAN pacemaker has been shown to shift caudally in patients with concomitant AF and SND, who also demonstrated a reduced sensitivity to sympathetic stimulation using isoprotenerol.54 The recurrence of AF after radiofrequency ablation has been predicted by the degree of post-shock SNRT, which has been suggested as an indicator for the level of atrial remodelling.55 SAN function after cardioversion remodels to normal levels over time suggesting that SAN electrical remodelling in AF may be reversible in some cases.56 The molecular correlate of these changes is a reduction in mRNA expression of both HCN2 and HCN4 isoforms in the SAN. This was demonstrated in a canine tachycardia pacing model, with downregulation of these key pacemaker channels by >50 % in the SAN and correspondingly reduced If density by 48 % during patch clamp of isolated SAN cardiomyocytes.57

Familial Sinoatrial Node Dysfunction Rare cases of inherited SND have allowed the analysis of specific gene mutations and subsequent channelopathies revealing their role in normal SAN pacemaking. DNA sequencing focusing on several candidate pacemaker genes has been used to screen patients with bradycardic phenotypes. These gene mutations give insight into their importance in SAN function for humans. Several point mutations or deletions within the HCN4 gene have been found to be associated with bradycardia or paroxysmal AF.58–62 One study screened a patient with idiopathic SND, detecting a heterozygous single base deletion leading to a truncated C-terminus.58 When this mutant HCN4 gene was expressed in vitro in single cells, patch clamp experiments demonstrated If insensitive to increased cAMP levels.58 Three other studies focused on related patients each detecting three different mutations, all of which expressed mutant HCN4 channels in vitro that only activated at more negative voltages.59–61 Another study focused on patients with the same Moroccan-Jewish ethnic background, which revealed a novel point mutation that also led to HCN4 channels activating at more negative voltages.62 The studies looking at family or ethnic ties all suggested an autosomal-dominant inheritance pattern. Each of these mutations affected different aspects of the HCN channel and this demonstrates that these parts of the HCN channel are all required to function correctly for maintenance of a normal heart rate. Mutations of the SCN5A gene lead to dysfunction of the Na+ channel Nav1.5, which is well known to be associated with a wide variety of cardiac diseases including long QT syndrome, Brugada syndrome, dilated cardiomyopathy, AF and SND.63 Since Nav1.5 is not specific to one area of the heart, some SCN5A mutations can cause a phenotype overlapping multiple syndromes in one patient.63 Although Nav1.5 is not present in the centre of the SAN, it is present in the periphery where it helps drive the action potential into the surrounding atrium,

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and so dysfunction of this channel may lead to delayed conduction, SAN exit block or sinus arrest.63,64 Multiple combinations of SCN5A mutations have been linked to SND with a suggested autosomalrecessive pattern of inheritance.63 Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited condition, which leads to life-threatening stress-induced episodes of ventricular tachycardia causing syncope and sudden death in young patients without structural heart disease. There are at least two gene mutations thought to cause CPVT including genes for RYR2 and calsequestrin 2 (CASQ2) which are both involved with Ca2+ cycling in the cardiac SR. Patients with either of these mutations demonstrate normal electrocardiograms except for a significantly lower resting heart rate.65,66 As mentioned above SAN pacemaking is known to depend on SR Ca2+ release and so bradycardia in CPVT is thought to be due to SR dysfunction within the SAN.65 Families demonstrating inherited RYR2 mutations show an autosomal-dominant mode of inheritance, whereas most cases of CASQ2 mutations show an autosomal-recessive pattern.65 Ankyrin-B (ANKB) mutations are associated with CPVT, long QT-syndrome and SND. One study reports on two families demonstrating long QT intervals, histories of sudden death, AF and pacemaker implantation due to severe bradycardia.67 Subsequent work in mice with heterozygous ANKB mutations demonstrated severe SND associated with either abnormal localisation or reduced expression of NCX1, Na+/K+-ATPase, inositol triphosphate receptor 3 (IP3) and Cav1.3.67

Athletes and Sinoatrial Node Dysfunction Endurance athletes undergo a significant amount of exercise training and often exhibit profound sinus bradycardia as a result, with some even requiring pacemaker implantation later in life.68 This bradycardia is normally put down to high vagal tone i.e. is thought to be neurally mediated. However ‘intrinsic heart rate’, revealed by full autonomic pharmacological blockade, has also been shown to be lower in exercise trained individuals.69 A recent study demonstrated training-induced intrinsic bradycardia in rats and mice and showed a downregulation of Hcn4 and Tbx3 in these animals compared with controls.70 This demonstrates electrical remodelling as the mechanism for bradycardia in athletes and raises the question whether this could be a prodrome of SND. It is possible that these molecular changes are present in ex-athletes who require pacemaker implantation for SND later in life.

Ischaemia and Sinoatrial Node Dysfunction Acute myocardial ischaemia involving the cardiac conduction pathways can commonly be seen to manifest in bradycardia due to abnormal autonomic tone, decreased perfusion or injury to SAN tissue.71,72 Ischaemia is often quoted as a cause of SND and disease of the main coronary vessels or sinus node artery has been implicated. Whether chronic ischaemia is a cause of SND is not clear. The incidence of both coronary artery disease and SND increase with age so patients may well have the two concomitantly. However, studies looking at the correlation in more detail show mixed results. Post-mortem angiography has been used to compare sinus node artery patency in patients with SND and those without. It showed no significant obstructions in any patient, but reduced filling in about

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20 % of patients with SND.73 One study comparing 46 patients with a history of inferior myocardial infarction showed that patients with severe sinus node artery stenosis (>75 %) demonstrated significantly lower intrinsic heart rates, longer cSNRTs and prolonged SACTs compared with moderate to no stenosis (<75 %).74 Another study demonstrated a lack of sinus node artery disease in patients with clinical SND yet severe sinus node artery disease in patients with normal SAN function.75 Furthermore, a post mortem study found no evidence of sinus node artery disease in any of its eight study patients with previously diagnosed SND.5 It is important to note therefore that a causal association between chronic ischaemia and SND has not yet firmly been established.

Future Prospects in Sinoatrial Node Research Controversies remain in SAN research. Although we understand how membrane and Ca2+ clock pacemaker mechanisms are mutually entrained to produce diastolic depolarisation, there is still debate over the relative importance of each for maintaining pacemaker activity.76 Blockade or knockout of If does not abolish pacemaking whereas blockade of Ca2+ cycling does.28,36,77 On the other hand Ca2+ cycling mechanisms are not specific to pacemaker tissue whereas HCN channels can be used as a marker for the SAN.78 Further work is needed to clarify this contentious issue. We have discussed the genes involved in SAN development including Shox2, Tbx18 and Tbx3, but there is still conflicting opinion about which genes have overarching control of this process. Tbx3 is thought to lead to expression of HCN channels in the CCS, but overexpressing Tbx3 in transgenic mice has a differential effect on inducing pacemaking depending on whether it is done in the embryo or adult, suggesting there are other mechanisms at play.79 Tbx18 is thought to primarily develop the morphology of the SAN head, but other groups have associated Tbx18 with HCN channel upregulation.7,80

5. 6.

10.

11.

12.

13.

Cunningham D, Charles R, Cunningham M, et al. Cardiac rhythm management UK national clinical audit report. National Institute for Cardiovascular Outcomes Research. 2011. National Institute for Health and Clinical Excellence. Dualchamber pacemakers for symptomatic bradycardia due to sick sinus syndrome and/or atrioventricular block. Technology Appraisal 88. London: NICE, 2005. Sodeck GH, Domanovits H, MeronG, et al. Compromising bradycardia: management in the emergency department. Resuscitation 2007;73:96–102. Thery C, Gosselin B, Lekieffre J, et al. Pathology of sinoatrial node. Correlations with electrocardiographic findings in 111 patients. Am Heart J 1977;93:735–40. Evans R, Shaw D. Pathological studies in sinoatrial disorder (sick sinus syndrome). Br Heart J 1977;39:778–86. Morris GM, Kalman JM. Fibrosis, electrics and genetics. Perspectives in sinoatrial node disease. Circ J 2014;78:1272–82. Christoffels VM, Smits GJ, Kispert A, et al. Development of the pacemaker tissues of the heart. Circ Res 2010;106:240–54. Hoogaars WM, Engel A, Brons JF, et al. Tbx3 controls the sinoatrial node gene program and imposes pacemaker function on the atria. Genes Dev 2007;21:1098–112. Hoogaars WMH, Tessari A, Moorman AFM, et al. The transcriptional repressor Tbx3 delineates the developing central conduction system of the heart. Cardiovasc Res 2004;62:489–99. Espinoza-Lewis RA, Yu L, He F, et al. Shox2 is essential for the differentiation of cardiac pacemaker cells by repressing Nkx2-5. Dev Biol 2009;327:376–85. Kapoor N, Liang W, Marbán E, et al. Direct conversion of quiescent cardiomyocytes to pacemaker cells by expression of Tbx18. Nat Biotechnol 2013;31:54–62. Wiese C, Grieskamp T, Airik R, et al. Formation of the sinus node head and differentiation of sinus node myocardium are independently regulated by Tbx18 and Tbx3. Circ Res 2009;104:388–97. Sanchez-Quintana D, Cabrera JA, Farre J, et al. Sinus node revisited in the era of electroanatomical mapping and catheter ablation. Heart 2005;91:189–94.

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These discrepancies suggest that our knowledge of the genetic control of pacemaking is not yet complete. In the last 15 years or so the field of ‘biopacemaking’ has been progressing, striving to develop techniques that replicate pacemaking tissue ectopically via the manipulation of the molecular mechanisms discussed above. Initially individual genes important for pacemaking were introduced to non-pacemaking tissue, e.g. IK,1 knockout or HCN channel upregulation using adenoviral vectors.14, 81,82 However, pacing was often either too slow or unreliable for direct translation into humans. In an attempt to reproduce the complexity of the SAN, groups are now either modulating multiple features simultaneously or using transcription factors.83 Tbx18 and Tbx3 are prime candidates currently being studied in animals.8,11 Overexpression of Tbx18 has had particular success, reprogramming ventricular cells into SAN-like cells leading to robust and autonomically sensitive ectopic pacing in large animals.11,80 However, other than identifying the most effective gene, there are many challenges remaining before human trials can be successful. Questions remain about strategies for safe and stable gene expression, optimal location of delivery and how effective these strategies will be for each of the varying SND aetiologies.

Conclusion Fibrosis, cell loss and coronary artery disease are often quoted as the main causes of SND. However it is clear that SND is not just one entity, and is rather the phenotype of many different disease processes. After over 100 years of studying the SAN and its disease we are still uncovering new insights into pacemaker function. Ion channel remodelling is now thought to be a major contributor to SND and the pattern of remodelling in different diseases can be wide and complex. A more complete understanding of the pathophysiology of SND will help us find ways to manipulate novel mechanisms in the search for alternative therapeutic options to the electronic pacemaker. n

14. Morris GM, D’Souza A, Dobrzynski H, et al. Characterization of a right atrial subsidiary pacemaker and acceleration of the pacing rate by HCN over-expression. Cardiovasc Res 2013;100:160–9. 15. Rubenstein DS, Fox LM, McNulty JA, et al. Electrophysiology and ultrastructure of eustachian ridge from cat right atrium: a comparison with SA node. J Mol Cell Cardiol 1987;19:965–76. 16. James TN, Sherf L, Fine G, et al. Comparative ultrastructure of the sinus node in man and dog. Circulation 1966;34:139–63. 17. Fedorov VV, Glukhov AV, Chang R, et al. Optical mapping of the isolated coronary-perfused human sinus node. J Am Coll Cardiol 2010;56:1386–94. 18. Matsuyama TA, Inoue S, Kobayashi Y, et al. Anatomical diversity and age-related histological changes in the human right atrial posterolateral wall. Europace 2004;6:307–15. 19. Dobrzynski H, Li J, Tellez J, et al. Computer threedimensional reconstruction of the sinoatrial node. Circulation 2005;111:846–54. 20. Boyett MR, Honjo H, Kodama I. The sinoatrial node, a heterogeneous pacemaker structure. Cardiovasc Res 2000;47:658–87. 21. Bleeker WK, Mackaay AJ, Masson-Pevet M, et al. Functional and morphological organization of the rabbit sinus node. Circ Res 1980;46:11–22. 22. Ramanathan C, Jia P, Ghanem R, et al. Activation and repolarization of the normal human heart under complete physiological conditions. Proc Natl Acad Sci USA 2006;103:6309–14. 23. Schuessler RB, Boineau JP, Bromberg BI. Origin of the sinus impulse. J Cardiovasc Electrophysiol 1996;7:263–74. 24. Gomes JA, Winters SL. The origins of the sinus node pacemaker complex in man: demonstration of dominant and subsidiary foci. J Am Coll Cardiol 1987;9:45–52. 25. Robinson RB, Siegelbaum SA. Hyperpolarization-activated cation currents: from molecules to physiological function. Annu Rev Physiol 2003;65:453–80. 26. DiFrancesco D. The role of the funny current in pacemaker activity. Circ Res 2009;106:434–46. 27. Baruscotti M, Bucchi A, Viscomi C, et al. Deep bradycardia and heart block caused by inducible cardiac-specific knockout of the pacemaker channel gene Hcn4.

Proc Natl Acad Sci USA 2011;108:1705–10. 28. Herrmann S, Stieber J, Stöckl G, et al. HCN4 provides a ‘depolarization reserve’ and is not required for heart rate acceleration in mice. EMBO J 2007;26:4423–32. 29. Harmar AJ, Hills RA, Rosser EM, et al. IUPHAR-DB: the IUPHAR database of G protein-coupled receptors and ion channels. Nucleic Acids Res 2009;37:D680–5. 30. Chandler NJ, Greener ID, Tellez JO, et al. Molecular architecture of the human sinus node: insights into the function of the cardiac pacemaker. Circulation 2009;119:1562–75. 31. Irisawa H, Brown HF, Giles W. Cardiac pacemaking in the sino-atrial node. Physiol Rev 1993;73:197–227. 32. Lei M Honjo H, Kodama I, Boyett MR. Heterogeneous expression of the delayed-rectifier K+ currents I K,r and I K,s in rabbit sinoatrial node cells. J Physiol 2001;535:703–14. 33. Chen B, Wu Y, Mohler PJ, et al. Local control of Ca2+-induced Ca2+ release in mouse sinoatrial node cells. J Mol Cell Cardiol 2009;47:706–15. 34. Cheng H, Lederer MR, Xiao RP, et al. Excitation-contraction coupling in heart: new insights from Ca2+ sparks. Cell Calcium 1996;20:129–140. 35. Mangoni ME, Traboulsie A, Leoni AL, et al. Bradycardia and slowing of the atrioventricular conduction in mice lacking Cav3.1/α1G T-type calcium channels. Circ Res 2006;98:1422–30. 36. Bogdanov KY, Vinogradova TM, Lakatta EG. Sinoatrial nodal cell ryanodine receptor and Na+-Ca2+ exchanger: molecular partners in pacemaker regulation. Circ Res 2001;88:1254–8. 37. Monfredi O, Maltsev VA, Lakatta EG. Modern concepts concerning the origin of the heartbeat. Physiology 2013;28:74–92. 38. Zipes DP, Jalife J. Cardiac Electrophysiology: From Cell to Bedside. Fifth edition. Philadelphie, US: Saunders, 2009. 39. Vinogradova TM, Brochet DX, Sirenko S, et al. Sarcoplasmic reticulum Ca2+ pumping kinetics regulates timing of local Ca2+ releases and spontaneous beating rate of rabbit sinoatrial node pacemaker cells. Circ Res 2010;107:767–75. 40. Guidelines for clinical intracardiac electrophysiologic studies. A report of the American College of Cardiology/American Heart Association Task Force on Assessment of Diagnostic and Therapeutic Cardiovascular Procedures (Subcommittee

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Arrhythmia Mechanisms to Assess Clinical Intracardiac Electrophysiologic Studies). J Am Coll Cardiol 1989;14:1827–42. 41. Alboni P, Malcarne C, Pedroni P, et al. Electrophysiology of normal sinus node with and without autonomic blockade. Circulation 1982;65:1236–42. 42. Sanders P, Morton JB, Kistler PM, et al. Electrophysiological and electroanatomic characterization of the atria in sinus node disease: evidence of diffuse atrial remodeling. Circulation 2004;109:1514–22. 43. Lamas GA, Lee K, Sweeney M, et al. The mode selection trial (MOST) in sinus node dysfunction: Design, rationale, and baseline characteristics of the first 1000 patients. Am Heart J 2000;140:541–51. 44. I Shiraishi, T Takamatsu, T Minamikawa, et al. Quantitative histological analysis of the human sinoatrial node during growth and aging. Circulation 1992;85:2176–84. 45. Lei M, Zhang H, Grace AA, et al. SCN5A and sinoatrial node pacemaker function. Cardiovasc Res 2007;74:356–65. 46. Yanni J, Tellez JO, Sutyagin PV, et al. Structural remodelling of the sinoatrial node in obese old rats. J Mol Cell Cardiol 2010;48:653–62. 47. Jones SA, Lancaster MK, Boyett MR. Ageing-related changes of connexins and conduction within the sinoatrial node. J Physiol 2004;560:429–37. 48. Tellez JO, Dobrzynski H, Greener ID, et al. Differential expression of ion channel transcripts in atrial muscle and sinoatrial node in rabbit. Circ Res 2006;99:1384–93. 49. Jones SA, Boyett MR, Lancaster MK. Declining into failure: the age-dependent loss of the L-type calcium channel within the sinoatrial node. Circulation 2007;115:1183–90. 50. Tellez JO, Mczewski M, Yanni J, et al. Ageing-dependent remodelling of ion channel and Ca2+ clock genes underlying sino-atrial node pacemaking. Exp Physiol 2011;96:1163–78. 51. Hao X, Zhang Y, Zhang X, et al. TGF-β1-mediated fibrosis and ion channel remodeling are key mechanisms in producing the sinus node dysfunction associated with SCN5A deficiency and aging. Circ Arrhythm Electrophysiol 2011;4:397–406. 52. Manios EG, Kanoupakis EM, Mavrakis HE, et al. Sinus pacemaker function after cardioversion of chronic atrial fibrillation: is sinus node remodeling related with recurrence? J Cardiovasc Electrophysiol 2001;12:800–6. 53. Elvan A, Wylie K, Zipes DP. Pacing-induced chronic atrial fibrillation impairs sinus node function in dogs: Electrophysiological remodeling. Circulation 1996;94:2953–60. 54. Joung B, Hwang HJ, Pak HN, et al. Abnormal response of superior sinoatrial node to sympathetic stimulation is a characteristic finding in patients with atrial fibrillation and symptomatic bradycardia/clinical perspective. Circ Arrhythm Electrophysiol 2011;4:799–807. 55. Park J, Shim J, Uhm JS, et al. Post-shock sinus node recovery time is an independent predictor of recurrence after

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catheter ablation of longstanding persistent atrial fibrillation. Int J Cardiol 2013;168:1937–42. 56. Sparks PB, Jayaprakash S, Vohra JK, et al. Electrical remodeling of the atria associated with paroxysmal and chronic atrial flutter. Circulation 2000;102:1807–13. 57. Yeh YH, Burstein B, Qi XY, et al. Funny current downregulation and sinus node dysfunction associated with atrial tachyarrhythmia: a molecular basis for tachycardiabradycardia syndrome. Circulation 2009;119:1576–85. 58. Schulze-Bahr E, Neu A, Friederich P, et al. Pacemaker channel dysfunction in a patient with sinus node disease. J Clin Invest. 2003;111:1537–45. 59. Milanesi R, Baruscotti M, Gnecchi-Ruscone T, et al. Familial sinus bradycardia associated with a mutation in the cardiac pacemaker channel. N Engl J Med 2006;354:151–7. 60. Nof E, Luria D, Brass D, et al. Point mutation in the HCN4 cardiac ion channel pore affecting synthesis, trafficking, and functional expression is associated with familial asymptomatic sinus bradycardia. Circulation 2007;116:463–70. 61. Duhme N, Schweizer PA, Thomas D, et al. Altered HCN4 channel C-linker interaction is associated with familial tachycardia-bradycardia syndrome and atrial fibrillation. Eur Heart J 2013;34:2768–75. 62. Laish-Farkash A, Glikson M, Brass D, et al. A novel mutation in the HCN4 gene causes symptomatic sinus bradycardia in Moroccan Jews. J Cardiovasc Electrophysiol 2010;21:1365–72. 63. Ruan Y, Liu N, Priori SG. Sodium channel mutations and arrhythmias. Nat Rev Cardiol 2009;6:337–48. 64. Butters TD, Aslanidi OV, Inada S, et al. Mechanistic links between Na+ channel (SCN5A) mutations and impaired cardiac pacemaking in sick sinus syndrome. Circ Res 2010;107:126–37. 65. Postma AV, Denjoy I, Hoorntje TM, et al. Absence of calsequestrin 2 causes severe forms of catecholaminergic polymorphic ventricular tachycardia. Circ Res 2002;91:e21–26. 66. Postma AV, Denjoy I, Kamblock J, et al. Catecholaminergic polymorphic ventricular tachycardia: RYR2 mutations, bradycardia, and follow up of the patients. J Med Genet 2005;42:863–70. 67. Le Scouarnec S, Bhasin N, Vieyres C, et al. Dysfunction in ankyrin-B-dependent ion channel and transporter targeting causes human sinus node disease. Proc Natl Acad Sci USA 2008;105:15617–22. 68. Baldesberger S, Bauersfeld U, Candinas R, et al. Sinus node disease and arrhythmias in the long-term follow-up of former professional cyclists. Eur Heart J 2008;29:71–8. 69. Boyett MR, D’Souza A, Zhang H, et al. Viewpoint: is the resting bradycardia in athletes the result of remodeling of the sinoatrial node rather than high vagal tone? J Appl Physiol 1985;114:1351–5. 70. D’Souza A, Bucchi A, Johnsen AB, et al. Exercise training reduces resting heart rate via downregulation of the funny channel HCN4. Nat Commun 2014;13:3775.

71. Rokseth R, Hatle L. Sinus arrest in acute myocardial infarction. Br Heart J 1971;33:639–42. 72. Ando’ G, Gaspardone A, Proietti I. Acute thrombosis of the sinus node artery: arrhythmological implications. Heart Rhythm 2003;89:E5. 73. Shaw DB, Linker NJ, Heaver PA, et al. Chronic sinoatrial disorder (sick sinus syndrome): a possible result of cardiac ischaemia. Br Heart J 1987;58:598–607. 74. Alboni P, Baggioni GF, Scarfò S, et al. Role of sinus node artery disease in sick sinus syndrome in inferior wall acute myocardial infarction. Am J Cardiol 1991;67:1180–4. 75. Engel TR, Meister SG, Feitosa GS, et al. Appraisal of sinus node artery disease. Circulation 1975;52:286–91. 76. Lakatta EG, DiFrancesco D. What keeps us ticking: a funny current, a calcium clock, or both? J Mol Cell Cardiol 2009;47:157–70. 77. Denyer JC, Brown HF. Pacemaking in rabbit isolated sinoatrial node cells during Cs+ block of the hyperpolarizationactivated current I f. J Physiol 1990;429:401–9. 78. Liu J, Dobrzynski H, Yanni J, et al. Organisation of the mouse sinoatrial node: structure and expression of HCN channels. Cardiovasc Res 2007;73:729–38. 79. Bakker ML, Boink GJ, Boukens BJ, et al. T-box transcription factor TBX3 reprogrammes mature cardiac myocytes into pacemaker-like cells. Cardiovasc Res 2012;94:439–49. 80. Hu YF, Dawkins JF, Cho HC, et al. Biological pacemaker created by minimally invasive somatic reprogramming in pigs with complete heart block. Sci Transl Med 2014;6:245ra294. 81. Miake J, Marban E, Nuss HB. Biological pacemaker created by gene transfer. Nature 2002;419:132–3. 82. Plotnikov AN, Sosunov EA, Qu J, et al. Biological pacemaker implanted in canine left bundle branch provides ventricular escape rhythms that have physiologically acceptable rates. Circulation 2004;109:506–12. 83. Boink GJJ, Duan L, Nearing BD, et al. HCN2/SkM1 gene transfer into canine left bundle branch induces stable, autonomically responsive biological pacing at physiological heart rates. J Am Coll Cardiol 2013;61:1192–201. 84. Chandler N, Aslanidi O, Buckley D, et al. Computer threedimensional anatomical reconstruction of the human sinus node and a novel paranodal area. Anat Rec (Hoboken) 2011;294:970–9. 85. Shibata N, Inada S, Mitsui K, et al. Pacemaker shift in the rabbit sinoatrial node in response to vagal nerve stimulation. Exp Physiol 2001;86:177–84. 86. Monfredi O, Dobrzynski H, Mondal T, et al. The anatomy and physiology of the sinoatrial node--a contemporary review. Pacing Clin Electrophysiol 2010;33:1392–406. 87. Zicha S, Fernandez-Velasco M, Lonardo G, et al. Sinus node dysfunction and hyperpolarization-activated (HCN) channel subunit remodeling in a canine heart failure model. Cardiovasc Res 2005;66:472–81.

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Arrhythmia Mechanisms

What is a Ca2+ wave? Is it like an Electrical Wave? P enelope A B o y d e n , 1 We n D u n 1 a n d B r u n o D S t u y v e r s 2 1. Department of Pharmacology, Columbia University, New York; 2. Faculty of Medicine, Division of Biomedical Sciences, Memorial University of Newfoundland, St. John’s, NL, Canada

Abstract Arrhythmia subcellular mechanisms are constantly being explored. Recent knowledge has shown that travelling Ca2+ waves in cardiac cells are critical for delayed afterdepolarisations and in some cases, early afterdepolarisations. In this review, we comment on the properties of cardiac Ca2+ waves and abnormal Ca2+ releases in terms of properties used to describe electrical waves; propagation, excitability and refractoriness.

Keywords Delayed afterdepolarisation, early afterdepolarisation, Ca2+ waves, arrhythmias Disclosure: The authors have no conflicts of interest to declare. Received: 12 January 2015 Accepted: 25 February 2015 Citation: Arrhythmia & Electrophysiology Review 2015;4(1):35–9 Access at: www.AERjournal.com Correspondence: Dr Penelope Boyden, Columbia University, 630 W 168th St NY NY 10032 US. E: Pab4@cumc.columbia.edu

Abnormalities in electrical rhythm were studied by Einthoven at the start of the 20th century. In the 1940s, studies by Bozler et al.1 described contractile signals that appeared to be ‘triggered’ heart beats. Today we use the term delayed afterdepolarisations (DADs) to refer to oscillations in voltage that follow a driven action potential.

absence of Ca2+ influx through the plasma membrane or mischievous Ca2+ wandering the cytosol, the Ca2+ in SR stays in the SR. This is because the SR ligand-operated Ca2+ channel, the ryanodine receptor channel (RyR), which guards this SR Ca2+ store, has a low probability of opening.

In the mid-1970s, progress was made when Lederer and Tsien developed a method to study the underlying electrical mechanism of DADs2 (see Figure 1). In a voltage clamped, multicellular canine Purkinje fibre, the transient depolarisation of the resting potential of the fibre was found to be due to a transient inward current (Iti) (see Figure 1A). Many initially challenged this idea but these authors went on to show that Iti was not an artifact and that the Iti they recorded in Purkinje fibres was Ca2+ dependent (see Figure 1B).2,3 This was a relatively new concept for cardiac electrophysiology; that is, the idea that Ca2+ inside the cell could feed back and affect the electrics of the cell’s membrane. In a recent review this was referred to as reverse mode excitation–contraction (EC) coupling.4

Interestingly, just as surface membrane ion channels (eg. Na channels) are positioned in a specific array6 to provide for smooth electrical wave propagation, RyR channel proteins in myocytes, Purkinje and atrial cells are clustered and aligned in a specific micro-anatomic pattern (see Figure 2).7,8,19 Presumably, and particularly in the tubulated structures of ventricular myocytes, this specific patterning is to allow for uniform Ca2+ release from SR during the action potential (forward mode EC coupling). The orderly pattern of RyRs on the SR sets up a series of potential release sites of Ca2+ in the cell.

Here we will discuss the Ca2+ wave and address the question: ‘Is it like the electrical wave with which we are all familiar?’

Functional Anatomy A propagating electrical wave utilises the energy of the chemical gradients set up by the cardiac sarcolemma.5 Electrical waves rely on activation of a series of ion channels (eg. Na channel proteins) for forward propagation of the wave. Propagation of a Ca2+ wave also depends on the energy stored in the myocyte. But in this case the energy comes from the presence of Ca2+ stored in the sarcoplasmic reticulum (SR). The SR is a specialised intracellular membrane structure that in a myocyte stores Ca2+ that has been pumped into it by a SR membrane pump, SERCA2. In the

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Ca 2+ -induced Ca 2+ Release Fabiato’s work on the properties of the cardiac SR provided a potential explanation for spontaneous Ca2+ release in mechanically skinned cells in which the SR and RyR were intact and excessive Ca2+ loading of the SR caused spontaneous Ca2+ release.9,10,11 The mechanism for increased probability of opening of RyR when the SR is heavily loaded with Ca2+ is still uncertain, but suggests that the RyR channel is sensitive to both cytosolic and luminal [Ca2+] of the SR. Hence, the oscillatory character of a triggered arrhythmia in myocardium with a high cellular Ca2+ load may be due to further increase of Ca2+ entry into the cells during driven action potentials, which causes even more Ca2+ loading of the SR. So as soon as the release process has recovered after the electrically evoked Ca2+ release, the overloaded SR again releases a fraction of its Ca2+ into the cytosol. The requirement that the Ca2+ release mechanism must recover first (refractoriness) would explain the presence of a delay between aftercontractions and afterdepolarisations and the preceding beat.

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Arrhythmia Mechanisms Figure 1: Evidence of I ti in Multicellular Canine Purkinje Fibres A

-10

-50

C 0

-10

V2–V1

5 mV

-80

5 sec

-100

2 sec

Panel A: The first manifestation of Ca2+ waves in cardiac cells, as observed by Lederer and Tsien 1976,2 was the appearance of Iti currents (arrows) in voltage-clamped multicellular Purkinje fibres. Note phase 4 activity in this Purkinje strand when clamp was off. Panel B: Multiple experiments including the one shown here illustrated the Cao dependence of Iti (Kass et al., 1978).3

Figure 2: Architecture of Ca 2+ Release Channels in Purkinje (A) and Atrial (B) Cells

Fluorescence Intensity Fluorescence intensity (% Maximum) (% maximum)

a 100

RyR2

50 IP3R1

25 0 0

µm

c c

Gap in RyR distribution

20 µm

Sarcolemma Sarcoplasmic reticulum 10 µm

Junction RyRs Non-junctional RyRs

10 µm 2+

The Ca release channels (RyR) are organised into clusters (red dots in A.b and A.c); the clusters distribution follows a transverse striated pattern that matches the striation of the contractile filaments (not shown here). In Purkinje cells, junctional RyRs co-localise with IP3 receptor channels under the membrane. Note that both cell types show a gap in the RyR2 distribution. The gap is absent when isoform non-specific RyR antibody is used (A.d), indicating the presence of a different RyR isoform in the ‘gap’ of Purkinje cells. The same RyR2 organisation is found in atrial cells (B.a, B.b) wherein the same gap is interpreted here as a space filled by sarcoplamic reticulum with no channel and separating ‘junctional’ and ‘Non-junctional’ RyRs (B.c). In both cell types, this microanatomy shown schematically in B.c sets the stage for successful Ca2+ wave propagation. Adapted from Boyden et al.,7 Thul et al.8 and Stuyvers et al.19

Ca2+ waves occurring in cardiac cells depend on the regenerative production of a diffusible molecule that triggers Ca2+ release from adjacent SR stores. Cytosolic Ca2+ is one such ion and thus the process is called Ca2+ induced (intracellular) Ca2+ release (CICR) (see Figure 3B).12 This schematic shows Ca2+ wave propagation from one RyR cluster to another. Calsequestrin (CASQ), a Ca2+ binding protein, is found in the SR lumen and aids wave propagation inside cells (see Figure 3C). The released Ca2+ constitutes a leak from the SR and tends to reduce the overload. This phenomenon has been observed in different forms, all of which fall under the general definition of Ca2+ leak: increased probability of opening of RyR in lipid bilayer experiments,13 a biochemically detectable loss of Ca2+ from the SR;14

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Ca2+ sparks in isolated cells and muscle;15,16 micro Ca2+ waves in isolated cells and muscle13,14 and Purkinje cells after infarction;7,19 and multicellular cellular Ca2+ waves.17–19 The threshold for Ca2+ leak is reduced in some arrhythmogenic mutations of the RyR,13 CASQ20 and in acquired dysfunction of the RyR such as in congestive heart failure and post MI.7,21–23 Intracellular Ca2+ waves can be seen in normal canine atrial and Purkinje myocytes during forward mode EC coupling (see Figure 4).7 Here, a line of Ca2+ release is seen peripherally just after the plateau of the AP and this Ca2+ then via CICR, sets up a Ca2+ transient that moves to the core of the Purkinje cell (see Figure 4).

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What is a Ca 2+ wave? Is it like an Electrical Wave?

Figure 3: Simple Schematic Showing the Important Components of Ca 2+ Wave Propagation

Figure 5: Ca 2+ Waves Lead to Spontaneous Depolarisations A

Cytosol SR

B Wave Propagation due to Ca diffusion in cytosol; Sensitivity of RyR Wave propagation due to Ca diffusion in cytosol; Sensitivity of RyR Wave Propagation due to Ca diffusion within SR;

CASQ

Wave propagation due to Ca diffusion within SR; CASQ Panel A: Elements included are RyR Ca2+ release channel (blue), SERCA pump (green) both in the sarcoplasmic reticulum (SR) membrane that separates myoplasm and SR lumen (orange). Panel B: Ca2+ in myoplasm (step 1A) acts on first RyR cluster to open channel to release Ca2+ stored in SR to the myoplasm (step 2). This Ca2+ then diffuses away (step 3) and interacts with anatomically close RyR cluster (see Figures 2B and C) to cause further CICR (step 4). This process is regenerative and relies on sensitivity of RyR to Ca2+. Panel C: Ca2+ wave propagation as in Panel B but now wave propagation is also occurring in SR lumen. This process is thought to depend on calsequestrin (CASQ). Adapted from Swietach et al.12

B a

Figure 4: AP-evoked Global Ca 2+ Transients in Purkinje Cells are Robust A c b a

During the interval between stimuli, Purkinje cells are quiescent, except for occasional large Ca2+ waves (not shown here), which propagate along the cells of the aggregates. Panel A shows fluorescence intensity (Ca2+ changes) in Purkinje cells during electrically evoked depolarisation. Note the fluorescence during an electrically-evoked Ca2+ transient in three ROIs is indicated. Small letters correspond to 3D surface plots (below) of ratio images of a section of this aggregate during the transient. Ca2+ concentration is reflected by both the colour and height of the surface. The first response to a stimulus is an increase in Ca2+ (panel a), which is present mostly at the aggregate’s periphery (panel b). Peak Ca2+ change occurs later in core of aggregate (panel c). Thin calibration bars correspond to 1 F/F0 unit and 333 ms, respectively, while white lines on surface plot (panel c) correspond to 10 µm. From Boyden et al., 2003.7

Figure 5A shows that spontaneous Ca2+ waves occur often during diastolic intervals in Purkinje cells dispersed from the infarcted heart.7 In some cases the waves formed varied oscillatory changes in voltage as

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Ca2+ of wave is pumped out of cell via the sodium-calcium exchanger (Iti) (see Figure 5B). However, in the same cell the oscillatory voltage change is large enough to reach threshold, triggering a nondriven AP (see Figure 6). In these cells the small voltage signals and triggered activity are sensitive to an agent that blocks Ca2+ release of the RyR protein, ryanodine.

Propagation Between Cardiac Cells

The magnitude of the depolarisation produced by the Ca2+ wave corresponds to the [Ca2+] and extent of the Ca2+ transients. Panel A: Selected F/F0 image frames from a Purkinje aggregate from the infarcted heart and concomitant membrane depolarisations (panel B). Relative time (t=0 first frame) are white numbers. In panel Aa sequence, t=0 to 700 ms corresponds to F/F0 during a large Ca2+ wave (see also a, panel B); In panel Ab, t=5266 to 5967 ms corresponds to F/F0 during two smaller waves which occur nearly simultaneously and propagate toward center of aggregate but stop before colliding (b, panel B); in panel Ac, t=12‚367 to 12‚967 ms corresponds to small micro Ca2+ transients which meander along upper section of aggregate (c, panel B). Colour bar indicates ratio values. Panel B: Transmembrane potential changes (thin black line above) and changes in F/F0 of ROIs in the spontaneously active Purkinje cell of panel A. Amplitude as well as spatial extent of the waves (see panel A) varied considerably, giving rise to a corresponding membrane depolarisation (denoted by a, b, c). Vertical line 15 mV. Image to right indicates positions of ROIs for this panel and panel 6B. Thin vertical and horizontal lines correspond to 1 F/F0 and 1,667 ms, respectively. Image frames of panel A derived from sections indicated by thin horizontal lines under Ca2+ tracings. From Boyden et al., 2003.7

Intercellular electrical transmission occurs via a set of ion channel proteins and specialised membrane structures called gap junctions.24 Each channel is formed by close apposition of two hemichannels each of which is in an opposing cell.25 Gap junctions can provide passage of many molecules (cAMP, Ca2+, IP3, ATP).26–28 In cardiac cells gap junctional conductance can be regulated acutely by pH, Ca2+, cAMP and cGMP.29 Therefore Ca2+ ions can flow through gap junctions as well as inhibiting gap junctional conductance. Since Ca2+ waves propagate along the cell, it is important to know whether they propagate between cells via gap junctions. Many have observed Ca2+ waves passing between two cardiac cells30 and have assumed a role for gap junctions. Ca2+ ions released upon RyR activation can travel as a wave across cells31 and propagate to adjoining cells via gap junctions.19 In cells transfected with both

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Arrhythmia Mechanisms Figure 6: Large Extensive Ca 2+ Waves Lead to Sufficient Depolarisation to Elicit Nondriven APs

Figure 7: Intercellular Ca 2+ Wave Propagation Side to side communication

Ca2+ wave propagation in a pair of side-to-side canine Purkinje cells. Frames 1 and 2 show the initial Ca2+ release from the SR in cell A. The Ca2+ release then propagates by CICR in cell A. Arrows in frames 3â&#x20AC;&#x201C;5 indicate the passage of the wave from cell A to cell B. By frame 8 sufficient Ca2+ has changed in cell B (yellow spot) to cause Ca2+ waves to propagate in both directions. The intracellular propagation velocity is ~60 Âľm/s-1. Panel A: Selected F/F0 image frames from the same infarct Purkinje shown in Figure 5 but during Ca2+ wave induced electrical activity. Time relative to t=0 of first frame is depicted by white numbers. Lower right image is bright field image of this aggregate early during experiment. The arrow denotes a probable cell border. Colour code as in Figure 5A. Panel B: Transmembrane potential changes (black line) and changes in F/F0 in several ROIs of spontaneously active Purkinje cell of panel A (MDP=-84.5 mV). Nondriven action potentials are triggered by the large cell wide Ca2+ waves (CW). Inset shows enlargement of the Ca2+ wave preceding synchronised Ca2+ release induced by the second action potential (arrow). Images presented in panel A are derived from those occurring during time of dotted line. Thick vertical and horizontal lines are one F/F0 unit and 3 s (1 F/F0, 417 ms for inset), respectively. Thin vertical black line is 12 mV. From Boyden et al., 2003.

Figure 8: Multicellular Ca 2+ Wave Propagation A

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connexin 43 (Cx43) and RyR receptors the propagation of waves between cells was sensitive to octanol.32 Furthermore, in this experimental cell model, both Ca2+ wave propagation and gap junctional conductance between paired cardiac cells are related to the state of tyrosine phosphorylation of Cx43.33 How the Ca2+ wave crosses the gap junction is unknown but extracellular disulphide bonds of the Cx43 proteins between the adjoining cells appear critical for wave propagation.32 Arguably the occurrence of Ca 2+ wave propagation from one cell to another is not a frequent event, but when one does happen, it appears to be due to a CICR mechanism (see Figure 7). In adult rat cells, Li et al. 30 assert that Ca 2+ wave propagation between cells mostly occurs at side-to-side junctions and the ultrastructure of the connections between the gap and SR release units is critical. Propagation failure occurs when distance between the disc membrane and neighbouring SR release unit is too large, such as occurs at end-to-end junctions. At the tissue level, the subcellular Ca2+ dynamics combine with cell coupling and tissue architecture to generate multicellular Ca2+ wave dynamics. We understand focal electrical excitations due to triggered activity but are the dynamics of Ca waves similar? Spontaneous Ca2+ releases that triggered Ca2+ waves have been mapped in both normal and failing heart tissues34 (see Figure 8).35 Notably each

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Shown are traces of two spontaneous Ca2+ release events (SCR) recorded from the same site in a single wedge preparation from a failing canine heart: one that resulted in a triggered beat (A) and one that did not (B). In A, above the last paced beat (S1) are three frames showing transmural (14 x 14 mm) calcium level (amplitude) at select time points, demonstrating the rapid, uniform pattern of calcium release during pacing (pacing symbol). Below the trace are several frames of calcium levels from select time points during the SCR and subsequent triggered beat (TA). All times shown are relative to the earliest site of calcium release, during pacing (top) or the SCR (bottom). The Epi and Endo are shown on the left and right sides of each contour, respectively. For the colour scale, black corresponds to diastolic calcium, red corresponds to subthreshold SCR, and the transition from red to green corresponds to the threshold for TA in A. Calcium release is much slower during the SCR compared with pacing. In B, the exact same format is shown, except that frames of calcium levels during pacing are not shown. The colour scale created for A was also used in B. In A and B, SCRs occur in a relatively large aggregate of myocardial cells and achieved a similar amplitude; however, the rate of SCR rise is much greater in A when TA occurred compared with B when TA did not. From Hoeker et al., 2009.35

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What is a Ca 2+ wave? Is it like an Electrical Wave?

amplitude and CICR or Ca2+ wave formation.37 Shortened refractoriness of this process has been seen in both acquired (post MI)38 and genetic disease.39 For example, loss of calsequestrin (CASQ) in SR of cells in some CVPT patients produces fast SR refilling and greater likelihood of a trigger for re-release40 and Ca2+ waves.

1. 2.

4. 5.

10.

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Bozler E. The initiation of impulses in cardiac muscle. Amer J Physiol 1943;138:273–82. Lederer WJ, Tsien RW. Transient inward current underlying arrhythmogenic effects of cardiotonic steriods in Purkinje fibers. J Physiol 1976;263:73–100. Kass RS, Lederer WJ, Tsien RW, Weingart R. Role of calcium ions in transient inward currents and aftercontractions induced by strophanthidin in cardiac Purkinje fibres. J Physiol (Lond) 1978;281:187–208. Ter Keurs HEDJ, Boyden PA. Calcium and arrhythmogenesis. Physiol Rev 2007;87:457–506. Kleber AG, Rudy Y. Basic mechanisms of cardiac impulse propagation and associated arrhythmias. Physiol Rev 2004;84:431–88. Dun W, Lowe JS, Wright PA, et al. Ankgrin-G participates in INa remodeling in myocytes from the broder zone of infarcted canine hearts. PloS ONE 2013;e78087. Boyden PA, Barbhaiya C, Lee T, Ter Keurs HEDJ. Nonuniform Ca2+ transients in arrhythmogenic purkinje cells that survive in the infarcted canine heart. Cardiovasc Res 2003;57:681–93. Thul R, Coombes S, Roderick HL, Bootman MD. Subcellular calcium dynamics in a whole-cell model of an atrial myocyte. Proc Natl Acad Sci 2012;109:2150–5. Fabiato A. Time and calcium dependence of activation and inactivation of calcium induced release of calcium from the sarcoplasmic reticulum of a skinned cardiac Purkinje cell. J Gen Physiol 1985;85:247–90. Fabiato A. Simulated calcium current can both cause loading in and trigger calcium release from the sarcoplasmic reticulum of a skinned canine cardiac Purkinje cell. J Gen Physiol 1985;85:291–320. Fabiato A. Spontaneous versus triggered contractions of calcium tolerant cardiac cells from the adult rat ventricle. Basic Res Cardiol 1985;80(Suppl 2):83–8. Swietach P, Spitzer KW, Vaughan-Jones RD. Modeling calcium waves in cardiac myocytes: importance of calcium diffusion. Front Biosci (Landmark Ed) 2010;15:661–80. Jiang D, Xiao B, Yang D, et al. RyR2 mutations linked to ventricular tachycardia and sudden death reduce the threshold for store-overload-induced Ca2+ release (SOICR). Proc Natl Acad Sci 2004;101:13062–7. Yano M, Ikeda Y, Matsuzaki M. Altered intracellular Ca2+ handling in heart failure. J Clin Invest 2005;115:556–64. Wier WG, ter Keurs HE, Marban E, et al. Ca2+ ‘sparks’ and waves in intact ventricular muscle resolved by confocal imaging. Circ Res 1997;81:462–9.

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5 5 6 3 6 7 3 11 6

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Electrical refractoriness is clearly related to time course of action potential repolarisation as well as the status of the sodium channel. In forward mode EC coupling, after the cellular action potential evoked Ca2+ transient due SR Ca2+ release, time is needed before a second Ca2+ release occurs of similar amplitude. Thus there is also a recovery process of Ca2+ release in cardiac cells that is independent of membrane voltage. In the electrically stimulated cell, the recovery of the SR Ca2+ release process or refractoriness is determined by recovery of the L-type calcium channel influx as well as the time course of the SR refilling. The latter can be examined by assessing the interval between spontaneous Ca2+ sparks occurring at the same release site (see Figure 9). Ca2+ spark termination is due to local depletion of Ca2+ within junctional SR. The time between one spark and another is related to the ryanodine sensitivity or threshold for Ca2+ release. How fast junctional SR refills after depletion is important for the recovery of both spark

a a

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Figure 9: Refractoriness of the Ca 2+ Release Events

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spontaneous event occurred in a region of myocardium comprised of many cells (~3000 cells).34 In failing myocardium it is the rate of rise of the Ca2+ releases (waves) rather than their amplitude that is associated with triggered beats. In atria from CASQ-/- mice, the runs of APs during nondriven electrical activity were always preceded by rises in Ca2+, however total time of atrial activation increases with number of beats.36

Panel A shows examples of line scan tracings (a–b) used to assess the refractoriness of Ca2+ releases in a normal Purkinje cell. Each fluorescent event represents a Ca2+ transient and corresponds to a Ca2+ release from a cluster of RyRs. Counting events along the scan indicates the regional density of active Ca2+ release sites (NSitesLine, Panel B) while horizontal event count reflects the frequency of Ca2+ release per site (SpkRateSite, Panel C).

Conclusion While cellular electrical events and Ca2+ waves can occur independently of each other, it is when they interact and feed back on each other that complicated arrhythmogenic behaviour can occur (eg. alternans).4 Each physiological process has its own mechanisms of initiation, propagation and refractoriness and thus would be expected to have its own possible targets for effective therapeutic agents. For example, CamKII,41 sodiumcalcium exchanger protein42 and EHD343 proteins have all emerged as possible targets for Ca2+-dependent arrhythmias. n

16. Shannon TR, Pogwizd SM, Bers DM. Elevated sarcoplasmic reticulum Ca2+ leak in intact ventricular myocytes from rabbits in heart failure. Circ Res 2003;93:592–4. 17. Miura M, Boyden PA, terKeurs HEDJ. Ca2+ waves during triggered propagated contractions in intact trabeculae: determinants of the velocity of propagation. Circ Res 1999;84:1459–68. 18. Lamont C, Luther PW, Wier WG. Intercellular Ca2+ waves in rat heart muscle. J Physiol 1998;512:669–76. 19. Stuyvers BD, Dun W, Matkovich SJ, et al. Ca2+ sparks and Ca2+ waves in Purkinje cells: a triple layered system of activation. Circ Res 2005;97:35–43. 20. di Barletta MR, Viatchenko-Karpinski S, Nori A, et al. Clinical phenotype and functional characterization of CASQ2 mutations associated with catecholaminergic polymorphic ventricular tachycardia. Circ 2006;114;1012–9. 21. Wehrens XHT, Lehnart SE, Reiken S, et al. Enhancing calstabin binding to ryanodine receptors improves cardiac and skeletal muscle function in heart failure. PNAS 2005;102:9607–12. 22. Yano M, Ono K, Ohkusa T, et al. Altered stoichiometry of FKBP12.6 versus ryanodine receptor as a cause of abnormal Ca2+ leak through ryanodine receptor in heart failure. Circ 2000;102:2131–6. 23. Bers DM, Eisner DA, Valdivia HH. Sarcoplasmic reticulum Ca2+ and heart failure: roles of diastolic leak and Ca2+ transport. Circ Res 2003;93:487–90. 24. Kleber AG, Rudy Y. Basic mechanisms of cardiac impulse propagation and associated arrhythmias. Physiol Rev 2004;84:431–88. 25. Yeager M. Structure of cardiac gap junction membrane channels. In: Spooner PM, Joyner RW, Jalife J, eds. Discontinuous Conduction in the Heart. First ed. Armonk: Futura; 1997;161–84. 26. Boitano S, Dirksen ER, Sanderson MJ. Intercellular propagation of calcium waves mediated by inositol triphosphate. Science 1992;258:292–5. 27. Saez JC, Connor JA, Spray DC, Bennett MV. Hepatocyte gap junctions are permeable to the second messenger, inositiol 1,4,5-trisphosphate and to calcium ions. Proc Natl Acad Sci 1989;86:2708–12. 28. Sandberg K, Ji H, Iida Y, Catt KJ. Intercellular communication between follicular angiotensin receptors and Xenopus laevis oocytes: mediation by an inositol 1,4,5-trisphosphatedependent mechanism. J Cell Biol 1992;117:157–67. 29. Rosen MR, Boyden PA. Is there a pharmacology of discontinuous conduction? In: Spooner PM, Joyner RW,

Jalife J, eds. Discontinuous Conduction in the Heart. First ed. Armonk: Futura, 1997; 471–82. 30. Li Y, Eisner DA, O’Neill SC. Do calcium waves propagate between cells and synchronize alternating calcium release in rat ventricular myocytes? J Physiol 2012;590:6353–61. 31. Zhang Y, Miura M, Ter Keurs HEDJ. Triggered propagated contractions in rat cardiac trabeculae; inhibition by octanol and heptanol. Circ Res 1996;79:1077–85. 32. Toyofukyu T, Yabuki M, Otsu K, et al. Intercellular calcium signaling via gap junction in connexin43 transfected cells. J Biol Chem 1998;273:1519–28. 33. Toyofuku T, Yabuki M, Otsu K, et al. Functional role of c-Src in gap junctions of the cardiomyopathic heart. Circ Res 1999;85:672–81. 34. Katra RP, Laurita KR. Cellular mechanism of calcium-mediated triggered activity in the heart. Circ Res 2005;96:535–42. 35. Hoeker GS, Katra RP, Wilson LD, et al. Spontaneous calcium release in tissue from the failing canine heart. Am J Physiol Heart Circ Physiol 2009;297:H1235–42. 36. Lou Q, Belevych AE, Liu B, et al. Alternating membrane potential/calcium interplay underlies repetitive focal activity in a genetic model of calcium dependent atrial arrhythmias. J Physiol 2015;593:1443–58. 37. Ramay HR, Liu OZ, Sobie EA. Recovery of cardiac calcium release is controlled by sarcoplasmic reticulum refilling and ryanodine receptor sensitivity. Cardiovasc Res 2011;91:598–605. 38. Belevych AE, Terentyev D, Terentyeva R, et al. Shortened Ca2+ signaling refractoriness underlies cellular arrhythmogenesis in a postinfarction model of sudden cardiac death. Circ Res 2012;110:569–77. 39. Brunello L, Slabaugh JL, Ho HT, et al. Decreased RyR2 refractoriness determines myocardial synchronization of aberrant Ca2+ release in a genetic model of arrhythmia. Proc Natl Acad Sci 2013;110:10312–7. 40. Liu N, Denegri M, Dun W, et al. Abnormal propagation of calcium waves and ultrastructural remodeling in recessive catecholaminergic polymorphic ventricular tachycardia. Circ Res 2013;113:142–52. 41. Pellicena P, Schulman H. CaMKII inhibitors: from research tools to therapeutic agents. Front Pharmacol 2014;5:21. 42. Nagy N, Kormos A, Kohajda Z, et al. Selective Na+/Ca2+ exchanger inhibition prevents Ca2+ overload-induced triggered arrhythmias. Br J Pharmacol 2014;171:5665–81. 43. Curran J, Makara MA, Little SC, et al. EHD3-dependent endosome pathway regulates cardiac membrane excitability and physiology. Circ Res 2014;115:68–78.

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Arrhythmia Mechanisms

Science Linking Pulmonary Veins and Atrial Fibrillation Saagar Mahida, Frederic Sacher, Nicolas Derval, Benjamin Berte, Seigo Yamashita, Darren Hooks, Arnaud Denis, Sana Amraoui, Meleze Hocini, Michel Haissaguerre and Pierre Jais Hôpital Cardiologique du Haut-Lévêque and Université Victor Segalen Bordeaux II, Bordeaux, France

Abstract Over the past few decades, significant progress has been made in understanding the mechanistic basis of atrial fibrillation (AF). One of the most important discoveries in this context has been that pulmonary veins (PV) play a prominent role in the pathogenesis of AF. PV isolation has since become the most widely used technique for treatment of paroxysmal AF. Multiple studies have demonstrated that the electrophysiological and anatomical characteristics of PVs create a proarrhythmogenic substrate. The following review discusses the mechanistic links between PVs and AF.

Keywords Pulmonary vein isolation, atrial fibrillation, ablation, pulmonary vein electrophysiology, pulmonary vein histology Disclosure: The authors have no conflicts of interest to declare. Received: 10 January 2015 Accepted: 18 March 2015 Citation: Arrhythmia & Electrophysiology Review 2015;4(1):40–3 Access at: www.AERjournal.com Correspondence: Saagar Mahida, MBChB, Hôpital Haut-Lévêque, Avenue de Magellan, 33604 Pessac, France. E: saagar7m7@yahoo.co.uk

Atrial fibrillation (AF) is the most commonly encountered arrhythmia in clinical practice. The discovery that pulmonary veins (PV) play a prominent role in the pathogenesis of AF has revolutionised the management of AF. PV isolation has become the most widely used technique for treatment of paroxysmal AF. Since the initial discovery implicating PVs in AF pathogenesis, the mechanistic link between PVs and AF has been the subject of intense interest. The aim of this review is to provide an overview of the evidence linking PVs with the pathogenesis of AF.

Historical Perspective Nearly a century ago, researchers postulated that focal atrial triggers play an important role in the genesis of AF.1 The first theories suggested that these triggers are distributed throughout the atria. In the ensuing years, multiple different theories emerged regarding AF maintenance. The circus movement theory proposed that a single rapid reentrant circuit drives AF.1–3 In the 1960s Moe et al. proposed the ´multiple wavelet´ hypothesis which postulates that AF is maintained by numerous reentrant wavelets that constantly meander through the atrium.4 A competing theory regarding AF maintenance focussed on the role of multiple high-frequency rotors as major drivers of AF.3 One of the most important discoveries regarding the mechanisms of AF came from studies by Jais et al. and Haissaguerre et al. in the late 1990s.5,6 They reported that in a subset of patients with paroxysmal AF, catheter ablation of focal triggers originating from the PVs effectively treated the arrhythmia. Their findings demonstrated that the PVs play an important role, both as triggers and drivers of AF (see Figure 1). Hence, after close to a century of research, the role of focal triggers in AF once again gained prominence.

Pulmonary Vein Anatomy The left atrial musculature extends from the atrium and envelopes the proximal PVs. The length of the PV sleeves varies between

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13 mm and 25 mm.7 PV morphology has been reported to influence arrhythmogenesis. The superior veins, which have longer muscular sleeves,7 have been reported to be more arrhythmogenic than the inferior veins.5 In autopsy studies the PV myocardium has been reported to be more hypertrophied and discontinuous in AF patients.8 However the presence of hypertrophy and discontinuity has not been a consistent finding in all studies.9,10 Intravascular ultrasound studies have reported that patients with AF have thicker PV myocardial tissue, with areas of regional thickening correlating with high-frequency potentials and PV ectopy.11 Imaging studies have found that PV dimension is larger in AF patients. Lin et al. reported that AF patients have more dilated superior PVs.12 Corroborating evidence came from Takase et al., who performed MRI studies in AF patients.13 Yamane et al. demonstrated that in AF patients, arrhythmogenic PVs have a larger diameter than nonarrhythmogenic PVs.14

Pulmonary Vein Histology A number of studies have reported the presence of ectopic pacemaker tissue within the PV myocardium. Blom et al. demonstrated that in human embryos, the myocardium around the PVs transiently stains for HNK-1, an antigen that is specific to the cardiac conduction system.15 In transgenic mice, Jongbloed et al. identified cells expressing antigens specific to the atrioventricular conduction system (CCS LacZ) at the PV orifice.16 Nguyen et al. performed biopsies of tissue from the PV–left atrial junction in AF patents and identified cells that were positive for the HCN4 channel, which underlies the pacemaker current.17 In PVs from explanted human hearts, Morel et al. found Cajal cells with positive immunostaining for HCN4.18 Cajal cells have previously been found to be able to depolarise spontaneously and act as pacemakers in smooth muscle cells.19 On the basis of these observations, it has been speculated that the PVs harbour cells with pacemaking function.

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Science Linking Pulmonary Veins and Atrial Fibrillation

Figure 1: Pulmonary Vein Trigger Driving Atrial Fibrillation A

A: Intracardiac recordings from a circular mapping catheter (lasso 1–2 – lasso 9–10) positioned in the left inferior pulmonary vein (LIPV). The recordings demonstrate rapid activity which is conducted to the atrium and drives a rapid atrial arrhythmia. Atrial signals are recorded in a decapolar catheter positioned in the coronary sinus (CS1–2 – CS9–10). RFp and RFd demonstrate signals recorded from an ablation catheter which is being used to electrically isolate the PV. The surface electrogram is demonstrated on the top. B: Following isolation of the LIPV, the vein continues to fire rapidly, however the impulses are not conducted to the left atrium. The atrium is in normal sinus rhythm. C: A radiographic image (anterior–posterior projection) demonstrating position of the circular mapping catheter in the LIPV, the ablation catheter at the ostium of the PV and the CS catheter in the coronary sinus.

Interestingly, findings from a study by Morel et al. suggested that patients with AF may have a higher density of Cajal cells in PVs.18 Ultrastructural imaging studies have also identified pacemaker-like cells in PVs. Masani et al. used electron microscopy to demonstrate that interspersed between normal atrial myocytes, the PVs harbour clear cells with ultrastructural characteristics that closely resemble sinus nodal cells. These cells were located in the intrapulmonary, preterminal portion of the PVs.20 Perez-Lugonez et al. reported that human explanted hearts harbour pale cells with morphological characteristics reminiscent of P cells, transition cells and Purkinje cells.21 While there were some potential technical limitations of the study, these findings were suggestive of the presence of conduction tissue in the walls of PVs.22 Gherghiceanu et al. performed electron microscopy and identified interstitial Cajal-like cells in the PV myocardium.23 It is important to note that, despite the studies outlined above, there exists some controversy regarding the existence of nodal cells in adult PVs. Hocini et al. performed histological analysis of canine PVs and did not identify any cells resembling conduction tissue. All the cells consistently demonstrated histological properties to atrial myocytes.24 Verheule et al. reported that in canine PVs, the morphology and distribution of connexins were the same as those observed elsewhere in the atrium.25 They did not observe significant ultrastructural changes between the PVs and the left atrium. These findings argue against the presence of specialised conduction tissue in the PV myocardium.

Genetics and Pulmonary Vein Arrhythmogenesis The genetic mechanisms linking PVs and AF are not well understood. However, potentially important findings have emerged from recent studies. The bulk of evidence relates to the PITX2 gene. PITX2 plays an important role during development of the pulmonary myocardium.26,27 Interestingly, genetic variants in proximity to PITX2 (4q25 locus) have demonstrated a consistent and robust association with AF in multiple population genetic studies.28,29 Functional studies in animal models have also linked altered expression of PITX2 with increased arrhythmia susceptibility. However these studies have not focused specifically on

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PVs.30,31 Further, risk variants at the PITX2 locus have been reported to predict AF recurrence in patients undergoing pulmonary vein isolation (PVI).32 In addition to PITX2, other transcription factor genes are involved in PV morphogenesis and could potentially play an important role AF susceptibility.33 However further research is necessary to determine whether these genes are relevant to PV-mediated arrhythmogenesis.

Pulmonary Vein Cellular Electrophysiology The cellular electrophysiological characteristics of PV myocytes have been reported to be distinct to those of atrial tissue. Ehrlich et al. reported that PVs have a shorter action potential duration and amplitude in addition to a lower upstroke velocity in comparison to the left atrium. In terms of the specific ionic currents underlying this observation, the inward rectifier current (IKs), the transient outward potassium (Ito) current and the L-type calcium current (ICaL) was reported to be lower. On the other hand, delayed rectifier current densities were greater in the PVs. In turn, the augmented delayed rectifier currents and the attenuated inward rectifier currents have been attributed to higher expression of ERG and KvLQT1 and downregulation of Kir2.3 expression in PVs compared with atrial myocytes. These channel subunits also demonstrate a distinct subcellular distribution in PV myocytes.34 The electrophysiological characteristics of PV myocytes have been reported to change in response to chronic rapid pacing. Chen et al. reported that in isolated canine myocytes, rapid atrial pacing results in a shortening of the action potential with a higher incidence of both early and late afterdepolarisations. Measurement of specific ionic currents demonstrated that the slow inward and transient outward currents were smaller, however the transient inward and pacemaker currents were larger.35 They also observed a higher incidence of spontaneous arrhythmias in PVs from chronically paced dogs.36 The action potential characteristics of PV myocytes have been reported to vary depending on location. Hocini et al. demonstrated that the action potential duration at the distal PV is shorter than that at the orifice.24 In contrast to the aforementioned studies by Chen et al., burst pacing did not result in early or late afterdepolarisations.

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Arrhythmia Mechanisms Figure 2: Potential Mechanisms of PV-Mediated Arrhythmia IKs’ Ito’ ICa

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with paroxysmal AF, the highest dominant frequency was recorded at the junction between the PVs and the left atrium. Adenosine is predicted to augment the inward rectifier potassium current. Therefore, the observed increase in dominant frequency strongly supports a re-entrant mechanism at the junction between the PV and the left atrium as a major driver of AF.

Depolarised RMP Automaticity and triggered activity

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PV fibre orientation Conduction slowing and fractionated electrograms

Reentry triggered activity and increased automaticity have all been proposed to play a role in PV mediated arrhythmogenesis. Reentry is potentially promoted by conduction slowing, altered fibre orientation and altered depolarising and repolarising currents. Increased automaticity and triggered activity is also likely to be mediated by specific alterations in PV cellular currents.

Kumagai et al. performed high-density mapping using a basket catheter and demonstrated anisoptopic conduction in addition to heterogeneity of the effective refractory period (ERP), both in the PV and at the PV–left atrial junction.42 Specifically, they demonstrated that the distal PV had a shorter ERP than the PV–left atrial junction. Further, the conduction delay from the PV–left atrial junction to the distal PV was longer than the delay from the distal PV to the PV–left atrium junction. These changes are predicted to create a substrate for re-entry. They also demonstrated reciprocating re-entrant circuits at the PV–left atrial junction.

Mechanisms of PV Arrhythmogenesis The basic mechanisms underlying PV arrhythmogenesis have yet to be fully characterised. It has been proposed that reentry, enhanced automaticity and triggered activity could all contribute to abnormal impulse generation. The potential mechanisms are discussed in more detail below (summarised in Figure 2).

Jais et al. reported that patients with AF display significant electrophysiological alterations when compared to those in sinus rhythm.43 Specifically, they demonstrated that in patients with AF, the ERPs were significantly shorter. They also demonstrated decremental conduction in the PVs. These changes are predicted to promote PV re-entry, which may drive AF.44

Re-entry Multiple studies have demonstrated that re-entry in the PV or at the PV–left atrial junction is a potentially important driver of AF. At a cellular level, as discussed above, in comparison with atrial myocytes, pulmonary venous cells have a shorter action potential duration, a slower upstroke velocity and a more depolarised resting membrane potential. These alterations in action potential characteristics are predicted to promote micro-reentry in the myocardial sleeves.37 Studies in animal models have demonstrated evidence of re-entry in PVs. In Langendorff-perfused dog hearts, Hocini et al. demonstrated complex arrangements of myocardial fibres with crossing over of parallel and diagonal fibres.24 There was evidence of slow and complex conduction over the PVs, which may be attributable to the fibre orientation. Regional conduction slowing is predicted to create a substrate for PV reentry. In canine left atrial preparations, Arora et al. demonstrated marked conduction slowing in the proximal PV relative to the distal vein. Atrial extrastimuli resulted in functional unidirectional conduction block and re-entry within the proximal PV.38 Chou et al. demonstrated that re-entry circuits induced by pacing clustered at the junction between the left atrium and the PVs.39 These regions of clustering of re-entry circuits corresponded with areas of abrupt change in myofibre orientation. Studies in human subjects have also provided evidence to support PV re-entry. Hsieh et al. demonstrated the presence of complex fractionated electrograms in the PVs, both during sinus rhythm and during atrial ectopy.40 The duration and characteristics of the fractionated electrograms varied significantly depending on the site of stimulation. These findings suggest that non-uniform anisotropy may underlie the observed fractionated electrograms.7 Atienza et al. demonstrated that administration of adenosine accelerated drivers and increased dominant frequency in both persistent and paroxysmal AF patients.41 In the subset of patients

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Automaticity and Triggered Activity As discussed previously, morphological studies have identified pacemaker-like cells in the PVs. These findings suggest that automaticity and triggered activity is potentially an important driver of PV-mediated arrhythmogenesis. However the majority of the morphological studies have not characterised the electrophysiological characteristics of the node-like tissue. The electrophysiogical studies that have demonstrated direct evidence of abnormal automaticity and triggered activity in PVs are discussed in more detail here. In an elegant series of experiments, Chen et el. investigated the action potential characteristics and ionic currents in canine PV myocytes. They demonstrated the presence of two distinct populations of PV myocytes: those with spontaneous pacemaker activity and those without. In response to rapid atrial pacing, the myocytes with pacemaker activity displayed faster beating rates in addition to a high incidence of early and delayed afterdepolarisations. Measurement of ionic currents demonstrated that these PVs have smaller slow inward and transient outward and larger transient inward and pacemaker currents.35 An attenuated IK1 current is predicted to enhance ectopic pacemaker activity. The sodium current has also been implicated as an important mediator of enhanced automaticity in PV myocytes. Malecot et al. demonstrated that PVs have a higher basal permeability to sodium compared with left atrial myocytes. Pharmacological blockade of the INa current resulted in a decrease in the incidence of catecholaminergic automatic activity by reducing the slope of slow depolarisation.45 Increased catecholaminergic activity is an important mediator of enhanced automaticity in PV myocytes. Dolsne et al. previously demonstrated that PV myocytes demonstrate differential responses in terms of response to catecholaminergic stimulation. Specifically, they reported that PVs demonstrate enhanced automaticity in response to

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Science Linking Pulmonary Veins and Atrial Fibrillation

catecholaminergic stimulation while left atrial cells do not. The effect was suppressed by administration of beta blockers.46

parasympathetic nerves, indicating that the parasympathetic system is an important mediator of PV-triggered activity.49

Multiple studies have reported the presence of triggered activity in PVs. Abnormalities in calcium handling are likely to be important mediators of PV triggered activity. Honjo et al. demonstrated that in rabbit PV preparation, administration of ryanodine promotes depolarisation of the resting membrane potential and generation of spontaneous pacing activity.47 They observed a consequent shift in the leading pacemaker from the sinus node to an ectopic PV focus. Patterson et al. demonstrated that autonomic nerve stimulation of PVs results in shortening of the PV action potential with associated early afterdepolarisations. They also demonstrated that enhanced calcium transients are important for generation of triggered activity.48 Chou et al. demonstrated that in canine PV preparations, rapid pacing induces focal discharge, which is mediated by spontaneous voltage-independent calcium release.39 The same group also reported that in a canine model or heart failure, administration of acetylcholine increases the incidence of triggered activity in the PVs. PVs with focal discharges had higher densities of

A number of different conditions enhance triggered activity in the PVs. In the presence of thyroid hormone, PV myocytes display early and late afterdepolarisations.50 Increases in temperature have also been reported to enhance early and late afterdepolarisatons.51 Finally, administration of beta adrenergic agonists has been reported to enhance early afterdepolarisations.52,53

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17.

18.

Winterberg H. Studien uber herzflimmern. I. Uber die wirkung des N. vagus und accelerans auf das Flimmern des Herzens. Pflugers Arch Physiol 1907;117:223–56. Scherf D, Romano J, Terranova R. Experimental studies on auricular flutter and auricular fibrillation. Am Heart J 1958;36:241–55. Jalife J, Berenfeld O, Mansour M. Mother rotors and fibrillatory conduction: a mechanism of atrial fibrillation. Cardiovasc Res 2002;54:204–16. Moe GK. On the multiple wavelet hypothesis of AF. Arch Int Pharmacodyn Ther 1962;140:183–8. Haissaguerre M, Jais P, Shah DC, et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med 1998;339:659–66. Jaïs PM, Haïssaguerre M, Shah DC, et al. A focal source of atrial fibrillation treated by discrete radiofrequency ablation. Circulation 1997;95:572–6. Nathan H, Eliakim M. The junction between the left atrium and the pulmonary veins. An anatomic study of human Hearts. Circulation 1966 34:412–22. Hassink RJ, Aretz HT, Ruskin J, et al. Morphology of atrial myocardium in human pulmonary veins: a postmortem analysis in patients with and without atrial fibrillation. J Am Coll Cardiol 2003;42:1108–14. Saito T, Waki K, Becker AE. Left atrial myocardial extension onto pulmonary veins in humans: anatomic observations relevant for atrial arrhythmias. J Cardiovasc Electrophysiol 2000;11:888–94. Tagawa M, Higuchi K, Chinushi M, et al. Myocardium extending from the left atrium onto the pulmonary veins: a comparison between subjects with and without atrial fibrillation. Pacing Clin Electrophysiol 2001;24:1459–63. Guerra PG, Thibault B, Dubuc M, et al. Identification of atrial tissue in pulmonary veins using intravascular ultrasound. J Am Soc Echocardiogr 2003;16:982–7. Lin WS, Prakash VS, Tai CT, et al. Pulmonary vein morphology in patients with paroxysmal atrial fibrillation initiated by ectopic beats originating from the pulmonary veins: implications for catheter ablation. Circulation 2000;101:1274–81. Takase B, Nagata M, Matsui T, et al. Pulmonary vein dimensions and variation of branching pattern in patients with paroxysmal atrial fibrillation using magnetic resonance angiography. Jpn Heart J 2004;45:81–92. Yamane T, Shah DC, Jaïs P, et al. Dilatation as a marker of pulmonary veins initiating atrial fibrillation. J Interv Card Electrophysiol 2002;6:245–9. Blom NA, Gittenberger-de Groot AC, DeRuiter MC, et al. Development of the cardiac conduction tissue in human embryos using HNK-1 antigen expression: possible relevance for understanding of abnormal atrial automaticity. Circulation 1999;99:800–6. Jongbloed MR, Schalij MJ, Poelmann RE, et al. Embryonic conduction tissue: a spatial correlation with adult arrhythmogenic areas. J Cardiovasc Electrophysiol 2004;15:349–55. Nguyen BL, Fishbein MC, Chen LS, et al. Histopathological substrate for chronic atrial fibrillation in humans. Heart Rhythm 2009;6:454–60. Morel E, Meyronet D, Thivolet-Bejuy F, et al. Identification and distribution of interstitial Cajal cells in human pulmonary veins. Heart Rhythm 2008;5:1063–7.

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Conclusions The PVs play a central role in the pathogenesis of AF. Significant progress has been made over the past two decades in understanding the basic mechanisms of PV arrhythmogenesis. Re-entry, automaticity or potentially a combination of mechanisms have been reported to underlie PV arrhythmogenicity. However the mechanisms of arrhythmia have not been fully elucidated. In the future, a more in-depth understanding of the science linking PVs and AF may result in the development of novel, more efficacious therapies. n

19. Harhun MI, Gordienko DV, Povstyan OV, et al. Function of interstitial cells of Cajal in the rabbit portal vein. Circ Res 2004;95:619–26. 20. Masani F. Node-like cells in the myocardial layer of the pulmonary vein of rats: an ultrastructural study. J Anat 1986;145:133–42. 21. Perez-Lugones A, McMahon JT, Ratliff NB, et al. Evidence of specialized conduction cells in human pulmonary veins of patients with atrial fibrillation. J Cardiovasc Electrophysiol 2003;14:803–9. 22. Anderson RH, Ho SY. “Specialized” conducting cells in the pulmonary veins. J Cardiovasc Electrophysiol 2004;15:121; author reply 121–3. 23. Gherghiceanu M, Hinescu ME, Andrei F, et al. Interstitial Cajallike cells (ICLC) in myocardial sleeves of human pulmonary veins. J Cell Mol Med 2008;12:1777–81. 24. Hocini M, Ho SY, Kawara T, et al. Electrical conduction in canine pulmonary veins: electrophysiological and anatomic correlation. Circulation 2002;105:2442–8. 25. Verheule S, Wilson EE, Arora R, et al. Tissue structure and connexin expression of canine pulmonary veins. Cardiovasc Res 2002;55:727–38. 26. Mommersteeg MT, Brown NA, Prall OW, et al. Pitx2c and Nkx2-5 are required for the formation and identity of the pulmonary myocardium. Circ Res 2007;101:902–9. 27. Wang J, Klysik E, Sood S, et al. Pitx2 prevents susceptibility to atrial arrhythmias by inhibiting left-sided pacemaker specification. Proc Natl Acad Sci USA 2010;107:9753–8. 28. Gudbjartsson DF, Arnar DO, Helgadottir A, et al. Variants conferring risk of atrial fibrillation on chromosome 4q25. Nature 2007;448:353–7. 29. Ellinor PT, Lunetta KL, Albert CM, et al. Meta-analysis identifies six new susceptibility loci for atrial fibrillation. Nat Genet 2012;44:670–5. 30. Kirchhof P, Kahr PC, Kaese S, et al. PITX2c is expressed in the adult left atrium, and reducing Pitx2c expression promotes atrial fibrillation inducibility and complex changes in gene expression. Circ Cardiovasc Genet 2011;4:123–33. 31. Scridon A, Fouilloux-Meugnier E, Loizon E, et al. Longstanding arterial hypertension is associated with Pitx2 down-regulation in a rat model of spontaneous atrial tachyarrhythmias. Europace 2015;17:160–5. 32. Husser D, Adams V, Piorkowski C, et al. Chromosome 4q25 variants and atrial fibrillation recurrence after catheter ablation. J Am Coll Cardiol 2010;55:747–53. 33. Mahida S. Transcription factors and atrial fibrillation. Cardiovasc Res 2014;101:194–202. 34. Melnyk P, Ehrlich JR, Pourrier M, et al. Comparison of ion channel distribution and expression in cardiomyocytes of canine pulmonary veins versus left atrium. Cardiovasc Res 2005;65:104–16. 35. Chen YJ, Chen SA, Chen YC, et al. Effects of rapid atrial pacing on the arrhythmogenic activity of single cardiomyocytes from pulmonary veins: implication in initiation of atrial fibrillation. Circulation 2001;104:2849–54. 36. Chen YJ, Chen SA, Chang MS, et al. Arrhythmogenic activity of cardiac muscle in pulmonary veins of the dog: implication for the genesis of atrial fibrillation. Cardiovasc Res 2000;48:265–73.

37. Ehrlich JR, Cha TJ, Zhang L, et al. Cellular electrophysiology of canine pulmonary vein cardiomyocytes: action potential and ionic current properties. J Physiol 2003;551:801–13. 38. Arora R, Verheule S, Scott L, et al. Arrhythmogenic substrate of the pulmonary veins assessed by high-resolution optical mapping. Circulation 2003;107:1816–21. 39. Chou CC, Nihei M, Zhou S, et al. Intracellular calcium dynamics and anisotropic reentry in isolated canine pulmonary veins and left atrium. Circulation 2005;111:2889–97. 40. Hsieh MH, Chen SA, Tai CT, et al. Double multielectrode mapping catheters facilitate radiofrequency catheter ablation of focal atrial fibrillation originating from pulmonary veins. J Cardiovasc Electrophysiol 1999;10:136–44. 41. Atienza F, Almendral J, Moreno J, et al. Activation of inward rectifier potassium channels accelerates atrial fibrillation in humans: evidence for a reentrant mechanism. Circulation 2006;114:2434–42. 42. Kumagai K, Ogawa KM, Noguchi H, et al. Electrophysiologic properties of pulmonary veins assessed using a multielectrode basket catheter. J Am Coll Cardiol 2004;43:2281–9. 43. Jais P, Hocini M, Macle L, et al. Distinctive electrophysiological properties of pulmonary veins in patients with atrial fibrillation. Circulation 2002;106:2479–85. 44. Nattel S, Bourne G, Talajic M. Insights into mechanisms of antiarrhythmic drug action from experimental models of atrial fibrillation. J Cardiovasc Electrophysiol 1997;8:469–80. 45. Malécot CO, Bredeloux P, Findlay I, et al. A TTX-sensitive resting Na permeability contributes to the catecholaminergic automatic activity in rat pulmonary vein. J Cardiovasc Electrophysiol 2015;26:311–9. 46. Doisne N, Maupoil V, Cosnay P, et al. Catecholaminergic automatic activity in the rat pulmonary vein: electrophysiological differences between cardiac muscle in the left atrium and pulmonary vein. Am J Physiol Heart Circ Physiol 2009;297:H102–8. 47. Honjo H, Boyett MR, Niwa R, et al. Pacing-induced spontaneous activity in myocardial sleeves of pulmonary veins after treatment with ryanodine. Circulation 2003;107:1937–43. 48. Patterson E, Po SS, Scherlag BJ, et al. Triggered firing in pulmonary veins initiated by in vitro autonomic nerve stimulation. Heart Rhythm 2005;2:624–31. 49. Chou CC, Nguyen BL, Tan AY, et al. Intracellular calcium dynamics and acetylcholine-induced triggered activity in the pulmonary veins of dogs with pacing-induced heart failure. Heart Rhythm 2008;5:1170–7. 50. Chen YC, Chen SA, Chen YJ, et al. Effects of thyroid hormone on the arrhythmogenic activity of pulmonary vein cardiomyocytes. J Am Coll Cardiol 2002;39:366–72. 51. Chen YJ, Chen YC, Chan P, et al. Temperature regulates the arrhythmogenic activity of pulmonary vein cardiomyocytes. J Biomed Sci 2003;10:535–43. 52. Tai CT, Chiou CW, Wen ZC, et al. Effect of phenylephrine on focal atrial fibrillation originating in the pulmonary veins and superior vena cava. J Am Coll Cardiol 2000;36:788–93. 53. Miyauchi Y, Hayashi H, Miyauchi M, et al. Heterogeneous pulmonary vein myocardial cell repolarization implications for reentry and triggered activity. Heart Rhythm 2005;2:1339–45.

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Diagnostic Electrophysiology & Ablation

Optimal Anticoagulation Strategy for Cardioversion in Atrial Fibrillation P hilipp Bushov en, Sv e n L i n z b a c h , M a t e Va m o s a n d S t e f a n H H o h n l o s e r Department of Cardiology, Division of Clinical Electrophysiology, JW Goethe University, Frankfurt, Germany

Abstract For many patients with symptomatic atrial fibrillation, cardioversion is performed to restore sinus rhythm and relieve symptoms. Cardioversion carries a distinct risk for thromboembolism which has been described to be in the order of magnitude of 1 to 3 %. For almost five decades, vitamin K antagonist therapy has been the mainstay of therapy to prevent thromboembolism around the time of cardioversion although not a single prospective trial has formally established its efficacy and safety. Currently, three new direct oral anticoagulants are approved for stroke prevention in patients with non-valvular atrial fibrillation. For all three, there are data regarding its usefulness during the time of electrical or pharmacological cardioversion. Due to the ease of handling, their efficacy regarding stroke prevention, and their safety with respect to bleeding complications, the new direct oral anticoagulants are endorsed as the preferred therapy over vitamin K antagonists for stroke prevention in non-valvular atrial fibrillation including the clinical setting of elective cardioversion.

Keywords Atrial fibrillation, cardioversion, stroke prevention, direct oral anticoagulants Disclosure: Stefan H Hohnloser, MD, FACC, FESC, FHRS, has served as a consultant for Bayer Healthcare, Boehringer Ingelheim, Bristol Myers Squibb, Johnson & Johnson and Pfizer. Philipp Bußhoven, MD, Sven Linzbach, MD, and Mate Vamos, MD, have no conflicts of interest to declare. Received: 8 October 2014 Accepted: 19 January 2015 Citation: Arrhythmia & Electrophysiology Review 2015;4(1):44–6 Access at: www.AERjournal.com Correspondence: Stefan H Hohnloser, MD, FACC, FESC, FHRS, Department of Cardiology, Division of Clinical Electrophysiology, JW Goethe University, Theodor-Stern-Kai 7, D 60590 Frankfurt, Germany. E: hohnloser@em.uni-frankfurt.de

Atrial Fibrillation, Cardioversion and Stroke Risk Atrial fibrillation (AF) is the most common serious chronic heart rhythm disorder with an estimated prevalence in the general population of around 1 %.1 The arrhythmia affects about 2.2 million persons in the US and 4.5 million individuals in the EU. Due to the advancing age of the population, the prevalence of AF is likely to increase even further.2 AF is associated with major morbidity and mortality, particularly due to thromboembolic complications. In patients older than 80 years, approximately 15 % of all strokes are attributable to AF. Moreover, AF-related strokes are known to be associated with higher mortality and more disability than strokes of other origin.3 The risk for thromboembolism exists even in younger patients, and even relatively short episodes of the arrhythmia have been shown to be linked to thromboembolic events.4 For many patients with symptomatic AF, cardioversion is performed to restore sinus rhythm and relieve symptoms. The first successful closed-chest defibrillation of a human was described by Zoll et al. in 1956.5 Soon thereafter, Lown and co-workers evaluated the utility of external cardioversion for non-lethal arrhythmias, such as AF or atrial flutter. At that time, most patients undergoing cardioversion of AF suffered from rheumatic valve disease such that the high risk for thromboembolism was well appreciated.6,7 To reduce the risk for thromboembolism, patients with mitral stenosis subjected to cardioversion ‘were generally treated with anticoagulant drugs for 3 to 4 weeks’ prior to the procedure.6,7 A few years later, the first systematic report on the incidence of stroke and systemic embolism in patients undergoing electrical cardioversion of AF was published by Bjerkelung and Orning. 8 They performed a non-randomised,

Hohnloser_FINAL.indd 44

prospective cohort study of 437 patients. In this classic study, 11 (6.8 %) embolic events occurred in 209 non-anticoagulated patients compared with two (1.1 %) in 228 subjects who had received appropriate anticoagulation therapy prior to the procedure. Albeit not a randomised study, these observations formed the cornerstone of the modern practice of anticoagulation in patients undergoing electrical or pharmacological cardioversion of AF. Of note, not a single randomised controlled trial has been conducted comparing vitamin K antagonist anticoagulation with placebo therapy in this clinical setting. Thus, anticoagulation practices surrounding cardioversion have been empirical since the advent of the procedure, based on the known risk for a serious complication. To make cardioversion safer, in the 1990s the use of pre-cardioversion transoesophageal echocardiography (TOE) was systematically evaluated. In a randomized controlled trial, Klein et al. demonstrated that the use of TOE to guide cardioversion management in patients with AF represents a clinically effective alternate strategy to conventional therapy with anticoagulation therapy by means of vitamin K antagonists for at least 3 weeks prior to the procedure.9 Of note, even when relying on the TOE strategy, patients had to be anticoagulated for at least 3 weeks following cardioversion. In essence, therefore, a period of oral anticoagulation is necessary, irrespective of whether a TOE-guided cardioversion strategy is followed or a conventional treatment approach. Hence, the most recent treatment guidelines for AF recommend that in patients with AF or atrial flutter for ≥48 hours, or unknown duration, anticoagulation with either a vitamin K antagonist or a direct oral anticoagulant (DOAC) is mandatory for at least 3 weeks prior to and 4 weeks after cardioversion.10,11

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Optimal Anticoagulation Strategy for Cardioversion in Atrial Fibrillation

Table 1: Pharmacology of Old and New Oral Anticoagulants Mechanism of

Apixaban Dabigatran Edoxaban Rivaroxaban Direct factor Xa Direct thrombin Direct factor Xa Direct factor Xa inhibitor

Warfarin Inhibitor of vitamin

action

inhibitor

K-dependent factors

Oral bioavailability

~50 %

~6.5 %

62 %

>95 %

80–100 %

Pro-drug No

Yes No No

Food effect

Yes (20 mg and 15 mg doses

Yes

need to be taken with food)

(foods high in vitamin K)

Renal clearance

~27 %

85%

49 %

~33 %

Tmax

3–4 hours

0.5–2 hours

1–2 hours

2–4 hours

3–5 days

Mean half-life (t1/2)

12 hours

12–17 hours

6–11 hours

5–9 hours (young) / 11–13 hours (elderly)

40 hours

Tmax = time taken to reach the maximum concentration.

Vitamin K Antagonist Therapy Prior to and Following Cardioversion Vitamin K antagonists have been the standard of care for stroke prevention in AF for the last 50 years. The shortcomings of vitamin K antagonists therapy have long been recognised and include the slow onset and offset of action, the narrow therapeutic window requiring frequent international normalised ratio (INR) measurements, the relatively high bleeding risk, and the numerous interactions of these drugs with food and other medications. A major drawback of warfarin particularly in the setting of cardioversion is its delayed onset of action. In fact, in many patients it will take 2 or more months to achieve adequate anticoagulation for cardioversion with warfarin.12,13 This delay implies persistence of symptoms and may render the arrhythmia more difficult to terminate. As a consequence, there is a need for heparin infusion or low molecular weight heparin as bridging therapy if the patient’s INR is not in the therapeutic range or if the patient is new to vitamin K antagonists. Unfortunately, bridging therapy is cumbersome for the patient and has been shown to be associated with an increased risk for bleeding complications. All of these problems similarly apply for the TOE-guided treatment approach when oral anticoagulation must be initiated immediately after cardioversion. Hence, there is a clear need for better treatment alternatives for patients scheduled for electrical or pharmacological cardioversion.

New Direct Oral Anticoagulants in the Setting of Cardioversion of Atrial Fibrillation Currently, four new oral anticoagulants, the direct thrombin inhibitor dabigatran and the factor Xa inhibitors (apixaban, rivaroxaban and edoxaban), have been approved for stroke prevention in AF in various jurisdictions. As shown in Table 1, these agents have predictable pharmacokinetics and pharmacodynamics, which makes them much easier to handle than the vitamin K antagonists. The rapid onset and offset of their anticoagulant effect is of particular advantage in the cardioversion setting. Patients are effectively anticoagulated after intake of 1 or 2 doses of one of these DOACs. All four DOACs have been compared with vitamin K antagonist therapy in patients with paroxysmal, persistent or permanent AF.14–17 In essence, all have at least the same or even superior efficacy as warfarin regarding prevention of thromboembolic events, and major bleeding events are less frequent with DOACs than with vitamin K antagonists (over an exposure of 1 to 3 years).17 Experience with the use of these DOACs in the clinical setting of cardioversion has been published for dabigatran, apixaban and rivaroxaban. The pivotal AF study of dabigatran, the Randomised Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial, included

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Hohnloser_FINAL.indd 45

18,113 patients randomised to dabigatran 110 mg twice daily, dabigatran 150 mg twice daily or warfarin.14 During the trial, 1,319 cardioversions were performed in 1,270 patients over a 24-month follow-up period.18 Although the duration of anticoagulation before cardioversion was not reported, it was recommended that patients assigned to dabigatran receive at least 3 weeks of therapy before cardioversion. Stroke and systemic embolism rates at 30 days were 0.8 % for dabigatran 110 mg, 0.3 % for dabigatran 150 mg, and 0.6 % for warfarin without significant differences between the treatment groups. Approximately 25 % of patients assigned to dabigatran underwent pre-cardioversion TOE of which only 1.8 % and 1.2 % were positive for left atrial thrombi. Major bleeding events were observed at similar rates in the three groups (1.7 %; 0.6 %; 0.6 %). In summary, therefore, this subanalysis of the RE-LY trial represents the first controlled experience with one of the DOACs in the setting of cardioversion and demonstrates its efficacy for prevention of thromboembolic events and bleeding complications similar to that of warfarin. More limited experience exists for apixaban in the setting of cardioversion. In the large pivotal AF trial of this compound, the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial, a total of 743 cardioversions were performed in 540 patients: 265 first cardioversions in patients assigned to apixaban and 275 in those assigned to warfarin.19 The mean time to the first cardioversion for patients assigned to warfarin and apixaban was 243±231 days and 251±248 days, respectively; 75 % of the cardioversions occurred by 1 year. Baseline characteristics of cardioverted patients did not differ between the two treatment arms. There were no strokes or systemic embolisms in subjects undergoing cardioversion, and major bleeding events were similarly rare (one patient in each group). During the 30-day follow-up period of this substudy, two patients in each group died. The investigators thus concluded that stroke and bleeding risks for patients undergoing cardioversion with apixaban were low and similar to those observed with warfarin. The third DOAC, rivaroxaban, was compared with warfarin in the pivotal 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) trial.16 The study protocol excluded patients for whom electrical cardioversion was planned. As a consequence, only 143 patients underwent electrical cardioversion over the median follow-up of 2.1 years,20 far too few patients to estimate benefits and risks for this DOAC compared with the standard of care with warfarin. For this reason, a separate study was conceptualised to examine the efficacy and safety of oral

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Diagnostic Electrophysiology & Ablation rivaroxaban in the setting of elective cardioversion, the Explore the Efficacy and Safety of Once-daily Oral Rivaroxaban for the Prevention of Cardiovascular Events in Patients with Nonvalvular Atrial Fibrillation Scheduled for Cardioversion (X-VERT) trial.21 X-VeRT is the first prospective randomised trial of a novel oral anticoagulant in patients with AF undergoing elective cardioversion. A total of 1,504 patients with AF >48 hours or of unknown duration were assigned to rivaroxaban (20 mg once daily, 15 mg if creatinine clearance was between 30 and 49 ml/minute) or dose-adjusted vitamin K antagonists in a 2:1 ratio. Importantly, investigators selected either an early (target period of 1–5 days after randomisation) or delayed (3–8 weeks) cardioversion strategy for their patients. The primary efficacy measure was a composite of stroke, transient ischaemic attack, peripheral embolism, myocardial infarction or cardiovascular death. The primary safety outcome was major bleeding. In the rivaroxaban group, there were five primary efficacy outcome events (two strokes) among 978 patients (0.51 %) compared with five (two strokes) in 492 warfarin-treated patients (1.02 %) (relative risk [RR] 0.50, 95 % confidence interval [CI] 0.15–1.73). In terms of the two cardioversion strategies, four patients in the rivaroxaban group experienced primary efficacy events following early cardioversion (0.71 %) and one following delayed cardioversion (0.24 %). In the vitamin K antagonists group, three patients had primary efficacy events following early cardioversion (1.08 %) and two following delayed cardioversion (0.93 %). Rivaroxaban was associated with a shorter time to cardioversion compared with vitamin K antagonists, particularly in the delayed cardioversion arm. The median time between randomisation and cardioversion was 22 days (interquartile range 21–26) for patients assigned to rivaroxaban compared with 30 days (range 23–42) for those who received warfarin therapy (p<0.001). Whereas only one rivaroxaban patient could not be cardioverted within the target time range of 21–25 days due to lack of compliance, a total

3. 4. 5.

Fuster V, Rydén LE, Cannom DS, et al. ACC/AHA/ESC 2006 Guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation 2006;114:e257–354. Miyasaka Y, Barnes ME, Gersh BJ, et al. Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence. Circulation 2006;114:119–25. Lin HJ, Wolf PA, Kelly-Hayes M, et al. Stroke severity in atrial fibrillation. The Framingham study. Stroke 1996;27:1760–4. Healey J, Connolly SJ, Gold MR, et al. Subclinical atrial fibrillation and the risk of stroke. N Engl J Med 2012;366:120–9. Zoll PM, Linenthal AJ, Gibson W, et al. Termination of ventricular fibrillation in man by externally applied electric countershock. N Engl J Med 1956;254:727–32. Lown B, Amarasingham R, Neuman J, et al. New method for terminating cardiac arrhythmias. Use of synchronized capacitor discharge. JAMA 1962;182:548–55. Lown B, Perlroth MG, Kaidbey S, et al., “Cardioversion” of atrial fibrillation. A report on the treatment of 65 episodes in 50 patients, N Engl J Med 1963;269:325–31. Bjerkelund CJ, Orning OM. The efficacy of anticoagulant therapy in preventing embolism related to D.C. electrical conversion of atrial fibrillation. Am J Cardiol 1969;23:208–16.

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10.

11.

12.

13.

14.

15.

16.

17.

18.

of 95 patients assigned to warfarin could not undergo cardioversion in the target time range because of inadequate anticoagulation (INR values outside the therapeutic range). This finding underscores the difficulties inherent to warfarin therapy mentioned above. In terms of the safety profile of rivaroxaban, there were no significant differences in terms of major bleeding events between the two treatment groups (six patients [0.6 %] in the rivaroxaban group and four patients [0.8 %] in the vitamin K antagonists group; RR 0.76, 95 % CI 0.21–2.67). The aforementioned studies therefore show in aggregate that all three DOACs represent effective and safe alternatives to vitamin K antagonist therapy in patients scheduled for cardioversion. In addition, there are now ‘real-world’ experiences published on the efficacy and safety of DOACs in everyday clinical practice showing that these compounds can be used safely and in a more timely fashion.22 Currently, two further randomised controlled studies are being performed comparing apixaban23 and edoxaban24, respectively, with vitamin K antagonist therapy in patients undergoing cardioversion. Due to their rapid onset and offset of action, the advantages of DOACs over vitamin K antagonists in the handling of patients undergoing cardioversion are obvious, allowing more patients to be cardioverted within shorter time periods. Whether this will eventually result in a reduction in healthcare resource utilisation needs further evaluation. The use of DOAC stroke prevention therapy in the AF population in general likely represents the preferred therapeutic strategy. For subjects undergoing electrical or pharmacological cardioversion with or without concomitant TOE, DOAC treatment is a good alternative to vitamin K antagonists in appropriately selected patients. This is already endorsed by guidelines10 and by practice recommendations of the European Society of Cardiology.25 n

Klein AL, Grimm RA, Murray RD, et al. Use of transesophageal echocardiography to guide cardioversion in patients with atrial fibrillation. N Engl J Med 2001;344:1411–20. Camm AJ, Lip GY, De Caterina R, et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation. Eur Heart J 2012;33:2719–49. January CT, Wann LS, Alpert JS et al. 2014 AHA/ACC/HRS Guideline for the management of patients with atrial fibrillation: Executive summary. J Am Coll Cardiol 2014;64:2246–80. Kim MH, Krishnan K, Jain S, et al. Time course and frequency of subtherapeutic anticoagulation for newly prescribed warfarin anticoagulation before elective cardioversion of atrial fibrillation or flutter, Am J Cardiol 2001;88:1428–31. Diener HC, Weber R, Lip GY, Hohnloser SH. Stroke prevention in atrial fibrillation: do we still need warfarin? Curr Opin Neurol 2012,25:27–35. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139–51. Granger C, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981–92. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883–91. Ruff TR, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet, 2013;383:955–62. Nagarakanti R, Ezekowitz MD, Oldgren J, et al. Dabigatran versus warfarin in patients with atrial fibrillation. An analysis

of patients undergoing cardioversion. Circulation 2011;123:131–6. 19. Flaker G, Lopes RD, Al-Khatib SM, et al. Efficacy and safety of apixaban in patients after cardioversion for atrial fibrillation. Insights from the ARISTOTLE trial. J Am Coll Cardiol 2014;63:1082–7. 20. Piccini JP, Stevens SR, Lokhnygina Y, et al. Outcomes after cardioversion and atrial fibrillation ablation in patients treated with rivaroxaban and warfarin in the ROCKET AF trial. J Am Coll Cardiol 2013;61:1998–2006. 21. Cappato R, Ezekowitz MD, Klein AL, et al. Rivaroxaban versus vitamin K antagonists for cardioversion in atrial fibrillation. Eur Heart J 2014;35:3346–55. 22. Arujuna A, Ooues G, Abbas A, et al. Electrical cardioversion of atrial fibrillation with the novel oral anticoagulants: A single centre UK-based registry experience. Europace 2014;16(Suppl 3):16. 23. Clinicaltrials.gov. Edoxaban vs. warfarin in subjects undergoing cardioversion of atrial fibrillation (ENSUREAF). Available at: https://www.clinicaltrials.gov/ct2/show/ NCT02072434 (accessed 2 February 2015). 24. Clinicaltrials.gov. Study of the blood thinner, apixaban, for patients who have an abnormal heart rhythm (atrial fibrillation) and expected to have treatment to put them back into a normal heart rhythm (Cardioversion) (EMANATE). Available at: https://www.clinicaltrials.gov/ct2/show/ NCT02100228 (accessed 2 February 2015). 25. Heidbuchel H, Verhamme P, Alings M, et al. EHRA practical guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation: executive summary. Eur Heart J 2013;34:2094–106.

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Diagnostic Electrophysiology & Ablation

Role of Rotors in the Ablative Therapy of Persistent Atrial Fibrillation Amir A Sc hric k e r, 1 J u n a i d Z a m a n 2 a n d S a n j i v M N a ra y a n 2 1. Department of Cardiovascular Medicine, University of California San Diego Medical Center, San Diego, US; 2. Department of Cardiovascular Medicine, Stanford Medicine, Stanford, California, US

Abstract Atrial fibrillation (AF) ablation is increasingly used to maintain sinus rhythm yet its results are sub-optimal, especially in patients with persistent AF or prior unsuccessful procedures. Attempts at improvement have often targeted substrates that sustain AF after it is triggered, yet those mechanisms are debated. Many studies now challenge the concept that AF is driven by self-sustaining disordered wavelets, showing instead that localised drivers (rotors) may drive disorder via a process known as fibrillatory conduction. Novel mapping using wide-area recordings, physiological filtering and phase analysis demonstrates rotors in human AF. Contact mapping with focal impulse and rotor modulation (FIRM) shows that localised ablation at sources can improve procedural success in many populations on long-term follow up and some newer approaches to rotor mapping are qualitatively similar. This review critically evaluates the data on rotor mapping and ablation, which advances our conceptual understanding of AF and holds the promise of substantially improving ablative outcomes in patients with persistent AF.

Keywords Atrial fibrillation, ablation, rotors, focal sources, substrate, trigger Disclosure: This work was supported by grants to Dr Sanjiv M Narayan from the NIH (HL70529, HL83359, HL103800) and the Doris Duke Charitable Foundation. Dr Narayan is co-author of intellectual property owned by the University of California Regents and licensed to Topera Inc. Dr Narayan is a consultant to Abbott Inc., Medtronic and the American College of Cardiology. Amir A Schricker and Junaid Zaman have no conflicts of interest to declare. Received: 24 January 2015 Accepted: 18 March 2015 Citation: Arrhythmia & Electrophysiology Review 2015;4(1):47–52 Access at: www.AERjournal.com Correspondence: Sanjiv Narayan, Stanford Medicine, 780 Welch Road, Suite CJ250F, Stanford, US, CA 94305. E: sanjiv1@stanford.edu

Catheter ablation is more effective than pharmacological therapy for the secondary prevention of patients with paroxysmal1,2 and persistent3,4 atrial fibrillation (AF) and has an emerging role in the primary prevention of paroxysmal AF.5,6 Nevertheless, in randomised clinical trials (RCTs) its success in treating patients with paroxysmal AF is 40–60 % for a single procedure and 70 % for multiple procedures at one year,1,2 and results for persistent AF are lower.7,8 Thus, there is an urgent unmet need to improve our understanding of mechanistic targets for AF in each patient, to match recent advances in ablation energy delivery and catheter positioning.

for different triggers from both atria – separated by 2.1 ± 1.7 cm from trigger sites (see Figure 1).13

This report reviews mechanistic data on human AF, mapping technologies that provide the opportunity to reconcile fundamental mechanisms in individual patients and their therapeutic application.

Self-sustaining disorganisation was traditionally considered the mechanism of AF maintenance. This mechanism is supported by computational models in which multiple wavelets sustain AF if there is enough room in the atrium (‘critical mass’),14 proposals that dissociation between the epicardium and endocardium may be contributory15 and plaque recordings from the atria of patients in the operating room showing re-entry without apparent organisation. Limitations to these studies are that fibrillatory maps are based upon recordings that poorly represent local activation;16 only small areas of the atria were mapped (<10–20 %) and while these studies show that disorganisation exists they did not test if it self-sustains. The success of widespread ablation or Maze surgery supports the concept of self-sustaining disorganisation, but are also consistent with coincidental ablation of localised sources.

Atrial Fibrillation Mechanisms AF is initiated by triggers predominantly near the pulmonary veins (PV),9 with increasingly recognised sites outside the PVs.10–12 To improve success, ablation to eliminate AF triggers should thus also target non-PV triggers, although they are transient and difficult to locate. Another potential ablative target is the mechanistic cascade by which triggers initiate AF, yet this is relatively unstudied. We recently showed – using wide-area mapping during spont aneous and induced AF – that the first cycles of AF after a trigger exhibit a single organised re-entrant spiral wave or focal driver (see Figure 1) that subsequently disorganises.13 Remarkably, these AF-initiating mechanisms may be relatively spatially fixed for each patient – even

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Thus, AF initiation is likely to be a two-step mechanistic process, in which 1) a trigger initiates an organised spiral wave or focal source at patient-specific anatomical sites that 2) lead rapidly to disorganisation to produce the classical AF phenotype. This begs the question of whether AF maintenance is driven by self-sustaining disorganisation, or whether disorganisation is actually sustained by localised AF drivers (rotors or focal drivers).

Localised sources for AF have been proposed for decades, supported by many clinical studies in the era of AF mapping and ablation. This

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Diagnostic Electrophysiology & Ablation Figure 1: Atrial Fibrillation Initiation via a Rotor in an 81-year-old Man with Paroxysmal Atrial Fibrillation

Figure 2: Process for Focal Impulse and Rotor Modulation-guided Mapping and Ablation A Basket placed first in RA

B Right atrial rotor in AF Superior vena cava

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Isochronal activation map depicting (A) the final sinus beat, with earliest activation (red) commencing at the low sinus node, followed by (B) a spontaneous premature atrial complex from the anterolateral right atrium (RA) causing slowed conduction in the inferior RA, after which a septal right atrial beat in (C) initiates atrial fibrillation (AF) via a rotor in the mid septal RA. Activation encounters late-activated tissue in the low septal RA from the prior beat, cannot activate clockwise and thus spins in the opposite direction. Figure adapted from Schricker et al., 2014.13

includes modulation or termination of AF by focal ablation or lesion sets insufficient to limit critical mass17,18 and anecdotes such as reproducible AF termination by catheter contact at one location.19 These observations directly support localised sources and contradict the concept of self-sustaining disorder. Indirect evidence for localised mechanisms include the spatiotemporal stability of AF,20 stable regions of high dominant frequency and consistent vectors of AF propagation.21 These models explain the success of hierarchical means of eliminating AF, rather than a probabilistic reduction in atrial mass alone.

Identification of Rotors in Human Atrial Fibrillation

6 5 4 3 Inferior mitral

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A: Basket placed first in the right atrium (RA) on anteroposterior fluoroscopy, that also shows coronary sinus and ablation catheters. B: Counterclockwise rotor in posterolateral RA on focal impulse and rotor modulation (FIRM) map, that is ablated with elimination confirmed on a remap. C: Basket is now placed in the left atrium (LA). D: Counterclockwise rotor in midposterior LA on FIRM map, also targeted for ablation. Figure adapted from Kowal et al., 2013.33

contact. Inter-electrode separation is 4â&#x20AC;&#x201C;6 mm along each spline, with interspline separation of ~5 mm near poles and ~10 mm at equatorial electrodes. This is theoretically sufficient to map re-entry circuits in human atria whose minimum wavelength is ~4â&#x20AC;&#x201C;5 cm.22 Direct electrode contact baskets overcome many limitations inherent to other mapping methods, such as potentially unreliable signals in AF from the inverse solution, limited mapping areas by surgical plaques, and toxicity from voltage-sensitive dyes. Nevertheless, improved basket resolution and compliance characteristics would further enhance mapping.

Separating Local from Far-field Activation

Focal impulse and rotor modulation (FIRM) mapping was first reported in 2011 to systematically and reproducibly identify localised drivers (rotors and focal sources) in human AF. Mechanistic studies demonstrate that such regions sustain human AF, clinical data report benefits for rotor ablation and multicentre RCTs are underway. Alternative techniques are increasingly available that reveal rotors and focal sources with many similarities but some differences to those identified by FIRM. While some differences may be explained methodologically, some will need pathophysiological studies to be reconciled. We summarise three basic principles that may have limited historical mapping of human AF, that were addressed specifically by FIRM and emerging mapping techniques.

Intra-cardiac AF signals exhibit significant spatiotemporal variability, yet are more discrete using monophasic action potential (MAP) recordings than apparent from traditional bipolar or unipolar clinical recordings. In this sense, MAP signals may be closer to optically recorded signals based on human atrial repolarisation time (MAP duration) at different rates in different regions of both atria,23 how this alters signal analysis during AF24 and how it combines with rate-dependent conduction slowing25 to cause localised re-entry during AF.26 This has been the basis of physiological filtering employed in FIRM mapping to separate principal components from noise.27

Wide-area Mapping

Traditional approaches to activation mapping are difficult to apply to AF. Firstly, rotors show precession (limited meander, see Figure 3), a biophysical property of the core (phase singularity) that generates variable spiral arms that may not produce a classical rotational sequence on fixed electrodes. Precession also causes complex Doppler effects on local electrograms which, combined with disorganisation of spiral arms (fibrillatory conduction), makes activation mapping even

FIRM records AF in both atria sequentially using direct-contact multi-electrode baskets (see Figure 2). Each basket comprises 64 electrodes, on eight splines of eight electrodes, advanced through the femoral veins to the right atrium (RA) and to the left atrium (LA) via transseptal puncture. Catheters are adjusted under fluoroscopic, echocardiographic and electro-anatomical guidance to optimise tissue

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Signal Processing Approaches to Identify and Track Precessing Rotors

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Role of Rotors in the Ablative Therapy of Persistent Atrial Fibrillation

Figure 3: Stable Atrial Fibrillation Rotor for Over 30 Minutes Baseline AF

Figure 4: Non-invasive Mapping Identifying Atrial Fibrillation Re-entrant and Focal Driver Domains

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Phase maps, created by electrocardiographic mapping, at successive snapshots in time showing a right atrial rotor during persistent atrial fibrillation (AF). Blue represents a depolarising wavefront. Rotational activation in this case shows a large spatial domain with minimal fibrillatory conduction (disorganisation) distant from the source. Figure adapted from Haissaguerre et al., 2014.37

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Inferior mitral valve A 58-year-old man in whom focal impulse and rotor modulation (FIRM) mapping of atrial fibrillation (AF) revealed a counterclockwise rotor in the mid-posterior left atrium stable for >30 minutes (10,227 cycles). Slight meandering (precession) of the rotor core is evident. Note the disorganised fibrillatory activity (blocked white arrows) at the periphery of the organised rotor. Figure adapted from Swarup et al., 2014.41

more difficult. In cell monolayers, rotor meandering causes fusion of action potentials to produce fractionated electrograms,28 that in clinical studies is further confused by the multiple technical causes of fractionated electrograms.29 These mechanisms may obscure rotors or give the illusion of rotors that are ‘unstable’ in activation maps, but are continuous if appropriate signal processing techniques are used. Phase mapping is a signal processing approach that is increasingly utilised to identify rotors and track them as they precess. Phase mapping was developed in animal studies over two decades ago using voltage sensitive dyes applied to action potentials.30 Put simply, phase mapping can identify AF rotors as sites where activation encroaches upon recovery – the core of a spiral wave. With a knowledge of local recovery time (repolarisation, action potential duration), rotors are identified as the crossing of lines of activation and recovery (phase singularities).

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Since the demonstration of sustained human AF rotors in the Conventional Ablation for Atrial Fibrillation With or Without Focal Impulse and Rotor Modulation (CONFIRM) trial31 and multicentre FIRM registry,32,33 other investigators have shown localised rotational activity using PentaRay catheters,34 point-by-point wide-area mapping with wavelet similarity analysis,35 small intra-operative plaques36 and the inverse solution from body surface electrocardiograms (ECGs).37

Late 180

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Differences Between Rotor Mapping Approaches

Few studies have compared the characteristics of human AF rotors between mapping techniques. However, an emerging literature shows several similarities between rotor-mapping techniques. As with FIRM, newer techniques reveal a similar prevalence of rotational and focal sources (essentially all mapped patients with persistent and paroxysmal AF), location of sources in regions that are reproducible for hours or days in each patient, a similar split between right and left atrial sources (30/70 %) and improved ablative outcomes by targeting rotors.35 The most obvious stated difference is in rotor stability, with inverse-solution ECG methods concluding less stable sources than FIRM. Although differences are unlikely to be fully reconciled without direct comparisons to contact recordings in the same patient, several factors may be at play. First, while rotors detected by contact electrodes move with the atria during respiration or systole, rotors detected on and referenced to the body surface will of course be less stable when projected onto the moving heart. The mere act of projecting electrograms from the heart to the body surface may also magnify instability. 38 Second, virtual electrograms from the inverse solution may not accurately depict contact electrograms in AF.39 Third, notwithstanding these differences, a recent study using the inverse solution37 showed a small number of AF drivers regions that were temporally stable (for days between mapping and ablation) in limited atrial regions targeted for ablation as in the CONFIRM trial.40 Finally, studying only short ECG segments between QRS complexes from the inverse solution37 may diminish stability evident when AF is mapped for longer periods.41 Re-mapping after rotor elimination may help to validate rotors that are physiological and eliminated by ablation, a central element of FIRM-guided ablation.

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Diagnostic Electrophysiology & Ablation Figure 5: Long-term Conventional Ablation for Atrial Fibrillation With or Without Focal Impulse and Rotor Modulation Follow-up Multiprocedure, p=0.007 1.0

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Atrial fibrillation (AF)-free survival for focal impulse and rotor modulation (FIRM)-guided ablation (blue) compared with conventional ablation (red) at three years (p=0.003). Figure adapted from Narayan et al., 2014.47

A second major difference between techniques is the spatial domain of organised spiral arms emanating from rotational sources. In FIRM maps, organised sources show spiral arms that disorganise via fibrillatory conduction (see Figure 3). Conversely, non-invasive phase maps often show organised activity (isolines) that often radiates across much/all of the atria from sources (see Figure 4). This is less consistent with fibrillatory conduction, and studies should determine if this difference represents smoothing from the body surface, algorithms used, or different definitions of sources.

5-10 cm2 of atrial tissue. This area is less than conventional PV isolation (typically >40 minutes, or areas of >20 cm2), ablation of lines or complex fractionated atrial electrograms. FIRM ablation is commonly added to PV isolation but has been performed alone. It is unclear how localised ablation eliminates rotors and different mechanisms may be at play in each patient. In computer models, ablation lesions placed within homogeneous atrial tissue will anchor an AF rotor to atrial tachycardia. Indeed, this result is commonly seen in FIRM studies. In more realistic non-uniform atrial models, ablation can terminate a rotor by several mechanisms including de-anchoring a rotor that meanders until it meets a non-conducting boundary and extinguishes, or eliminating regions of low excitability such that the wave front and back meet in remaining regions of high excitability and terminate. Ablation may also modify substrate more generally, such as by potential autonomic factors. A major discussion point is why AF does not acutely terminate whenever sources are eliminated – and in general why AF does not have to be terminated by ablation to achieve clinical success.46 There are several hypotheses on this topic. First, it is possible that additional sources continue in unmapped regions of the atrium, that sustain AF acutely but are insufficient to sustain AF long-term. Second, AF may be a two-step process in which a driver interacts with fibrillatory conduction. The extent of time for which fibrillatory conduction can sustain AF without a driver before ‘burning out’ is unclear, but may be seconds to minutes in control patients, or minutes to hours in AF patients with remodelled atria. Ongoing studies are addressing these mechanisms.

Clinical Results of Rotor Ablation Studies have recently proposed electrogram-similarity approaches as surrogates for human AF rotors.35,42 Due to precession, there may theoretically be no fixed location where electrograms represent a rotor core,30,43 but this interesting approach may identify regions related to AF sources that should be tested in clinical trials. In FIRM maps, precessing rotors in human AF produce electrograms that are regular in some cases and ‘fractionated’ in others.29

Approach To Focal Impulse and Rotor Modulation-based Rotor Ablation

Conventional Ablation for Atrial Fibrillation With or Without Focal Impulse and Rotor Modulation Trial In this first trial of rotor/source mapping and ablation, 92 patients with drug-refractory AF underwent 107 consecutive ablation procedures. Cases were prospectively enrolled in one of two arms: FIRM-guided (34 %), whereby patients underwent FIRM-guided ablation followed by conventional ablation, or FIRM-blinded (66 %), who only underwent conventional ablation. The FIRM-blinded group still had FIRM mapping performed, offline, but was not used to guide therapy. The primary long-term endpoint was freedom from AF.

Ablation of Atrial Fibrillation Sources The principle for FIRM-guided ablation is that rotors should be targeted directly for ablation until they are eliminated on remaps. This is repeated for each AF source site with re-mapping to demonstrate progressive changes in AF. In FIRM-guided ablation, sources are ablated directly over their precession areas. The reason for the direct ablation approach is historical: in early cases of FIRM, rotors in the mid-RA or mid-LA were targeted first as part of a planned line of ablation to non-conducting obstacles, but AF terminated before lines were completed. Accordingly, direct source ablation has become the default method, to cover the rotor precession areas of 2–3 cm2 (or 6–10 non-overlapping lesions of ~5–7 mm diameter).29 Many catheters have been used, including 3.5 mm tip open-irrigated radiofrequency (Thermocool, BiosenseWebster, Diamond Bar, CA), 8 mm tip non-irrigated radiofrequency (Blazer, Boston Scientific, Natick, MA), or cryoablation44 and robotic navigation.45 Typically two to three simultaneous rotors are identified within a given patient, requiring ~15–20 minutes of ablation covering

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Localised sources were found in 97 % of all cases, with 2.1±1.0 sources per patient. Localised sources were mostly rotors (70 %) and lay in widespread locations (76 % LA and 24 % RA). Long-term follow up revealed that freedom from AF in the FIRM-guided limb was higher than in the conventional therapy limb at one and subsequently at three years (77.8 versus 38.5 %, p<0.001) (see Figure 5).47

Focal Impulse and Rotor Modulation Outcomes in Multicentre Trials Multicentre experiences in more than 30041 patients at over 10 independent laboratories support these results from FIRM-guided ablation.44,48 Notably as demonstrated by Miller et al.,44 even in largely persistent AF patients (71 %), FIRM-guided ablation achieved outcomes similar to those from CONFIRM, namely 80.5 % single-procedure freedom from AF, that trended higher in patients without prior ablation. Results were similar for persistent and paroxysmal AF (p=0.89). The additional recurrence from atrial tachycardias (including typical atrial flutter) in these studies has been approximately 10 %.

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Role of Rotors in the Ablative Therapy of Persistent Atrial Fibrillation

Clinical Data for other Rotor Mapping Approaches Other approaches to target rotors have validated the importance of rotors as therapeutic targets in human AF, although with fewer data. The largest series to date is from the non-invasive ECG imaging approach, which recruited persistent AF patients with similar LA size to the FIRM guided group in CONFIRM.37 Ablation of rotational and focal ‘driver domains’ produced a similar freedom from AF at 12 months as the previously described stepwise ablation approach, but with less ablation time. Compared with the CONFIRM trial, this study had a higher rate of AT recurrences, which may reflect longer ablation or different patients, used different monitoring (thrice-monthly Holter monitoring versus implanted continuous monitoring in most FIRMguided patients in CONFIRM) and more patients continued use of antiarrhythmic drugs than in CONFIRM. Overall, this study confirms the importance of localised sources in persistent AF and their potential for localised ablative treatment. Recently, results from a high-frequency source ablation (HFSA) approach showed non-inferiority at 12 months versus PV isolation (PVI), with improved safety outcomes.49 This builds upon solid translational research documenting sites of high dominant frequency (DF) as being responsible for driving AF50 but may differ from FIRMguided rotor ablation as technical issues regarding DF interpretation51 and spatiotemporal stability52 may mean a meandering rotor may not precisely co-localise with the site of highest DF.

Limitations from Rotor Mapping Studies. Both CONFIRM and other rotor mapping studies were non-randomised. The control populations in the non-invasive mapping study37 were from a non-consecutive historical cohort, which limits direct comparison. RCTs are underway, comparing source elimination with or without conventional ablation to conventional ablation alone. Endocardial mapping may also miss epicardial sources (and vice versa), or interpret intra-mural re-entry as focal breakthroughs, but currently simultaneous

Wilber DJ, Pappone C, Neuzil P, et al. Comparison of antiarrhythmic drug therapy and radiofrequency catheter ablation in patients with paroxysmal atrial fibrillation: a randomized controlled trial. JAMA 2010;303(4):333–40. 2. Packer DL, Kowal RC, Wheelan KR, et al. Cryoballoon ablation of pulmonary veins for paroxysmal atrial fibrillation: first results of the North American Arctic Front (STOP AF) pivotal trial. J Am Coll Cardiol 2013;61(16):1713–23. 3. Oral H, Pappone C, Chugh A, et al. Circumferential pulmonary-vein ablation for chronic atrial fibrillation. N Engl J Med 2006;354(9):934–41. 4. Ganesan AN, Shipp NJ, Brooks AG, et al. Long-term outcomes of catheter ablation of atrial fibrillation: a systematic review and meta-analysis. JAHA 2013;2(2):e004549. 5. Nielsen JC, Johannessen A, Raatikainen P, et al. Radiofrequency ablation as initial therapy in paroxysmal atrial fibrillation. New Engl J Med 2012;367:1587–95. 6. Morillo CA, Verma A, Connolly SJ, et al. Radiofrequency ablation vs antiarrhythmic drugs as first-line treatment of paroxysmal atrial fibrillation (RAAFT-2): a randomized trial. JAMA 2014;311(7):692–700. 7. Calkins CH. 2012 HRS/EHRA/ECAS Expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design. Heart Rhythm 2012;9(4):632–96. 8. Parkash R, Tang AS, Sapp JL, et al. Approach to the catheter ablation technique of paroxysmal and persistent atrial fibrillation: a meta-analysis of the randomized controlled trials. J Cardiovasc Electrophysiol 2011;22(7):729–38. 9. Haissaguerre M, Jais P, Shah DC, et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med 1998;339(10):659–66. 10. Schmitt C, Ndrepepa G, Weber S, et al. Biatrial multisite mapping of atrial premature complexes triggering onset of atrial fibrillation. Am J Cardiol 2002;89(12):1381–87. 11. Weber S, Ndrepepa G, Schneider M, et al. Electrophysiological differences of the spontaneous onset of paroxysmal and persistent atrial fibrillation. Pacing Clin Electrophysiol 2007;30(3):295–303.

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wide-area endocardial–epicardial mapping required to resolve such detail is not clinically feasible.

Clinical Implications The identification of rotors that sustain human AF provides a novel paradigm for understanding AF mechanisms and offers a mechanistically focused patient-specific approach to catheter ablation. This is of particular significance for 1) patients with persistent AF, as recent data suggest that adding linear or complex fractionated atrial electrogram (CFAE) ablation does not improve the ~50 % success of PVI alone in patients with persistent AF53 and 2) patients with postablation AF, who often have isolated or minimally re-connected PVs at redo procedures. Further studies should compare rotors and regions of fibrillatory conduction between invasive and non-invasive approaches. Mechanistic studies should examine whether rotors lie near regions of atrial fibrosis detectable using magnetic resonance imaging (MRI) or ganglionic plexi, that may provide additive methods to image and target therapy. Notwithstanding the success of rotor-based ablative therapy in many single-centre studies, the results from ongoing multicentre trials will ultimately determine its wider role.

Conclusions Improving outcomes for the growing number of patients with AF requires a deeper and unifying understanding of AF mechanisms. Identification of rotors sustaining human AF is now clinically feasible using available technology and a growing body of evidence shows that ablation targeting such rotors can improve long-term outcomes compared with conventional strategies alone. Rotor mapping and ablation may be of particular benefit in patients with persistent AF, in whom ablative targets are less clear. Results of multiple studies, including long-term data from CONFIRM, demonstrate that the patient-tailored therapy can reduce rates in patients with all types of AF, while reducing unnecessary ablation lesions. Multicentre RCTs are ongoing to better define the role of rotor ablation in the ablative treatment of persistent AF. n

12. Lau CP, Chun-Wah Siu D, Tse HF, Pulmonary vein in pathogenesis of persistent atrial fibrillation: an unsettled controversy. J Cardiovasc Electrophysiol 2014;25(5):477–8. 13. Schricker AA, Lalani GG, Krummen DE, et al. Rotors as drivers of atrial fibrillation and targets for ablation. Curr Cardiol Rep 2014;16(8):509. 14. Moe GK, Abildskov JA. Atrial fibrillation as a self-sustaining arrhythmia independent of focal discharge. Am Heart J 1959;58(1):59–70. 15. Eckstein J, Zeemering S, Linz D, et al. Transmural conduction is the predominant mechanism of breakthrough during atrial fibrillation: evidence from simultaneous endo-epicardial high-density activation mapping, Circ Arrhythm Electrophysiol 2013;6(2):334–41. 16. Narayan SM, Wright M, Derval N, et al. Classifying fractionated electrograms in human atrial fibrillation using monophasic action potentials and activation mapping: evidence for localized drivers, rate acceleration, and nonlocal signal etiologies. Heart Rhythm 2011;8(2):244–53. 17. Herweg B, Kowalski M, Steinberg JS. Termination of persistent atrial fibrillation resistant to cardioversion by a single radiofrequency application. Pacing Clin Electrophysiol 2003;26(6):1420–3. 18. Narayan SM, Krummen DE, Shivkumar K, et al. Treatment of atrial fibrillation by the ablation of localized sources: the Conventional Ablation for Atrial Fibrillation With or Without Focal Impulse and Rotor Modulation: CONFIRM trial. J Am Coll Cardiol 2012;60(7):628–36. 19. Tzou WS, Saghy L, Lin D. Termination of persistent atrial fibrillation during left atrial mapping. J Cardiovasc Electrophysiol 2011;22(10):1171–3. 20. Lazar S, Dixit S, Marchlinski FE, et al. Presence of left-to-right atrial frequency gradient in paroxysmal but not persistent atrial fibrillation in humans. Circulation 2004;110(20):3181–6. 21. Gerstenfeld EP, Sahakian AV, Swiryn S. Evidence for transient linking of atrial excitation during atrial fibrillation in humans. Circulation 1992;86(2):375–82. 22. Rappel WJ, Narayan SM. Theoretical considerations for mapping activation in human cardiac fibrillation. Chaos 2013;23(2):023113.

23. Narayan SM, Kazi D, Krummen DE, et al. Repolarization and activation restitution near human pulmonary veins and atrial fibrillation initiation: a mechanism for the initiation of atrial fibrillation by premature beats. J Am Coll Cardiol 2008c;52(15):1222–30. 24. Narayan SM, Krummen DE, Kahn AM, et al. Evaluating fluctuations in human atrial fibrillatory cycle length using monophasic action potentials. Pacing Clin Electrophysiol 2006;29(11):1209–18. 25. Lalani GG, Schricker A, Gibson M, et al. Atrial conduction slows immediately before the onset of human atrial fibrillation: a bi-atrial contact mapping study of transitions to atrial fibrillation. J Am Coll Cardiol 2012;59(6):595–606. 26. Schricker AA, Lalani GG, Krummen DE, et al. Human atrial fibrillation initiates via organized rather than disorganized mechanisms. Circ Arrhythm Electrophysiol 2014;7(5):816–24. 27. 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(5):447–54. 28. Yamazaki M, Vaquero LM, Hou L, et al. Mechanisms of stretch-induced atrial fibrillation in the presence and the absence of adrenocholinergic stimulation: interplay between rotors and focal discharges. Heart Rhythm 2009;6(7):1009–17. 29. Narayan SM, Shivkumar K, Krummen DE, et al. Panoramic electrophysiological mapping but not individual electrogram morphology identifies sustaining sites for human atrial fibrillation (AF rotors and focal sources relate poorly to fractionated electrograms). Circ Arrhythm Electrophysiol 2013;6(1):58–67. 30. Davidenko JM, Pertsov AV, Salomonsz R, et al. Stationary and drifting spiral waves of excitation in isolated cardiac muscle. Nature 1992;355(6358):349–51. 31. Narayan SM, Shivkumar K, Mittal S, et al. Conventional ablation for atrial fibrillation with or without focal impulse and rotor modulation: the CONFIRM trial (late breaking clinical trial abstract). Heart Rhythm 2011;8(5S):LB–04. 32. Miller JM, Kowal RC, Swarup V, et al. Initial independent outcomes from focal impulse and rotor modulation ablation for atrial fibrillation: multicenter FIRM registry,

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Diagnostic Electrophysiology & Ablation J Cardiovasc Electrophys 2014;25(9):921–9. 33. Kowal RC, Daubert J, Day JD, et al. Results of Focal Impulse and Rotor Modulation (FIRM) for atrial fibrillation are equivalent between patients treated in San Diego compared with sites new to FIRM ablation: an extended multi-center experience (abstract). Heart Rhythm 2013;10(5S):S479. 34. Ghoraani B, Dalvi R, Gizurarson S, et al. Localized rotational activation in the left atrium during human atrial fibrillation: Relationship to complex fractionated atrial electrograms and low-voltage zones. Heart Rhythm 2013;10(12):1830–8. 35. Lin YJ, Lo MT, Lin C, et al. Prevalence, characteristics, mapping, and catheter ablation of potential rotors in nonparoxysmal atrial fibrillation. Circ Arrhythm Electrophysiol 2013;6(5):851–8. 36. Lee G, Kumar S, Teh A, et al. Epicardial wave mapping in human long-lasting persistent AF: transient rotational circuits, complex wavefronts and disorganized activity. Eur Heart J 2014:35(2):86–97. 37. Haissaguerre M, Hocini M, Denis A, et al. Driver domains in persistent atrial fibrillation. Circulation 2014;130(7):530–8. 38. Rodrigo M, Guillem MS, Climent AM, et al. Body surface localization of left and right atrial high frequency rotors in atrial fibrillation patients: a clinical-computational study. Heart Rhythm 2014;11(9):1584–91. 39. Earley M, Abrams D, Sporton S, et al. Validation of the non-contact mapping system in the left atrium during permanent atrial fibrillation and sinus rhythm. J Am Coll Cardiol 2006;48(3):485–91.

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40. Kalifa J, Avula UM. Ablation of driver domains during persistent atrial fibrillation: a call for more understanding. Circulation 2014;130(7):525–7. 41. Swarup V, Baykaner T, Rostamian A, et al. Stability of rotors and focal sources for human atrial fibrillation: focal impulse and rotor mapping (FIRM) of AF sources and fibrillatory conduction. J Cardiovasc Electrophysiol, 2014;25(12):1284–92. 42. Ng J, Gordon D, Passman RS, et al. Electrogram morphology recurrence patterns during atrial fibrillation. Heart Rhythm 2014;11(11):2027–34. 43. Zlochiver S, Yamazaki M, Kalifa J, et al. Rotor meandering contributes to irregularity in electrograms during atrial fibrillation. Heart Rhythm 2008;5(6):846–54. 44. Miller JM, Kowal RC, Swarup V, et al. Initial independent outcomes from focal impulse and rotor modulation ablation for atrial fibrillation: multicenter FIRM registry. J Cardiovasc Electrophysiol 2014;25(9):921–9. 45. Lin T, Kuck KH, Ouyang F, et al. First in-human robotic rotor ablation for atrial fibrillation. Eur Heart J 2014;35(22):1432. 46. Elayi CS, Di Biase L, Barrett C, et al. Atrial fibrillation termination as a procedural endpoint during ablation in long-standing persistent atrial fibrillation. Heart Rhythm 2010;7(9):1216–23. 47. Narayan SM, Baykaner T, Clopton P, et al. Ablation of rotor and focal sources reduces late recurrence of atrial fibrillation compared with trigger ablation alone: extended follow-up of the CONFIRM trial (Conventional Ablation for Atrial Fibrillation With or Without Focal Impulse and Rotor

Modulation). J Am Coll Cardiol 2014;63(17):1761–8. 48. Shivkumar K, Ellenbogen KA, Hummel JD, et al. Acute termination of human atrial fibrillation by identification and catheter ablation of localized rotors and sources: first multicenter experience of focal impulse and rotor modulation (FIRM) ablation. J Cardiovasc Electrophysiol 2012;23(12):1277–85. 49. Atienza 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 RADARAF Trial. J Am Coll Cardiol 2014;64(23):2455–67. 50. Berenfeld O, Mandapati R, Dixit S, et al. Spatially distributed dominant excitation frequencies reveal hidden organization in atrial fibrillation in the Langendorff-perfused sheep heart. J Cardiovasc Electrophysiol 2000;11(8):869–79. 51. Ng J, Kadish AH, Goldberger JJ. Technical considerations for dominant frequency analysis. J Cardiovasc Electrophysiol 2007;18(7):757–64. 52. Jarman JW, Wong T, Kojodjojo P, et al. Spatiotemporal behavior of high dominant frequency during paroxysmal and persistent atrial fibrillation in the human left atrium. Circ Arrhythm Electrophysiol 2012;5(4):650–8. 53. Verma A, Jiang C-Y, Betts TR, et al. Optimal method and outcomes of catheter ablation of persistent atrial fibrillation: results of the prospective, randomized STAR AF 2 trial. Hot Line report. Presented at: ESC Congress 30 August – 3 September 2014; Barcelona, Spain.

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Device Therapy Management of Cardiovascular Implantable Electronic Devices Infections in High-Risk Patients Ch a r l e s Ke n n e r g r e n Sahlgrenska University Hospital, Gothenburg, Sweden

Abstract The incidence of infection following implantation of cardiovascular implantable electronic devices (CIEDs) is increasing, as is the number of pulse generator replacements and upgrades. The rate of infections is rising faster than the rate of device implantation, mainly due to the increasing age and number of comorbidities of patients receiving the devices. Patients with a CIED infection usually require hospitalisation, multiple consultations, prolonged intravenous antibiotics and, in the majority of cases, CIED explantation and replacement. A significant proportion die of their infection. CIED infection therefore represents a substantial health and economic burden, and management of infections is critical. Numerous risk factors have been identified including host, procedure and device-related factors. Established strategies for preventing CIED infections include intravenous antibiotics and aseptic techniques. The TYRX™ Absorbable Antibacterial Envelope offers potential as an effective method to reduce CIED infections. Several studies have found a statistically significant association between antibacterial envelope use and reduced incidence of CIED infection in high-risk patients. A prospective, randomised trial to further evaluate this potentially important strategy for CIED infection prophylaxis is underway.

Keywords Cardiovascular implantable electronic device infections, cardiac resynchronisation, implantable cardioverter-defibrillators, antibacterial envelope Disclosure: Charles Kennergren has presented on behalf of, advised and/or performed scientific studies with Boston Scientific, Biotronic, ELA/Sorin, Medtronic/Vitatron/ TYRX, Mentice, Sim Suite, St Jude. Acknowledgement: Medical Media Communications Ltd provided medical writing and editing support to the author, funded by Medtronic. Received: 12 January 2015 Accepted: 27 February 2015 Citation: Arrhythmia & Electrophysiology Review 2015;4(1):53–7 Access at: www.AERjournal.com Correspondence: Charles Kennergren MD PhD FETCS FHRS, Senior Consultant, Associate Professor, Department of Cardiothoracic Surgery, Sahlgrenska University Hospital, S 413 65 Goteborg, Sweden. E: charles.kennergren@vgregion.se

The implantation of cardiovascular implantable electronic devices (CIEDs) including permanent pacemakers (PPMs), implantable cardioverter-defibrillators (ICDs) and cardiac resynchronisation therapy (CRT-D [with defibrillator] and CRT-P [with pacemaker]) devices are lifesaving procedures, and the expanding indications for device use have led to a marked increase in implantation procedures in recent decades. Advances in manufacturing technology have resulted in the availability of smaller, more sophisticated devices that are easier to implant. Furthermore, a growing body of evidence supports their beneficial effects on quality of life as well as potential costeffectiveness.1 As a result of increased life expectancy, physicians will increasingly encounter patients with CIEDs. However, there is growing concern about the rate of infections in patients receiving CIEDs, since the incidence of CIED infection is increasing out of proportion to CIED implantation.2–4 A third of patients receiving CIEDs show signs of bacterial colonisation,5 some of which result in clinically evident CIED infection. A US study reported an increase in the number of CIED implantations from 199,516 in 2004 to 222,940 in 2006, a 12 % increment. However, in the same period, the number of CIED infections increased from 8,273 to 12,979, a 57 % increment.3 In another study, during the period 1993 to 2008, the incidence of CIED infection increased from 1.5 % to 2.41 %, with a marked increase noted in 2004, which coincided with an increase in

Kennergren_FINAL.indd 53

the incidence of diabetes and renal failure among device recipients (see Figure 1).4 Numerous reasons for this rise in CIED infections have been proposed. More older patients are receiving CIEDs, and higher rates of comorbidity may predispose them to poor wound healing and diminished host immune defences.3,4,6,7 In addition, younger patients are receiving CIEDs, and an increasing number of patients are surviving long enough to require pulse generator changes and lead revisions,8 which are associated with a higher infection rate.9,10 Newer techniques are associated with longer procedure times: implantation of CRT-P requires careful placement of the left ventricular pacing lead in the optimal coronary sinus branch in order to optimise clinical benefit, extending case times by around 20–90 minutes and thus allowing more time for pocket or hardware contamination.11 There is also an increasing proportion of ICDs8 and dual chamber devices (DDD);7 ICDs are associated with higher infection rates than PPMs.8,12 Patients with an ICD have a higher prevalence of congestive heart failure and abdominal generator placement, and more undergo electrophysiological study prior to device implantation.13 CIED infections result in significant morbidity and mortality, frequently require device explantation and, if indicated, reimplantation.14–17 When subsequent care and re-implantation is considered, the cost may be substantially higher. Patients have longer durations of hospital stays

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Device Therapy Diagnosis and Management of CIED Infections

Figure 1: Increasing Burden of CIED Infections with Time 3.0

400,000 350,000 300,000

2.0 250,000 1.5

200,000 150,000

1.0

100,000 0.5

Number of implantations

Rate of CIED infection (%)

2.5

50,000

0.0

0 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008

Year Blue line = rate of CIED infection (%); Red line = number of implantations. Adapted from Greenspon et al., 2011.4

Table 1: Risk Factors for CIED Infections

Diagnosis of CIED infection can be challenging, with symptoms ranging from local pocket erosion to full-blown sepsis.19 Clinical presentation includes symptoms such as erythema, warmth, tenderness, purulent discharge or erosion of generator or leads through the skin,20 and up to 30 % of patients present with nonspecific symptoms only, such as fever and malaise. Local pocket infections vary in onset and can occur more than a year after implantation.21 While diagnosis is straightforward in patients presenting with inflammatory conditions or lead erosion, differentiating between early postoperative haematoma and pocket infection is more difficult. Infections may be local or systemic; Staphylococcus infections are most common (60–80 % of reported cases) since Staphylococcus species are frequent colonisers of the skin and have the ability to produce a biofilm on the device surface, enabling them to evade host immune defences.22 Nonstaphylococcal infections are diverse and have a relatively low virulence and mortality rate.23 Recent data suggest a trend to more resistant organisms.8

Systemic infections, which include bacteraemia and lead-related endocarditis, also show wide variation in onset time; when divided into two groups, the late onset group had a mean onset of 31 months.24 Patient Factors Remote infection sites are seen in patients with late infection; late 37,38,40 Diabetes 3.2–3.5 infection should therefore be considered in any CIED patient who 37,38,57 Renal insufficiency 4.6–6.3 13,38 presents with fever, bloodstream infection or signs of sepsis, even if Systemic anticoagulation 2.6–3.4 13 the device pocket appears uninfected.25 It is essential to obtain at least Chronic corticosteroid use 9.1 13 History of malignancy 4.0 two sets of blood cultures before the initiation of antimicrobial therapy 40 Underlying heart disease 3.1 in all patients with systemic infections since its presentation may be Device Factors indolent;26 in patients with Staphylococcus aureus bacteraemia (SAB), 13 Prior CIED infection - positive blood cultures may be the only sign of infection.27 In cases 31 Abdominal generator - of positive blood cultures, a transoesophageal echocardiogram (TOE) 13,40 ≥3 leads 4.0–5.4 should be performed to evaluate for the possibility of underlying CIED30 Epicardial lead placement - related endocarditis.26 Risk Factor

Odds Ratio (where available)

Reference

Generator changes, device upgrades

1.7–3.1

33,37,38

or other revision Procedural Factors 33

Procedure time

Temporary pacing prior to implantation

2.5

Fever within 24 hours of implantation

5.8

Early re-interventions

15.0

10,33

Post-operative haematoma at pocket site

Physician experience

2.5

and increased risk of in-hospital death.16 The rate of 1-year mortality following infection can be high (16.9 %), even after removal of the device,15 and was associated with a 1.9-fold increased risk of mortality compared with patients who did not experience CIED infection. After controlling for possible confounders, this represents a 2.4-fold increased risk of mortality.15 This results in a significant health and economic burden that may counteract the benefits of the devices; the total cost of an infection has been estimated at up to $53,000 per case, with intensive care accounting for almost half of the total cost.16 The annual cost of CIED infections in the US has been estimated at a minimum $285 million.18 The cost may, however, vary significantly depending on the type of healthcare system and the type of infection. This article will review methods of management and prevention of CIED infections, with a focus on the TYRX™ Absorbable Antibacterial Envelope, which offers potential as a cost-effective method to reduce CIED infections.

Kennergren_FINAL.indd 54

Current management of CIED infection depends on the clinical presentation and the causative pathogen. Most CIED infections require removal of the whole system, and administration of IV antibiotics.28,29 Transvenous explantation is the preferred technique, but has been associated with a low rate of complications including haemothorax, laceration of the superior vena, damage to the tricuspid valve and cardiac tamponade.20,26 Satisfactory control of the infection is required before implantation of a replacement device may be considered.

Risk Factors for CIED Infections The rising rates and diagnostic challenges of CIED infections have led to numerous studies investigating risk factors for infection (see Table 1). Early CIEDs required the implantation of epicardial leads, which were associated with high infection rates.30 Subsequent advances have led to the majority of electrode leads being implanted via the transvenous route; epicardial lead placement usually occurs if transvenous implantation is not feasible. Likewise, studies on infection rates have led to pectoral implantation of generators rather than abdominal placement.31 Important device-related risk factors for infection include device revision or upgrade,32 the use of more than two pacing leads and the need for early pocket re-exploration.10,13 The presence of multiple leads increases the risk of central venous thrombosis in the area of the leads and is a potential site of secondary seeding of microorganisms.13 Procedure-related factors include: procedure time, temporary pacing prior to implantation, fever within 24-hour of implantation, early pocket re-entry and postoperative

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Management of Cardiovascular Implantable Electronic Devices Infections in High-Risk Patients

Patient factors that have been associated with an increased risk of CIED infections include younger age, male gender35,36 and renal insufficiency.8,37,38 The infection risk is particularly high in patients with renal failure undergoing chronic haemodialysis via an implanted central catheter. Such patients are at risk of recurrent bacteraemia from their dialysis catheter and subsequent seeding of the device leads and pulse generator.37 The use of anticoagulation therapy using warfarin is also associated with increased infection risk, possibly due to the increased risk of pocket haematoma, which may cause delayed wound healing or require surgical evacuation.13,38 Chronic use of immunosuppressant drugs such as corticosteroids is also a risk factor for CIED infection.13 Numerous other patient-related factors have been associated with increased risk of CIED infection, including a history of malignancy, underlying heart disease, fever within 24 hours of implantation and lack of antibiotic prophylaxis.10,20,33,38–40 Diabetes has been associated with surgical site infections among cardiothoracic surgery patients41 and has been identified with higher risk of CIED infection.37 The Centers for Disease Control and Prevention (CDC) have recommended adequate control of serum blood glucose levels in all diabetic patients and the avoidance of preoperative hyperglycaemia.42 A clinical risk score prior to implantation has been proposed: a recent study has developed a novel scoring index to risk stratify patients and proposed seven independent risk factors that predict infection.43 These comprise early pocket re-exploration, male sex, diabetes, upgrade procedure, heart failure, hypertension and glomerular filtration rate <60 mL/min. The study proposed a composite risk score (0–25; C index 0.72; 95 % confidence interval 0.61–0.83) using these seven factors: and identified three groups: low risk (score 0–7; 1 % infection), medium risk (score 8–14; 3.4 % infection), and high risk (score ≥15; 11.1 % infection). While these studies provide a valuable insight into CIED infection risk factors, many are small, single-centre studies and there is a need for larger, more representative studies to identify the most important factors that are responsible for the development of CIED infection.

Strategies to Reduce CIED Infection Numerous strategies to reduce CIED infection have been proposed. Adherence to aseptic techniques during implantation is important, and the use of chlorhexidine-alcohol for skin preparation and mupirocin nasal ointments have been reported.44,45 Pocket irrigation has been used but has not been proven to reduce infection risk. The antimicrobial treatment of pacemaker casings with antiseptics has also recently been investigated in vitro and early studies showed promising results.46 Other products have been investigated but have not been successful in preventing CIED infections. Collagen impregnated with antibiotic such gentamicin-impregnated collagen sponge (Collatamp G), has been used to prevent sternal wound infection in cardiac surgery,47 but there is no evidence to support its use in preventing CIED infections. A gentimycin-collagen fleece (Septocoll) has been used in other applications.48 To date, the only intervention proven in randomised clinical trials to reduce infections is intravenous prophylaxis using antibiotics.49 A double-blinded study included 1,000 consecutive patients who

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Figure 2: The TYRX™ Absorbable Antibacterial Envelope

Figure 3: Interim Results from the Citadel/Centurion Trials P< 0.001 2.00

1.88

P< 0.001

1.80

1.67

1.60 CIED Infection Rate (%)

haematoma at the pocket site.33 In addition, physician experience is important; a study found a significantly higher risk of ICD infection within 90 days of implantation in patients whose device was implanted by physicians in the lowest quartile of procedural volume (odds ratio [OR] 2.47 compared with physicians in the highest-volume quartile).34

1.40 1.20 1.00 0.80 0.60 0.40 0.20 0.00

0.10 Citadel/ Centurion

Krahn et al. Circ EP 2011

Gould et al. JAMA 2006

Source: Henrikson, 2013.54

presented for CIED implantation or generator replacement. Patients were randomised to prophylactic antibiotics (intravenous administration of 1g of cefazolin immediately before the procedure) or placebo. The trial was terminated early after enrollment of 649 patients due to a significantly lower rate of infection rates in the antibiotic arm (0.63 % in antibiotic arm vs 3.28 %; RR 0.19; p=0.016).49 Vancomycin may be used in patients who are allergic to cephalosporins, have methicillinresistant Staphylococcus aureus (MRSA) colonisation or in institutions that have a high prevalence of MRSA infection.26 Pocket infection may be reduced using an antibiotic envelope. The TYRX™ Absorbable Antibacterial Envelope (formerly AIGISRx ® R, Medtronic TYRX, Inc.) is constructed from a bioabsorbable multifilament knitted mesh polymer made of glycolide, caprolactone and trimethylene carbonate that is coated with a bioabsorbable polyarylate polymer and comprises two flat, rectangular sheets that are sealed on three sides (see Figure 2). The envelope holds the CIED in place, preventing CIED migration; elutes antimicrobial agents minocycline and rifampicin for a minimum of seven days; and then is fully absorbed approximately nine weeks after implantation. The device is available in two sizes:

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Device Therapy Table 2: Summary of clinical studies investigating the efficacy and safety of the TYRX Antibacterial Envelope Study type

Outcomes

References

Retrospective

634, 49 %

CIED implantation was

cohort study,

had at least successful in 99.5 % of

mean 1.9 months 3 risk

procedures. Major infections

follow-up

rate 0.48 after 1.9 ± 2.4

factors

months follow-up. Retrospective

260, mean

One CIED infection among

cohort study,

2.8 ± 1.2

patients who received an

min 90 days

risk factors

antibacterial envelope

follow-up

(0.4 %), compared with 19 (3 %) in controls (odds ratio [95 % CI] 0.13 [0.02–0.95]; p=0.04).

Observational

2,891

In the pre-envelope era, an

cohort study,

infection occurred in 25

consecutive

(1.5 %) of 1,651 patients. After

patients

its availability, an envelope was

used in 275 (22 %) of 1,240 patients; an infection occurred in 8 (0.6 %) patients in this era (p=0.029 vs pre-envelope). Prospective,

1,000

Infection occurred in 0.2 %

observational

of patients who received the

multicentre cohort

envelope compared with 1.9 %

study, interim 180

who did not receive

day data available

the envelope (p<0.001).

medium for PPMs and large for ICD/CRT devices. Implantation requires a subcutaneous pocket ~10 % larger than normal to accommodate the envelope. The TYRX Absorbable Antibacterial Envelope received US Food and Drug Administration (FDA) clearance in May 2013 and the CE Mark in September 2014.

Clinical Evidence Evaluating the Efficacy of the TYRX Antibacterial Envelope At present, there are no published data on the TYRX Absorbable Envelope, but a substantial body of clinical data supports the efficacy of the previous generation non-absorbable envelope. The absorbable envelope has antibiotic efficacy identical to that of its predecessor and was regarded by the FDA as substantially equivalent, forming the basis for its approval. The efficacy of the non-absorbable antibacterial envelope has been evaluated in a preclinical study that demonstrated antimicrobial efficacy against Staphylococcus epidermidis, Staphylococcus capitis, Escherichia coli and Acinetobacter baumannii, as well as the elimination of biofilm on the implanted device.50 Clinical data describing the efficacy of the non-absorbable antibacterial envelope are summarised in Table 2. The COMMAND (Cooperative Multicenter Study Monitoring a CIED Antimicrobial Device) retrospective cohort study was conducted at 10 medical centres in the US and comprised 642 consecutive CIED patients who had undergone initial implantation or revision/replacement procedures utilising the antibacterial envelope. Almost half (49 %) had three or more predefined risk factors. The study reported only three major infections (0.48 %; 95 % confidence interval [CI] 0.17–1.40). The infections followed one ICD revision and two CRT-D replacements. There were seven deaths; none was a result of the antibacterial envelope or the CIED procedure. However, the follow-up was short at the time of reporting (1.9 ± 2.4

Kennergren_FINAL.indd 56

months).51 A retrospective single-centre cohort study included 260 patients presenting with at least two of the following risk factors within two weeks of original implantation: diabetes, renal insufficiency (creatinine ≥1.5 mg/dL 24 hours prior to implantation), systemic anticoagulation, chronic daily corticosteroid use, fever or leucocytosis 24 hours prior to implantation, prior documented CIED infection, or at least three transvenous leads. A historical control group (n = 639) was derived from a patient database. The study found a reduced rate of CEID infections after a minimum of 90 days follow-up among patients who received an antibacterial envelope (0.4 % compared with 3 %; odds ratio [OR] 0.13; 95 % CI 0.02–0.95; p=0.04).52 A recent study of the infection rate associated with use of the nonabsorbable envelope followed 2,891 consecutive patients for six months in the pre-envelope and post-envelope era.43 In the pre-envelope era, the infection rate among 1,651 patients was 1.5 %. In the post-infection era, an envelope was used in 275 (22 %) of 1,240 patients; an infection occurred in 0.6 % patients in this era (p=0.029 vs pre-envelope). Two prospective multicentre cohort studies involving 66 US centres (n=1,000) are currently in progress. The Citadel study (TYRX Envelope for Prevention of Infection Following Replacement with an Implantable Cardioverter-Defibrillator) aims to compare the rate of CIED infection and mechanical complication after CIED replacement with an ICD and non-absorbable antibacterial envelope, to that after replacement with an ICD and no antibacterial envelope (NCT01043861). The study population in the Centurion trial (TYRX Envelope for Prevention of Infection Following Replacement With a Cardiac Resynchronization Therapy Device) comprises patients who have undergone CIED replacement with a CRT (NCT01043705). The historical control group in both trials consists of 533 Canadian patients in a retrospective study, all of whom underwent CIED replacement because of device advisories or recalls.53 The major device infection rate in this study during a mean 2.7 months following device replacement was 1.9 %, compared with 0.1 % in 90-day data reported in Citadel/Centurion (see Figure 3).54 The chief device-related complication recorded during the study was major pocket haematoma in 1.5 % of patients who received the envelope vs 2.25 % in the historical controls. This required a change in patient management, such as open drainage or transfusion. More recently presented interim data showed that the low infection rate was maintained at 180 days.55 Infection occurred in 0.2 % of patients who received the envelope compared with 1.9 % who did not receive the envelope (p<0.001). In addition, there was a low rate of device mechanical complications (4.0 %) in patients who received the envelope. Currently there are no published data on the effectiveness of the newer fully absorbable version of the antibacterial envelope. The WRAP-IT (Worldwide Randomized Antibiotic Envelope Infection Prevention Trial) is a multicentre, single blinded randomised study and is currently recruiting in over 200 clinical sites worldwide.56 This study will evaluate the ability of the TYRX Absorbable Envelope to reduce major CIED infections during 12 months following CIED generator replacement, upgrade, revision or de novo CRT-D implant. Patients (n=6,988) will be randomised 1:1 to envelope versus no envelope. Its primary endpoint is the rate of major CIED infections through 12 months resulting in one or more of the following: CIED system removal, CIED pocket revision, CIED infection treated with antibiotic therapy if the subject is not a candidate for system removal and death due to CIED infection. Secondary objectives include all cause mortality within 12 months and CIED removal due to pain without any clear infection. The estimated study completion date is December 2017.

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Management of Cardiovascular Implantable Electronic Devices Infections in High-Risk Patients

Discussion and Concluding Remarks Despite advances in the understanding of the pathogenesis, risk factors and management of CIED infections, the infection rate is rising faster than the rate of implantation of CIEDs, representing an important, expensive and potentially preventable complication of device implantation. The TYRX Absorbable Antibacterial Envelope represents a significant clinical advance. Since the TYRX Absorbable Antibacterial Envelope only recently received its CE mark, the author’s early experience is limited but suggests that it is easy to use and is associated with a very low early complication rate. The major disadvantage of the envelope is the cost. It is important to select patients for implantation according to risk of CIED infection. However,

1. Beck H, Boden WE, Patibandla S, et al. 50th anniversary of the first successful permanent pacemaker implantation in the United States: historical review and future directions. Am J Cardiol 2010;106:810–8. 2. Cabell CH, Heidenreich PA, Chu VH, et al. Increasing rates of cardiac device infections among Medicare beneficiaries: 1990–1999. Am Heart J 2004;147:582–6. 3. Voigt A, Shalaby A, Saba S. Continued rise in rates of cardiovascular implantable electronic device infections in the United States: temporal trends and causative insights, Pacing Clin Electrophysiol 2010;33:414–9. 4. Greenspon AJ, Patel JD, Lau E, et al. 16-year trends in the infection burden for pacemakers and implantable cardioverterdefibrillators in the United States 1993 to 2008. J Am Coll Cardiol 2011;58:1001–6. 5. Kleemann T, Becker T, Strauss M, et al. Prevalence of bacterial colonization of generator pockets in implantable cardioverter defibrillator patients without signs of infection undergoing generator replacement or lead revision. Europace 2010;12:58–63. 6. Kurtz SM, Ochoa JA, Lau E, et al. Implantation trends and patient profiles for pacemakers and implantable cardioverter defibrillators in the United States: 1993-2006. Pacing Clin Electrophysiol 2010;33:705–11. 7. Greenspon AJ, Patel JD, Lau E, et al. Trends in permanent pacemaker implantation in the United States from 1993 to 2009: increasing complexity of patients and procedures. J Am Coll Cardiol 2012;60:1540–5. 8. Greenspon AJ, Patel JD, Lau E, et al. Inpatient vs. outpatient device implantation surgery: impact on cardiac implantable electronic device infection. Poster presentation Po02–43. Heart Rhythm Society 34th Annual Scientific Session, May 8–11, Denver, CO, US. 9. Borleffs CJ, Thijssen J, de Bie MK, et al. Recurrent implantable cardioverter-defibrillator replacement is associated with an increasing risk of pocket-related complications. Pacing Clin Electrophysiol 2010;33:1013–9. 10. Klug D, Balde M, Pavin D, et al. Risk factors related to infections of implanted pacemakers and cardioverter-defibrillators: results of a large prospective study. Circulation 2007;116:1349–55. 11. Cleland JG, Daubert JC, Erdmann E, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005;352:1539–49. 12. Uslan DZ, Sohail MR, St Sauver JL, et al. Permanent pacemaker and implantable cardioverter defibrillator infection: a population-based study. Arch Intern Med 2007;167:669–75. 13. Sohail MR, Uslan DZ, Khan AH, et al. Risk factor analysis of permanent pacemaker infection. Clin Infect Dis 2007;45:166–73. 14. Chua JD, Wilkoff BL, Lee I, et al. Diagnosis and management of infections involving implantable electrophysiologic cardiac devices. Ann Intern Med 2000;133:604–8. 15. de Bie MK, van Rees JB, Thijssen J, et al., Cardiac device infections are associated with a significant mortality risk. Heart Rhythm 2012;9:494–8. 16. Sohail MR, Henrikson CA, Braid-Forbes MJ, et al. Mortality and cost associated with cardiovascular implantable electronic device infections. Arch Intern Med 2011;171:1821–8. 17. Baman TS, Gupta SK, Valle JA, et al. Risk factors for mortality in patients with cardiac device-related infection. Circ Arrhythm Electrophysiol 2009;2:129–34. 18. Ellis CRaK MJ. Rising infection rate in cardiac electronic device implantation; the role of the AIGISRx® Antibacterial Envelope in prophylaxis. Comb Prod Ther 2011;1:1–9. 19. Tarakji KG, Chan EJ, Cantillon DJ, et al. Cardiac implantable electronic device infections: presentation, management, and patient outcomes. Heart Rhythm 2010;7:1043–7. 20. Sohail MR, Uslan DZ, Khan AH, et al. Management and outcome of permanent pacemaker and implantable cardioverterdefibrillator infections. J Am Coll Cardiol 2007;49:1851–9.

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given the substantial expense associated with infections, it is hoped that the use of the envelope in high-risk patients will prove cost-effective in the long-term. A 2011 report (based on the TYRX Non-absorbable Envelope) suggested that the estimated absolute risk reduction associated with the use of the antibacterial envelope is 2.5 %, generating a number of 40 patients needed to treat to prevent one infection. In conclusion, use of the TYRX Absorbable Antibacterial Envelope appears to be a promising strategy with the potential to reduce CIED infections, but clinical experience is limited. There is a need for large, multicentre, randomised data to fully establish the clinical benefits and cost effectiveness of the absorbable antibacterial envelope. The results of the ongoing WRAP-IT trial are eagerly awaited. n

21. Welch M, Uslan DZ, Greenspon AJ, et al. Variability in clinical features of early versus late cardiovascular implantable electronic device pocket infections. Pacing Clin Electrophysiol 2014;37:955–62. 22. Dy Chua J, Abdul-Karim A, Mawhorter S, et al. The role of swab and tissue culture in the diagnosis of implantable cardiac device infection. Pacing Clin Electrophysiol 2005;28:1276–81. 23. Viola GM, Awan LL, Darouiche RO. Nonstaphylococcal infections of cardiac implantable electronic devices. Circulation 2010;121:2085–91. 24. Greenspon AJ, Rhim ES, Mark G, et al. Lead-associated endocarditis: the important role of methicillin-resistant Staphylococcus aureus. Pacing Clin Electrophysiol 2008;31:548–53. 25. Greenspon AJ, Prutkin JM, Sohail MR, et al. Timing of the most recent device procedure influences the clinical outcome of lead-associated endocarditis results of the MEDIC (Multicenter Electrophysiologic Device Infection Cohort). J Am Coll Cardiol 2012;59:681–7. 26. Baddour LM, Epstein AE, Erickson CC, et al. Update on cardiovascular implantable electronic device infections and their management: a scientific statement from the American Heart Association. Circulation 2010;121:458–77. 27. Uslan DZ, Dowsley TF, Sohail MR, et al. Cardiovascular implantable electronic device infection in patients with Staphylococcus aureus bacteremia. Pacing Clin Electrophysiol 2010;33:407–13. 28. Wilkoff BL, Love CJ, Byrd CL, et al. Transvenous lead extraction: Heart Rhythm Society expert consensus on facilities, training, indications, and patient management: this document was endorsed by the American Heart Association (AHA). Heart Rhythm 2009;6:1085–104. 29. Deharo JC, Bongiorni MG, Rozkovec A, et al. Pathways for training and accreditation for transvenous lead extraction: a European Heart Rhythm Association position paper. Europace 2012;14:124–34. 30. Lai KK, Fontecchio SA. Infections associated with implantable cardioverter defibrillators placed transvenously and via thoracotomies: epidemiology, infection control, and management. Clin Infect Dis 1998;27:265–9. 31. Mela T, McGovern BA, Garan H, et al. Long-term infection rates associated with the pectoral versus abdominal approach to cardioverter- defibrillator implants. Am J Cardiol 2001;88:750–3. 32. Poole JE, Gleva MJ, Mela T, et al. Complication rates associated with pacemaker or implantable cardioverter-defibrillator generator replacements and upgrade procedures: results from the REPLACE registry. Circulation 2010;122:1553–61. 33. Romeyer-Bouchard C, Da Costa A, Dauphinot V, et al. Prevalence and risk factors related to infections of cardiac resynchronization therapy devices. Eur Heart J 2010;31:203–10. 34. Al-Khatib SM, Lucas FL, Jollis JG, et al. The relation between patients’ outcomes and the volume of cardioverter-defibrillator implantation procedures performed by physicians treating Medicare beneficiaries. J Am Coll Cardiol 2005;46:1536–40. 35. Lin YS, Hung SP, Chen PR, et al. Risk factors influencing complications of cardiac implantable electronic device implantation: infection, pneumothorax and heart perforation: a nationwide population-based cohort study. Medicine (Baltimore) 2014;93:e213. 36. Sohail M, Henrikson C, Braid-Forbes MJ, et al. Risk factors associated with implantable cardioverter-defibrillatorinfection in Medicare beneficiaries. Circulation 2012;126:A14543. 37. Bloom H, Heeke B, Leon A, et al. Renal insufficiency and the risk of infection from pacemaker or defibrillator surgery. Pacing Clin Electrophysiol 2006;29:142–5. 38. Lekkerkerker JC, van Nieuwkoop C, Trines SA, et al. Risk factors and time delay associated with cardiac device infections: Leiden device registry. Heart 2009;95:715–20. 39. Margey R, McCann H, Blake G, et al. Contemporary

management of and outcomes from cardiac device related infections. Europace 2010;12:64–70. 40. Herce B, Nazeyrollas P, Lesaffre F, et al. Risk factors for infection of implantable cardiac devices: data from a registry of 2496 patients. Europace 2013;15:66–70. 41. Latham R, Lancaster AD, Covington JF. The association of diabetes and glucose control with surgical-site infections among cardiothoracic surgery patients. Infect Control Hosp Epidemiol 2001;22:607–12. 42. Mangram AJ, Horan TC, Pearson ML, et al. Guideline for prevention of surgical site infection, 1999. Centers for Disease Control and Prevention (CDC) Hospital Infection Control Practices Advisory Committee. Am J Infect Control 1999;27:97– 132; quiz 3–4; discussion 96. 43. Mittal S, Shaw RE, Michel K, et al. Cardiac implantable electronic device infections: incidence, risk factors, and the effect of the AigisRx antibacterial envelope. Heart Rhythm 2014;11:595–601. 44. Darouiche RO, Wall MJ Jr, Itani KM, et al. Chlorhexidine-alcohol versus povidone-iodine for surgical-site antisepsis. N Engl J Med 2010;362:18–26. 45. Bode LG, Kluytmans JA, Wertheim HF, et al. Preventing surgical-site infections in nasal carriers of Staphylococcus aureus. N Engl J Med 2010;362:9–17. 46. Marsch G, Mashaqi B, Burgwitz K, et al. Prevention of pacemaker infections with perioperative antimicrobial treatment: an in vitro study. Europace 2014;16:604–11. 47. Raja SG, Salhiyyah K, Rafiq MU, et al. Impact of gentamicincollagen sponge (Collatamp) on the incidence of sternal wound infection in high-risk cardiac surgery patients: a propensity score analysis. Heart Surg Forum 2012;15:E257–61. 48. Holzer B, Grussner U, Bruckner B, et al., Efficacy and tolerance of a new gentamicin collagen fleece (Septocoll) after surgical treatment of a pilonidal sinus Colorectal Dis 2003;5:222–7. 49. de Oliveira JC, Martinelli M, Nishioka SA, et al. Efficacy of antibiotic prophylaxis before the implantation of pacemakers and cardioverter-defibrillators: results of a large, prospective, randomized, double-blinded, placebo-controlled trial. Circ Arrhythm Electrophysiol 2009;2:29–34. 50. Hansen LK, Brown M, Johnson D, et al. In vivo model of human pathogen infection and demonstration of efficacy by an antimicrobial pouch for pacing devices. Pacing Clin Electrophysiol 2009;32:898–907. 51. Bloom HL, Constantin L, Dan D, et al. Implantation success and infection in cardiovascular implantable electronic device procedures utilizing an antibacterial envelope. Pacing Clin Electrophysiol 2011;34:133–42. 52. Kolek MJ, Dresen WF, Wells QS, et al. Use of an antibacterial envelope is associated with reduced cardiac implantable electronic device infections in high-risk patients. Pacing Clin Electrophysiol 2013;36:354–61. 53. Gould PA, Krahn AD. Canadian Heart Rhythm Society Working Group on Device A, Complications associated with implantable cardioverter-defibrillator replacement in response to device advisories. JAMA 2006;295:1907–11. 54. Henrikson CA, Sohail MR, Simons GR et al. CITADEL/CENTURION study interim analysis: use of an antibacterial envelope is associated with very low 90-day CIED infection rates. Late Breaking Clinical Trials III. Abstract LB03-01. Presented at Heart Rhythm 34th Annual Scientific Sessions, 2013. 55. Henrikson CA. Citadel & Centurion studies. Poster presentation at European Heart Rhythm Association (EHRA), Cardiostim 18–21 June 2014, Nice, France. 56. World-wide Randomized Antibiotic Envelope Infection Prevention Trial (WRAP-IT). Available at: http://clinicaltrials. gov/ct2/show/NCT02277990. Accessed 23 March 2015. 57. Dasgupta A, Montalvo J, Medendorp S, et al. Increased complication rates of cardiac rhythm management devices in ESRD patients. Am J Kidney Dis 2007;49:656–63.

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Device Therapy Balloon Devices for Atrial Fibrillation Therapy Andreas Metzner, Erik Wissner, Tina Lin, Feifan Ouyang and Karl-Heinz Kuck Asklepios Klinik St. Georg, Hamburg, Germany

Abstract Ablation of atrial fibrillation (AF) is an established treatment option for symptomatic patients refractory to antiarrhythmic medication. In patients with paroxysmal AF, ablation can be offered as first-line therapy when performed in an experienced centre. The accepted cornerstone for all ablation strategies is isolation of the pulmonary veins. However, it is still challenging to achieve contiguous, transmural, permanent lesions using radio-frequency current (RFC) based catheters in conjunction with a three-dimensional mapping system and the learning curve remains long. These limitations have kindled interest in developing and evaluating novel catheter designs that incorporate alternative energy sources. Novel catheters include balloon-based ablation systems, incorporating different energy modalities such as laser (HeartlightTM, CardioFocus, Marlborough, MA, US), RFC (Hot Balloon Catheter, Hayama Arrhythmia Institute, Kanagawa, Japan) and cryo-energy (ArcticFront, Medtronic, Inc., Minneapolis, MN, US). While the cryoballoon (CB) and the radiofrequency hot balloon (RHB) are single-shot devices, the endoscopic ablation system (EAS) allows for point-by-point ablation. The CB and EAS are well established as safe, time-efficient and effective ablation tools. Initial studies using the RHB could also demonstrate promising results. However, more data are required.

Keywords Atrial fibrillation, ablation, pulmonary vein isolation, balloon catheter, cryoballoon, endoscopic ablation system, hot balloon Disclosure: Andreas Metzner, Erik Wissner and Karl-Heinz Kuck are consultants for Medtronic and have received lecture fees. Tina Lin and Feifan Ouyang have no conflicts of interest to declare. Received: 6 December 2014 Accepted: 25 February 2015 Citation: Arrhythmia & Electrophysiology Review 2015;4(1):58–61 Access at: www.AERjournal.com Correspondence: Andreas Metzner, MD, Dept. Cardiology, Asklepios-Klinik St. Georg, Lohmuehlenstr. 5, 20099 Hamburg, Germany E: AndreasMetzner1@web.de

Atrial fibrillation (AF) is the most common cardiac arrhythmia affecting 1.5–2 % of the general population.1 In the current clinical guidelines, catheter ablation is recommended in addition to drug-based antiarrhythmic therapy for patients suffering from symptomatic, drugrefractory AF. However, catheter ablation, if performed at an experienced centre, may also serve as first-line therapy in patients with paroxysmal AF (PAF).1 Currently, pulmonary vein isolation (PVI) is accepted as the cornerstone of the ablative strategy in patients with PAF but also in persistent forms of AF. Recent evidence from the STAR-AF II study presented at ESC, demonstrated that PVI alone proved to be non-inferior when compared with more extensive ablation strategies such as ablation of complex fractionated atrial electrograms (CFAE) or linear lesions in addition to PVI in patients with persistent AF.2 However, achieving contiguous, transmural, permanent lesions using radio-frequency current (RFC) based catheters in conjunction with a three-dimensional mapping system, remains a real challenge with a long learning curve. These limitations have led to the development and evaluation of novel catheter designs incorporating alternative energy sources. These catheter designs include RFC-based spiral mapping and ablation catheters (PVACTM, Medtronic, Inc., Minneapolis, MN, USA; nMARQTM, Biosense Webster, Inc., Diamond Bar, CA, USA), as well as balloonbased ablation systems utilising different energy modalities such as laser (HeartlightTM,CardioFocus, Marlborough, MA, USA), RFC (Hot Balloon Catheter, Hayama Arrhythmia Institute, Kanagawa, Japan) and cryo-energy (ArcticFront, Medtronic, Inc., Minneapolis, MN, USA). The cryoballoon (CB) and endoscopic ablation system (EAS) are now well established as safe, clinically effective and time-efficient ablation

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tools. The radiofrequency hot balloon (RHB) has also shown potential for safe and effective PVI, although more data are needed.

Cryoballoon-based Pulmonary Vein Isolation The most established balloon-based ablation system is the CB and the first-generation CB was introduced approximately 10 years ago. It consists of a non-compliant balloon which is available in two different diameters (23 mm and 28 mm) and utilises N2O as the refrigerant. A stiff wire or modified spiral mapping catheter (AchieveTM, Medtronic Inc., Minneapolis, MN, US) is inserted via a central lumen of the catheter shaft, allowing safe manipulation within the left atrium and stable balloon-positioning along the ostium of the target PV. The firstgeneration CB utilised four injection jets for balloon cooling at a rather proximal position of the CB. Consequently, the zone of maximal cooling was along the balloon equator, sparing the distal tip. Using the first-generation CB and a freeze cycle duration of 300 ms, successful PVI was typically followed by a bonus freeze cycle of the same duration. Multiple studies demonstrated high acute success rates of 92–100 % after PVI using the first-generation CB,3,4 and the learning curve was short as demonstrated in the Sustained Treatment of Paroxysmal Atrial Fibrillation (STOP-AF) study.5 The one-year clinical success rate after PVI using the first-generation CB was 73 %.4 However, upon longer follow-up in a prospective, observational study by Vogt et al., rates of freedom from atrial tachyarrhythmias dropped to 62 % after a single procedure and 76 % after multiple procedures during 30 months of clinical follow-up.6 Similarly, Neumann et al. reported a 5-year single-procedure clinical success rate of 53 %. In

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Balloon Devices for Atrial Fibrillation Therapy

summary, 5-year clinical success rates are comparable to the longterm 47 % success rates obtained after RFC-based ablation.7,8 A high rate of electrical PV reconduction was demonstrated in patients with AF recurrence after first-generation CB-based PVI9 and the use of more than one bonus freeze cycle did not result in improved clinical outcomes.10 Regarding the safety profile, ablation using the first-generation CB was associated with a low rate of PV stenosis (0.9 %), cardiac tamponade (0.57 %) and clinically apparent transient ischaemic attack (TIA) or stroke (0.32 %).3 The incidence of transient or persistent right phrenic nerve paralysis (PNP) as a characteristic complication of balloon-based PVI was reported to be 6.4 %, while the rate of persistent PNP (≥1 year) was considerably lower at 0.37 %.3 The incidence of oesophageal thermal injury was between 0 % and 17 %, depending on balloon size.11,12 An atrio-oesophageal fistula after firstgeneration CB-based PVI was reported as a case report.13 The second-generation CB (ArcticFront AdvanceTM, Medtronic Inc., Minneapolis, MN, US) introduced in 2012 features a modified refrigerant injection system with eight injection jets located at a more distal balloon position. The result is more homogeneous cooling of the complete distal balloon hemisphere including the distal tip (see Figure 1). Similar to the first-generation CB, the rate of acute PVI is 99–100 %.14–16 However, recently published single-centre studies demonstrate a superior 1-year success rate ranging from 80 % to 86 %.15–17 With regards to complications using the second-generation CB, an initial report described an incidence of PNP of 19.5 %.18 In contrast, a study from our centre reported a rate of 3.5 %, which is in line with the rate of PNP using the first-generation CB.19 The incidence of ablation-related oesophageal thermal lesions using the 28 mm second-generation CB increased to 12–19 %.20,21 Safety cut-offs demonstrating a high sensitivity and specificity have been developed to prevent thermal lesion formation.20,21 Prospective studies are needed to validate these safety cut-offs. As demonstrated in another interesting study, the rate of real-time recordings from the Achieve catheter increased from 49 % using the first-generation CB to 76 % with the second-generation CB.22 Visualising PV recordings during cryoablation is a prerequisite for an individualised ablation strategy that takes into account the time taken to isolate the target PV. The ongoing ‘FIRE AND ICE’ trial (NCT01490814) is the first to compare the acute and long-term efficacy as well as the safety profile of the second-generation CB with conventional RFC ablation in a prospective, randomised, multicentre fashion. Recruitment is expected to be completed in early 2015. This study will help to clarify the future role of the second-generation CB for catheter ablation of PAF.

Figure 1: The Second-generation Cryoballoon A

A. Offers a more homogeneous cooling of the distal hemisphere and distal balloon tip compared with the first-generation CB; B. Increased incidence of oesophageal thermal lesions using the second-generation 28 mm cryoballoon. Modified from Metzner et al.20

Figure 2: Endoscopic View of a Pair of Left-sided Pulmonary Veins With a Visible Laser (green) Along the Anterior Portion of the Pulmonary Vein Ostium

post

ant

Endoscopic Pulmonary Vein Isolation The EAS is a balloon-based ablation system incorporating a titratable laser energy source and a miniature 2F endoscope, allowing for a spectacular view into the target PV (see Figure 2). The first-generation EAS consisted of a non-compliant balloon available in three sizes20,25, and 30 mm diameter) filled and flushed with heavy water (D2O). In addition to the embedded endoscope, the central balloon shaft contained the laser source, which could be titrated from 6.3 W/cm to 7.6 W/cm. Energy was applied via two separate laser arcs of 90° or 150°. In early studies, acute PVI was achieved in 91 % of targeted PVs.23 The AF recurrence rate after 1 year of clinical follow-up was 40 %. However, since the laser arc spanned at least 90°, optimal balloon-to-PV contact was a prerequisite for effective and safe energy transfer. In addition, optimal ostial sealing was hampered by the noncompliant characteristics of the balloon.

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ant = anterior; post = posterior.

The current generation EAS consists of a compliant balloon adjustable in size from 9–35 mm that easily adapts to the individual PV diameter. The laser arc covers 30° of a complete circle, facilitating an individualised ablation line design in a point-by-point fashion. In addition, the current EAS offers energy titration in five steps ranging from 5.5 W to a maximum of 12 W. Higher energy levels are typically applied along the anterior left atrial wall, which is characterised by thicker cardiac tissue, and lower energy levels are used along the thinner posterior wall. Titrating down energy levels along the posterior wall is essential due to the close proximity of extra-cardiac anatomical structures such as the oesophagus.

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Device Therapy Table 1: Specific Characteristics of Balloon-based Ablation Systems Cryoballoon

Endoscopic

Radiofrequency

Ablation System

Hot Balloon

yes

28 mm)

(9–35 mm)

(25–35 mm)

Energy source

N 2O

laser

radiofrequency

Titratable energy

yes

Compliant balloon no (23 mm or

current source ‘Over-the-wire’

yes

Single-shot device yes

yes

Individual ablation no

yes

line design

Initial studies demonstrated the feasibility of EAS-guided PVI with convincing acute and mid-term clinical efficacy and a favourable safety profile.24 The rate of acute PVI using the EAS ranges from 98 % to 100 %.24–26 The high rate of acute PVI translated into an 86 % durable isolation rate after three months as assessed by Dukkipati et al.25 However, applied energy levels in the initial studies were not standardised and influenced by parameters such as balloon-to-tissue contact, the target site along the PV or by the proximity of extra-cardiac structures such the oesophagus or the phrenic nerve. Consequently, our group systematically evaluated the effect of three different energy settings (posterior 5.5 W/ anterior 7 W vs 7 W/8.5 W vs 8.5 W/10 W) on the acute procedural efficacy and safety in a cohort of 30 patients. The use of higher energy levels (8.5 W/10 W) was associated with a significant increase in the rate of acute PVI after a purely visuallyguided ablation circle, thus reducing the need for time-consuming gapmapping and re-ablation. At the same time, the application of higher energy settings did not compromise the safety profile.27 A similar study was performed by Bordignon et al. investigating the effect of energy titration on clinical efficacy and safety in a cohort of 60 patients with AF.28 The authors compared a low dose (LD) protocol (30 patients, 5.5–8.5 W) with a high dose (HD) protocol (30 patients, >8.5 W) and found that the rate of electrical PVI after completion of a purely visually-guided ablation circle was higher in the HD group compared with the LD group (89 % vs 69 %), that the proportion of patients in whom all PVs were isolated after a single ablation circle per PV was higher in the HD group (70 % vs 39 %), and that the recurrence rate of AF was lower in the HD group during a median follow-up of 311 (261–346) days (17 % vs 40 %). A comparable rate of oesophageal thermal lesions in patients treated with the EAS (18 %) and those treated with RF energy (15 %) was observed.29 However, the quality of lesions differed in that ulcerations were found in 57 % of the EAS group and in none of the RFC group. Furthermore, in a multicentre analysis of 200 patients the incidence of PNP was 2.5 % and the incidence of pericardial tamponade 2 %.30 However, no stroke, TIA, atrio-oesophageal fistula or significant PV

Camm AJ, Lip GY, De Caterina R, et al. 2012 focused update of the ESC guidelines for the management of atrial fibrillation: an update of the 2010 ESC guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J 2012;33(21):2719–47. Verma A, Sanders P, Macle L, et al. Substrate and trigger ablation for reduction of atrial fibrillation trial-part II (STAR AF II): design and rationale. Am Heart J 2012;164(1):1–6.

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stenosis occurred. In another study from our centre, the incidence of silent cerebral ischaemic lesions after endoscopic ablation was evaluated and reported at 11.4 %, which was not statistically different from irrigated RF (18.2 %) or cryoablation (5 %).31 One-year clinical follow-up data from a prospective, multicentre study in patients with PAF showed a single-procedure clinical success rate of 63 % off anti-arrhythmic medication.26 These results were confirmed by Dukkipati et al. reporting a 1-year success rate off anti-arrhythmic drugs of 60.2 % after one or two procedures.30 Furthermore, Sediva et al. performed a clinical follow-up of 48 months and showed that even 75 % of patients with PAF remained in stable SR after EAS-guided ablation.32 Future modifications of the system may include electrodes on the balloon surface to provide real-time electrical information from the PVs, fluorescence techniques to show transmurality of lesions, and/ or an adjustable laser arc size. A study in the US recently completed enrolment comparing endoscopic EAS ablation with RF-based ablation in a multicentre, prospective, randomised fashion (NCT01456000). First results are expected in early 2015.

Hot Balloon-based Pulmonary Vein Isolation The RHB (Hayama Arrhythmia Institute, Kanagawa, Japan) consists of a compliant balloon (diameter 25–35 mm) which is introduced into and manipulated within the LA via a 13F steerable transseptal sheath. The catheter shaft houses two lumen. A guide-wire allowing for safe manipulation (‘over-the-wire’ technique) is introduced via one lumen, while a composite of contrast medium and saline is injected via the second lumen. The RHB is inflated and positioned along the respective PV and after verification of optimal PV occlusion the inner fluid is heated up to 70–75°C via a RFC generator with a maximal output of 200 W. The RHB temperature is automatically regulated by RFC energy output at a preselected value.33–35 During ablation, cooling of the oesophagus is performed according to the intraluminal oesophageal temperature measured with a temperature probe. PN pacing is continuously performed during ablation along the septal PVs. Initial studies could assess a promising acute efficacy in combination with a beneficial safety profile. In a study performed by Sohara et al. 100 patients with PAF or persistent AF were treated by RHB-based PVI and an additional LA box lesion. Acute ablation success was achieved in all patients and after 1-year clinical follow-up 92 patients were in stable SR off antiarrhythmic drugs. No atrial-to-oesophageal fistula and no permanent PN-palsy occurred.36 In a recent study a reduced incidence of oesophageal thermal injury was demonstrated if the oesophagus was actively cooled when the endoluminal temperature exceeded 39°C.37

Conclusions The second-generation CB as well as the EAS and the RHB are innovative balloon-based ablation systems that have proven safe and clinically effective. Ongoing studies such as the FIRE AND ICE trial comparing the systems to RFC-based ablation will further clarify their role in the treatment of AF. n

Andrade JG, Khairy P, Guerra PG, et al. Efficacy and safety of cryoballoon ablation for atrial fibrillation: a systematic review of published studies. Heart Rhythm 2011;8:1444–51. 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. 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. Vogt J, Heintze J, Gutleben KJ, et al. Long-term outcomes after cryoballoon pulmonary vein isolation: results from a prospective study in 605 patients. J Am Coll Cardiol 2013;61(16):1707–12. Neumann T, Wójcik M, Berkowitsch A, et al. Cryoballoon ablation of paroxysmal atrial fibrillation: 5-year outcome

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10.

11.

12.

13.

14.

15.

16.

17.

after single procedure and predictors of success. Europace 2013;15(8):1143–9. Ouyang F, Tilz R, Chun J, et al. Long-term results of catheter ablation in paroxysmal atrial fibrillation: lessons from a 5-year follow-up. Circulation 2010;122(23):2368–77. Fürnkranz A, Chun KR, Nuyens D, et al. Characterization of conduction recovery after pulmonary vein isolation using the “single big cryoballoon” technique. Heart Rhythm 2010;7(2):184–90. Chun KR, Fürnkranz A, Köster I, et al. Two versus one repeat freeze-thaw cycle(s) after cryoballoon pulmonary vein isolation: the alster extra pilot study. J Cardiovasc Electrophysiol 2012;23(8):814–9. Ahmed H, Neuzil P, d’Avila A, et al. The esophageal effects of cryoenergy during cryoablation for atrial fibrillation. Heart Rhythm 2009;6(7):962–9. Fürnkranz A, Chun KR, Metzner A, et al. Esophageal endoscopy results after pulmonary vein isolation using the single big cryoballoon technique. J Cardiovasc Electrophysiol 2010;21(8):869–74. Stöckigt F, Schrickel JW, Andrié R, Lickfett L. Atrioesophageal fistula after cryoballoon pulmonary vein isolation. J Cardiovasc Electrophysiol 2012;23(11):1254–7. Chierchia GB, Di Giovanni G, Sieira-Moret J, et al. Initial experience of three-minute freeze cycles using the second-generation cryoballoon ablation: acute and short-term procedural outcomes. J Interv Card Electrophysiol 2014;39:145–51. Fürnkranz A, Bordignon S, Schmidt B, et al. Improved procedural efficacy of pulmonary vein isolation using the novel second-generation cryoballoon. J Cardiovas Electrophysiol 2013;24:492–7. 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(2):288–92. Ciconte G, Chierchia GB, DE Asmundis C, et al. Spontaneous and adenosine-induced pulmonary vein reconnection after cryoballoon ablation with the second-generation device. J Cardiovasc Electrophysiol 2014;25(8):845–51.

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18. Casado-Arroyo R, Chierchia GB, Conte G, et al. Phrenic nerve paralysis during cryoballoon ablation for atrial fibrillation: a comparison between the first- and second-generation balloon. Heart Rhythm 2013;10(9):1318–24. 19. Metzner A, Rausch P, Lemes C, et al. The incidence of phrenic nerve injury during pulmonary vein isolation using the second-generation 28 mm cryoballoon. J Cardiovasc Electrophysiol 2014;25:466–70. 20. 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(4):769–75. 21. Fürnkranz A, Bordignon S, Schmidt B, et al. Luminal esophageal temperature predicts esophageal lesions after second-generation cryoballoon pulmonary vein isolation. Heart Rhythm 2013;10(6):789–93. 22. 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(5):492–7. 23. Reddy VY, Neuzil P, Themistoclakis S, et al. Visually-guided balloon catheter ablation of atrial fibrillation: experimental feasibility and first-in-human multicenter clinical outcome. Circulation 2009;120(1):12–20. 24. Schmidt B, Metzner A, Chun KR, et al. Feasibility of circumferential pulmonary vein isolation using a novel endoscopic ablation system. Circ Arrhythm Electrophysiol 2010;3(5):481–8. 25. Dukkipati SR, Neuzil P, Kautzner J, et al. The durability of pulmonary vein isolation using the visually guided laser balloon catheter: Multicenter results of pulmonary vein remapping studies. Heart Rhythm 2012;9(6):919–25. 26. Metzner A, Wissner E, Schmidt B, et al. Acute and long-term clinical outcome after endoscopic pulmonary vein isolation: results from the first prospective, multicenter study. J Cardiovasc Electrophysiol 2013;24(1):7–13. 27. Metzner A, Wissner E, Schoonderwoerd B, et al. The influence of varying energy settings on efficacy and safety of endoscopic pulmonary vein isolation. Heart Rhythm

2012;9(9):1380–5. 28. Bordignon S, Chun KR, Gunawardene M, et al. Energy titration strategies with the endoscopic ablation system: lessons from the high-dose vs. low-dose laser ablation study. Europace 2013;15(5):685–9. 29. Metzner A, Schmidt B, Fuernkranz A, et al. Esophageal temperature change and esophageal thermal lesions after pulmonary vein isolation using the novel endoscopic ablation system. Heart Rhythm 2011;8(6):815–20. 30. Dukkipati SR, Kuck KH, Neuzil P, et al. Pulmonary vein isolation using a visually guided laser balloon catheter: the first 200-patient multicenter clinical experience. Circ Arrhythm Electrophysiol 2013;6(3):467–72. 31. Wissner E, Metzner A, Neuzil P, et al. Asymptomatic brain lesions following laserballoon-based pulmonary vein isolation. Europace 2014;16(2):214–9. 32. Sedivá L, Petrů J, Skoda J, et al. Visually guided laser ablation: a single-centre long-term experience. Europace 2014;16(12):1746–51. 33. Tanaka K, Satake S, Saito S, et al. A new radiofrequency thermal balloon catheter for pulmonary vein isolation. J Am Coll Cardiol 2001;38:2079–86. 34. Sohara H, Satake S, Tanaka K, Watanabe Y. Simultaneous pulmonary vein and adjacent leftatrium ablation using a radiofrequency hot balloon catheter to treat atrial fibrillation: feasibility, safety, and long-term results in an initial far eastern clinical trial. Europace 2006;8(Suppl I):264. 35. Sohara H, Takeda H, Ueno H, Satake S. Monitoring the esophageal temperature during hot balloon catheter ablation for atrial fibrillation to avoid asymptomatic esophageal ulcer. Circulation J 2008;72(Suppl I):711. 36. Sohara H, Takeda H, Ueno H, et al. Feasibility of the radiofrequency hot balloon catheter for isolation of the posterior left atrium and pulmonary veins for the treatment of atrial fibrillation. Circ Arrhythm Electrophysiol 2009;2(3):225–32. 37. Sohara H, Satake S, Takeda H, et al. Prevalence of esophageal ulceration after atrial fibrillation ablation with the hot balloon ablation catheter: what is the value of esophageal cooling? J Cardiovasc Electrophysiol 2014;25(7):686–92.

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Device Therapy

Computer Modelling for Better Diagnosis and Therapy of Patients by Cardiac Resynchronisation Therapy Marieke Pluijmert, 1 Joost Lumens, 1 Mark Potse, 2 Tammo Delhaas, 1 Angelo Auricchio 2,3 and Frits W Prinzen 4 1. Department of Biomedical Engineering, Cardiovascular Research Institute, Maastricht, The Netherlands; 2. Centre for Computational Medicine in Cardiology, Universita della Svizzera Intaliana, Lugano, Switzerland; 3. Fondazione Cardiocentro Ticino, Lugano, Switzerland; 4. Department of Physiology, Cardiovascular Research Institute, Maastricht, The Netherlands

Abstract Mathematical or computer models have become increasingly popular in biomedical science. Although they are a simplification of reality, computer models are able to link a multitude of processes to each other. In the fields of cardiac physiology and cardiology, models can be used to describe the combined activity of all ion channels (electrical models) or contraction-related processes (mechanical models) in potentially millions of cardiac cells. Electromechanical models go one step further by coupling electrical and mechanical processes and incorporating mechano-electrical feedback. The field of cardiac computer modelling is making rapid progress due to advances in research and the ever-increasing calculation power of computers. Computer models have helped to provide better understanding of disease mechanisms and treatment. The ultimate goal will be to create patient-specific models using diagnostic measurements from the individual patient. This paper gives a brief overview of computer models in the field of cardiology and mentions some scientific achievements and clinical applications, especially in relation to cardiac resynchronisation therapy (CRT).

Keywords Computer model, bidomain model, monodomain model, finite element model, cardiac resynchronisation therapy, heart failure Disclosure: Marieke Pluijmert, Mark Potse and Tammo Delhaas have no conflicts of interest to declare. Angelo Auricchio is a consultant to Biosense Webster, Biologics Delivery Systems Group, Bristol-Myers Squibb, DC Devices, EBR Systems, Infobionics, Leadexx, Medtronic, Resmed and Sorin Group. He has received speaker fees from Biotronik GmBH, Medtronic, Resmed and Sorin Group. Joost Lumens received a grant within the framework of the Dr E Dekker programme of the Dutch Heart Foundation (NHS-2012T010). Frits W Prinzen has received research grants from Boston Scientific, Biologics Delivery Systems Group, Cordis Corporation, EBR Systems, Medtronic, MSD, Proteus Biomedical and St Jude Medical. Received: 14 June 2014 Accepted: 20 January 2015 Citation: Arrhythmia & Electrophysiology Review 2015;4(1):62–7 Access at: www.AERjournal.com Correspondence: Frits W Prinzen, Professor of Physiology, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands. E: frits.prinzen@maastrichtuniversity.nl

The number of cardiac devices being implanted, especially cardiac resynchronisation therapy (CRT) pacemakers and implantable cardioverter defibrillators (ICDs), continues to rise. Important determinants of the clinical benefit of CRT are the electrical and structural substrate and the site of implantation. While clinical studies and experimental work have provided a large amount of evidence for certain approaches, evidence is lacking in some areas, particularly regarding mechanisms of disease. Large inter-patient variability exists and so there is a quest to tailor therapy to the individual patient. It is here that computer models may assist in the diagnosis and the design of the therapy. By definition, models are simplified representations of reality. Such simplification can help to identify important features of a (patho-) physiological process, although the same simplification may also lead to erroneous interpretation of observations when boundaries of validity, determined by fundamental model assumptions, are ignored. The value of a model can be illustrated by the example of Einthoven’s triangle for interpretation of the electrocardiogram (ECG), proposed by this Dutch investigator more then a century ago (see Figure 1).1 It assumes the human body to be an equilateral triangle, with uniform electrical conduction and the heart in the middle. All three assumptions are clearly wrong, but this model is still used in everyday

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practice, because many aspects of the ECG and its frontal leads can be well understood through its use. However, the Einthoven triangle model is not accurate enough to predict highly localised electrical abnormalities. To paraphrase Einstein: ‘a model has to be as simple as possible, but not simpler’. It is crucial to be aware of the assumptions made in the creation of simple models, while recognising that fair predictions may often be made by such models. Mathematical models have become more complex due to increasing computing power and greater quantities of experimental data. This development carries the risk that models become so complicated that the investigator may not know exactly what is going on. At this point the model may become a black box, which is not so different from an in vivo experiment. Therefore, it seems justified to state that ‘a model has to be as complicated as necessary, but not more complicated’. In other words, it seems wise to choose a model that best suits the research question.

Electrophysiological Models The entire process of electromechanical activation starts with the action potential. It is now more than 50 years since Hodgkin and Huxley developed their model of the action potential of the squid

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

giant axon,2 which is the basis for current mathematical models of cardiac electrophysiology.

Figure 1: Einthoven’s Triangle as an Example of a Simple Model

Nowadays a series of electrophysiological models for cardiac muscle cells are available, with key differences from one another.3 These single cell models can be coupled using simulated gap junctions to predict interactions between cells, such as propagation of the action potential and repolarisation. In whole heart models, electrophysiological properties are most accurately described when a distinction is made between the intracellular and interstitial domains. In the so-called bidomain equations conductive properties of cardiac tissue are modelled as a combination of these two domains (see Figure 2). Bidomain models can simulate the effects of external stimuli and defibrillation currents,4,5 as well as predict the smaller and prolonged calcium transients and action potential duration (APD) observed in myocytes from failing hearts.6 Electrical models need high temporal and spatial resolution, due to the steepness of the membrane potential upstroke and the resulting steep spatial potential gradients. Consequently, published models of the human heart have 10–100 million elements.7,8 These models can calculate all the electrical processes, ranging from ion currents at the cellular level to body surface ECGs, in which the heart is simulated to be within a chest model.

Several anatomical assumptions are clearly wrong, but yet the model is useful in electrocardiogram interpretation. (From http://www.medicine.mcgill.ca/physio/vlab/cardio/ setup.htm).

Figure 2: Simplified Representation of a Bidomain Model

If impulse propagation alone is to be computed, the eikonal diffusion equation can be used. This equation is derived from the bidomain model and solves only for activation times. This approach is computationally less demanding and has been successfully applied in finite-element models of the heart that focus on mechanics.9

Some Achievements of Electrical Models In bidomain models, a larger heart size decreases global electrotonic effects and unmasks intrinsic APD differences between cell types, thus increasing APD dispersion. 10 Similarly, a high-resolution magnetic resonance imaging (MRI)-based rabbit heart model was able to mechanistically demonstrate the role of blood vessels and endocardial trabeculations in ventricular impulse propagation. 11 These results underscore the regional differences in activation attributable to shortcut pathways and indicate the important role that microstructure of the heart may play in impulse propagation. A host of literature now describes computer-modelling studies in cardiac arrhythmias and their resolution by defibrillation, which has been reviewed recently.4 Potse et al. used a reaction diffusion model that enabled investigation of the entire chain, from cellular cardiac electrophysiology to bodysurface ECG signals and endocardially derived electrograms.5,12 This model has been used for questions relating to Brugada syndrome13 and ST-segment analysis in infarcted hearts.14,15 More recently, the model was used to better understand the effect of decreased tissue conductivity on ventricular activation pattern and QRS morphology. Conductivity reduction in the left ventricular (LV) wall, as in the case of pressure overload hypertrophy,16 resulted in a significant left axis deviation in the frontal plane of the ECG and a moderate increase in QRS duration. The simulated ECG had a morphology similar to left bundle branch block (LBBB) but with a much lower amplitude.8 Combination of LBBB and low conductivity resulted in an unchanged (LBBB-specific) conduction pattern in combination with prolonged but smaller QRS complexes.8

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This diagram illustrates the simulation of the behaviour of ion channels in membranes of myocytes, electrical coupling between myocytes and the resultant extracellular currents, which can be recorded at the body surface as an electrocardiogram.

Small QRS amplitudes may thus indicate ‘low quality’ myocardium and may indicate increased risk of arrhythmias,17 an important indicator for ICD need in a CRT candidate. This model observation may be used to improve interpretation of the ECG. Particularly in the case of serial ECG measurements, detailed information about electrical and structural remodelling may be deciphered by analysing QRS duration, morphology and amplitude. In order to create patient-specific models, the patients’ anatomy is reconstructed using MRI or computed tomography (CT) scans. While fibre and sheet orientation are important for impulse propagation, these data are usually not available for individual patients, and so the fibre orientations in the models are commonly rule-11 or atlas-based.18 Subsequently, parameters describing impulse conduction are adjusted until the predicted activation sequence mimics that measured using endocardial mapping. Niederer et al. have described this process for a single patient.19 Electrophysiological verification can be performed using both surface ECG and cardiac electrograms.20 Parameters of the bidomain model were adjusted to match activation times measured at the LV endocardium and the morphology of the body surface ECG. Important steps were removal of the Purkinje system in the LV and the choice of location of earliest activation in the right ventricular (RV) wall, as well as adjustment of myocardial conductivity. While these steps resulted

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Device Therapy Figure 3: Comparison of Measured and Simulated Data in One Patient A

amplitude. The maximum conductivity of the inward rectifier current (IK1) was reduced to blunt the peaks of the T waves. Model-fitting in patients with dyssynchronous heart failure suggests that in these hearts there is no retrograde conduction of the electrical impulse from the working myocardium into the Purkinje system, that myocardial conductivity is considerably lower than in normal myocardium and that a ventricular gradient is at least partially preserved.20

Mechanical Models C D

A) Simulated activation times on the endocardia of both ventricles; the colour scale is in milliseconds (ms). B) Simulated against measured activation times on the left-ventricular endocardium; scales in ms. C) Measured electrocardiogram (ECG) (red) and simulated ECG (black). D) Polar diagram of the left-ventricular endocardium showing measured activation times (circles with time in ms) and simulated activation times (coloured dots). Same colour scale as panel A. Measured (red) and simulated electrograms (black) from five indicated locations are shown. From Potse et al., 2014.20

Figure 4: Results from a Biventricular FEM Based on the LV FEM 32 During Normal Sinus Rhythm, Left Bundle Branch Block and Biventricular Pacing

The deformation of the heart during the cardiac cycle is determined by the mechanical equilibrium between forces developed by active contraction of the myofibres, passive stretch of the connective tissue matrix, pressure in the cardiac cavities and pressure exerted by the pericardium. Mathematical models of cardiac mechanics help to improve understanding of these complex interactions under (ab)normal conditions. Early model studies indicated that myofibre orientation is an important determinant of local myocardial tissue stress and strain.21–23 It was demonstrated that fibre stress and strain during systole are likely to be distributed homogeneously across the wall. Based on this assumption of homogeneity, the ‘one-fibre model’ was developed that relates local myofibre mechanics, in terms of fibre stress and strain, to global cardiac pump mechanics, in terms of cavity pressure and volume.24 This relatively simple but well-designed model is the basis of the CircAdapt model.25 More recent versions use a biventricular model of the heart that provides important and reliable information about the mechanical interaction between the two ventricles.26–28 For a more detailed analysis of deformations in 3D, finite element models (FEM) have been developed.29,30 FEMs account for the spatial variation in myofibre and sheet orientation across the walls.31 Most studies have implemented a rule-based variation in fibre orientation. Alternatively, the myofibre orientation can be allowed to change locally in response to local fibre cross-fibre shear until they achieve a preferred mechanical loading state.32 This adaptation in fibre orientation leads to a more homogeneous strain distribution and improved pump function. Figure 4 shows preliminary results of activation times and distribution of mechanical work in a normal heart and hearts with LBBB and with CRT.

Some Achievements of Mechanical Models

Left: Activation times calculated by solving the Eikonal-diffusion equation. Normal activation was generated by using two right ventricular (RV) and three left ventricular (LV) breakthrough sites, left bundle branch block (LBBB) by removing the LV breakthrough sites and biventricular pacing by starting activation at the two pacing sites. Right: Pattern of myofibre work density (area of local stress–strain loop). Especially in LBBB, early activation coincides with low work and late activation with high work, similar to experimental findings.34,56,57 FEM = finite element model.

in close approximation to the measured activation sequence and QRS complex, repolarisation parameters were adjusted to match the T wave (see Figure 3). Heterogeneity in the maximum conductivity of the slow delayed rectifier current (IKs) was introduced using an inverse linear relation with the depolarisation time, mimicking a ‘ventricular gradient’. The slope of this relationship was used to tune the T-wave

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When applied to the case of asynchronous activation, models of cardiac mechanics were able to simulate the characteristic relationship between activation and mechanics that has been observed in experiments33,34 and patients.35,36 In early-activated regions, a rapid early systolic fibre shortening was found, followed by strongly reduced late systolic shortening. Later-activated regions were characterised by early systolic lengthening followed by pronounced systolic shortening.37,38 These models proved helpful for understanding the observed deformation patterns. Using a FEM, Kerckhoffs et al.39 simulated various combinations of dilatation, systolic and diastolic heart failure and dyssynchrony in order to evaluate the performance of various indices of mechanical dyssynchrony (circumferential uniformity ratio estimate [CURE],40 internal stretch fraction [ISF]41 and time delay in peak shortening between opposing walls [the most frequently used measure]). CURE and ISF, metrics of distribution of strain magnitudes, were sensitive to the combination of activation sequence and dilatation, whereas time to peak shortening was not.42

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

Leenders et al. studied the mechanism of the septal strain patterns in LBBB patients. Using the CircAdapt model containing wall segments representing the RV free wall, septum and LV free wall, they were able to demonstrate how double-, early- and late-peak septal strain patterns could originate from different combinations of a true electrical substrate of mechanical dyssynchrony whether or not in combination with regional differences in myocardial contractility (see Figure 5).35 A recent clinical study supported these findings and showed that double-and early-peak septal strain patterns are highly predictive for CRT response.43 In another CircAdapt study, during gradual pre-excitation of the septum compared with the LV free wall, the time to peak shortening in the septum shortened in two major steps, providing a poor quantitative reflection of true dyssynchrony.36 Together with the data published by Kerckhoffs et al.42 these observations plead for the use of parameters of dyssynchrony that describe the shortening/deformation pattern rather than the time to peak shortening. A recent study with the CircAdapt model compared the haemodynamic effects of LV and biventricular pacing, supported by measurements in patients and in the canine model of dyssynchronous heart failure. LV pacing consistently provided similar haemodynamic benefit to biventricular pacing, despite the larger dyssynchrony (though opposite to that during LBBB). The model was able to provide an explanation for this paradoxical finding: LV pacing results in pre-stretching of the RV free wall, which subsequently increases its workload, thereby supporting the LV in its pump function through mechanical ventricular interaction.28

Figure 5: Measured and Simulated Septal Deformation Patterns for a Normal Healthy Subject (NORMAL) and Three Representative Patients (LBBB-1, LBBB-2 and LBBB-3)

In the lower panel simulated left ventricular (LV) free wall strain patterns indicated by dashed lines. Starting from the normal simulation (lower left corner), similar characteristic septal deformation patterns are obtained as measured in the study population by simple model simulations, i.e. classic left bundle branch block (LBBB) (25 and 75 ms delay of septal and left-ventricular free wall (LVFW) activation, respectively) with normal myocardial contractility (LBBB-1), LBBB with additional septal hypocontractility (LBBB-2) and LBBB with additional septal and LVFW hypocontractility (LBBB-3).35

Figure 6: Whole-heart Modelling ECG, EP parameters

Circulatory parameters Circulatory system

Electromechanical Models Various electromechanical models of the ventricles have been reviewed extensively elsewhere.44 Historically, large-scale models were aimed at either electrophysiology or mechanics. As a consequence, most combined models are weakly coupled, i.e. electrophysiology (in particular activation sequence) is computed separately from mechanical behaviour. In its ultimate form, models of cardiac electromechanics properly describe the physical and physiological processes linking cardiac electrophysiology and mechanics, i.e. calcium handling and cross-bridge formation. Here, models describing the calcium-force relation come into play, such as those developed by Rice45 and Niederer.46 Models that implement the effect of mechano-electrical feedback in the generation of arrhythmias47 are a further step in the complete integration of electromechanics. A similarly integrated approach is required in studies on local mechanical load as a determinant of local APD and contractility.48,49 Medically relevant models for device therapy, especially CRT, are required to cover many aspects. Abnormal electrical impulse conduction (requiring electrophysiological models) gives rise to abnormal contraction (to be captured by mechanical models), which leads to worsening pump function (calculated by haemodynamic models, preferably of the entire circulation). Moreover, heart failure may lead to complicated molecular and cellular remodelling, which require models linking these subcellular processes with properties at the tissue and organ level. Figure 6 shows many of the processes that may need to be measured and modelled when studying dyssynchronous heart failure and application of CRT. Clearly, implementing this all in a model is a huge undertaking.

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Monodomain/Bidomain

Ca2+

Continuum mechanics

Cellular Ionic Model Cellular Myofilamental Model

Electrical component

Mechanical component

Upper row: General approach to modelling cardiac electromechanical function. Lower row, from left to right: computational meshes of the canine heart (electrical and mechanical), fibre and sheet orientations obtained from canine heart diffusion weighed MRI and the CircAdapt model of entire heart and circulation. Modified from Trayanova et al., 2011.4

Some Results from Electromechanical Models Early electromechanical measurements indicated that the time interval between depolarisation and the onset of muscle shortening (electromechanical delay [EMD]) was longer in late- than in earlyactivated regions of paced ventricles.50 Later measurements51 indicated that EMD is larger in the subepicardium than in the subendocardium. Computer models indicated that the more pronounced a region was prestretched, the longer was its EMD.7,37 The most detailed study on this topic used a combination of measurements in animals in situ, isolated trabeculae, patients and a computer model. These studies provided evidence that it is not prestretch itself but the rate of rise of LV pressure (LV dP/dtmax) at the time of depolarisation that is the direct determinant of the length of EMD.52 This group also showed that the use of a measure of â&#x20AC;&#x2DC;true active force developmentâ&#x20AC;&#x2122; rather than onset of shortening, provides a delay between electrical and mechanical activation that is independent of timing of activation or ischaemia.53

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Device Therapy As a large portion of CRT non-responders are heart failure patients with chronic myocardial infarction, it is important to understand the impact of the infarct on cardiac dyssynchrony and resynchronisation. Kerckhoffs et al. demonstrated that increased infarct scar size diminishes the improvement of ventricular function following biventricular CRT in the LBBB failing heart.54 In these simulations, however, impulse conduction was not influenced by the scar tissue. Niederer employed bidomain modelling to investigate a combination of two effects: scar and multisite pacing. Postero-lateral scar was simulated in two severities, creating a 50 % and 90 % reduction in conductivity, thus implementing the slower conduction in the scar. This study indicated that, in the presence of postero-lateral scar, multisite pacing offers a better haemodynamic response than conventional CRT. This effect was associated with a larger LV activation wave, as induced by multisite pacing.55

Future Perspectives As discussed above, studies using computer models have primarily contributed to better understanding mechanistic aspects of cardiac electromechanics. The ultimate goal of the modelling work is, however, to serve as a system that supports clinical decision-making and thereby to improve diagnosis and therapy planning. Nowadays, patients with heart disease undergo a large number of diagnostic measurements, such as ECG, echocardiography, CT and/or cardiac MRI. Each of these modalities provides some information about the heart and circulation, but in order to achieve the complete picture of the disease, data of different modalities need to be combined.

6. 7.

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Einthoven W, Fahr G, de Waart A. Über die Richtung und die manifeste Grösse der Potentialschwankungen im menschlichen Herzen und Über den Einfluss der Herzlage auf die Form des Elektrokardiogramms. Pflüger Arch ges Physiol 1913;150:275–315. Hodgkin AL, Huxley AF. A quantitative description of membrane current and its application to conduction and excitation in nerve. J Physiol 1952;117:500–44. Niederer SA, Fink M, Noble D, Smith NP. A meta-analysis of cardiac electrophysiology computational models. Exp Physiol 2009;94.5:486–95. Trayanova NA. Whole-heart modeling: applications to cardiac electrophysiology and electromechanics. Circ Res 2011;108:113–28. Potse M, Dube B, Richer J, et al. A comparison of monodomain and bidomain reaction-diffusion models for action potential propagation in the human heart. IEEE Trans Biomed Eng 2006;53:2425–35. Priebe L, Beuckelmann DJ. Simulation study of cellular electric properties in heart failure. Circ Res 1998;82:1206–23. Gurev V, Constantino J, Rice JJ, Trayanova NA. Distribution of electromechanical delay in the heart: insights from a three-dimensional electromechanical model. Biophys J 2010;99:745–4. Potse M, Krause D, Bacharova L, et al. Similarities and differences between electrocardiogram signs of left bundlebranch block and left-ventricular uncoupling. Europace 2012;Suppl 5:v33–9. Colli-Franzone P, Guerri L,Tentoni S. Mathematical modeling of the excitation process in myocardial tissue: influence of fiber rotation on wavefront propagation and potential field. Math Biosci 1990;101:155–235. Sampson KJ, Henriquez CS. Electrotonic influences on action potential duration dispersion in small hearts: a simulation study. Am J Physiol Heart Circ Physiol 2005;289:H350–60. Bishop MJ, Plank G, Burton RA, et al. Development of an anatomically detailed MRI-derived rabbit ventricular model and assessment of its impact on simulations of electrophysiological function. Am J Physiol Heart Circ Physiol 2010;298:H699–718. Potse M, Vinet A, Opthof T, Coronel R. Validation of a simple model for the morphology of the T wave in unipolar electrograms. Am J Physiol Heart Circ Physiol 2009;297:H792–801. Hoogendijk MG, Potse M, Vinet A, et al. ST segment elevation by current-to-load mismatch: an experimental and computational study. Heart Rhythm 2011;8:111–8. Hoogendijk MG, Potse M, Linnenbank AC, et al. Mechanism of right precordial ST-segment elevation in structural heart disease: Excitation failure by current-to-load mismatch. Heart Rhythm 2010;7:238–48.

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Computer models are able to handle this complex dataset quite well, thereby improving diagnosis and healthcare, for example in the better selection of CRT patients and improved therapy planning. Reality forces us to acknowledge that there is still a long way to go. Patient-specific models that fully and reliably replicate an individual patient’s characteristics and affect the clinicians’ diagnostic and therapeutic work-up are still under development. Part of the problem is that the data used for the mathematical description of these physiological principles have been derived from animal myocardium models (from species ranging from mouse to dog), often from isolated cells and membrane patches kept in specific solutions and sometimes at temperatures different from body temperatures. As a consequence, the values obtained in isolated set-ups may not be those prevalent in real life. It is the experience of many builders of computer models that, even after years of work meticulously connecting many molecular properties, the calculated final physiological signal, such as action potential or LV pressure curve, deviates from measured ones. Frequently, therefore, gaps are filled by new model parameters, allowing to adjust (or tweak) the model predictions to the real measurements. While this may appear disappointing, the true scientific merit of this is that computer models help us to ‘know what we do not know’. And for a complicated chain of processes, from ion channels contributing to membrane potential through calcium and contraction to total cardiac pump function, we have to acknowledge that there are many uncertainties to solve. Nevertheless, as mentioned in the introduction, relatively simple problems may already be solved with relatively simple models. n

15. Potse M, Coronel R, Falcao S, et al. The effect of lesion size and tissue remodeling on ST deviation in partial-thickness ischemia. Heart Rhythm 2007;4:200–6. 16. Severs NJ, Bruce AF, Dupont E, Rothery S. Remodelling of gap junctions and connexin expression in diseased myocardium. Cardiovasc Res 2008;80:9–19. 17. Danik SB, Liu F, Zhang J, et al. Modulation of cardiac gap junction expression and arrhythmic susceptibility. Circ Res 2004;95:1035–41. 18. Lombaert H, Peyrat JM, Croisille P, et al. Human atlas of the cardiac fiber architecture: study on a healthy population. IEEE Trans Med Imaging 2012;31:1436–47. 19. Niederer SA, Plank G, Chinchapatnam P, et al. Length-dependent tension in the failing heart and the efficacy of cardiac resynchronization therapy. Cardiovasc Res 2011;89:336–43. 20. Potse M, Krause D, Murzilli R, et al. Patient-specific modeling of cardiac electrophysiology in heart-failure patients. Europace 2014;16:iv56–61. 21. Arts T, Reneman RS, Veenstra PC. A model of the mechanics of the left ventricle. Ann Biomed Eng 1979;7:299–318. 22. Bovendeerd PHM. The mechanics of the normal and ischemic left ventricle during the cardiac cycle. A numerical and experimental analysis. Maastricht University: doctoral thesis, 1990. 23. Bovendeerd PHM, Arts T, Delhaas T, et al. Regional wall mechanics in the ischemic left ventricle: numerical modeling and dog experiments. Am J Physiol 1996;270:H398–410. 24. Arts T, Bovendeerd PHM, Prinzen FW, Reneman RS. Relation between left ventricular cavity pressure and volume and systolic fiber stress and strain in the wall. Biophys J 1991;59:93–102. 25. Arts T, Delhaas T, Bovendeerd P, et al. Implementing adaptation rules results in self-shaping of heart and circulation, the CircAdapt model. Am J Physiol 2005;288:H1943–54. 26. Lumens J, Delhaas T, Kirn B, Arts T. Three-wall segment (TriSeg) model describing mechanics and hemodynamics of ventricular interaction. Ann Biomed Eng 2009;37:2234–55. 27. Lumens J, Arts T, Broers B, et al. Right ventricular free wall pacing improves cardiac pump function in severe pulmonary arterial hypertension: a computer simulation analysis. Am J Physiol Heart Circ Physiol 2009;297:H2196–205. 28. Lumens J, Ploux S, Strik M, et al. Comparative electromechanical and hemodynamic effects of left ventricular and biventricular pacing in dyssynchronous heart failure: electrical resynchronization versus left–right ventricular interaction. J Am Coll Cardiol 2013;62:2395–403. 29. Kerckhoffs RC, Faris OP, Bovendeerd PH, et al. Electromechanics of paced left ventricle simulated by straightforward mathematical model: comparison with experiments. Am J Physiol Heart Circ Physiol 2005;289:H1889–97.

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