AER 3.2

Arrhythmia & Electrophysiology Review Volume 3 • Issue 2 • Summer 2014

www.AERjournal.com

Volume 3 • Issue 2 • Summer 2014

Cardiac or Other Implantable Electronic Devices and Sleep-disordered Breathing – Implications for Diagnosis and Therapy Henrik Fox, Thomas Bitter, Klaus-Jürgen Gutleben, Dieter Horstkotte and Olaf Oldenburg

Cardiac Autonomic Denervation for Ablation of Atrial Fibrillation George D Katritsis and Demosthenes G Katritsis

Genetic Discoveries in Atrial Fibrillation and Implications for Clinical Practice Saagar Mahida

Mechanisms of Atrial Fibrillation – Reentry, Rotors and Reality Jonathan Waks and Mark Josephson

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Left to Right Dominant Frequency Gradients in the Sheep Left and Right Atria

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Major Ganglionated Plexi Targeted for Catheter Ablation

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AER3.2_FC+spine.indd All Pages

IRGP

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Reduce Stroke Risk Protect Your AF Patients One tablet, once daily for 24-hour stroke prevention2-4

ESC Guidelines recommend novel OACs for non-valvular AF5 Xarelto® is indicated for the prevention of stroke and systemic embolism in eligible adult patients with non-valvular AF with one or more risk factors1

Simple Protection for More Patients

AF: Atrial Fibrillation, OACs: oral anticoagulants ▼ This medicinal product is subject to additional monitoring Xarelto® 10, 15 and 20 mg film-coated tablets (rivaroxaban) Prescribing Information (Refer to full Summary of Product Characteristics (SmPC) before prescribing) Presentation: 10mg/15mg/20mg rivaroxaban tablet Indication(s): 10mg Prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery.

15mg/20mg - 1. Prevention of stroke & systemic embolism in adult patients with non-valvular atrial fibrillation with one or more risk factors such as congestive heart failure, hypertension, age ≥ 75, diabetes mellitus, prior stroke or transient ischaemic attack (SPAF). 2. Treatment of deep vein thrombosis (DVT) & pulmonary embolism (PE), & prevention of recurrent DVT & PE in adults (see W&P for haemodynamically unstable PE patients).

Posology & method of administration: 10mg - Dosage 10 mg rivaroxaban orally once daily; initial dose should be taken 6 to 10 hours after surgery provided haemostasis established.

Recommended treatment duration: Dependent on individual risk of patient for VTE determined by type of orthopaedic surgery: for major hip surgery 5 weeks; for major knee surgery 2 weeks. 15mg/20mg - SPAF: 20 mg orally o.d. with food. DVT & PE: 15 mg b.i.d. for 3 weeks followed by 20 mg o.d. for continued treatment & prevention of recurrent DVT & PE; take with food.

10mg/15mg/20mg - Refer to SmPC for full information on duration of therapy & converting to/from Vitamin K antagonists (VKA) or parenteral anticoagulants. For patients who are unable to swallow whole tablets, refer to SmPC for alternative methods of oral administration. Renal impairment: mild (creatinine clearance 50-80 ml/min) - no dose adjustment; 10mg - moderate (creatinine clearance 30-49 ml/min) – no dose adjustment. Severe (creatinine clearance 15-29ml/min) - limited data indicate rivaroxaban concentrations are significantly increased, use with caution. 15mg/20mg - moderate & severe renal impairement limited data indicates rivaroxaban plasma concentrations are significantly increased, use with caution – SPAF: reduce dose to 15mg o.d., DVT & PE: 15 mg b.i.d. for 3 weeks, thereafter 20mg o.d. Consider reduction from 20mg to 15mg o.d. if patient’s bleeding risk outweighs risk for recurrent DVT & PE; 10mg/15mg/20mg - Creatinine clearance <15 ml/min - not recommended. Hepatic impairment: Do not use in patients with coagulopathy & clinically relevant bleeding risk including cirrhotic patients with Child Pugh B & C patients. Paediatrics: Not recommended. Contra-indications: Hypersensitivity to active substance or any excipient; active clinically significant bleeding; lesion or condition considered to confer a significant risk for major bleeding (refer to SmPC); concomitant treatment with any other anticoagulants except when switching therapy to or from rivaroxaban or when unfractionated heparin is given at doses necessary to maintain an open central venous or arterial catheter; hepatic disease associated with coagulopathy & clinically relevant bleeding risk including cirrhotic patients with Child Pugh B & C; pregnancy & breast feeding. Warnings & precautions: 10mg - Not recommended in patients: undergoing hip fracture surgery; receiving concomitant systemic treatment with strong CYP3A4 and P-gp inhibitors, i.e. azole-antimycotics

bayer.indd 1

or HIV protease inhibitors; with creatinine clearance <15 ml/min.

Please note - Increased risk of bleeding, therefore careful monitoring for signs/ symptoms of bleeding complications & anaemia required after treatment initiation in patients: with severe renal impairment, with moderate renal impairment concomitantly receiving other medicinal products which increase rivaroxaban plasma concentrations; treated concomitantly with medicinal products affecting haemostasis; with congenital or acquired bleeding disorders, uncontrolled severe arterial hypertension, active ulcerative gastrointestinal disease (consider appropriate prophylactic treatment for at risk patients), vascular retinopathy, bronchiectasis or history of pulmonary bleeding.

Take special care when neuraxial anaesthesia or spinal/ epidural puncture is employed due to risk of epidural or spinal haematoma with potential neurologic complications.

15mg/20mg - Clinical surveillance in line with anticoagulant practice is recommended throughout the treatment period.

Discontinue if severe haemorrhage occurs. In studies mucosal bleedings & anaemia were seen more frequently during long term rivaroxaban treatment compared with VKA treatment – haemoglobin/haematocrit testing may be of value to detect occult bleeding. The following sub-groups of patients are at increased risk of bleeding & should be carefully monitored after treatment initiation so use with caution: in patients with severe renal impairment or with renal impairment concomitantly receiving medicinal products which increase rivaroxaban plasma concentrations; in patients treated concomitantly with medicines affecting haemostasis. Not recommended in patients: with creatinine clearance <15 ml/min; with an increased bleeding risk (refer to SmPC); receiving concomitant systemic treatment with azole-antimycotics or HIV protease inhibitors; with prosthetic heart valves; with PE who are haemodynamically unstable or may receive thrombolysis or pulmonary embolectomy. If invasive procedures or surgical intervention are required stop Xarelto use at least 24 hours beforehand. Restart use as soon as possible provided adequate haemostasis has been established. See SmPC for full details. 10mg/15mg/20mg - There is no need for monitoring of coagulation parameters during treatment with rivaroxaban in clinical routine, if clinically indicated rivaroxaban levels can be measured by calibrated quantitative anti-Factor Xa tests. Elderly population – Increasing age may increase haemorrhagic risk. Xarelto contains lactose. Interactions: Concomitant use with strong inhibitors of both CYP3A4 & P-gp not recommended as clinically relevant increased rivaroxaban plasma concentrations are observed. Avoid coadministration with dronedarone. Use with caution in patients concomitantly receiving NSAIDs, acetylsalicylic acid (ASA) or platelet aggregation inhibitors due to the increased bleeding risk.

Concomitant use of strong CYP3A4 inducers should be avoided unless patient is closely observed for signs and symptoms of thrombosis. Pregnancy & breast feeding: Contra-indicated.

Effects on ability to drive and use machines: syncope (uncommon) & dizziness (common) were reported. Patients experiencing these effects should not drive or use machines.

Undesirable effects: Common: anaemia, dizziness, headache,

eye haemorrhage, hypotension, haematoma, epistaxis, haemoptysis, gingival bleeding, GI tract haemorrhage, GI & abdominal pains, dyspepsia, nausea, constipation, diarrhoea, vomiting, pruritus, rash, ecchymosis, cutaneous & subcutaneous haemorrhage, pain in extremity, urogenital tract haemorrhage, renal impairment, fever, peripheral oedema, decreased general strength & energy, increase in transaminases, post-procedural haemorrhage, contusion, wound secretion. Serious: cf. CI/ Warnings and Precautions – in addition: thrombocythemia, angioedema and allergic oedema, occult bleeding/haemorrhage from any tissue (e.g. cerebral & intracranial, haemarthrosis, muscle) which may lead to complications (incl. compartment syndrome, renal failure, fatal outcome), syncope, tachycardia, abnormal hepatic function, hyperbilirubinaemia, jaundice, vascular pseudoaneurysm following percutaneous vascular intervention. Prescribers should consult SmPC in relation to full side effect information. Overdose: No specific antidote is available. Legal Category: POM. Package Quantities and Basic NHS Costs: 10mg - 10 tablets: £21.00, 30 tablets: £63.00 and 100 tablets: £210.00. 15mg – 14 tablets: £29.40, 28 tablets: £58.80, 42 tablets: £88.20, 100 tablets: £210.00; 20mg – 28 tablets: £58.80, 100 tablets £210.00 MA Number(s): 10mg - EU/1/08/472/001-10, 15mg/20mg - EU/1/08/472/011-21 Further information available from: Bayer plc, Bayer House, Strawberry Hill, Newbury, Berkshire RG14 1JA, U.K. Telephone: 01635 563000. Date of preparation: January 2014.

Xarelto® is a trademark of the Bayer Group.

References: 1. Xarelto® 15mg and 20mg Summary of Product Characteristics. United Kingdom: Bayer HealthCare AG. http:// www.medicines.org.uk/emc/medicine/25586/SPC 2. Patel MR, Mahaffey KW, Garg J, et al.; ROCKET AF Investigators. Xarelto versus warfarin in non-valvular atrial fibrillation. N Engl J Med 2011; 365(10): 883-891. 3. Kubitza D, Becka M, Roth A, Mueck W. The Influence of Age and Gender on the Pharmacokinetics and Pharmacodynamics of Rivaroxaban-An Oral, Direct Factor Xa Inhibitor. J Clin Pharmacol. 2013 Mar; 53(3):249-55. 4. Kubitza D, Becka M, Roth A, et al. The influence of age and gender on the pharmacokinetics and pharmacodynamics of rivaroxaban-an oral, direct factor xa inhibitor. J Clin Pharmacol. 2013; 53(3):249255. 5. Camm AJ et al. Eur Heart J. 2012; 33(21):2719–2747.

Adverse events should be reported.

Reporting forms and information can be found at www.mhra.gov.uk/yellowcard.

Adverse events should also be reported to Bayer plc. Tel.: 01635 563500, Fax.: 01635 563703, Email: phdsguk@bayer.co.uk April 2014

L.GB.03.2014.5853t

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Volume 3 • Issue 2 • Summer 2014

Editor-in-Chief Demosthenes Katritsis Athens Euroclinic, Greece

Section Editor – Arrhythmia Mechanisms / Basic Science

Section Editor – Clinical Electrophysiology and Ablation

Section Editor – Implantable Devices

Andrew Grace

Karl-Heinz Kuck

Angelo Auricchio

University of Cambridge, UK

Asklepios Klinik St Georg, Hamburg, Germany

Fondazione Cardiocentro Ticino, Lugano, Switzerland

Etienne Aliot

Warren Jackman

Antonio Raviele

University Hospital of Nancy, France

University of Oklahoma Health Sciences Center, Oklahoma City, US

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

University Hospital Uppsal, Sweden

Mark Josephson

Frédéric Sacher

Johannes Brachmann

Beth Israel Deaconess Medical Center, Boston, US

Klinikum Coburg, II Med Klinik, Germany

Josef Kautzner

Bordeaux University Hospital / LIRYC / INSERM 1045

Pedro Brugada

Institute for Clinical and Experimental Medicine, Prague, Czech Republic

Carina Blomström-Lundqvist

University of Brussels, UZ-Brussel-VUB, Belgium

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

Alessandro Capucci Università Politecnica delle Marche, Ancona, Italy

Ken Ellenbogen Virginia Commonwealth University School of Medicine, US

Samuel Lévy Aix-Marseille Université, France

Gregory YH Lip University of Birmingham Centre for Cardiovascular Sciences, UK

Antonis Manolis Athens University School of Medicine, Greece

Francis Marchlinski University of Pennsylvania Health System, Philadelphia, US

Jose Merino

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

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

Jesper Hastrup Svendsen Rigshospitalet, Copenhagen University Hospital, Denmark

Juan Luis Tamargo University Complutense, Madrid, Spain

Sotirios Tsimikas

Hospital Universitario La Paz, Spain

University of California San Diego, US

Sanjiv M Narayan

Panos Vardas

University of California San Diego, US

Heraklion University Hospital, Greece

Mark O’Neill

Marc A Vos

St Vincenz-Hospital Paderborn and University Hospital Magdeburg, Germany

King’s College, London, UK

University Medical Center Utrecht, The Netherlands

Hein Heidbuchel

Maria Cecilia Hospital, Italy

Katja Zeppenfeld

University Hospital Leuven, Belgium

Sunny Po

Gerhard Hindricks

Leiden University Medical Center, The Netherlands

University of Leipzig, Germany

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

Carsten W Israel

Christopher Piorkowski

JW Goethe University, Germany

University of Dresden, Germany

Sabine Ernst Royal Brompton and Harefield NHS Foundation Trust, UK

Andreas Götte

Carlo Pappone

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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Douglas P Zipes Krannert Institute of Cardiology, Indianapolis, US

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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 image © | shutterstock.com Lifelong Learning for Cardiovascular Professionals

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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: Summer 2014

• 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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Distribution and Readership

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, which comprises experts appointed for their experience and knowledge of a specific topic.

• An experienced team of Editors and Technical Editors.

From 2014 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 Deputy 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 manuscripts from other journals within Radcliffe cardiovascular portfolio – namely, Interventional Cardiology Review and European Cardiology Review. n

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© RADCLIFFE CARDIOLOGY 2014

14/08/2014 16:19

Contents

Foreword

68

Arrhythmia & Electrophysiology Review – Onwards and Upwards

Professor Karl-Heinz Kuck, Section Editor – Clinical Electrophysiology and Ablation

Asklepios Klinik St Georg, Hamburg, Germany

69

Arrhythmia Mechanisms

Genetic Discoveries in Atrial Fibrillation and Implications for Clinical Practice

Saagar Mahida

Leeds General Infirmary, Leeds, UK

76

Short QT Syndrome – Review of Diagnosis and Treatment Boris Rudic, 1 Rainer Schimpf 2 and Martin Borggrefe 3

1. Fellow in Cardiac Electrophysiology; 2. Associate Professor and Senior Electrophysiologist;

3. Director of the Department; 1st Department of Medicine-Cardiology, University Medical Centre Mannheim, Germany

80

Inherited Arrhythmias – Where do we Stand?

Demosthenes G Katritsis, 1 Bernard J Gersh 2 and A John Camm 3

1. Athens Euroclinic, Athens, Greece; 2. Mayo Medical School, Rochester, MN, US;

3. St George’s University of London, UK

Clinical Arrhythmias

85

Dental Procedures in Patients with Atrial Fibrillation and New Oral Anticoagulants Pepie Tsolka

Assistant Professor, Department of Dental Technology, Faculty of Health and Caring Professions,

Technological Educational Institute of Athens, Athens, Greece

90

Mechanisms of Atrial Fibrillation – Reentry, Rotors and Reality

Jonathan W Waks 1 and Mark E Josephson 2

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1. Clinical Fellow in Cardiac Electrophysiology, Harvard Medical School, Harvard-Thorndike Electrophysiology Institute and Arrhythmia Service, Beth Israel Deaconess Medical Center, Boston, US; 2. Herman C. Dana Professor of Medicine, Harvard Medical School, Chief of the Cardiovascular Division, Beth Israel Deaconess Medical Center and Director, Harvard-Thorndike Electrophysiology Institute and Arrhythmia Service, Beth Israel Deaconess Medical Center, Boston, US

© RADCLIFFE CARDIOLOGY 2014

15/08/2014 10:55

ARRHYTHMIAS, PACING, RESYNCHRONISATION AT

ESC Congress 2014 Visit Village 9 to be updated to the modern management of arrhythmias from diagnostic to therapeutic options. www.escardio.org/ESC2014

Best of ESC Congress 2014 Extend your ESC Congress experience on Thursday 4 September 20:00-21:00 (CET) Register now for free to watch THE online event! www.escardio.org/bestofesc2014

ESC CONGRESS 365 View thousands of videos, slides, abstracts and reports from ESC Congress in a unique digital library.

Online, anytime, for free!

Topic: Arrhythmias & Pacing www.escardio.org/365

European Society of Cardiology

ESC 2014_2015.indd 65

#esccongress

29 Aug - 2 Sept WWW.ESCARDIO.ORG/ESC2015

escardiodotorg

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Contents

Diagnostic Electrophysiology & Ablation 101

Limited Ablation for Persistent Atrial Fibrillation Using Preprocedure Reverse Remodelling

David Slotwiner 1 and Jonathan Steinberg 2

1. Assistant Professor of Cardiology, Hofstra North Shore-LIJ School of Medicine, and Associate

Director – Cardiac Electrophysiology Laboratory, Long Island Jewish Medical Center;

2. Adjunct Professor of Medicine, University of Rochester School of Medicine, and Director,

Arrhythmia Institute, The Valley Health System, New York and New Jersey, US

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New Ablation Technologies and Techniques

Saagar Mahida, Benjamin Berte, Seigo Yamashita, Nicolas Derval,

Arnaud Denis, Ashok Shah, Sana Amraoui, Meleze Hocini, Michel Haissaguerre, Pierre Jais and Frederic Sacher

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

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Cardiac Autonomic Denervation for Ablation of Atrial Fibrillation

George D Katritsis 1 and Demosthenes G Katritsis 2

1. Academic Foundation Trainee, John Radcliffe Hospital, Oxford University Clinical Academic Graduate School, Oxford, UK; 2. Director, Department of Cardiology, Athens Euroclinic, Athens, Greece

Device Therapy 116

Cardiac or Other Implantable Electronic Devices and Sleep-disordered Breathing – Implications for Diagnosis and Therapy

Henrik Fox, 1 Thomas Bitter, 2 Klaus-Jürgen Gutleben, 3 Dieter Horstkotte 4 and

Olaf Oldenburg 5

1. Cardiologist, 2. Pneumologist, 3. Co-chair of Electrophysiology, 4. Head, 5. Senior Cardiologist, Department of Cardiology, Heart and Diabetes Centre North Rhine-Westphalia, Ruhr University Bochum, Bad Oeynhausen, Germany

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Can we Modulate the Autonomic Nervous System to Improve the Life of Patients with Heart Failure? The Case of Vagal Stimulation Peter J Schwartz

Professor and Head, Centre for Cardiac Arrhythmias of Genetic Origin, IRCCS Istituto Auxologico Italiano,

Milan, Italy

123

Remote Monitoring for Follow-up of Patients with Cardiac Implantable Electronic Devices Renato Pietro Ricci, 1 Loredana Morichelli 1 and Niraj Varma 2

1. Department of Cardiology, San Filippo Neri Hospital, Rome, Italy; 2. Cardiac Pacing and Electrophysiology,

Cleveland Clinic, Cleveland, Ohio, US

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Foreword

Arrhythmia & Electrophysiology Review – Onwards and Upwards

I

t was an honour to accept Dr Demosthenes Katritsis’ invitation to supply the foreword to the August 2014 edition of Arrhythmia & Electrophysiology Review (AER), following my appointment as Section Editor – Clinical Electrophysiology and Ablation for the journal.

AER, with its editorial mission of providing concise, practical reviews on heart rhythm disorders for the education of both arrhythmologists and general cardiologists, continues to grow as an invaluable resource of quality review articles for the cardiology community, which is testament to the editorship of Dr Katritsis, the editorial board, and the contributing authors and reviewers.

This issue covers a range of topics of real interest with a number of articles focused on inherited arrhythmias and genetics, ablation techniques and implantable cardiac device issues, written by a panel of experienced and respected cardiologists.

I trust that you will find this edition of AER an enjoyable contribution to your continued educational development on heart rhythm disorders.

Professor Karl-Heinz Kuck, Section Editor – Clinical Electrophysiology and Ablation Asklepios Klinik St Georg, Hamburg, Germany

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Arrhythmia Mechanisms

Genetic Discoveries in Atrial Fibrillation and Implications for Clinical Practice Saagar Mahida Leeds General Infirmary, Leeds, UK

Abstract Atrial fibrillation (AF) is an arrhythmia with a genetic basis. Over the past decade, rapid advances in genotyping technology have revolutionised research regarding the genetic basis of AF. While AF genetics research was previously largely restricted to familial forms of AF, recent studies have begun to characterise the genetic architecture underlying the form of AF encountered in everyday clinical practice. These discoveries could have a significant impact on the management of AF. However, much work remains before genetic findings can be translated to clinical practice. This review summarises results of studies in AF genetics to date and discusses the potential implications of these findings in clinical practice.

Keywords Atrial fibrillation, genetics, familial AF, linkage analysis, candidate gene association studies, genome-wide association studies, risk stratification Disclosure: The author has no conflicts of interest to declare.

Received: 14 May 2014 Accepted: 4 July 2014 Citation: Arrhythmia & Electrophysiology Review 2014;3(2):69–75 Access at: www.AERjournal.com Correspondence: Saagar Mahida, MB ChB, Leeds General Infirmary, Great George Street, Leeds, LS1 3EX, UK. E: saagar7m7@yahoo.co.uk

Atrial fibrillation (AF) is a highly prevalent arrhythmia that represents an important burden on healthcare systems. The presence of AF is associated with an increased risk of conditions such stroke, heart failure and dementia. Further, AF is associated with increased mortality. Over the past half century, significant advances have been made in understanding the pathobiology of AF. Important among these have been the demonstration that AF is a heritable disease and the identification of genetic variants underlying AF. The following review provides an overview of research in AF genetics followed by a discussion on the potential applicability of AF genetics research to clinical practice. The literature review was conducted in the PubMed database between January 1940 and January 2014.

Historical Perspective The first reports suggesting a genetic basis of AF emerged in the 1940s when Wolff described an AF pedigree with a number of affected siblings.1 In the ensuing decades, multiple rare AF pedigrees with monogenic patterns of inheritance were described. However, it was not until 2003 that the first mutation in an AF family was reported. Using classic genetic techniques, such as linkage analysis and candidate gene screening, Chen et al. identified a potassium channel mutation in a four-generation pedigree with autosomal dominant AF. Over the next few years, much of the research in AF genetics focused on familial forms of the arrhythmia and led to the identification of additional genetic mutations (discussed in more detail in the next section).2–31 Around the same time as the first reports of causative mutations in AF pedigrees, epidemiological studies began to emerge suggesting that the form of AF encountered in everyday clinical practice also has a significant genetic component. The first large population-based study to report familial clustering of AF came from investigators

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at the Framingham Heart Study. They reported that more than a third of AF cases in the general population have a relative with the arrhythmia.32 Two subsequent studies from Iceland and the US also reported familial aggregation in cohorts of lone AF patients.33,34 More recently, a Danish study involving more than 9,000 lone AF patients demonstrated a strong familial component to the arrhythmia.35 While familial AF is caused by single gene mutations, the form of AF encountered in everyday clinical practice is likely to be a more complex trait, which is caused by multiple genetic variants interacting with environmental factors. The identification of the genetic architecture underlying the common form of AF has represented a challenging task. Candidate gene association studies have attempted to identify common variants underlying AF with limited success.

The recent emergence of next-generation sequencing (NGS) technology has enhanced the ability of researchers to identify genetic variants underlying complex traits. Since 2007, genome-wide association studies (GWAS) have used NGS technology to identify multiple variants underlying AF. NGS technology has also led to the development of exome sequencing and whole genome sequencing, which allow simultaneous sequencing of the entire protein coding region or the whole genome, respectively. These are promising techniques for the identification of causative variants in AF pedigrees as well as AF populations. However, as yet, they have not been widely applied to AF genetics research.

Rare Mutations in Familial Atrial Fibrillation Linkage analysis and candidate-gene sequencing have identified multiple mutations in monogenic AF families and isolated AF cases.2–31 Linkage analysis involves performing genotyping of markers distributed

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Arrhythmia Mechanisms Table 1: Summary of Monogenic Mutations Associated with Atrial Fibrillation Gene

Gene Product

Functional Effect of Mutations

Mutations

KCNQ1

α subunit of Iks channel

Gain-of-function (increased Iks)

S140G, V141M, S209P

Associated Conditions

2–4

KCNE1

β subunit of Iks channel

Gain-of-function (increased Iks)

G25V, G60D

30

KCNE2

β subunit of Iks channel

Gain-of-function (increased Iks) R27C

5

KCNE5

β subunit of Iks channel

Gain-of-function (increased Iks) L65F

6

KCNJ2

Kir 2.1 channel

Gain-of-function (increased IK1) V93I

7

KCNA5

Kv1.5 channel

Loss-of-function (reduced Ikur)

8,106,107

E375X, T527M, A576V, E610K

Y155C, D469E, P488S

KCNA5

Kv1.5 channel

Gain-of-function (increased Ikur)

E48G, A305T, D322H

KCND3

α subunit of Ito channel

Gain-of-function (increased Ito) A545P Gain-of-function (increased Ito, IKr) V17M

Reference

107 29

KCNE3

β subunit of Ito, IKr channel

ABCC9

SUR2a subunit IKATP channel Loss-of-function (reduced IKATP) T1547I

26

SCN5A

α subunit of INa channel

10

Predicted loss-of-function

D1275N

DCM, abnormal conduction

31

(reduced INa)

SCN5A

α subunit of INa channel

Loss-of-function (reduced INa) N1986K

11

SCN5A

α subunit of INa channel

Gain-of-function (increased INa)

12, 25, 108

M1875T, K1493R, R340Q, R1626H, R340Q, D1819N, V1951M.

D1819N, R1897W, V1951M

SCN1B

β subunit of INa channel

Loss-of-function (reduced INa)

R85H, D153N

13

SCN2B

β subunit of INa channel

Loss-of-function (reduced INa)

R28Q, R28W

13

SCN3B

β subunit of INa channel

Loss-of-function (reduced INa)

R6K, L10P, M161T

109

Reduced nuclear membrane

R391H

110

NUP155 Nucleoporin

associated with LQTS

permeability

GJA5

Impaired intercellular

P88S, M163V, G113N, I75F, V85I,

electrical coupling

L221I, L229M, Q49X, A96S

Connexin-40

14, 111–114

NPPA

ANP

Elevated levels of mutant ANP

c.456-457delAA

15

RYR2

Ryanodine receptor 2

Gain-of-function (increased

S4153R

CPVT

28

E169K

HCM

27

Holt-Oram Syndrome

16

Ca2+ leak from SR)

JPH2

Loss-of-function (increased

Junctophilin-2

Ca2+ leak from SR)

TBX5

T-box transcription factor

Gain-of-function

G125R

GATA4

GATA transcription factor

Loss-of-function

S70T, S160T, Y38D, P103A,

17–19, 24

G16C, H28D, M247T

GATA5

GATA transcription factor

Loss-of-function

W200G, Y138F, C210G

20, 21

GATA6

GATA transcription factor

Loss-of-function

G469V, Y235S

22, 23

DCM = dilated cardiomyopathy; HCM = hypertrophic cardiomyopathy; Ca2+ = calcium; LQTS = long-QT syndrome; SR = sarcoplasmic reticulum.

Figure 1: Monogenic Mutations Implicated in Atrial Fibrillation HCN4

CAV1/CAV2

KCNN3

ISK

If Cytoplasmic actin

SYNPO2L SYNE2 Sarcomere

PITX2

PRRX2

ZFHX2

Illustration demonstrating monogenic mutations that have been identified using classical genetic studies.

throughout the genome and investigating the transmission of these markers with disease within a pedigree.36 Markers that transmit closely with disease lie in proximity to the disease-causing mutation. Therefore, identifying a series of markers that transmit closely with disease narrows the search space for the disease-causing variant to a defined subsegment of the genome. The genes within the sub-segment can then be screened to identify a causative mutation. However, conventional genotyping techniques are often time consuming and demanding.

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The majority of reported mutations for familial forms of AF are located in genes that encode ion channel subunits (see Figure 1 and Table 1). The identification of these mutations led researchers to question whether single-gene mutations in ion channel genes also contribute to the heritability of the common form of AF in the general population.

Early reports from candidate-gene screening studies suggest that these mutations are not prevalent in the general population.11,13,30,37–41 Of note, however, the genes identified in AF pedigrees are significantly more likely to harbour rare variants in cohorts of lone AF patients compared with control populations.42 While the mutations identified in monogenic AF pedigrees are rare, their identification has provided interesting insights into the pathogenic basis of AF. Both gain-of-function and loss-of-function mutations in genes encoding potassium and sodium channel subunits have been reported to underlie familial AF.2–9,11–13,25,26,29–31,43 Gain-offunction potassium channel mutations are predicted to influence AF by shortening the atrial effective refractory period, an effect that would be predicted to promote atrial re-entry.44 Loss-of-function potassium channel mutations are predicted to promote triggered activity in the atrium, which is also an important contributor to the genesis of AF.8 Gain-of-function sodium channel mutations are predicted to promote triggered activity.25 Loss-of-function sodium channel mutations are predicted to shorten the wavelength of an impulse circulating around

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Table 2: Summary of Results from Candidate-gene Association Studies in Atrial Fibrillation Cohorts Gene KCNE1

Gene Product β subunit of Iks channel

Polymorphism Comment 38G

Odds Ratio of Association 1.73, 1.80, 1.90

Reference 46, 48, 115

KCNE5

β subunit of Iks channel

97T

0.52

49

KCNH2

α subunit of IKr channel

K897T

1.25

47

SCN5A

α subunit of INa channel

H558R

1.6

40

GNB3

β3-subunit of heterotrimeric G protein

C825T

0.46

50

eNOS

Endothelial nitric oxide synthase

2786C

1.50

46

eNOS

Endothelial nitric oxide synthase

G894T

3.2

55

GJA5 Connexin-40

–44AA/+71GG

1.51

52

GJA5

A/G

1.18, 1.30

114, 116

Connexin-40

Associated with Cx40 mRNA

expression in atrial tissue

AGT Angiotensinogen

M235T

2.5

117

AGT Angiotensinogen

G-6A

3.3

117

AGT Angiotensinogen

G-217A

2.0

117

AGT Angiotensinogen

T174M

1.2

54

AGT Angiotensinogen

20C/C

1.5

54

ACE

Angiotensin I converting enzyme

D/D

1.5

55

ACE

Angiotensin I converting enzyme

D/D

1.89

56

MMP2

Matrix metalloproteinase-2

C1306T

8.1

57

IL10

Interleukin 10

A-592C

0.32

57

IL6

Interleukin 6

G-174C

3.25

58

C-65G

1.98

51

SLN Sarcolipin

Figure 2: Genetic Variants Identified by Genome-wide Association Studies

↑mANP

↑IKAPT ABCC9

↑Ito KCND3, KCNE3

↑KCNJ2

↓INa SCN5A, SCN1B, SCN2B ↑IK1KCNJ2

Ito

IKAPT

KCNJ2

IK1

↓IKS KCNQ1, KCNE1, KCNE2, KCNE5

SCN5A

KCNQ1

IKs

SCN1B ABCC9

KCNE3

SCN2B

IKur

KCNE5 KCNE2

INa

↓IKur KCNA5

KCNE1

NUP155 ↑Ca2+ JPH2

↓Nuclear permeability

GJA5 ↓Electrical coupling

RYR2

Sarcoplasmic reticulum

TBX5

GATA4

GATA5

GATA6

Illustration demonstrating genes implicated in genome-wide association studies.

a re-entry circuit.45 The potential mechanistic links between non-ion channel mutations and AF pathogenesis are less clearly understood.

Common Genetic Variants and Atrial Fibrillation in the General Population Identifying the genetic basis of the common form of AF in the general population is a more challenging task. Genetic association studies are valuable tools in this context. In contrast to family-based studies, which investigate co-segregation of genetic variants, population-based association studies investigate the co-occurrence of genetic variants in affected individuals. It is important to emphasise that in contrast to family-based studies, in which the reported mutations have large effect sizes and are directly responsible for causing the trait,

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association studies identify variants with small effect sizes that confer an increased risk of disease. Functional validation of the role of these variants in disease pathogenesis is typically more difficult.

The majority of early association studies in AF were candidategene association studies.40,46–58 Candidate gene studies focus on specific genes that are selected based on a priori knowledge of their function, and compare the frequency of the variants between cohorts of individuals with and without disease.59 To date, a number of candidate-gene association studies have identified common variants that are more prevalent in AF populations compared with control populations.40,46–58 Often, the candidate genes have been selected based on results of studies in familial AF. As summarised in Table 2, a

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Arrhythmia Mechanisms Table 3: Summary of Results from Genome-wide Association Studies in Atrial Fibrillation Cohorts Locus Marker SNP Nearest Gene Product

Gene 4q25 rs2200733 PITX2 Paired-like homeodomain 2 transcription factor 16q22 rs2106261

ZFHX3

Location of SNP Relative Reference to the Nearest Gene 150 kb upstream 61, 62, 64, 118–120

Zinc finger homeobox 3 transcription factor

Intronic

62, 121

1q21 rs13376333 KCNN3

Small conductance calcium-activated potassium channel,

Intronic

63, 64

(subtype 3)

1q24 rs3903239 PRRX1

Paired related homeobox 1 transcription factor

46 kb upstream

64

7q31 rs3807989 CAV1

Caveolin 1

Intronic

64

9q22 rs10821415 C9orf3

Chromosome 9 open reading frame 3

Intronic

64

10q22 rs10824026 SYNPO2L

Synaptopodin 2-like actin associated protein

5 kb upstream

64

14q23 rs1152591

SYNE2

Spectrin repeat containing, nuclear envelope 2

Intronic

64

15q24 rs7164883

HCN4

Hyperpolarization activated cyclic nucleotide-gated potassium

Intronic

64

channel 4

SNP = single nucleotide polymorphism.

range of common variants in ion channel and non-ion channel genes have been associated with AF. Overall, however, candidate-gene association studies have been associated with limited success due to a low pre-test probability of the selected variants being involved in disease pathogenesis and poor reproducibility.59 The recent advent of GWAS has led to significant progress in our understanding of the genetic basis of AF. GWAS involve genotyping up to a million common variants, or single nucleotide polymorphisms (SNPs), distributed throughout the genome and comparing their frequency between AF and control cohorts.60 As opposed to candidate gene studies, GWAS are unbiased and therefore may identify previously unsuspected genes that play an important role in disease pathogenesis.

Four large GWAS have been performed in AF cohorts to date.61–64 The results of these studies are summarised in Figure 2 and Table 3. The common variants identified by GWAS are located either within or in proximity to compelling candidate genes for AF. The ion channel genes, KCNN3 and HCN4, have been identified at two of the GWAS loci for AF.63,64 KCNN3 encodes a calcium-activated potassium channel (SK3 channel), which is abundantly expressed in the atrium.65 HCN4 encodes the hyperpolarisation-activated, cyclic nucleotide-gated cation channel 4, which underlies the pacemaker potential.66 Two of the GWAS loci for AF harbour the cardiac transcription factor genes PITX2 and PRRX1.

These homeobox transcription factors are critical mediators of cardiac development. PITX2 mediates asymetrical development of the heart and inhibits left-sided pacemaker specification.67–69 PRRX1 has been implicated as a mediator of development of the pulmonary veins.70 SYNPO2L, MYOZ1 and CAV1 also represent potentially interesting genes at GWAS loci. SYNPO2L and MYOZ1 encode signalling proteins that localise to the Z-disc and modulate cardiac sarcomeric function.71,72 CAV1 is an important membrane protein, which plays a role in cellular signalling, and has been demonstrated to interact with ion channels, including HCN4 and KCNN3.73–76

While compelling candidate genes have been identified at GWAS loci, it is important to note that the mechanistic link between the GWAS variants and the function of these genes represents a challenge. This point is underscored by the fact that, to date, more than 1,000 GWAS risk variants have been identified for a range of diseases, while only a handful have been comprehensively functionally validated.80 GWAS rarely identify causative genetic variants directly. Rather, the variants identified by GWAS typically act as markers that point to a disease causing variant.60 The prevailing theory regarding the mechanistic link between the causative variants at GWAS loci and disease pathogenesis is that these variants alter the quantity of target gene expression, possibly through altered function of transcription regulatory elements.81 Interestingly, researchers have recently demonstrated that the rare variants identified in population-based genetic studies may contribute to variable penetrance of causal mutations in familial forms of AF. In a study involving 11 AF pedigrees, in whom the causative mutation was known, Ritchie et al. demonstrated that the presence of the risk variants at the 4q25 locus predicted whether mutation carriers developed AF.82 As discussed above, variants at the 4q25/PITX2 locus have consistently been demonstrated to influence AF in multiple population-based studies. These findings suggest that the heritability of AF is influenced by complex interactions between common and rare variants.

Clinical Relevance The identification of genetic variants that contribute to AF susceptibility has potentially important implications for management of the arrhythmia. On the one hand, these variants could be of value for determining risk of future AF in asymptomatic individuals. On the other, they could uncover novel molecular targets for pharmacotherapy and potentially be of use in predicting response to therapy in AF patients. The following section discusses the potential utility of genetic information for management of AF patients.

Risk Stratification for Atrial Fibrillation In addition to the variants identified in the aforementioned GWAS for AF, common variants that have previously been implicated in GWAS for Brugada syndrome have also been demonstrated to influence risk in AF. AF is commonly observed as a co-existing condition in pedigrees with Brugada syndrome.77,78 Paradoxically, variants that have been demonstrated to confer increased risk of Brugada syndrome have a protective effect in AF patients.79 Further functional studies are necessary to determine the mechanisms underlying these observations.

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The identification of asymptomatic individuals who are at high risk of developing AF is an important public health concern. Current risk-stratification strategies, which are based mainly on conventional risk factors, are associated with significant limitations.83–86 Following the success of GWAS, the potential use of genotype-based risk stratification for AF has received significant interest. Initial attempts at using GWAS risk variants to predict risk have been associated with limited success. For instance, Smith et al. demonstrated that when considered in combination with conventional risk factors, genotype

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information from two AF GWAS loci (chromosome 4 and 16) did not have an impact on risk stratification.87 Similarly, Everett et al. reported that the inclusion of 12 risk variants at nine GWAS loci did not significantly enhance risk stratification.88 However, more recently, encouraging results have emerged from a study by Lubitz et al. who demonstrated that when considered in combination, four risk variants at the 4q25/PITX2 locus and eight variants at other loci resulted in a fivefold gradient in AF risk.89 The results were consistent in cohorts of European and Japanese descent.

It is important to note that the variants identified to date are associated with modest effect sizes and collectively account for only a proportion of the heritability estimated for AF. Before clinically applicable risk stratification algorithms can be developed for AF, a significant proportion of the ‘missing heritability‘ of AF needs to be uncovered.

The identification of the missing heritability of complex phenotypes like AF represents a major hurdle. Some of the missing heritability may be accounted for by additional common variants. GWAS are designed to identify common variants; however, some common variants may have been overlooked as current thresholds for statistical significance are high. Potential strategies for the identification of additional common variants include performing GWAS in larger cohorts and cohorts from different ethnic backgrounds.90 A significant proportion of the missing heritability of AF is likely to be accounted for by rare variants and structural variants in the genome.90 Examples of structural variation in the genome include tandem repeat sequences, insertions and deletions, copy number variants, translocations and inversions. GWAS are not designed to identify rare variants or structural variants. As discussed previously, a number of novel genotyping technologies have emerged since GWAS, including exome sequencing and whole genome sequencing. These represent promising techniques for the identification of rare variants underlying complex traits at a population level. While genotyping techniques for the identification of structural variants are currently less effective, they are constantly evolving.

Identification of Novel Therapeutic Targets for Atrial Fibrillation The identification of the genetic architecture underlying AF has the potential to uncover novel therapeutic targets for the arrhythmia.

GWAS are of particular interest in this context as they are agnostic and therefore commonly identify previously unsuspected genes underlying complex traits. As discussed previously, GWAS have identified a number of compelling candidate genes at the AF risk loci.

These findings have spawned additional functional studies that have focused on candidate genes and have demonstrated that genes such as KCNN3 and PITX2 influence AF susceptibility.91–96 It is important to note that while the aforementioned studies suggest that candidate genes at GWAS loci potentially influence AF susceptibility, focusing drug development efforts on these candidate genes would be premature. Before GWAS findings can be translated to drug development, more comprehensive functional validation is necessary.

GWAS typically characterise the association between marker variants and AF. The aims of post-GWAS analysis include identification of the causative variants at the GWAS loci and characterisation of the mechanistic link between these variants and target genes. A detailed discussion of post-GWAS functional analysis is beyond the scope of this review and has previously been reviewed extensively.81

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In addition to GWAS, exome sequencing and whole genome sequencing could potentially identify important therapeutic targets for AF. Population-based exome sequencing projects are already currently under way in AF cohorts and promise to identify multiple additional candidate genes. As is the case with GWAS however, these genes will have to be comprehensively functionally validated.

Overall, while findings from population-based genetic studies are promising, it may take more than a decade of research from the discovery of a novel gene to the development of a drug that can be used in clinical practice.97

Genotype-based Prediction of Response to Atrial Fibrillation Therapies In addition to uncovering novel therapeutic targets for AF, information from genetic studies could potentially be of value in predicting responses to established therapies. The influence of genotype on response to antiarrhythmic drugs has been investigated in two recent studies. In a relatively small cohort of AF patients, Parvez et al. demonstrated that the GWAS risk variants at the 4q25 locus independently predict successful rhythm control with antiarrhythmic therapy.98 The same group also demonstrated that variants in the gene encoding the β1-adrenergic receptor (β1-AR) predict response to rate control therapy with beta blockers.99 Multiple studies have reported that genotype also influences response to anticoagulant therapy. Variants in genes such as VKORC1, CYP2C9 and CYP4F2 have been identified as potential mediators of response to warfarin therapy.100,101 These genes encode proteins that are either involved in the vitamin K pathway or in warfarin metabolism.102 Attempts have been made to incorporate these genes into algorithms designed to predict warfarin response.

While some studies have suggested potential clinical utility of these algorithms, the results have not been consistent.102 A more detailed discussion on pharmacogenomics of warfarin therapy is beyond the scope of this review.

The role of genotype-based prediction of therapeutic response has also been investigated for non-pharmacological interventions.

Husser et al. demonstrated that the variants at the 4q25 locus predict response to catheter ablation for AF. Specifically the presence of the risk variants predicted both early and late recurrences of AF following pulmonary vein isolation.103 Further evidence linking SNPs at the 4q25 locus and response to catheter ablation came from a more recent study from Shoemaker et al.104 Finally, Parvez et al. reported that SNPs at 4q25 predict recurrence of AF following successful direct current cardioversion.105 Overall, the above studies have demonstrated promising results suggesting that genotypic data can be of value in to predicting response to both pharmacological and non-pharmacological therapies. However, most of these studies have been limited to small numbers of patients and have focused on small numbers of variants.

Further research with large, prospective randomised studies that include multiple genetic variants is currently needed to more clearly define the role of genetic data in predicting response.

Conclusions In recent years, research into the genetic basis of AF has undergone a revolution. Significant progress has been made in identifying the genetic substrate underlying the common form of AF encountered

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Arrhythmia Mechanisms in everyday clinical practice. Genotyping technologies are constantly evolving and promise to uncover more genes and molecular pathways

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75. 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;53:187–95.

76. Lin MT, Adelman JP, Maylie J. Modulation of endothelial SK3 channel activity by Ca2+-dependent caveolar trafficking. Am J Physiol Cell Physiol 2012;303:C318–27.

77. Makiyama T, Akao M, Tsuji K, et al. High risk for bradyarrhythmic complications in patients with Brugada syndrome caused by SCN5A gene mutations. J Am Coll Cardiol 2005;46:2100–2106.

78. Bordachar P, Reuter S, Garrigue S, et al. Incidence, clinical implications and prognosis of atrial arrhythmias in Brugada syndrome. Eur Heart J 2004;25:879–84.

79. Andreasen L, Nielsen JB, Darkner S, et al. Brugada syndrome risk loci seem protective against atrial fibrillation. Eur J Hum Genet, 2014 [Epub ahead of print] doi:10.1038/ejhg.2014.46.

80. Hindorff LA, MacArthur J, Morales J, et al. A catalog of published genome-wide association studies. National Human Genome Institute, 2014. Available at: www.genome.gov/gwastudies (accessed 21 July 2014).

81. Freedman ML, Monteiro AN, Gayther SA, et al. Principles for the post-GWAS functional characterization of cancer risk loci.

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82. Ritchie MD, Rowan S, Kucera G, et al. Chromosome 4q25 variants are genetic modifiers of rare ion channel mutations associated with familial atrial fibrillation. J Am Coll Cardiol 2012;60:1173–81.

83. Schnabel RB, Sullivan LM, Levy D, et al. Development of a risk score for atrial fibrillation (Framingham Heart Study): a community-based cohort study. Lancet 2009;373:739–45.

84. Schnabel RB, Aspelund T, Li G, et al. Validation of an atrial fibrillation risk algorithm in whites and African Americans.

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85. Chamberlain AM, Agarwal SK, Folsom AR, et al. A clinical risk score for atrial fibrillation in a biracial prospective cohort (from the Atherosclerosis Risk in Communities [ARIC] study), Am J Cardiol, 2011;107:85–91.

86. Lubitz SA, Husser D, Genomic risk scores in atrial fibrillation: predicting the unpredictable? Eur Heart J 2013;34:2227–9.

87. Smith JG, Newton-Cheh C, Almgren P, et al. Genetic polymorphisms for estimating risk of atrial fibrillation in the general population: a prospective study. Arch Intern Med 2012;172:742–4.

88. Everett BM, Cook NR, Conen D, et al. Novel genetic markers improve measures of atrial fibrillation risk prediction. Eur Heart J 2013;34:2243–51.

89. Lubitz SA, Lunetta KL, Lin H, et al. Novel genetic markers associate with atrial fibrillation risk in Europeans and Japanese. J Am Coll Cardiol 2014;63:1200–10.

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90. Manolio TA, Collins FS, Cox NJ, et al. Finding the missing heritability of complex diseases. Nature 2009;461:747–53.

91. Mahida S, Mills RW, Tucker NR, et al. Overexpression of KCNN3 results in sudden cardiac death. Cardiovasc Res 2014;101:326–34.

92. Zhang XD, Timofeyev V, Li N, et al. Critical roles of a small conductance Ca2+-activated K+ channel (SK3) in the repolarization process of atrial myocytes. Cardiovasc Res 2014;101:317–25.

93. Qi XY, Diness JG, Brundel BJ, et al. Role of smallconductance calcium-activated potassium channels in atrial electrophysiology and fibrillation in the dog. Circulation 2014;129:430–40.

94. 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.

95. 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.

96. Chinchilla A, Daimi H, Lozano-Velasco E, et al. PITX2 insufficiency leads to atrial electrical and structural remodeling linked to arrhythmogenesis. Circ Cardiovasc Genet 2011;4:269–79.

97. Sanseau P, Agarwal P, Barnes MR, et al. Use of genomewide association studies for drug repositioning, Nat Biotechnol 2012;30:317–20.

98. Parvez B, Vaglio J, Rowan S, et al. Symptomatic response to antiarrhythmic drug therapy is modulated by a common single nucleotide polymorphism in atrial fibrillation. J Am Coll Cardiol 2012;60:539–45.

99. Parvez B, Chopra N, Rowan S, et al. A common beta1adrenergic receptor polymorphism predicts favorable response to rate-control therapy in atrial fibrillation. J Am Coll Cardiol 2012;59:49–56.

100. Lanham KJ, Oestreich JH, Dunn SP, Steinhubl SR. Impact of genetic polymorphisms on clinical response to

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101. Takeuchi F, McGinnis R, Bourgeois S, et al. A genome-wide association study confirms VKORC1, CYP2C9, and CYP4F2 as principal genetic determinants of warfarin dose. PLoS Genet 2009;5:e1000433.

102. Turner RM, Pirmohamed M. Cardiovascular pharmacogenomics: expectations and practical benefits.

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103. 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.

104. Shoemaker MB, Muhammad R, Parvez B, et al. Common atrial fibrillation risk alleles at 4q25 predict recurrence after catheter-based atrial fibrillation ablation. Heart Rhythm 2013;10:394–400.

105. Parvez B, Shoemaker MB, Muhammad R et al. Common genetic polymorphism at 4q25 locus predicts atrial fibrillation recurrence after successful cardioversion. Heart Rhythm 2013;10:849–55.

106. Yang Y, Lin X, Yang Y, et al. Novel KCNA5 loss-of-function mutations responsible for atrial fibrillation. J Hum Genet 2009;54:277–83.

107. Christophersen IE, Olesen MS, Liang B, et al. Genetic variation in KCNA5: impact on the atrial-specific potassium current IKur in patients with lone atrial fibrillation. Eur Heart J 2013;34:1517–25.

108. Olesen MS, Yuan L, Liang B, et al. High prevalence of long QT syndrome-associated SCN5A variants in patients with earlyonset lone atrial fibrillation. Circ Cardiovasc Genet 2012;5:450–9.

109. Olesen MS, Jespersen T, Nielsen JB, et al. Mutations in sodium channel beta-subunit SCN3B are associated with early-onset lone atrial fibrillation. Cardiovasc Res 2011;89:786–93.

110. Oberti C, Wang L, Li L, et al. Genome-wide linkage scan identifies a novel genetic locus on chromosome 5p13 for neonatal atrial fibrillation associated with sudden death and variable cardiomyopathy. Circulation 2004;110:3753–9.

111. Sun Y, Yang YQ, Gong XQ, et al. Novel germline GJA5/ connexin40 mutations associated with lone atrial fibrillation impair gap junctional intercellular communication. Hum Mutat 2013;34:603–9.

112. Yang YQ, Liu X, Zhang XL, et al. Novel connexin40 missense mutations in patients with familial atrial fibrillation. Europace 2010;12:1421–7.

113. Yang YQ, Zhang XL, Wang XH, et al. Connexin40 nonsense mutation in familial atrial fibrillation. Int J Mol Med 2010;26:605–10.

114. Christophersen IE, Holmegard HN, Jabbari J, et al. Rare variants in GJA5 are associated with early-onset lone atrial fibrillation. Can J Cardiol 2013;29:111–6.

115. Liang C, Li X, Xu Y, et al. KCNE1 rs1805127 polymorphism increases the risk of atrial fibrillation: a meta-analysis of 10 studies. PLoS One 2013;8:e68690.

116. Wirka RC, Gore S, Van Wagoner DR, et al. A common connexin-40 gene promoter variant affects connexin-40 expression in human atria and is associated with atrial fibrillation. Circ Arrhythm Electrophysiol 2011;4:87–93.

117. Tsai CT, Lai LP, Lin JL, et al. Renin-angiotensin system gene polymorphisms and atrial fibrillation. Circulation 2004;109:1640–6.

118. Kaab S, Darbar D, van Noord C, et al. Large scale replication and meta-analysis of variants on chromosome 4q25 associated with atrial fibrillation. Eur Heart J 2009;30:813–9.

119. Viviani Anselmi C, Novelli V, Roncarati R, et al. Association of rs2200733 at 4q25 with atrial flutter/fibrillation diseases in an Italian population. Heart 2008;94:1394–6.

120. Shi L, Li C, Wang C, et al. Assessment of association of rs2200733 on chromosome 4q25 with atrial fibrillation and ischemic stroke in a Chinese Han population. Hum Genet 2009;126:843–9.

121. Gudbjartsson DF, Holm H, Gretarsdottir S, et al. A sequence variant in ZFHX3 on 16q22 associates with atrial fibrillation and ischemic stroke. Nat Genet 2009;41:876–8.

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Short QT Syndrome – Review of Diagnosis and Treatment Boris R udi c , 1 Ra i n e r S c h i m p f 2 a n d M a r t i n B o r g g r e f e 3 1. Fellow in Cardiac Electrophysiology; 2. Associate Professor and Senior Electrophysiologist; 3. Director of the Department 1st Department of Medicine-Cardiology, University Medical Centre Mannheim, Germany

Abstract Short QT syndrome (SQTS) is an inherited cardiac channelopathy characterised by an abnormally short QT interval and increased risk for atrial and ventricular arrhythmias. Diagnosis is based on the evaluation of symptoms (syncope or cardiac arrest), family history and electrocardiogram (ECG) findings. Mutations of cardiac ion channels responsible for the repolarisation orchestrate electrical heterogeneity during the action potential and provide substrate for triggering and maintaining of tachyarrhythmias. Due to the malignant natural history of SQTS, implantable cardioverter defibrillator (ICD) is the first-line therapy in affected patients. This review summarises current data and addresses the genetic basis and clinical features of SQTS.

Keywords Sudden cardiac death, ventricular fibrillation, genetic, ECG, risk stratification Disclosure: The authors have no conflicts of interest to declare.

Received: 12 May 2014 Accepted: 27 June 2014 Citation: Arrhythmia & Electrophysiology Review 2014;3(2):76–9 Access at: www.AERjournal.com Correspondence: Boris Rudic MD, 1st Department of Medicine-Cardiology, University Medical Centre Mannheim, Theodor-Kutzer-Ufer 1-3, D-68167 Mannheim, Germany. E: boris.rudic@umm.de

Short QT syndrome (SQTS) is a rare, inheritable channelopathy of the heart characterised by abnormally short QT intervals on the electrocardiogram (ECG) and an increased propensity to develop atrial and ventricular tachyarrhythmias in the absence of structural heart disease.1,2 SQTS was first described as a new clinical entity by Gussak et al. in 2000.1 Until then shortening of the QT interval had only been reported in the context of electrolyte imbalances (hyperkalaemia, hypercalcaemia), hyperthermia, acidosis and endocrine disorders. The familial nature and arrhythmogenic potential of the disease were further confirmed by Gaita et al.2 They described six patients with SQTS in two unrelated European families with a family history of sudden death in association with short QT intervals on the ECG. Since its recognition in 2000, significant progress has been made in defining the clinical, molecular and genetic basis of SQTS as well as the therapy options. Today, SQTS is usually defined as QTc ≤330 ms, or QTc interval <360 ms and one or more of the following: history of cardiac arrest or syncope, family history of sudden cardiac death (SCD) at age 40 or younger or a family history of SQTS.3 The purpose of this review is to summarise the available data and to discuss recent advances in the diagnosis and therapy of SQTS.

Establishing the Diagnosis – Electrocardiographic Criteria The ECG constitutes the mainstay of the diagnosis of SQTS. The hallmark ECG finding is an abnormally short QTc. Although it may appear reasonable to assume that a shorter QTc could predispose to a higher risk for ventricular arrhythmias, to date, there is no evidence to support this hypothesis.4–6 Controversy exists about the exact cut-off value for the short QTc interval.

Population-based and genetic studies show that QTc interval <330 ms is extremely rare.6–8 Data from over 10,000 adults suggest that, in the

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healthy population, the prevalence of QTc <340 ms is approximately 0.5 % (with 95 % confidence interval).6 Therefore, males with QTc ≤330 ms and females with QTc ≤340 ms have abnormally short QT and should be considered to have SQTS, even if they are asymptomatic. However, it should be emphasised that the prognosis of patients with asymptomatic SQTS still remains undefined. Individuals with QTc <320 ms who reached adulthood without developing life-threatening arrhythmias have been reported.7,9 Anttonen et al.6 further reported a low rate of all-cause mortality in individuals with QTc intervals <320 ms. However, since only middle-aged subjects were included in their study, the findings may not be applicable to a younger population. On the contrary, subjects with a ratecorrected QT interval >450 ms had greater all-cause and cardiovascular mortality than those with normal or short QT intervals. Nielsen et al.10 recently reported an increased risk for cardiovascular death in patients with QTc intervals <379 ms. The hazard ratio was more pronounced in women than in men and in patients of 50–70 years of age.

Population studies also show that relatively small number of individuals have QTc intervals <360 ms (males) and <370 ms (females), respectively, so that these values probably should be regarded as ‘short’. A diagnosis of SQTS should be considered when such patients present with cardiac arrest, unexplained syncope or atrial fibrillation (AF) at a young age. As for patients with QT prolongation, the first step in clarifying the diagnosis among patients with ‘short QT’ is performing repeat ECGs to further study the QT duration and T-wave morphology at different heart rates.11 When the diagnosis of SQTS is suspected, resting 12-lead ECG should be performed at a heart rate within normal limits. The QT interval should be measured when the heart rate is <100 bpm and preferably less than 80 bpm, because all QTc formulae will overcorrect the true QTc intervals at higher heart rates, leading to a false negative diagnosis. Holter monitoring or long-term ECG

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Figure 1: Baseline Electrocardiogram (ECG) Recording (Standard 12-lead ECG, Paper Speed 25 mm/s) of a 25-year-old Male with Short QT Syndrome

Figure 2: Putative Molecular Mechanism of Short QT Syndrome

Normal action potential duration

Shortened action potential duration

Normal QT interval

Short QT interval

Note the short QT interval, tall, peaked T waves and nearly absent ST segments.

monitoring becomes necessary in such cases to make the correct diagnosis. In addition to the QTc interval there are several other ECG findings that may facilitate the correct diagnosis (see Figure 1): • The QRS complex is directly followed by a T wave; ST segment is usually absent.12 • T waves are tall, peaked, symmetrical and narrow-based • Rate-dependent prolongation of the QT interval at slow heart rates is abrogated in SQTS patients, remaining below the lower limit of normal values.13 • Often a prominent U wave can be observed, separated by an isoelectric T–U segment.14 • Longer Tpeak – Tend interval may be observed, suggestive of augmented transmural dispersion of refractoriness.15 • Depression of the PQ segment, due to a heterogeneous abbreviation of atrial repolarisation, most prominently in inferior and anterior leads.16

Molecular Mechanism/Genetics SQTS is a rare, sporadic or autosomal dominant disorder characterised by markedly accelerated cardiac repolarisation and manifested by atrial and ventricular arrhythmias, and/or SCD. To date, causative mutations in potassium17–19 and calcium channel genes20,21 have been identified. Gain-of-function mutations of potassium and lossof-function mutations of calcium channels result in an abbreviated repolarisation phase during action potential and shortening of the QT interval (see Figure 2). Because of heterogeneous contribution of repolarising ion currents within the heart, there is an inhomogeneity and dispersion of repolarisation, which provides substrate for the development of both atrial and ventricular tachyarrhythmias. Three main genetic variants have been described in the SQTS (see Table 1), involving potassium channel genes also associated with the long QT syndrome (LQTS). However, while mutations in the potassium channel genes causing LQTS are loss-of-function mutations, those observed in SQTS are gain-of-function mutations.

The SQTS subtype SQT-1 is caused by mutations in KCNH2 (HERG), the gene also responsible for LQT-2. Genetic screening of the first two reported families with SQTS and SCD led to the identification of two different missense mutations in KCNH2 that caused the same amino acid change in the cardiac IKr channel.17 In one family, a missense mutation with a cytosine to guanine substitution at nucleotide 1764

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Gain-of-function mutations of potassium and loss-of-function mutations of calcium channels result in an abbreviated repolarization phase during action potential and shortening of the QT interval. Illustration adapted from Gollob et al., 2011,28 with permission from Elsevier.

on KCNH2 was reported, while in the second family a cytosine to adenine substitution at the same nucleotide was observed. Both mutations led to a substitution of asparagine at codon 588 with a positively charged lysine.

To further elucidate the mechanism of QT interval shortening, the mutated KCNH2 channel (N588K) was co-expressed with and without the ancillary β-subunit MiRP1 (KCNE2) in human embryonic kidney cells (TSA201) and patch-clamp experiments were performed. Whole-cell recordings demonstrated that the N558K missense mutation abolished rectification of the current at plateau voltages, which results in a significant increase of IKr during the early phases of the action potential and leads to an abbreviation of the action potential and thus to abbreviation of the QT interval. Shortening of ventricular action potential is supposed to be linked to a shortening of the effective refractory period, thus causing an increased ventricular and atrial susceptibility to premature stimulation, leading to AF and ventricular fibrillation (VF).

Genetic heterogeneity in the SQTS was indicated by the findings of Bellocq et al.18, who identified a mutation in KCNQ1 (V307L) in a 70-year-old patient with abnormally short QTc duration (302 ms) and aborted SCD. Similar to the findings by Brugada et al.,17 the mutation in KCNQ1 caused a gain of function of IKs, resulting in an abbreviation of the action potential duration and shortening of the QT interval in vitro. The KCNQ1 gene is therefore not only responsible for LQT-1, but also for SQT-2. A missense mutation in KCNQ1 was reported in a neonate presenting with in utero bradycardia and postpartum short QT intervals and AF.22 To characterise the physiological consequences of the V141M mutation, Xenopus oocytes were injected with complimentary RNA (cRNA) encoding wild-type KCNQ1 or mutant V141M KCNQ1 subunits, with or without KCNE1. Computer modeling showed that the mutation would accelerate the activation kinetics of human ventricular myocytes and abolish pacemaker activity of the sinoatrial node, by a loss of voltage-dependent channel gating.22 In 2005, SQT-3 was introduced by Priori et al.19 and was associated with a novel gain-of-function mutation in the KCNJ2 gene, encoding for the strong inwardly rectifying channel protein Kir2.1. The loss-of-function mutations of KCNJ2 are responsible for LQT-7. In two affected family

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Arrhythmia Mechanisms Table 1: Genes Associated with Short QT Syndrome SQTS Subtype SQT-1

Gene Name Chromosomal Location KCNH2 7q35-7q36

Protein Name Function SQTS Mechanism Kv11.1 α-subunit IKr Gain-of-function17

SQT-2

KCNQ1 11p15.5

Kv7.1 α-subunit IKs Gain-of-function18

SQT-3

KCNJ1 17q23.1-17q24.2 Kir2.1 α-subunit IK1 Gain-of-function19

SQT-4

CACNA1C 12p13.3

SQT-5

CACNB2 10p12

Cav1.2 α-subunit IL,Ca Loss-of-function20 Cavβ2 β2-subunit IL,Ca Loss-of-function20

SQT-6

CACNA2D1 7q21-7q22

Cavδ1

δ1-subunit IL,Ca Loss-of-function21

SQTS = short QT syndrome.

members a single base-pair substitution (G514A) in the KCNJ2 gene could be identified, resulting in an amino acid change from aspartic acid to asparagine at position 172 (D172N) in the Kir2.1 potassium channel.

Functional characterization of the mutation demonstrated a significant increase in the outward IK1 current, and strongly suggests that myocardial tissues carrying the D172N mutation in the Kir2.1 channel should be capable of sustaining stable functional reentry at high frequencies.19 Finally, Antzelevitch et al.20 reported three cases in which the Brugada Syndrome phenotype and a family history of SCD was combined with shorter-than-normal QT intervals (≤360 ms). In these three cases a mutation in genes encoding the α1- or β2b- subunits of the cardiac L-type calcium channel were identified, with three specific mutations in CACNB2b (S481L) and CACNA1C (A39V and G490R) declared responsible for the ECG phenotype. To determine the contribution of each mutation to the clinical phenotype, each of the wild-type and mutated CACNA1C and CACNB2b mutations were expressed in Chinese hamster ovary cells. The results of patch-clamp experiments indicate that all the mutations cause a major loss of function in calcium channel activity.20 The QTc observed in these three cases and in affected family members ranged from 330 to 370 ms, a longer QTc interval than that observed in SQTS subtypes 1–3. Another overlapping phenotype of short QT interval and Brugada-like ECG has been reported in a 40-year-old Chinese patient with family history of SCD.23 The QT interval was 320 ms and the ECG showed a Brugada-like pattern in precordial leads.

Lastly, Templin and co-workers21 introduced SQT-6, when they reported a novel mutation in the CACNA2D1 gene, which presumably led to short QT interval (QTc 329 ms) and documented VF in an otherwise healthy 17-year-old female. Functional analysis showed that the discovered missense mutation (p.Ser755Thr) in CACNA2D1 decreases the current of the L-type calcium channel, which is responsible for the cardiac action potential plateau phase and the cytoplasmic Ca2+ transients regulating the contraction force.24 Whether mutations in CACNA2D1 may cause other manifestations of J-wave syndrome remains to be investigated.25 A systematic overview of causative genes in SQT1-6 is shown in Table 1.

From Bench to Bedside – Clinical Presentation of SQTS SQTS has been described only in few families worldwide. There have been approximately 80 SQTS cases reported so far. All probands presented with a QTc below 320 ms without evident structural heart disease. In the largest available case series of 45 genetically screened and followed SQTS patients reported recently, most patients have experienced symptoms.5 Often the first symptom of the disease may be lone AF in the absence of structural heart disease. However, ventricular arrhythmias and sudden cardiac arrest may also be the first symptom, which makes early diagnosis challenging.

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The available data suggest that patients are at risk throughout their lifetime, with a peak between the second and fourth decades.26 This distribution is thought to be due to the peak in testosterone plasma levels, which may cause shortening of the QT interval, especially in male adolescents. Mean age at diagnosis is 23 years, with predominant occurrence in male patients. Cardiac arrest seems to be the most frequent presenting symptom (up to 40 %).5 Palpitations are very common (30 %), followed by syncope (25 %) and AF, which is the first presenting symptom in up to 20 % of patients. Forty-seven percent of patients were asymptomatic and were diagnosed due to strong family history. Strong family history of arrhythmic symptoms including SCD is a common finding. The circumstances of onset of symptoms are highly variable, and episodes of SCD have been reported during or following loud noise, at rest, during exercise and during daily activities.4 The yield of genetic screening is low and varies between 15 % and 25 %, despite the fact that a familial association is present in the majority of patients.

Risk Stratification in SQTS – Does QT Length Really Matter?

The greatest challenge for the management of patients with SQTS remains the paucity of risk identificators. Scoring systems that include clinical and ECG criteria are established in the case of congenital long QT syndrome.27 Correspondingly, the SQTS diagnostic criteria proposed by Gollob et al.28 are composed of four different components: ECG, clinical history, family history and genotype. In order to be eligible to receive points in the last three sections, a minimum of 1 point must be received from the ECG criteria. An overall score of 4 points or greater indicates a high-probability diagnosis of SQTS, whereas 2 points or fewer makes a diagnosis of SQTS a low probability. Patients with a score of 3 points are considered to have an intermediate probability of having SQTS. In an effort to explore the risk-stratifying prognostic value of the Gollob score, a modification of the proposed diagnostic criteria was suggested to predict events in a paediatric cohort of SQTS.29 Twenty-five paediatric SQTS patients were followed over six years, during which time 56 % (14 patients) had symptoms (survived cardiac death, syncope and AF).

Subjects with a modified Gollob score of ≤3 corresponded to a low probability of cardiac events, whereas patients with a higher score were more often symptomatic. In contrast to these findings, Mazzanti et al.5 recently reported a cohort of 47 SQTS patients and 26 affected family members, who were enrolled and followed over a mean period of five years. The observed annual event rate for cardiac arrest was 10.6 % among patients who already experienced cardiac arrest, and only 0.4 % in patients without history of cardiac arrest at initial presentation.

The authors did not observe a relationship between the original28 and prognostic29 Gollob score and a probability of cardiac events, as the majority of subjects with a score ≤3 (low risk) experienced cardiac arrest and should therefore be regarded at high risk. However, history

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of survived cardiac arrest at the initial presentation proved to be a strong predictor of recurrent ventricular arrhythmias over the course of time. As emphasised by the authors, this information is important when considering the indication for implantable cardioverter defibrillator (ICD) therapy especially in young SQTS patients or infants with history of survived cardiac arrest.5 The high rate of cardiac events in the Mazzanti et al. cohort further corroborates observations from earlier studies4,26,29 and underscores the malignant nature of SQTS. However, one must also take into account a high probability of inappropriate ICD shocks in paediatric patients, which in the study of Villafane et al.29 by far exceeded the rate of appropriate shocks. Finally, Anttonen et al.30 observed repolarisation differences between symptomatic patients and asymptomatic individuals with shortened QT intervals. The authors concluded that an interval measured from the J point (Jp) to the highest point of the T wave (Tpeak) less than 150 ms identifies symptomatic SQTS patients from asymptomatic individuals with short QT intervals.

Therapeutic Options As with other inherited channelopathies, there are principally two options for therapeutic interventions. Due to the malignant nature of SQTS, the ICD is recommended in symptomatic SQTS patients who are either survivors of sudden cardiac arrest and/or have documented spontaneous sustained ventricular tachyarrhythmias with or without syncope (Class I recommendation).3 A unique problem with ICDs in SQTS stems from one of the syndrome’s main features on ECG: the tall and peaked T wave that closely follows the R wave can sometimes be interpreted as a short R–R interval, provoking an inappropriate shock from the ICD.31 The high prevalence of AF in SQTS patients may present a clinical challenge for appropriate ICD programming. Reprogramming the decay delay, sensitivity or both generally prevents inappropriate discharges. Villafane et al.29 reported a remarkably high rate of inappropriate ICD therapies of up to 64 % in six years in a large paediatric cohort of SQTS patients, which accentuates the need for sophisticated and durable ICD devices.

1. Gussak I, Brugada P, Brugada J, et al. Idiopathic short QT interval: a new clinical syndrome? Cardiology 2000; 94:99–102.

2. Gaita F, Giustetto C, Bianchi F, et al. Short QT syndrome: a familial cause of sudden death. Circulation 2003;108:965–70.

3. Priori SG, Wilde AA, Horie M, et al. Executive summary: HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes. Heart Rhythm 2013;10:e85–e108.

4. Giustetto C, Di Monte F, Wolpert C, et al. Short QT syndrome: clinical findings and diagnostic-therapeutic implications. Eur Heart J 2006;27:2440–7.

5. Mazzanti A, Kanthan A, Monteforte N, et al. Novel insight into the natural history of short QT Syndrome. J Am Coll Cardiol 2014;63:1300–8.

6. Anttonen O, Junttila MJ, Rissanen H, et al. Prevalence and prognostic significance of short QT interval in a middle-aged Finnish population. Circulation 2007;116:714–20.

7. Funada A, Hayashi K, Ino H, et al. Assessment of QT intervals and prevalence of short QT syndrome in Japan. Clin Cardiol 2008;31:270–4.

8. Kobza R, Roos M, Niggli B, et al. Prevalence of long and short QT in a young population of 41,767 predominantly male Swiss conscripts. Heart Rhythm 2009;6:652–7.

9. Gallagher MM, Magliano G, Yap YG, et al. Distribution and prognostic significance of QT intervals in the lowest half centile in 12,012 apparently healthy persons. Am J Cardiol 2006;98:933–5.

10. Nielsen JB, Graff C, Rasmussen PV, et al. Risk prediction of cardiovascular death based on the QTc interval: evaluating age and gender differences in a large primary care population. Eur Heart J 2014;35:1335–4.

11. Viskin S. The QT interval: too long, too short or just right.

Heart Rhythm 2009;6:711–5.

12. Borggrefe M, Wolpert C, Antzelevitch C, et al. Short QT syndrome. Genotype-phenotype correlations. J Electrocardiol 2005;38:75–80.

13. Gussak I, Liebl N, Nouri S, et al. Deceleration-dependent shortening of the QT interval: a new electrocardiographic phenomenon? Clin Cardiol 1999;22:124–6.

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Although the ICD remains the mainstay of therapy for SQTS, pharmacological therapy may be useful as an adjunct to the ICD or may be used for primary prevention in cases in which the patient refuses an ICD or in young children in whom the implantation of an ICD may be problematic.

Gaita et al.32 tested four different antiarrhythmic drugs including flecainide, sotalol, ibutilide and hydroquinidine in six patients with SQT-1. Only hydroquinidine prolonged the QT interval to normal levels, increased ventricular ERP and rendered VF noninducible. Class Ic and III antiarrhythmic drugs failed to do so. Quinidine also restored the QT–RR relationship toward the normal range.33 In a one-year followup, patients treated with hydroquinidine remained asymptomatic and no further episodes of ventricular arrhythmia were detected.

Schimpf et al.34 reported clinical efficacy of disopyramide, another Class Ia antiarrhythmic drug, in two patients with SQT-1, consistent with the experimental data from heterologous expression of N588K KCNH2 mutant channels. Oral administration of disopyramide in these patients increased the QT interval and ventricular refractory period and abbreviated the Tpeak–Tend interval. Other class III antiarrhythmic drugs including d-sotalol, amiodarone and nifekalant were also sporadically reported to be effective in treating VT/VF storm and prolonging atrial and ventricular effective refractory periods and normalising the QT interval.35,36 AF is a common clinical problem in SQTS. Some SQTS patients exhibit only AF.37 Propafenone has been shown to be effective in preventing frequent paroxysms of AF with no recurrence of arrhythmia for more than two years without any effect on QT interval.38 In summary, the pharmacological therapy of patients with SQTS is still poorly defined, mainly due to a lack of large-scale evidence.

Hydroquinidine seems to be the first-line therapy for SQTS patients and based on the guidelines3 should be considered the most effective pharmacological therapy in SQTS. n

14. Schimpf R, Antzelevitch C, Haghi D, et al. Electromechanical coupling in patients with the short QT syndrome: further insights into the mechanoelectrical hypothesis of the U wave.

Heart Rhythm 2008;5:241–5.

15. Extramiana F, Antzelevitch C. Amplified transmural dispersion of repolarization as the basis for arrhythmogenesis in a canine ventricular-wedge model of short-QT syndrome.

Circulation 2004;110:3661–6.

16. Tulumen E, Giustetto C, Wolpert CC, et al. PQ segment depression in short QT syndrome patients: A novel marker for diagnosing short QT syndrome? Heart Rhythm 2014;11:1024–30.

17. Brugada R, Hong K, Dumaine R, et al. Sudden death associated with short-QT syndrome linked to mutations in HERG. Circulation 2004;109:30–5.

18. Bellocq C, van Ginneken AC, Bezzina CR, et al. Mutation in the KCNQ1 gene leading to the short QT-interval syndrome.

Circulation 2004;109:2394–7.

19. Priori SG, Pandit SV, Rivolta I, et al. A novel form of short QT syndrome (SQT3) is caused by a mutation in the KCNJ2 gene.

Circ Res 2005;96:800–7.

20. Antzelevitch C, Pollevick GD, Cordeiro JM, et al. Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death. Circulation 2007;115:442–9.

21. Templin C, Ghadri JR, Rougier JS, et al. Identification of a novel loss-of-function calcium channel gene mutation in short QT syndrome (SQTS6). Eur Heart J 2011;32:1077–88.

22. Hong K, Piper DR, Diaz-Valdecantos A, et al. De novo KCNQ1 mutation responsible for atrial fibrillation and short QT syndrome in utero, Cardiovasc Res 2005;68:433–40.

23.

Hong K, Hu J, Yu J, Brugada R. Concomitant Brugada-like and short QT electrocardiogram linked to SCN5A mutation, Eur J Hum Genet 2012;20:1189–92.

24. Berridge MJ, Bootman MD, Lipp P. Calcium – a life and death signal. Nature 1998;395:645–8.

25. Antzelevitch C, Yan GX, J wave syndromes. Heart Rhythm 2010;7:549–58.

26. Giustetto C, Schimpf R, Mazzanti A, et al. Long-term follow-

up of patients with short QT syndrome. J Am Coll Cardiol 2011;58:587–95.

27. Schwartz PJ, Moss AJ, Vincent GM, Crampton RS. Diagnostic criteria for the long QT syndrome. An update. Circulation 1993;88:782–4.

28. Gollob MH, Redpath CJ, Roberts JD. The short QT syndrome: proposed diagnostic criteria. J Am Coll Cardiol 2011;57:802–12.

29. Villafane J, Atallah J, Gollob MH, et al. Long-term follow-up of a pediatric cohort with short QT syndrome. J Am Coll Cardiol 2013;61:1183–91.

30. Anttonen O, Junttila MJ, Maury P, et al. Differences in twelve-lead electrocardiogram between symptomatic and asymptomatic subjects with short QT interval. Heart Rhythm 2009;6:267–71.

31. Schimpf R, Wolpert C, Bianchi F, et al. Congenital short QT syndrome and implantable cardioverter defibrillator treatment: inherent risk for inappropriate shock delivery.

J Cardiovasc Electrophysiol, 2003;14:1273–7.

32. Gaita F, Giustetto C, Bianchi F, et al. Short QT syndrome: pharmacological treatment, J Am Coll Cardiol 2004;43:1494–9.

33. Wolpert C, Schimpf R, Giustetto C, et al. Further insights into the effect of quinidine in short QT syndrome caused by a mutation in HERG. J Cardiovasc Electrophysiol 2005;16:54–8.

34. Schimpf R, Veltmann C, Giustetto C, et al. In vivo effects of mutant HERG K+ channel inhibition by disopyramide in patients with a short QT-1 syndrome: a pilot study.

J Cardiovasc Electrophysiol 2007;18:1157–60.

35. Mizobuchi M, Enjoji Y, Yamamoto R, et al. Nifekalant and disopyramide in a patient with short QT syndrome: evaluation of pharmacological effects and electrophysiological properties. PACE 2008;31:1229–32.

36. Lu LX, Zhou W, Zhang X, et al. Short QT syndrome: a gene case report and review of literature. Resuscitation 2006;71:115–21.

37. Hong K, Bjerregaard P, Gussak I, Brugada R. Short QT syndrome and atrial fibrillation caused by mutation in KCNH2. J Cardiovasc Electrophysiol 2005;16:394–6.

38. Bjerregaard P, Gussak I. Short QT syndrome. Ann Noninvasive Electrocardiol 2005;10:436–40.

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Arrhythmia Mechanisms

Inherited Arrhythmias – Where do we Stand?

Demost henes G K a t r i t s i s , 1 B e r n a r d J G e r s h 2 a n d A J o h n Ca m m 3 1. Athens Euroclinic, Athens, Greece; 2. Mayo Medical School, Rochester, MN, USA; 3. St George’s University of London, UK

Abstract This review discusses inherited arrhythmias and conduction disturbances due to genetic disorders. Known channel mutations that are responsible for these conditions are presented, the indications and value of genetic testing are discussed, and a glossary of terms related to the discipline of genetic cardiology has been compiled.

Keywords Inherited arrhythmias; conduction disturbances ; genetic channelopathies; mutations Disclosure: The authors have no conflicts of interest to declare.

Acknowledgement: This article first appeared in Chapter 56: Definitions of inherited arrhythmias. In: Katritsis DG, Gersh BJ, Camm AJ. Clinical Cardiology Current Practice Guidelines. Oxford, UK: Oxford University Press, 507–12. Published with kind permission of Oxford University Press.

Citation: Arrhythmia & Electrophysiology Review 2014;3(2):80–4 Access at: www.AERjournal.com Correspondence: Dr D. Katritsis, Athens Euroclinic, 9 Athanassiadou Street, Athens 11521, Greece. E: dkatritsis@euroclinic.gr, dgkatr@otenet.gr

Inherited arrhythmias comprise a group of disorders with inherited susceptibility to arrhythmias and conduction disturbances due to mutations in genes mainly encoding the Na+, and K+ channels, and other arrhythmogenic mechanisms such as those linked to Ca++ transport (Table 1).1 The majority of heritable cardiomyopathies and channelopathies are associated with disease-susceptibility genes characterised by incomplete penetrance, ie low likelihood that the mutation will cause clinically recognisable disease. Thus, although these disease entities are monogenic, there is variable penetrance, which reflects contribution by modifier genes, thus resulting in diverse phenotypes.2 Usually they are familial, rather than sporadic, and autosomal dominant rather than autosomal recessive.

Genetic testing has now emerged as a useful clinical tool for the diagnosis and risk stratification of genetic conditions but distinguishing pathological mutations from innocent genetic variants is not always straightforward.

Currently, genetic testing may put the diagnosis in long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT), Brugada syndrome (BrS) and hypertrophic obstructive cardiomyopathy (HOCM), and may also facilitate risk stratification in LQTS and HOCM.3 According to the 2010 consensus statement of HRS/EHRA, genetic testing is recommended in cases with a sound clinical suspicion for the presence of a channelopathy or a cardiomyopathy when the positive predictive value of a genetic test is high (likelihood of positive result >40 % and signal/noise ratio <10) (Table 2).4 The conventional approach of genetic linkage analysis has been replaced with the newer approach of genome-wide association studies (GWAS), and high-throughput, next-generation DNA sequencing (NGS).5 The application of high-throughput techniques for whole genome and exome sequencing are exciting future advancements of this technology,6–8 although questions remain about its clinical applicability and cost-effectiveness.9 In November 2013,

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the FDA approved marketing of four diagnostic devices that can be used for high-throughput gene sequencing.

The DNA of humans consists of the same nucleotide sequence, but normal variations in small sections of sequence or single nucleotides do exist among individuals (polymorphisms). Single nucleotide substitutions that occur with a measurable frequency (ie >0.5 % allelic frequency) among a particular ethnic population are called singlenucleotide polymorphisms, whereas those that occur less frequently are termed mutations.

Glossary of Terms Allele: One of several alternative versions of a particular gene. An allele can refer to a segment of DNA or even a single nucleotide.

The normal version of genetic information is often considered the ‘wild-type’ or ‘normal’ allele. The vast majority of the human genome represents a single version of genetic information. One phenotype may be controlled by multiple alleles, but only a combination of two will determine the phenotype. For example, the blood group gene has three alleles – A, B and O – but people only have a twoallele phenotype.

Autosomal Dominant: The situation in which the disease can be expressed even when just one chromosome harbours the mutation.

Autosomal Recessive: The situation in which the disease is expressed only when both chromosomes of a pair are abnormal.

Cascade Testing: Procedure whereby all first-degree relatives of a genotype-positive index case are tested in concentric circles of relatedness. If one of the family members is genotype positive, all his/ her first-degree relatives should be tested, continuing this process for each genotype-positive family member.

© RADCLIFFE CARDIOLOGY 2014

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Inherited Arrhythmias – Where do we Stand?

Table 1: Known channel mutations in genetic channelopathies. New mutations are continuously discovered.

Most conditions are inherited in an autosomal dominant pattern, although both recessive (JLN1, JLN2, CPVT2) and X-linked patterns (BRS) have been described Chromosomal Gene Protein Current Locus 11p15.5 KCNQ1 Kv7.1 IKs

Function

Syndrome

Phenotype

Loss of function

LQTS1

Long QT

Loss of function

JLNS

Long QT, deafness

Gain of function

SQTS

Short QT

Gain of function

AF

Atrial fibrillation

Loss of function

LQTS2

Long QT

Gain of function

SQTS

Short QT

7q35-q36

KCNH2 HERG

IKr

Gain of function

AF

Atrial fibrillation

Gain of function

LQT3

Long QT

Loss of function

BrS1

Brugada syndrome

Loss of function

AF

Atrial fibrillation

Loss of function

PCCD

Conduction defects

Loss of function

SSS

Sick sinus syndrome

Loss of function

DCM

Dilated cardiomyopathy

Gain of function

MEPPC

Ventricular premature conductions

Loss of function

LQTS

3p21

4q25-q27

SCN5A Nav1.5 INa

ANKB

Ankyrin B

INa-K,

21q22.1 2

KCNE1 MinK

IKs

Loss of function

LQTS

Long QT Atrial fibrillation CPVT Long QT

Loss of function

JLNS

Long QT, deafness

Loss of function

AF

Atrial fibrillation

Loss of function

LQTS

Long QT

Gain of function

AF

Atrial fibrillation

21q22.1

KCNE2 MiRP1

IKr

17q24.3

KCNJ2 Kir2.1

IK1

Loss of function

LQTS

Long QT, AV block,\potassium-sensitive

periodic paralysis, hypoplastic mandible

(Andersen-Tawil syndrome)

Gain of function

SQTS

Short QT

Gain of function

AF

Atrial fibrillation

Gain of function

LQTS

Long QT, syndactyly, septal defects

12p13.3

CACNA1C Cav1.2

ICa

(Timothy syndrome)

Loss of function

BrS

Brugada syndrome

Loss of function

SQTS

Short QT

Gain of function

LQTS

Long QT

3p24

CAV3 Caveolin-3

11q23.3

SCN4B Navβ4 INa

Gain of function

LQTS

Long QT

7q21-q22

AKAP9

Reduced due to

LQTS

Long QT

LQTS

Long QT

LQTS

Long QT

A-kinase anchorin

INa IKs

(yotiao)

20q11.2

SNTA1

α-1 syntrophin

INa

loss of cAMP sensitivity Increased due to S-nitrosylation of SCN5A

11q24.3

KCNJ5

Kir3.4 subunit

IKAch

Loss of function

14q32.11

CALM1

Calmodulin 1

Ca kinetics

Defective Ca binding LQTS

IVF

14q32.11

CALM2

10p12.33

CACNB2b Cavbeta2β ICa

Calmodulin 2

Ca kinetics

7q21-q22

CACNA2D1 Cavα2δ-1 ICa

13p22.3

GPD1L

19q13

glycerol-3-phosphate INa

Long QT Idiopathic ventricular fibrillation

Defective Ca binding LQTS

Long QT

Loss of function

Short QT

SQTS

Loss of function

BrS

Brugada syndrome

Loss of function

SQTS

Short QT

Loss of function

BrS

Brugada syndrome

Reduced

BrS

Brugada syndrome

Loss of function

BrS

Brugada syndrome

Brugada syndrome

dehydrogenase 1-like

SCN1B Navβ1 INa

Conduction disease Atrial fibrillation

11q13.4

KCNE3

beta subunit

Ito, Iks

Gain of function

BrS

11q23.3

SCN3B

beta subunit

INa

Loss of function

BrS

Brugada syndrome

15q24.1

HCN4 HCN4

I f

Loss of function

BrS

Brugada syndrome

1p13.3

KCND3 Kv4.3 Ito

Gain of function

BrS

Brugada syndrome

(Continued)

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Arrhythmia Mechanisms Table 1: Known Channel Mutations in Genetic Channelopathies (Continued) Chromosomal Gene Locus 12p11.23 KCNJ8 17p13.1

MOG1

Protein

Current

α subunit

IKATP

Gain of function

BrS, ERS

Brugada syndrome

MOG1 (RAN guanine

INa

Impaired trafficking

BrS

Brugada syndrome

BrS

Brugada syndrome

Loss of function

BrS

Brugada syndrome

Reduced

BrS

Brugada syndrome

BrS

Brugada syndrome

nucleotide release

factor 1)

3p21.2-p14.

SLMAP SLMAP

INa

Impaired trafficking

Phenotype

of channel

Xq22.3

KCNE5

β subunit

3q29

DLG1

synapse-associated 97 Junction

Ito

PKP-2 plaphilin-2

Syndrome

of channel

3

12p11

Function

functions

INa

Loss of function

ARVC Arrhythmogenic

1q42-43

RyR2

Cardiac ryanodine

Ca kinetics

Diastolic Ca

cardiomyopathy

CPVT1

Catecholaminergic tachycardia

receptor release bradycardia,

AF, AV block, dilated

cardiomyopathy

1p13-21

CASQ2

Cardiac calsequestrin Ca kinetics

Diastolic Ca

CPVT2

Catecholaminergic tachycardia

release

17q23

KCNJ2 Kir2.1

Ik1

Loss of function

CPVT3

Catecholaminergic tachycardia

14q32.11

CALM1

Calmodulin 1

Ca kinetics

Binding to RyR2

CPVT

Catecholaminergic tachycardia

6q22.31

TRDN

Triadin

Ca kinetics

Binding to RyR2

CPVT

Catecholaminergic tachycardia

IKs=rectifier K current, slow component. IKr=rectifier K current, rapid component. INa=inward Na current. INa-K=Na/- ATPase current (Na/K pump). INa-Ca=Na-Ca exchanger current.

IK1=inward rectifier K channel. ICa=Ca current. SSS: sick sinus syndrome, ERS: early repolarisation syndrome, MOGI: Multicopy suppressor of Gsp1 (Navβ1 partner), CPVT: catecholaminergic polymorphic VT, MEPPC: multifocal ectopic Purkinje-related premature contractions.

Table 2: Yield and Signal-to-Noise Associated with Disease-Specific Genetic Testing (HRS/EHRA Statement 2011) Disease LQTS

Yield of Genetic Test* 75 % (80%)

% of Control with a rare VUS# 4%

Signal-to-Noise (S:N) Ratio+ 19:1

CPTV

60 % (70%)

3 %

20:1

BrS

20 % (30%)

2 % (just SCN5A)

10:1

CCD Unknown

Unknown

Unknown

SQTS

3 %

Unknown

AF Unknown

Unknown

Unknown

HCM

60 % (70 %)

~5 % (unpublished data)

12:1

ACM/ARVC

60 %

16 %

4:1

DMC

30 %

Unknown

Unknown

DMC + CCD

Unknown

4 % (for SCN5A and LMNA)

Unknown

LVNC

17 %–41 %

Unknown

Unknown

Unknown

Unknown

Unknown

RCM Unknown

* Yield of Genetic Test is a published/unpublished estimate, derived from unrelated cases with unequivocal disease phenotype. First number is the yield associated with the targeted major gene scan. The number in parentheses is the total yield when including all known disease-associated genes that have been included in commercial disease gene panels.

When only a single percentage is provided, this represents the estimate from a comprehensive disease gene panel. These yield values represent estimates for whites with the particular disease phenotype. Evidence is lacking to establish point estimates for minority populations. # % of controls with a rare variant of uncertain significance (VUS) represents a frequency of rare amino acid substitutions found in whites in the major disease-associated genes that, had it been found in a case, would have been reported as a ‘possible disease-associated mutation’. This number does not include the frequency of rare genetic variants present in the minor disease-associated genes. Thus it represents a lower point estimate for the potential false positive rate. + The signal-to-noise (S:N) ratio is derived by dividing the yield by the background rate of VUS in controls. This provides a sense of the positive predictive value of a positive genetic test result. HRS/EHRA 2011 expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies, Heart Rhythm 2011;8:1308-39, by permission of Oxford University Press.

Compound heterozygosity: more than one genetic defect in the same gene.

Digenic heterozygosity: more than one genetic defect in a second complementary gene.

Expressivity: The level of expression of the phenotype.When the manifestations of the phenotype in individuals who have the same genotype are diverse, the phenotype is said to exhibit variable expressivity.

Epigenetics: Mitotically and/or meiotically heritable variations of gene function that cannot be explained by changes of DNA sequence.

Genotype: A person’s genetic or DNA sequence composition at a particular location in the genome.

Exome: The subset of the human genome that encodes proteins (1–2 % of the total genome); it encompasses approximately 19,000 genes.

Genotypic heterogeneity: Genetic variability among individuals with similar phenotypes.

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Genotype–phenotype plasticity: The concept that the link between genotype and phenotype is subject to broad variability with as yet limited predictability.

Genome-wide association studies: Examination of many common genetic variants in individuals with and without a disease trait, to identify a possible higher frequency (ie association) of singlenucleotide polymorphisms in people with the trait.

Haploinsufficiency: The situation in which an individual who is heterozygous for a certain gene mutation or hemizygous at a particular locus, often due to a deletion of the corresponding allele, is clinically affected because a single copy of the normal gene is incapable of providing sufficient protein production for normal function. This is an example of incomplete or partial dominance.

Heterozygote: An individual who has different alleles at a particular gene locus on homologous chromosomes (carrier of a single copy of the mutation).

Homozygote: An individual who has the same allele at a particular gene locus on homologous chromosomes (carrier of a double copy of the mutation).

Matrilinear inheritance: Women but not men transmit the disease to offspring (male or female), as happens with disease due to mitochondrial DNA mutations.

Modifier: Gene variants or environmental factors that are insufficient to cause observable disease on their own, but which are capable of interacting with the disease gene to alter the phenotype.

Mutation: A change of the DNA sequence within the genome. A mutation considered in the context of a genetic disease usually refers to an alteration that causes a Mendelian disease, whereas a genetic polymorphism refers to a common genetic variation observed in the general population.

Mutation – Deletion/Insertion: The removal (deletion) or addition (insertion) of nucleotides to the transcript that can be as small as a single nucleotide insertion/deletion or as large as several hundreds to thousands of nucleotides in length.

Mutation – Disease Causing: A DNA sequence variation that represents an abnormal allele and is not found in the normal healthy population but exists only in the disease population and produces a functionally abnormal product.

Mutation – Frameshift: Insertions or deletions occurring in the exon that alter the ‘reading frame’ of translation at the point of the insertion or deletion and produce a new sequence of amino acids in the finished product. Frameshift mutations often result in a different product length from the normal gene product by creating a new stop codon, which produces either a shorter or longer gene product depending on the location of the new stop codon.

Mutation – Germline: Heritable change in the genetic make-up of a germ cell (sperm or ovum) that when transmitted to an offspring is incorporated into every cell in the body.

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Mutation – In-Frame Insertion/Deletion: In-frame insertions and deletions occur when a multiple of three nucleotides is affected and result in single or multiple amino acids being removed or added without affecting the remainder of the transcript.

Mutation – Missense: A single nucleotide substitution that results in the exchange of a normal amino acid in the protein for a different amino acid.

Mutation – Nonsense: A single nucleotide substitution resulting in a substitution of an amino acid for a stop codon. A nonsense mutation results in a truncated (shortened) gene product at the location of the new stop codon.

Mutation – Somatic: Variants/mutations are said to be somatic if they occur in cells other than gametes. Somatic mutations cannot be transmitted to offspring.

Penetrance: The likelihood that a gene mutation will have any expression at all. In the situation in which the frequency of phenotypic expression is less than 100%, the genetic defect is said to be associated with reduced or incomplete penetrance.

Phenocopy: An individual who manifests the same phenotype (trait) as other individuals of a particular genotype but does not possess this genotype himself/herself.

Phenotype: A person’s observed clinical expression of disease in terms of a morphological, biochemical or molecular trait.

Phenotypic heterogeneity: Phenotypic variability among individuals with similar genotypes.

Polymorphism: Normal variations at distinct loci in the DNA sequence.

The vast majority of the human genome represents a single version of genetic information. The DNA from one person is mostly made up of the same nucleotide sequence as another person. However, there are many small sections of sequence or even single nucleotides that differ from one individual to another.

Proband or index case or propositus: The first affected family member who seeks medical attention for a genetic disease.

Single Nucleotide Polymorphism (SNP): A single nucleotide substitution that occurs with a measurable frequency (i.e. >0.5 % allelic frequency) among a particular ethnic population(s).

SNP – Nonsynonymous: A single nucleotide substitution whereby the altered codon encodes for a different amino acid or terminates further protein assembly, i.e. introduces a premature stop codon.

SNP – Synonymous: A single nucleotide substitution occurring in the coding region (exon), whereby the new codon still specifies the same amino acid.

X-linked inheritance: a recessive mode of inheritance in which a mutation in a gene on the X chromosome causes the phenotype to be expressed in males (who are necessarily hemizygous for the gene mutation) and in females who are homozygous for the gene mutation.

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Arrhythmia Mechanisms 1. Leenhardt A, Denjoy I, Guicheney P. Catecholaminergic polymorphic ventricular tachycardia. Circ Arrhythm Electrophysiol. 2012;5:1044–52.

2. Golbus JR, Puckelwartz MJ, Fahrenbach JP, et al. Populationbased variation in cardiomyopathy genes. Circ Cardiovasc Genet.

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3. Tester DJ, Ackerman MJ. Genetic testing for potentially lethal, highly treatable inherited cardiomyopathies/channelopathies in clinical practice. Circulation. 2011;123:1021–37.

4. Ackerman MJ, Priori SG, Willems S, et al. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies: This document

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9. Dewey FE GM, Pan C, Goldstein BA, et al. Clinical interpretation and implications of whole-genome sequencing.

JAMA 2014;311:1035–45.

This article is reprinted from Chapter 56: Definitions of inherited arrhythmias, in: Clinical Cardiology Current Practice Guidelines, pages 507–12.

c

lu

des acc

e

Current Practice Guidelines

in

OxfO rd Med icin Onl ine e

to

tO

des acc

ss

c

lu

e

Clinical Cardiology

was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA). Europace 2011;13:1077–109.

5. Roberts R, Marian AJ, Dandona S, Stewart AF. Genomics in cardiovascular disease. J Am Coll Cardiol 2013;61:2029–37.

6. Dewey FE, Pan S, Wheeler MT, et al. DNA sequencing: Clinical applications of new DNA sequencing technologies.

Circulation 2012;125:931–44.

7. Schwartz P, Ackerman MJ, George AL, et al. Impact of genetics on the clinical management of channelopathies. J Am Coll Cardiol 2013;62:169–80.

8. Ganesh SK AD, Assimes TL, Basson CT, et al; on behalf of the

First edition, 2013.

Authors: Katritsis DG, Gersh BJ, Camm AJ. Publisher: Oxford University Press, Oxford UK. ISBN: 978-0-19-968528-8 Arrhythmia & Electrophysiology Review readers can receive a 30 % discount on the cover price of this book at the Oxford University Press

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Clinical Arrhythmias

Dental Procedures in Patients with Atrial Fibrillation and New Oral Anticoagulants Pe p i e Ts o l k a Assistant Professor, Department of Dental Technology, Faculty of Health and Caring Professions, Technological Educational Institute of Athens, Athens, Greece

Abstract This review discusses the basic pharmacology of new oral anticoagulants that are used for prevention of thromboembolism in patients with atrial fibrillation. It presents available evidence, and provides recommendations for the management of patients requiring invasive procedures in dental practice.

Keywords New oral anticoagulants; dental procedures; atrial fibrillation Disclosure: The author has no conflicts of interest to declare.

Received: 23 July 2014 Accepted: 29 July 2014 Citation: Arrhythmia & Electrophysiology Review 2014;3(2):85–9 Access at: www.AERjournal.com Correspondence: Dr P Tsolka, 13 K Palama, Neo Psychiko, 15451 Athens, Greece. E: ptsolka@otenet.gr

Novel oral anticoagulants (NOACs) represent new options for preventing stroke in patients with atrial fibrillation (AF), and have been approved for use in North America and Europe. They carry a 50 % lower risk of intracranial haemorrhage compared with warfarin, no clear interactions with food, fewer interactions with medications and no need for frequent laboratory monitoring and dose adjustments.

Although they lack a specific reversal agent, their use is increasing in the western world, thus imposing upon the dentists the task of performing invasive procedures in this setting with a continually higher frequency.

Magnitude of the Problem AF is the most common sustained arrhythmia in humans and affects 1–2 % of the general population worldwide. It affects three to six million people in the US,1,2 while in Asian countries its incidence is slightly lower.3,4 In the EU, 8.8 million adults over 55 years were estimated to have AF in 2010 and this number is expected to double by 2060 to 17.9 million.5 According to the first global assessment of AF, conducted within the framework of the Global Burden of Diseases (GBD), Injuries and Risk Factors Study, the estimated global prevalence of AF in 2010 was 33.5 million (20.9 million men and 12.6 million women), with almost five million new cases occurring each year.6 The prevalence of AF increases with age, from approximately 2 % in

Clinical Perspective • I n patients with normal renal function taking dabigatran, rivaroxaban or apixaban, invasive dental procedures can be carried out without interruption of the medication, but should be performed as late as possible after the most recent dose, ideally >12 hours).

• P atients requiring complex oral/maxillofacial surgery may need discontinuation of oral anticoagulants for at least 24 hours preoperatively.

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the general population, to 5–15 % at 80 years.2,7,8 Thus, AF represents a modern epidemic, and the practicing dentist is expected to deal with these patients at a continually increasing frequency.

AF is associated with significant morbidity, including a two- to seven-fold increased risk for stroke (average 5 % per year).9–12 In the Framingham Study the percentage of strokes attributable to AF increases steeply from 1.5 % at 50–59 years of age to 23.5 % at 80–89 years of age.11 Approximately 20 % of all strokes are due to AF,13 and paroxysmal AF carries the same stroke risk as permanent or persistent AF.14 Thus, chronic anticoagulation is necessary for patients with AF and CHA2DS2VASc score ≥2, whereas no anticoagulation may only be recommended in patients with negligible risk and a score of 0. The novel oral anticoagulants are now recommended for nonvalvular AF as a potential alternative to warfarin by both the European Society of Cardiology (ESC) and American College of Cardiology (ACC)/American Heart Association (AHA) (see Table 1). Dabigatran is preferred to warfarin for non-valvular AF by the ESC13 and the Canadian Cardiology Society.15 NOACs are direct thrombin (dabigatran) or factor Xa (rivaroxaban, apixaban, edoxaban) inhibitors. They carry a 50 % lower risk of intracranial haemorrhage compared with warfarin, no clear interactions with food, fewer interactions with medications and no need for frequent laboratory monitoring and dose adjustments.16–18 Their main disadvantages are the lack of a reliable, specific antidote, specific assays to measure anticoagulant effect, and considerably higher cost than warfarin.19 NOACs do not interact with food but with inhibitors (or inducers) of P-glycoprotein transporters and cytochrome P450 (CYP) 3A4.

A practical guide by the European Heart Rhythm Association (EHRA) has been published and a website created (www.NOACforAF.eu).20 The use of NOACs is continually increasing in the western world and, apart from AF, they are also used both for therapy and prevention of venous thromboembolism,21,22 i.e. pulmonary embolism and deep vein thrombosis, a disease entity with an annual incidence of approximately 1.2 cases per 1,000 adults.23,24

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Clinical Arrhythmias Table 1: New Oral Anticoagulants for Atrial Fibrillation

Dose

Dabigatran 150 or 110 bd

Rivaroxaban 20 mg od

Apixaban Edoxaban 2.5-5 mg bd 30-60 mg od

75 mg bd if CrCl 15-30 ml/min

15 mg od if CrCl 15-30 ml/min

2.5 mg bd if

(no data in renal impairment)

CrCl ≥ 1.5 mg/dL,

≥ 80 years of age,

body weight ≤ 60 kg

Target

Thrombin (Factor II)

Factor Xa

Factor Xa

Factor Xa

Half life

12–14 h

9–13 h

8–11 h

8–10 h

Renal clearance

80 %

60 %

25 %

40 %

Onset of action

2 h

2.5–4 h

3 h

1–5 h

bd = twice daily; od = once daily; CrCl = creatinine clearance.

Table 2: Classification of Dental Procedures Dental Procedure • Supragingival scaling

Presumed Bleeding Risk Low

Peri-procedural Recommendations* Continue therapeutic anticoagulation

Moderate

Continue therapeutic anticoagulation

• Extensive maxillofacial surgery

High

Consider reducing or completely

• Periodontal surgery

reverse anticoagulation

• Simple restorative treatment • Local anaesthetic injections (buccal infiltration, intraligamentary or mental block) • Impressions and other prosthetic procedures • Local anaesthesia by inferior alveolar or other regional nerve blocks or floor of mouth infiltrations • Subgingival scaling and root surface instrumentation (RSI) • Subgingival crown and bridge preparations • Endodontics. Standard root canal treatment • Simple extractions • Incision and drainage of swellings • Biopsies

• Alveolar surgery (bone removal) • Multiple extractions *For all procedures, local measures can be used to prevent or control bleeding (local pressure, site packing, additional suturing, topical haemostat, mouth rinses).

Assessment of Activity and Reversal of NOACs Dabigatran Activated partial thromboplastin time (aPTT) and thrombin clotting time (TCT or thrombin time) may be used for assessment of anticoagulant action, although not to guide dosage since the correlation is not linear. A normal aPTT indicates the absence of a significant dabigatran effect, whereas an aPTT >2.5 times the control 8–12 hours after dabigatran dosing is suggestive of excess anticoagulant activity.25 The Hemoclot® direct thrombin inhibitor assay (HYPHEN BioMed; France) provides an accurate measure of dabigatran drug levels.25 There is no specific antidote to dabigatran, but fresh frozen plasma and activated prothrombin complex concentrates (aPCC, 80 U/kg Factor Eight Inhibitor Bypassing Activity [FEIBA]; Baxter, Vienna, Austria) may be helpful.25–27 Recombinant activated factor VII (rVIIa, NovoSeven®, NovoNordisk, Bagsvaerd, Denmark) has also been proposed but data supporting its usefulness are lacking.28 Note that unlike the prothrombin complex concentrates (PCCs) in Europe and Canada, which contain all four vitamin K-dependent procoagulant proteins, those currently available in the US contain little or no factor VII.25

Apixaban and Rivaroxaban Prothrombin time and, especially, anti-Xa assays (heparin) may be used as rough estimates of the anticoagulant effect. No specific antidotes exist, but the recombinant factor Xa andexanet alpha (Portola Pharmaceuticals; CA, USA) given as a bolus 600 or 720 mg and followed by an infusion of 4 mg/min for one hour, has been successfully tried. Infusion-related reactions and postural dizziness

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were the only side-effects seen in 10 % of patients.29 PCCs (50 IU/kg) are also recommended, and are probably preferred to aPCC.30 Apixaban and rivaroxaban are not removed by dialysis, being protein bound. Packed red cells in anaemia, platelet transfusions in patients receiving concurrent antiplatelet therapies, and fresh frozen in the presence of dilutional coagulopathy or disseminated intravascular coagulation, may also be tried as general measures.28 Edoxaban and betrixaban are Xa antagonists that have also been successfully tried in patients with non-valvular AF, but few data on their clinical use exist.

Dental Procedures in Patients on NOACs Dental treatment performed in patients receiving oral anticoagulant drug therapy is becoming increasingly common in dental offices. Frequently raised questions concern the accompanying thromboembolic and bleeding risks of the various anticoagulation regimens relative to invasive dental procedures. Many dental procedures do not involve a significant risk of bleeding and therefore no special measures are required when treating patients who take an oral anticoagulant drug.

However, there are procedures that carry a risk of significant bleeding and for which the dentist must consider the management of the patient in relation to their anticoagulant therapy (see Table 2).

Peri-procedural Anticoagulation In patients on warfarin, procedures at low bleeding risk do not require interruption of anticoagulation, provided the international normalised

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Table 3: Proposals for General Dental Practitioners Treating Patients on Novel Oral Anticoagulants 1. Continuation of Oral Antithrombotic Medication a. Do not interrupt single or dual TAR (such as ASA, clopidogrel, and carbasalate calcium). b. Do not interrupt VKAs if the INR is less than 3.5. c. Do not interrupt NOACs (direct thrombin inhibitors or Xa-inhibitors, such as apixaban, dabigatran, and rivaroxaban).

Note: The anticoagulation regime does not require alteration when single-dose antibiotics for prophylaxis are provided; miconazole is contraindicated when VKAs or NOACs are taken.

2. Preoperative Measures a. Inform the patients that minor bleeding or oozing from gingival mucosa may be more common when not interrupting OAM during dental procedures. b. Check INR in patients using VKA at least 24–72 hours before the dental procedure; refer patients whose INR is higher than 3.5 to the hospital for evaluation and treatment. c. Advise patients on NOACs not to take medication 1–3 hours immediately before dental treatment. d. Assess the patients’ complete medical history and discuss with the physician in charge if renal or liver disorders are suspected or known; when INR ≥ 3.5 or the planned procedures are more extensive. e. Schedule extraction of more than three teeth over a larger number of visits (i.e., divide the load) and plan the surgeries earlier in the day and at the beginning of the week.

3. Perioperative Measures a. Minimise surgical trauma and reduce areas of periodontal surgery and scaling and root planing (per quadrant). b. Aim at primary closure of surgical wounds, including extraction wounds, using absorbable sutures.

4. Postoperative Measures a. Compress with gauze for 15–30 minutes after the surgical procedure; use coagulating agents, such as gelatin sponges, oxidised regenerated cellulose, synthetic collagen, or tranexamic acid mouthwash in 4.8% aqueous solution, for 1–2 days after the surgery, using 10 ml, four times a day for two minutes. b. Remove nonabsorbable sutures, if used, after 4–7 days. c. Do not prescribe NSAIDs and COX-2 inhibitors as analgesics to any patient on any antithrombotic medications. d. Provide the patients with oral and written instructions about the expected postoperative course and the measures they can take if bleeding occurs.

OAM = oral antithrombotic medication; TAR = thrombocyte aggregation inhibitor; ASA = acetylsalicylic acid; VKA = vitamin K antagonist; INR = international normalised ratio; NOAC = novel oral anticoagulant; NSAID = nonsteroidal anti-inflammatory drug; COX-2 = cyclooxygenase-2.37 Reproduced with kind permission of van Dierman et al.37

ratio (INR) is <4.0, whereas moderate and high-risk procedures are performed with an INR<1.5.31 Heparin bridging is not necessary, apart from in patients with certain mechanical valves. In a recent metaanalysis, heparin bridging for invasive procedures and surgery in patients receiving vitamin K antagonists for AF, prosthetic heart valve or venous thromboembolism conferred a greater than five-fold increased risk for bleeding, whereas the risk of thromboembolic events was not significantly different between bridged and nonbridged patients.32 Few data exist for NOACs. These agents are not indicated for anticoagulation in patients with prosthetic heart valves.33 Dentists, therefore, will encounter them in patients with AF and venous thromboembolism. There has been recent evidence that continuation or short-interruption of NOACs are safe strategies for most invasive procedures.34 Thus, dental procedures that involve manipulation of the gingival or periapical region of the teeth or perforation of the oral mucosa including uncomplicated teeth extractions do not require interruption of anticoagulation.34 For subgingival scaling, a small area should be scaled first to assess the amount of bleeding before instrumentation of larger areas is carried out. Local anaesthetics solutions containing a vasoconstrictor should be used unless contraindicated on other medical grounds. An aspirating syringe must be used for all local anaesthetic injections.35,36 Procedures with a relatively higher risk of bleeding such as multiple extractions or minor oral/maxillofacial surgery can also be safely performed without interruption of NOACs, provided they are carried out 12 hours after last dosing of dabigatran and 10 hours after last dosing of rivaroxaban or apixaban (see Table 1). Current available information suggests that the risk of bleeding in patients undergoing invasive dental procedures (for example up to three dental extractions, up to three dental implants and periodontal surgery) is low, provided

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Table 4: European Heart Rhythm Association 2013: Last Intake of NOAC Before Elective Surgical Intervention No important bleeding risk and/or adequate local haemostasis possible: perform 12–24 hours after last intake

Dabigatran Apixaban/Rivaroxaban

Low Risk High Risk

Low Risk

High Risk

CrCl ≥80 mL/min

≥24 h

≥48 h

≥24 h

≥48 h

CrCl 50–80 mL/min

≥36 h

≥72 h

≥24 h

≥48 h

CrCl 30–50 mL/min

≥48 h

≥96 h

≥24 h

≥48 h

CrCl 15–30 mL/min

not indicated

≥36 h

Low and high risk refers to operative bleeding; CrCl = creatinine clearance.

≥48 h 20

that local haemostatic measures (suturing, ideally with resorbable sutures, gelatin sponge, gauze soaked in 5 % tranexamic acid, tranexamic acid mouth rinse) are used (see Table 3).37 For more serious surgical operations, (major oral/maxillofacial surgery), the lack of data necessitates an empirical approach.

In general, for surgical operations, depending on the risk of bleeding and renal function, preoperative interruption of NOACs for one to seven days has been recommended.25,38 The 2013 EHRA report recommends shorter intervals.20 Dabigatran should be discontinued for at least 24 hours (or longer in renal impairment) in patients requiring major oral/maxillofacial surgery (see Table 3).39 Additionally, consideration should be given to performing a thrombing clotting time (TT) or an aPTT 6–12 hours prior to surgery. The renal function of the patient should be also taken into account (see Table 4).

If discontinuation of anticoagulation is not considered safe and extensive oral surgery is required, peri-operative bridging anticoagulation with an appropriate dose of low molecular weight heparin (LMWH) or

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Clinical Arrhythmias Table 5: Risk of Stroke in Atrial Fibrilation CHAD2DS2VASc Score Risk Factor

Score

Congestive heart failure/left ventricular dysfunction

1

Hypertension

1

Age >75

2

Diabetes mellitus

1

Stroke/transient ischaemic attack/thromboembolism

2

Vascular disease (MI, peripheral artery disease, aortic plaque)

1

Age 65–74

1

Sex category (i.e. female sex)

1

Adjusted Stroke Rate According to CHA2DS2-VASc Score Score

Adjusted Stroke Rate (% year)

0

0.0 %

1

1.3 %

2

2.2 %

3

3.2 %

4

4.0 %

5

6.7 %

6

9.8 %

7

9.6 %

8

6.7 %

9

15.2 %

Conclusions Data on patients taking NOACs and who are undergoing dental procedures are scarce, and an empirical approach is inevitable regarding the management of these patients. Based on available evidence, the following recommendations can be made:

Previous stroke, TIA, systemic embolism, and age ≥75 years are considered major risk factors.44 MI = myocardial infarction.

Reproduced with kind permission of Katritsis et al. and Oxford University Press.44

unfractionated heparin is recommended.39 It should be noted, however, that bridging with heparin is, on most occasions, not necessary and may increase the risk of bleeding.34 In a recent analysis of data from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RELY) trial, interruption of dabigatran (two days) or warfarin (five days) for allowance of surgery was not associated by a significant occurrence of stroke and systemic embolism although heparin bridging was used in <80 % of patients on dabigatran, and major bleeding was not different in the two treatment groups.40 However, discontinuation of rivaroxaban in the ROCKET AF for at least three days was associated with a higher incidence of stroke compared with discontinuation of warfarin.41 Thus, in patients with a CHADS2DS2VASC score >4, i.e. >5 % annual risk of stroke (see Table 5), or those with a history of stroke who require temporary

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interruption of oral anticoagulation, bridging therapy with LMWH should be considered, especially when a newer oral anticoagulant is used.42 If urgent surgery or intervention is required in these patients, the risk of bleeding must be weighed against the clinical need for the procedure.

Evaluation of common coagulation tests (aPTT for dabigatran; sensitive prothrombin time [PT] for FXa inhibitors) or of specific coagulation test (direct thrombin time [dTT] for dabigatran; chromogenic assays for FXa inhibitors) can be considered for assessment of anticoagulation intensity, but no clinical experience exists.20 Surgery should be deferred, if possible, until at least 12 hours and ideally 24 hours after the last dose.

Nonspecific anti-haemorrhagic agents, such as rVIIa or PCCs, should not be given for prophylactic reversal due to their uncertain benefit: risk ratio.43 Reinitiation of these agents should be delayed for 24–48 hours and once a stable clot or complete haemostasis is assured, since within one to two hours of reinitiation the patient will be anticoagulated. For procedures with immediate and complete haemostasis NOACs can be resumed six to eight hours after the intervention.

• I n patients with normal renal function taking dabigatran, rivaroxaban or apixaban, simple invasive dental procedures can be carried out without interruption of the medication.

• All procedures should be performed as late as possible after the most recent dose, ideally >12 hours).

• Local haemostatic measures should be used routinely in these patients.

• Patients requiring oral/maxillofacial surgery may need discontinuation of oral anticoagulants for at least 24 hours pre-operatively, but always in consultation with treating physician.

• If stopped pre-operatively, NOACs should only be recommenced when a stable clot or adequate haemostasis has been achieved (typically 24–48 hours post-operatively).

• If post-operative bleeding occurs, oral anticoagulant therapy should be stopped, and local haemostatic measures applied. n

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12. Jonathan P. Piccini, Bradley G. Hammill, et al. Clinical course of atrial fibrillation in older adults: The importance of cardiovascular events beyond stroke. Eur Heart J 2014;35:250–6.

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14. Hart RG, Pearce LA, Rothbart RM, et al. Stroke with intermittent atrial fibrillation: Incidence and predictors during aspirin therapy. Stroke prevention in atrial fibrillation investigators. J Am Coll Cardiol 2000;35:183–7.

15. Gillis AM, Verma A, Talajic M, et al. Canadian cardiovascular society atrial fibrillation guidelines 2010: Rate and rhythm management. Can J Cardiol 2011;27:47–59.

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17. 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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warfarin in patients with atrial fibrillation: A meta-analysis of randomised trials. Lancet 2014;383:955–62.

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20. 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.

21. Fontana P, Goldhaber SZ, Bounameaux H. Direct oral anticoagulants in the treatment and long-term prevention of venous thrombo-embolism. Eur Heart J 2014;35:1836–43.

22. Verhamme P, Bounameaux H. Direct oral anticoagulants for acute venous thromboembolism: closing the circle? Circulation 2014;129:725–7.

23. Heit JA. The epidemiology of venous thromboembolism in the community. Arterioscler Thromb Vasc Biol 2008;28:370–2.

24. Piazza G, Goldhaber SZ. Acute pulmonary embolism: Part i: Epidemiology and diagnosis. Circulation 2006;114:e28–32.

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Clinical Arrhythmias

Mechanisms of Atrial Fibrillation – Reentry, Rotors and Reality Jona t h a n W Wa k s 1 a n d M a r k E J o s e p h s o n 2 1. Clinical Fellow in Cardiac Electrophysiology, Harvard Medical School, Harvard-Thorndike Electrophysiology Institute and Arrhythmia Service, Beth Israel Deaconess Medical Center, Boston, US; 2. Herman C. Dana Professor of Medicine, Harvard Medical School, Chief of the Cardiovascular Division, Beth Israel Deaconess Medical Center and Director, Harvard-Thorndike Electrophysiology Institute and Arrhythmia Service, Beth Israel Deaconess Medical Center, Boston, US

Abstract Atrial fibrillation (AF) is the most common sustained arrhythmia encountered in clinical practice, yet our understanding of the mechanisms that initiate and sustain this arrhythmia remains quite poor. Over the last 50 years, various mechanisms of AF have been proposed, yet none has been consistently observed in both experimental studies and in humans. Recently, there has been increasing interest in understanding how spiral waves or rotors – which are specific, organised forms of functional reentry – sustain human AF and how they might be therapeutic targets for catheter-based ablation. The following review describes the historical understanding of reentry and AF mechanisms from earlier in the 20th century, advances in our understanding of mechanisms that are able to sustain AF with a focus on rotors and complex fractionated atrial electrograms (CFAEs), and how the study of AF mechanisms has resulted in new strategies for treating AF with novel forms of catheter ablation.

Keywords Atrial fibrillation, rotor, reentry, arrhythmia mechanisms, complex fractionated atrial electrograms, pulmonary vein isolation Disclosure: The authors have no conflicts of interest to declare.

Received: 6 August 2014 Accepted: 8 August 2014 Citation: Arrhythmia & Electrophysiology Review 2014;3(2):90–100 Access at: www.AERjournal.com Correspondence: Mark E Josephson, Harvard-Thorndike Electrophysiology Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, 185 Pilgrim Road, Baker 4, Boston, MA 02215. E: mjoseph2@bidmc.harvard.edu

Atrial fibrillation (AF), the most common sustained arrhythmia, is a leading cause of stroke, and is associated with significant morbidity and mortality worldwide. Despite its frequency, clinical importance, and advances in technology and our knowledge of the molecular, ionic and physiological fundamentals of cardiac electrophysiology, our limited understanding of the mechanisms that initiate and sustain AF has prevented us from being able to truly cure this arrhythmia with antiarrhythmic drugs and/or ablation. This contrasts with other arrhythmias, such as AV nodal tachycardia or circus movement tachycardia using an accessory pathway, which have well-defined mechanisms and circuits that can be safely targeted with high rates of cure. The observations that AF may have different mechanisms in different patients, and that paroxysmal, persistent and permanent forms of AF may differ in how they are initiated and sustained, only serves to reinforce our lack of understanding of this ubiquitous arrhythmia.

Historical Mechanisms of Atrial Fibrillation and the Multiple Wavelet Hypothesis

a specific mechanism with the technology of the time. In 1959, Moe et al. described the ‘multiple wavelet hypothesis’ of AF which extended the concept of reentry to include multiple simultaneous atrial reentrant circuits with separate initiating and sustaining factors. According to this theory, if a critical number of reentrant wavefronts existed in an appropriate atrial substrate (a combination of atrial size and mass, conduction velocity and tissue refractory period) these wavefronts could continually re-excite the atria resulting in chaotic, fibrillatory conduction. 8 The multiple wavelet hypothesis was further supported by an early computer model of AF in which propagation of multiple atrial impulses demonstrated selfperpetuating activity with many similarities to clinical AF in humans.9 Moe et al. demonstrated that it was probabilistically unlikely that a large number of simultaneous wavefronts would all die out simultaneously, and AF would therefore perpetuate. However, if the number of simultaneous wavelets were small and/or below a critical value (between 15 and 30 in Moe’s computer model),9 at some point all reentrant wavefronts would be simultaneously extinguished, and AF would therefore terminate.8,9

Interest and understanding of the mechanism of AF began to take form in the early 1900s. Given the chaotic and irregular nature of AF on the surface electrocardiogram, rapid firing of automatic atrial foci was considered a potential mechanism. However, after the seminal work of Mayer 1, Mines 2 and Garrey 3 in laying the foundation for describing and understanding reentrant arrhythmias, atrial reentrant circuits emerged as the likely drivers of AF. 4–7 Although these theories were conceptually sound, it was impossible to prove

Allessie et al. provided experimental evidence supporting this mechanism in a canine heart model of AF where four to six simultaneous reentrant wavelets were needed to sustain arrhythmia.10 Further evidence supporting multiple wavelets in AF was demonstrated in a separate model, which evaluated the effect of various antiarrhythmic drugs on canine myocardium. This model demonstrated that termination of AF was associated with a reduction

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in the number of simultaneous atrial reentrant wavelets.11,12 Cox et al. subsequently mapped multiple reentrant atrial wavefronts during human AF, and this formed the basis for the surgical maze procedure in which multiple, small, electrically-isolated atrial compartments were created to prevent sustained reentry.13 More recently it has become accepted that separate mechanisms may be responsible for triggering and sustaining AF. Focal discharges (especially from within the pulmonary veins, as described by Haissaguerre et al)14 can initiate AF. However, AF maintenance probably involves some form of reentrant activity, with the observed irregular fibrillatory activity caused by ‘wavebreak’ of the main reentrant wavefront into multiple chaotic daughter wavelets as a consequence of inhomogeneity in atrial structure, refractoriness and conduction velocity.15 Additionally, the mechanisms that sustain AF may evolve over time as the atria electrically and structurally remodel and AF progresses from paroxysmal, to persistent and then permanent forms.

This concept has been supported by multiple studies which have demonstrated more frequent reentrant drivers of AF in patients with longstanding arrhythmia.

Figure 1: Schematics of Anatomic and Functional Reentrant Circuits A

B

Scar

Refractory Tissue

Wavefront

Wavefront Wavetail

Excitable gap Wavetail

No Excitable Gap

A. A simple reentrant circuit around an anatomic barrier (scar). The wavefront is represented by the blue arrow, and the wavetail is represented by the end of blue shading.

The size of the circuit’s excitable gap is shown between the wavefront and wavetail in white.

B: Leading circle reentry. There is no excitable gap as the wavefront continuously encroaching on the wavetail. Because of constant centripetal activation of the center of the circuit, this area becomes refractory and unexcitable which allows reentry to sustain itself in the absence of an anatomic barrier.

Figure 2: Leading Circle Reentry

Functional Reentry and the Leading Circle Model Functional reentry in its simplest form can be described by the ‘leading circle model’, first described by Allessie et al. in 1977.16 In this model, circus movement of a unidirectional wavefront results in constant centripetal activation of the centre of the circuit which renders it continuously refractory. This refractory area then forms a functional barrier which can sustain reentry in a way similar to a fixed anatomic barrier such as a scar (see Figure 1). In the leading circle model, unidirectional block in tissue allows an impulse to initiate circus movement in one direction, with the impulse simultaneously spreading radially outwards to activate the adjacent myocardium and radially inwards towards the centroid of the circuit.

The wavelength of the circuit – defined as the product of the impulse conduction velocity and the tissue refractory period – describes the distance traveled by the wavefront during the refractory period.

Wavelength is critical to understanding how reentry is established in this model. Consider a prototypical circular reentrant circuit with a circumference or path-length equal to the wavelength of the circuit (see Figure 2A). This circuit will have no excitable gap and will rotate continuously with the leading edge of the impulse (the wavefront) encroaching on tissue which has just recovered excitability (the wavetail). This will therefore define the smallest circuit which can sustain reentry. A smaller circuit, with path length less than wavelength, would occur in areas located closer towards the centroid of the circuit (see Figure 2C). This smaller circuit will not be able to sustain reentry because the circulating wavefront will encounter refractory tissue and will therefore block and terminate.

A larger circuit, with path length greater than wavelength, would occur in areas located radially further away from the centroid of the circle (see Figure 2B) and can sustain reentry with an excitable gap. However, if conduction velocity throughout the atria remains relatively fixed, this larger reentrant circuit will rotate and activate the surrounding myocardium at a slower frequency.

The ‘leading circle’ reentrant circuit with its path length/circumference equal to its wavelength (see Figure 2A) is thus the smallest circuit that can sustain reentry. By virtue of its smallest size it also rotates

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Wavelength = X0

A

Velocity = V0 Rotational Frequency = V0/X0 = f0

Wavefront

Wavetail No Excitable Gap

B

Wavelength = X1 > X0 Velocity = V0 Rotational Frequency = V0/X1 = f1 < f0

Wavefront

Excitable gap Wavetail C Wavelength = X2 < X0 Circuit terminates as X2 is < the minimum path length X0

A: Leading circle reentry. No excitable gap is present, and the circuit rotates with a frequency of f0.This is the smallest circuit which can sustain functional reentry.

B: Functional reentrant circuit larger than the leading circle. An excitable gap is present and the circuit rotates with a frequency of f1 which is slower than f0.

C: Functional reentrant circuit smaller than the leading circle. This circuit cannot sustain reentry as the circulating wavefront encounteres refractory tissue and will therefore block and terminate. See text for additional details.

with the highest frequency, and so will ‘overdrive’ and suppress all larger circuits while maintaining a core of refractory tissue towards

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Clinical Arrhythmias Figure 3: Experimental Exidence of Leading Circle Reentry

Membrane potentials located in a straight line (A through D) through a clockwise reentrant circuit in atrial tissue with a cycle length of 105 milliseconds. Fibres 3 and 4, which are located in the centre of the circle, are activated twice as often, but they do not reach normal amplitude and cannot propagate out of the centre of the circuit, rendering it functionally unexcitable because the tissue is continually depolarised. Reproduced with permission from Allessie et al.16

Figure 4: Schematic of a Rotor

1

Wavelength

2

3 CORE

1

2

3

Wave front

Wave tail

Velocity vector

Phase singularity

Points 1–3 represent a gradient of action potential duration along the curvature of the rotor.

See text for additional details. Reproduced with permission from Pandit et al.22

its centre.6 Reentry compatible with the leading circle model was elegantly demonstrated by Allessie et al. in experiments on rabbit myocardium. Here, rapid activation by a circular reentrant wavefront maintained a reduced membrane potential and therefore tissue refractoriness in the centre of the circuit (see Figure 3).16

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The multiple wavelet hypothesis of AF and the leading circle model of reentry complement each other, as the number of reentrant circuits that can be sustained is dependent on wavelength and atrial size. Large atria and small reentrant circuits (short wavelength due to a short atrial refractory period and/or slow conduction velocity) allow multiple reentrant circuits to form and increase the probability of sustaining AF, while small atria (or surgically partitioned atria as in the maze procedure) and large reentrant circuits (long wavelengths) are unlikely to be able to sustain reentry and AF. 4 These observations also complement experimental human studies which have demonstrated increased rates of AF in patients with enlarged left atria17, intra-atrial conduction defects,18–20 or abnormal atrial refractory periods. 18,20,21 Recent experimental data have suggested, however, that although functional reentry may be of critical importance in initiating and sustaining AF, it is significantly more complex than can be accounted for by only leading circle reentry with multiple simultaneous wavelets.

Functional Reentry Due to Rotors/Spiral Waves Recent computational and experimental data have suggested that special types of functional reentry may be of critical importance in sustaining AF. Rotors, or spiral waves, describe a specific type of functional reentry where, instead of being circular, the wavefront has a curved or spiral form, and the wavefront and wavetail meet at a focal point called a phase singularity (PS). Unlike the leading circle model, however, the wavefront velocity in a rotor is not constant, depending instead on wavefront curvature due to current source–sink mismatch associated with the propagation of nonplanar wavefronts. The wavefront in close proximity to the PS is the region of highest curvature, and therefore is also the area of slowest wavefront conduction velocity (see Figure 4). In fact, at the PS, the wavefront curvature is so high and conduction velocity is so slow, that the propagating wavefront is unable to invade a core of tissue in the centre of the rotor. This tissue core is therefore effectively unexcitable, thus forming an area of functional block similar to the centre of a leading circle reentrant circuit. Unlike the leading circle model, tissue at the core of a rotor is not truly refractory. Because conduction velocity at the PS is so slow, tissue in the core is simply extremely difficult to penetrate and excite.

This fundamental difference has important implications for the behaviour of reentrant circuits driven by rotors as compared with leading circles. A reentrant circuit in the leading circle model must remain fixed in space because the centre of the circuit is completely unexcitable. A rotor, however, is able to move through space and, due to constant source–sink current mismatch at the PS and core, under certain circumstances the rotor can meander in various complex forms which in turn have important effects on rotor behaviour and sustainability.6,22 The variable curvature of a rotor establishes a gradient of conduction velocity, and because the core constantly acts as a current sink from cells in close proximity to the core, this in turn also establishes gradients of action potential duration (APD) and wavelength which rise with increasing distance from the PS.6,22 As a result of these gradients, rotors establish a gradient of excitable gap and heterogeneous conduction properties that also follow the spiral shape of the rotor and influence its behaviour.22 Rotors can theoretically and experimentally form when a wavefront interacts with some form of barrier, either due to a structural obstacle such as a scar or functional myocardial electrical inhomogeneity or

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Mechanisms of Atrial Fibrillation – Reentry, Rotors and Reality

anisotropy. As a wavefront passes through a barrier it can, under certain conditions, bend and break into two daughter wavelets by a process called vortex shedding. This is somewhat analogous to the flow of turbulent water around an obstacle in a river.22 Due to variations in wavefront curvature and velocity caused by the barrier, these daughter wavelets can, under the proper conditions, form and rotate around a PS. In certain instances they will anchor in place (often to areas around the pulmonary veins and in areas of heterogeneous atrial tissue) and form stable rotors.23 As the rotating wavefronts spread away from the PS and core, they interact with other areas of anatomic or functional inhomogeneity in myocardium and fragment. They can then induce multiple disorganised ‘fibrillatory’ waves which then induce the chaotic atrial activation associated with AF.24 Tissue anisotropy, which is likely to be a critical determinant of rotor formation, can also allow the formation of rotors without the requirement of a fixed structural barrier or tissue inhomogeneity.

Consider a homogenous medium being uniformly and continuously depolarised from a fixed site. If a premature extrastimulus is delivered from a distant site during phase three repolarisation, the extrastimulus will conduct into the area which has fully repolarised while blocking in the area which remains refractory. The excitation wavefront of the premature stimulus will therefore bend and, under favourable circumstances, can initiate spiral wave reentry around a functionally unexcitable core (see Figure 5).25,26 Thus, rotor formation requires areas of non-uniform repolarisation, either due to fixed tissue inhomogeneity, or transient repolarisation non-uniformities due to the delivery of premature stimuli from multiple sites.25

Evidence for Rotors and Other High Frequency Sources as Drivers of AF

Figure 5: Initiation of Spiral Reentry in a Continuous, Uniform Sheet Model

Upper left panel: A uniform conditioning stimulus is applied. Upper right panel: A premature stimulus applied at a site distant from the conditioning stimulus initiates clockwise circus movement tachycardia (reentry). Lower panels: The spiral reentry wave continues to rotate around an inexcitable core and is able to meander in space. See text for additional details.

Reproduced with permission from van Capelle and Durrer.26

Figure 6: Simultaneously Recorded Electrograms, Pseudoelectrograms and Corresponding Fast Fourier Transformations During an AF Episode

Mapping studies have demonstrated the existence of localised, organised and high frequency drivers in AF, some of which are thought to represent rotor-like activity. The rotor model of AF maintains that although AF appears to be a chaotic and disorganised rhythm, it is actually being continually driven by the highly organised activity of a limited number of high frequency reentrant circuits. These produce wavefronts that eventually degenerate into chaotic and fibrillatory atrial activity at a distance.23 Early evidence of organised, high frequency drivers of AF was demonstrated by Schuessler et al. using isolated, perfused canine right atria (RA) with induction of AF using extrastimuli in the setting of various concentrations of acetylcholine (ACh). At lower concentrations of ACh, non-sustained, rapid, repetitive responses were induced and activation mapping demonstrated multiple reentrant wavelets and circuits. With higher doses of ACh the number of wavelets increased until a critical point at which sustained AF was induced, and the multiple reentrant circuits collapsed into one stable, high-frequency circuit that drove the resulting fibrillatory conduction.27 Evidence of high-frequency reentrant activity was demonstrated in a Langendorff-perfused sheep heart model in which AF was again induced with rapid atrial pacing in the presence of ACh. A bipolar mapping electrode and optical fluorescence recordings were used to sample atrial electrical activity at various left atrial (LA) and RA sites, and fast Fourier transformation was used to define the dominant frequency (DF) of local activation at each site. Despite the apparently chaotic atrial activation during AF, Fourier frequency analysis revealed an ordered gradient of stable DFs between the LA and RA (see Figure

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The highest frequency (14.7 Hz) and greatest amount of organisation (single, narrow frequency peak) is seen in the LAA base. There is a gradient of frequency and disorganisation between the LA and RA. RAFW = right atrial free wall; LAA = left atrial appendage; PV = pulmonary vein; Endo = endocardial; LA = left atrium; RA = right atrium.

Reproduced with permission from Mandapati et al.28

6). The sites with the highest DF were mostly located in the posterior LA near the pulmonary vein ostia, and with optical mapping these sites corresponded to rotor-like reentry with a very rapid cycle length at the maximum DF (mean frequency 14.7 Hz).28 Similar LA to RA DF

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Clinical Arrhythmias Figure 7: Left to Right Dominant Frequency Gradients in the Sheep Left and Right Atria

Numbers represent measured dominant frequencies at various atrial sites. BB = Bachmann’s bundle; IPP = inferoposterior pathway; LA = left atrium, RA: right atrium; Reproduced with permission from Mansour et al.29

gradients were reproduced in a subsequent study by the same group (see Figure 7).29 Because the frequency of rotational activity was so high, only tissue in close proximity to the rotor could activate in a 1:1 fashion, and at distant sites the wavefronts underwent wavebrake and initiated chaotic and fibrillatory conduction.29 Lazar et al. extended the concept of DF mapping to humans and demonstrated LA to RA DF gradients in patients with paroxysmal AF, with the highest DFs at the junction between the pulmonary veins and the LA. This gradient, however, was not present among patients with persistent AF, again suggesting a different mechanism for sustaining AF of longer duration.30 The correlation between sites of high DF and rotor-like activity was not assessed in this study. In a later study by the same group, atrial DF gradients were assessed before and after pulmonary vein isolation (PVI). Although all patients did not have a pre-procedure DF gradient, LA to RA DF gradients in patients with paroxysmal AF were abolished with successful ablation. The presence of a pre-ablation LA to RA DF gradient was correlated with improved freedom from recurrence of AF after conventional PVI, and patients with recurrence of AF after PVI also had recurrence of LA to RA DF gradients at the time of repeat ablation.31 Studies that have explored a strategy of real-time DF mapping and ablation at the site of maximal DF have resulted in improved freedom from AF recurrence.32 It is important to realise, however, that although animal studies have correlated sites of maximal DF with rotor-like activity, it remains unclear if all sites of maximal DF represent areas of rotor-like reentry or other types of localised reentry, especially in humans. Further studies with high-resolution mapping systems will be needed to further define the local activation in areas of high DF, and to determine if these sites are truly caused by functional reentry due to rotors.

The Influence of Ion Channels and Antiarrhythmic Drugs on Rotors in AF Rotor dynamics are fundamentally governed by the activity of ion channels, and experiments have demonstrated that potassium channels have an important role in defining rotor behaviour. In the previously described Langendorff perfused sheep heart model, AF and rotors were induced with rapid atrial pacing in the setting of ACh, which, among its multitude of biologic actions, potentiates the effects of a specific inward rectifying potassium channel IKACh. The link between IKACh, DF gradients, and rotor dynamics was

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explored by measuring the density of IKACh in the sheep atria. The highest density of IKACh was localised at LA sites with the highest DFs and the majority of observed rotors, and increased concentrations of ACh resulted in both an increased number of rotors and a higher frequency of rotor rotation.33 In transgenic mouse models, overexpression of the inward rectifying potassium channel I K1 resulted in rotors which were two to three times as rapid (50–60 Hz vs. 20–25 Hz) and significantly longer lasting (one hour vs. 10 seconds) compared to rotors induced in wild-type mice.34 Similar effects on rotor dynamics have been observed with overexpression of the rapid delayed rectifying potassium current IKr in tissue culture, and in vitro IKr gradients (and resulting APD gradients) have been shown to be critical in reducing rotor meander, increasing rotor frequency and stability and inducing wavebreak and fibrillatory conduction.35 Jalife and colleagues performed in vitro experiments evaluating the effect of varying concentrations of IKr in neonatal rat ventricular myocytes and demonstrated higher DF and increased rotor activity with IKr overexpression. In addition, they found that wave break and fibrillatory conduction were most likely to occur at areas with an abrupt transition in IKr concentration.36 The importance of potassium channels in AF dynamics has also been extended to humans using patch clamp and Western blot analysis of atrial tissue from patients with chronic AF, paroxysmal AF and no history of AF undergoing cardiac surgery. Western blot analysis demonstrated increased expression of IK1 subunits in patients with chronic AF compared with patients with paroxysmal AF or no AF. Additionally, in patients with any AF, the basal LA IK1 current was up-regulated two-fold compared with patients without AF. Interestingly, a LA to RA gradient of potassium current (analogous to LA to RA DF gradients) was also only observed in patients with paroxysmal AF. In vivo human studies using DF and rotor mapping during electrophysiological studies have also demonstrated that administration of adenosine increases rotor frequency to a greater extent in patients with persistent AF compared with paroxysmal AF likely due to differential effects on IKACh.37 Increased inward potassium current (through multiple potassium channels) causes shorter APD and resting membrane hyperpolarisation.

Given the importance of IKACh, IK1 and probably other similar inwardly rectifying potassium channels, it would make sense that drugs that block these channels would slow and/or destabilise rotors resulting in termination of AF and prevention of reinduction. These electrophysiological effects of potassium channel drugs on rotor dynamics have been observed in animal models,22,35 although studies in humans are currently lacking.

Sodium channel blockade by antiarrhythmic drugs can terminate AF and prevent its re-induction, presumably by slowing conduction and making reentry unfavourable. Proposed mechanisms of AF rotor termination with sodium channel blockade include: an increase in rotor size so that the rotor extinguishes at tissue boundaries; reduced anchoring of the rotor which promotes meander of the core and eventual termination; reduced rotational frequency and a reduction in the number of daughter wavelets that can generate new rotors to sustain AF.38

Therapeutically Targeting High Frequency Drivers and Rotors in Human AF The strongest clinical evidence for high-frequency rotors and focal drivers and their critical role in maintaining human AF comes from

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Mechanisms of Atrial Fibrillation – Reentry, Rotors and Reality

Computational AF mapping demonstrated the presence of rotors and focal impulses in 97 % of patients, and 70 % of stable drivers demonstrated rotational activity potentially consistent with rotors (see Figure 8). Patients with persistent AF had more rotors and focal impulses than patients with paroxysmal AF (median 2 vs. 1, p=0.03). Three quarters of rotors and focal impulses were located in the LA (including sites far removed from the pulmonary veins), and interestingly, one-quarter of sources were located in the RA, an area often neglected during conventional PVI. FIRM ablation prior to conventional PVI achieved AF termination in 56 % of patients after a median of only 2.1 minutes of ablation.

In comparison, the conventional PVI group achieved AF termination with ablation in only 9 % of patients (p<0.001). During median followup of 273 days, freedom from any AF after a 3-month blanking period was significantly higher in the FIRM-guided ablation group than in the conventional PVI group (82.4 % vs. 44.9 %, p<0.001).39 Importantly, the rate of freedom from AF in the conventional PVI group was lower than would be expected based on other contemporary series.40 The authors then retrospectively analysed computational AF maps in the patients who underwent only conventional PVI to determine the location of rotors and focal impulses in these patients and to see if ablation lesions performed blindly as part of the conventional PVI procedure coincidently eliminated these sources. When conventional PVI coincidently eliminated a rotor or focal impulse, freedom from AF during follow-up was four-fold higher than in patients in whom AF drivers were not eliminated (80.3 % vs. 18.2 %, p<0.001). There was no difference in freedom from AF recurrence if all AF sources were ablated using FIRM-guided ablation or by coincidence in the conventional PVI group (p=0.551). Patients who had some but not all rotors or focal impulses ablated by coincidence had intermediate success.41 Narayan et al. have also presented preliminary results from the PRECISE-PAF (Precise Rotor Elimination Without Concomitant Pulmonary Vein Isolation For Subsequent Elimination Of Paroxsymal AF) trial, which evaluated FIRM-guided ablation without conventional PVI in 31 patients with paroxysmal AF and no prior ablation. After a mean follow-up of 223 days, 83 % of patients remained free of recurrent AF.42 The results suggest that by eliminating the rotors that sustain AF, it is not necessary to eliminate the triggers for AF (which come predominantly from the pulmonary veins).This study has not yet

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Figure 8: Example of a Left Atrial Rotor Visualised with FIRM Mapping AF Rotor in Low Left Atrium

Processed Intracardiac Signals Activation along rotor path

Left Atrium Superior Mitral C D E F G H A B

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

2nd revolution (AF2) C D E F G H A B

0ms 200

A5 A6 A7 H7 G7 G6 H6 H5

0ms

H4 H3

200

H2 A2 A3

0ms

3rd revolution (AF3)

AF1 AF2 AF3

200

Lateral

Septal

Right Atrium Superior Vena Cava Lateral Tricuspid

work by Narayan et al. In the CONFIRM (Conventional Ablation for Atrial Fibrillation With or Without Focal Impulse and Rotor Modulation) trial, conventional PVI was compared with focal impulse and rotor modulation (FIRM) guided ablation followed by conventional PVI. In a non-randomised fashion, 92 patients with drug-refractory paroxysmal (29 %) or persistent (71 %) AF underwent ablation during which 64-pole basket catheters were used to map the right and left atria and construct AF activation maps using special computational protocols. Importantly, patients who presented in sinus rhythm (SR) had to have AF induced for mapping purposes. Using these AF activation maps, the operators looked for stable (defined as lasting more than 10 minutes), high frequency drivers of AF defined as rotors (areas of spiral or rotational activation) or focal impulses (repetitive focal activation without clear rotation). In the FIRM-guided group these areas were then targeted with focal ablation followed by conventional PVI. The primary endpoint was acute termination of AF or slowing of the AF cycle length by ≥10 %.

100 ms

The rotor is rotating in a clockwise direction as noted by the arrow, and the colors represent activation time of each point in the atrium (see scale). Three rotations corresponding to the electrograms shown in AF1 through AF3 are shown. Reproduced with permission from Narayan et al.39

been formally published, and given the very small sample size, lack of a control group and short follow-up, it is difficult to draw meaningful conclusions from the results.

The results of the CONFIRM study are impressive, and other small studies using similar technology have demonstrated similar results.43 However, given the non-randomised patient assignment, small numbers of patients and relatively short-term follow-up, these results will certainly have to be replicated in a large randomised trial with longer follow-up before FIRM-guided ablation can be incorporated into regular clinical practice.

Limitations of Targeting Rotors with Ablation for the Treatment of AF The CONFIRM trial provides the best human evidence that rotorlike reentry is of key importance in sustaining AF.39 This conclusion, however, has many caveats and limitations, and there remains uncertainty as to whether AF is truly the result or rotors or if it is secondary to other simpler reentrant mechanisms.

Observing rotors in human AF requires overcoming multiple technical obstacles, and the way in which presumed rotors were mapped in the CONFIRM trial reveals some critical limitations of this technology.

Electrograms were obtained with a 64-pole basket catheter (Constellation® Catheter; Boston Scientific, MA, US)39 which provides a relatively low resolution map of the atria. Given the irregular 3D structure of the atria, all catheter splines/electrodes will not be in contact with atrial tissue simultaneously, and far fewer than 64 points are likely being recorded at any given time. There is also the potential for far-field signals to be interpreted as local, especially since unipolar electrograms were used in the analysis. A related issue is that ‘rotors’ were observed after significant proprietary computational processing, averaging and interpolation of raw electrogram data.44,45 With low resolution mapping, poor local tissue-electrode contact and heavy signal processing and interpolation, it is possible that

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Clinical Arrhythmias the observed ‘rotor’ activity is an artifactual representation of other forms of reentry. Additionally, with the resolution available with current generation FIRM mapping, it is only possible to observe rotational activity distant from the rotor core and not near or within the rotor core itself.

This does not mean that the ‘rotors’ targeted in the CONFIRM trial were not clinically important. Ablation of these areas did indeed correlate with both termination of AF and a significant reduction in rates of AF recurrence, but the technical aspects of the trial limit the ability to conclude that the observed reentry was truly rotor activity and not another form of reentry. The aetiology of focal impulses – seen in 30 % of patients in the CONFIRM trial – are also not necessarily explained by rotors. It remains unclear if these sites represent microrotors, which are simply too small to see with the current mapping catheter resolution, or if they represent other forms of local microreentry or even triggered activity.

Rotors Do Not Consistently Sustain AF Although rotors were found in the majority of patients in the CONFIRM trial,39 other mapping studies of human AF have not consistently demonstrated rotor-like reentry. This raises concerns about the trial’s conclusions regarding mechanisms of AF. If rotors were truly present in over 90 % of patients with AF, and if they were critical to the maintenance of the rhythm, it would be expected that many other AF mapping studies would also find a similarly high prevalence of rotors.

This, however, has not been consistently observed.

In a study of high-density mapping of persistent AF and pacinginduced AF during cardiac surgery, Allessie et al. found no evidence of stable rotors or other focal sources driving AF. Instead, they observed multiple wavelets constrained by lines of continuously-changing functional block. The main feature that differentiated persistent AF from AF induced in the operating room was an increase in the dissociation of atrial muscle bundles.46 Data from our group, in which eight patients with chronic AF and 11 patients with electricallyinduced AF had intraoperative RA mapping performed for up to 12 seconds with a 240 electrodes, reached similar conclusions. Patients with chronic AF tended to have more complex patterns of atrial activation, with multiple wavelets propagating around multiple arcs of functional conduction block, which were predominantly oriented perpendicular to the tricuspid annulus, and areas of random and complete reentry, suggesting a critical role for tissue anisotropy in the pathogenesis of AF.47 These data also suggest that AF induced with rapid atrial pacing (such as prior to FIRM mapping and rotor ablation) may utilise different mechanisms than chronic AF. Studies or models that use pacing for the induction of AF to study mechanisms of the arrhythmia may therefore not be completely applicable to naturally occurring or long-lasting AF. Kalman and colleagues performed intraoperative mapping using high density epicardial electrodes of multiple focal areas within the LA and RA in patients with persistent AF. They recorded activity over multiple 10-second periods and looked for multiple wavefronts, rotational circuits, focal sources and disorganised activity. Interestingly, in the majority of patients rapid transitions between multiple (mean 3.8 ± 1.6) unstable activation patterns were seen. Patients predominantly had multiple wavefronts or completely disorganised atrial activity during AF, and only 5.5 % of maps demonstrated stable activation patterns during the 10 seconds of data acquisition. No patients had

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sustained focal activity lasting more than two beats or sustained rotational circuits (rotors).48 Rudy and colleagues utilised novel noninvasive electrocardiographic imaging (ECGI) to map activation in atrial fibrillation and found that 92 % of of patients demonstrated multiple wavelets driving AF, while only 15 % demonstrated circular reentry compatible with rotor activity.49

Complex Fractionated Atrial Electrograms as Potential Drivers in AF Complex fractionated atrial electrograms (CFAEs) have recently attracted interest in terms of their relationship to the maintenance of AF and as potential ablation targets. Fractionated electrograms can be caused by multiple mechanisms, but in general represent areas of myocardium with separated or disorganised myocardial fibres that cause slowed, dyssynchronous, and/or anisotropic local conduction.50,51 In human AF it has been proposed that fractionated electrograms may be caused by local collision of multiple wavelets, zones of slow conduction, local reentry, areas adjacent to high frequency sites where wavebreak and fibrillatory conduction occur or direct autonomic innervation.51,52 Fractionated electrograms can be fixed and caused by anatomic barriers such as scar or inhomogeneous tissue, or they may be functional, dynamic and related to changes in wavefront propagation throughout the myocardium. It has been further proposed that these fractionated sites are important in sustaining AF,53 and that targeting fractionated electrograms with ablation can terminate AF and prevent its re-induction or recurrence.52,54–60 The data supporting these conclusions are rather weak overall, with only a few small, randomised clinical trials providing guidance, and different studies have arrived at disparate conclusions regarding the importance, or lack thereof, of fractionated electrograms in the pathogenesis of AF. Ablation of CFAEs in the treatment of AF was initially proposed in a 2004 study of 121 patients with AF, 47 % of whom had paroxysmal AF. Ablating areas of CFAEs – defined as local bipolar electrograms with greater than two deflections, continuous activation or a cycle length ≤ 120 milliseconds – without conventional PVI resulted in acute termination of AF in 95 % of patients, with 76 % of patients remaining free of AF without repeat ablation at one year. Of note, many CFAE sites were located around the pulmonary veins, and it is unclear if CFAE ablation coincidently resulted in isolation of the pulmonary veins.56 These results would support the conclusion that the areas of CFAEs were either drivers of AF or important to perpetuating AF, but follow-up studies of CFAE ablation without concomitant PVI have demonstrated disappointing results. In a subsequent study of 100 patients with chronic AF who underwent CFAE ablation alone, after an average follow-up of 14 months, only 33 % of patients remained free of arrhythmia without antiarrhythmic medications; 55 % of patients developed recurrence of AF; and 44 % of patients required a repeat ablation procedure.61 In another study of 77 patients with persistent AF comparing CFAE ablation alone with CFAE ablation with PVI, over an average follow-up period of 13 months, 41 % of patients who had CFAE ablation alone had recurrence of AF compared with 9 % of patients who had CFAE ablation with PVI (p=0.008).62 Di Biase et al. randomised 103 patients with paroxysmal AF to CFAE ablation, PVI, or the combination of CFAE ablation and PVI and found that freedom from atrial tachyarrhythmia at one year was present in only 23 % of patients who underwent CFAE ablation alone compared with 89 % in the PVI group, and 91 % in the CFAE plus PVI group (p<0.001 for a three-way comparison).63

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Interest thus shifted to using CFAE ablation as an adjunctive procedure during standard PVI. Elayi et al. randomised 144 patients with long-standing permanent AF to circumferential pulmonary vein ablation, antral PVI or CFAE ablation followed by PVI. The study showed that at an average of 16 months of follow-up, freedom from AF recurrence was present in 61 % of the patients who received CFAE ablation and PVI, 40 % of patients who received PVI and only 11 % of patients who received circumferential pulmonary vein ablation (p<0.001 for a three-way comparison). 64 Similarly, in the STAR-AF (Substrate and Trigger Ablation for Reduction of AF) trial, 100 patients with high burden paroxysmal or persistent AF were randomised to CFAE ablation alone, PVI alone or the combination of PVI and CFAE ablation. After one year of follow-up, the combination of PVI and CFAE ablation had the highest freedom from recurrent AF (74 %) compared with PVI alone (48 %) and CFAE ablation alone (29 %) (p=0.004). However when paroxysmal and persistent patients were analysed separately, an improvement in freedom from recurrent AF with PVI plus CFAE ablation compared with PVI alone was only present among patients with persistent AF.54 A 200-patient case-control study demonstrated that targeting CFAEs in addition to PVI had no effect on freedom from AF in patients with paroxysmal AF and only marginally improved the success rate of PVI in the subset of patients with persistent or permanent AF (success rate 82 % for PVI and CFAE ablation vs. 72 % for PVI alone, p=0.047).65 Multiple other studies, however, have found that targeting CFAEs provided no additional freedom from AF over PVI alone even among patients with permanent AF.57,59,60,63 A recent meta-analysis evaluated the outcomes in 622 patients across seven trials that compared PVI with PVI plus adjunctive CFAE ablation. It concluded that the addition of CFAE ablation to PVI resulted in only a modest increase in maintenance of sinus rhythm (SR) without antiarrhythmic drugs (relative risk [RR] 1.17, 95 % confidence interval [CR] 1.03-1.33, p=0.019) and in subgroup analyses only patients with non-paroxysmal AF derived any benefit (RR 1.35, 95 % CI 1.04-1.75, p=0.022).66 These studies of CFAE ablation support observations that patients with non-paroxysmal AF tend to have less success with conventional PVI alone, and they complement the previous data describing how patients with paroxysmal AF and non-paroxysmal AF appear to have variations in AF drivers. These results, however, must be interpreted with caution given the small sample sizes and the highly variable criteria for defining CFAEs which limits the ability to combine the results of such studies. Importantly, the majority of studies comparing PVI with either PVI and CFAE ablation or CFAE ablation alone did not require testing each isolated vein for entrance and exit block, and this may be one reason for the apparent benefit of CFAE ablation in some studies. A large scale randomised control trial of CFAE ablation in addition to standard PVI has not yet been performed.

Complex Fractionated Electrograms are Passive Bystanders in AF Observations that CFAE ablation without PVI results in very high rates of AF recurrence54,61–63,65 suggest that CFAEs are not drivers of AF. In fact, the vast majority of areas of observed fractionation are actually functional and passive electrophysiological manifestations.

In a study of patients with AF and healthy controls who underwent mapping of fractionation during SR (in all patients) and AF (in AF patients only), there was no correlation between the location of fractionated electrograms during SR and during AF.67 Additionally,

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the extent of electrogram fractionation in patients with and without AF was similar, and areas of fractionation did not correlate with abnormal voltage or atrial scarring in any patients, suggesting that fractionation was functional in nature.67 Jadidi et al. mapped CFAEs – defined as an electrogram with at least four deflections or continuous activation – in AF, SR and with coronary sinus pacing in 18 patients with AF (nine persistent AF and nine paroxysmal AF).

Although patients with persistent AF had more fractionation than did patients with paroxysmal AF, the distribution of fractionated electrograms was quite dynamic and variable, depending on the direction and rate of atrial activation during AF, sinus rhythm or atrial pacing, with minimal overlap between rhythms. In fact, less than 5 % of the LA area demonstrated fractionation in both SR and AF. In addition, areas of fractionation did not correlate with areas of abnormal voltage or scar, and electrogram fractionation was predominantly functional due to wavefront collision.68 The vast majority of fractionated electrograms therefore played no role in the genesis or maintenance of AF, and targeting these areas during catheter ablation of AF would be time consuming, unnecessary and ineffective.

Although CFAEs appear to be predominantly functional and are thus unlikely to represent drivers of AF, it has been proposed that they might be spatially related to rotors or other high frequency AF drivers.

This association could explain the success of some CFAE-guided ablation strategies. The local electrogram around presumed rotor activity is quite regular with very low levels of signal fractionation, but just beyond the local area of the rotor, at points where wavebreak and fibrillatory conduction occur, high levels of electrogram fractionation have been observed,55 and fractionated electrograms have also been spatially correlated with areas of high DF during AF.69 It has therefore been proposed that localising CFAEs may be an indirect way of localising rotor or high DF activity, and ablating CFAEs may therefore coincidently terminate AF or improve freedom from AF recurrences by coincidently destroying these other focal, organised AF drivers.55 Given the predominantly functional nature of CFAEs, however, this explanation seems unlikely, and Narayan’s group has demonstrated that CFAEs are largely spatially unrelated to sites of rotors or other focal AF drivers.70 Nevertheless, all CFAEs may not be equivalent,71 and fractionation may evolve over time as AF transitions from paroxysmal to persistent.72 Ablation of fractionated electrograms which demonstrate continuous activity or temporal activation gradients have been shown to be more strongly associated with AF slowing or termination,73 and the subset of CFAEs that persist in AF, sinus rhythm or with atrial pacing might also be important in the pathophysiology of AF, with a potential role as an ablation target.68 To evaluate this possibility, the SELECT AF (Selective Complex Fractionated Atrial Electrograms Targeting for AF) trial randomised 86 patients to PVI and either ablation of all CFAEs or ablation of only CFAE regions with continuous electric activity.

Although both CFAE ablation strategies resulted in similar rates of AF termination (37 % and 28 %, p=0.42), at one year of follow-up, patients who underwent generalised CFAE ablation had a significantly higher rate of freedom from atrial tachycarrhythmias compared with those who had selective CFAE ablation (50 % vs. 28 %, p=0.03).74 As of yet, there are no clinical trial data to suggest that specific types of CFAEs are especially critical to the pathogenesis or maintenance of AF, or that targeting specific types of CFAEs can improve outcomes after catheter ablation.

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Clinical Arrhythmias Another significant limitation in applying results from studies evaluating CFAE ablation is that there is no consensus on what defines a CFAE. Criteria used in studies are subjective and variable, including electrograms with various numbers of deflections, continuous atrial activation or electrograms with very short mean cycle lengths.66 Automatic computer algorithms have been developed to remove some of the subjectivity in distinguishing important areas of fractionation, but in one study using such a method, 86 % of LA sites were classified as having CFAEs.75 Despite the initial excitement surrounding the relation of CFAEs to AF, CFAEs are non-specific electrophysiological manifestations which are unlikely to be drivers of AF, and coincidental ablation of reentrant circuits and AF drivers likely explains the occasional success when CFAEs are targeted with ablation. CFAE ablation has minimal effect on patient outcomes, and can result in increased procedure times and an increased potential for complications.

The Influence of the Autonomic Nervous System and Ganglionated Plexi on AF The autonomic nervous system is likely to have a role in clinical AF.76,77 Both sympathetic and parasympathetic stimuli may be involved,76 although in humans, the extent and importance of autonomic influences vary based on patient characteristics and comorbidities.78 Ganglionated plexi (GP) are epicardial networks of autonomic nervous tissue present near the junctions between the pulmonary veins and LA.79,80 GP connect the extrinsic autonomic nervous system (brain, spinal cord, and ganglia/nerves outside of the heart) to the intrinsic autonomic nervous system within the heart, and are important mediators by which autonomic stimuli influence AF and other arrhythmias.81 Autonomic signals to the heart via GP exert important electrophysiological effects including altering atrial refractory periods,81,82 increasing the frequency of triggered atrial premature beats that can subsequently initiate AF,83 and increasing the vulnerability of atrial tissue to the induction of AF.81,84,85 Animal studies have demonstrated that stimulation of GP located around the pulmonary veins can reduce the number of atrial extrastimuli required to initiate AF, and that neuronal/autonomic blockade with drugs or GP ablation can prevent AF induction.86,87 Because GP are located near the pulmonary veins, conventional PVI can often coincidently eliminate these areas, and it has been suggested that ablation of GP may help explain the success of PVI. In an early study, Pappone and colleagues assessed for vagal responses (bradycardia, hypotension, heart block or asystole) which occurred within a few seconds after the onset of ablation. If such a response occurred, ablation was continued until the vagal response terminated and could not be re-induced with repeat ablation. The most common sites of vagal responses were located at the junctions between the pulmonary veins and LA where GP are located. Patients who had complete vagal denervation, as defined by elimination of all vagal responses at completion of PVI, had reduced rates of AF recurrence at one year (85% vs. 99%, p=0.0002).88 Other studies have localised GP by use of high-frequency simulation, although data have suggested that an anatomic approach is preferred over high-frequency stimulation or identification of areas with vagal responses, which are both insensitive methods to identify GP.89 Katritsis and colleagues studied the benefit of GP ablation by randomising 242 patients with paroxysmal AF to standard PVI

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alone, GP ablation alone or PVI with additional GP ablation. GP were anatomically targeted by ablating at their expected locations around the pulmonary veins. At two years post-ablation, 56% of patients who had conventional PVI alone, 48% of patients who had GP ablation alone and 74% of patients who had a combination of PVI and GP ablation were free of recurrent AF or atrial tachycardias.

Patients who had PVI with GP ablation had a HR for recurrence of arrhythmia of 0.53 (p=0.022) and 0.42 (p=0.001) compared with patients who had PVI alone and patients who had GP ablation alone, respectively. Surprisingly, over the entire two years of followup there was no statistically significant difference in recurrence of atrial tachyarrhythmias between patients who had PVI alone or GP ablation alone (p=0.31), although after one year patients who had GP ablation alone began to experience more arrhythmia recurrences than patients who had PVI alone. The similar and then divergent results for the PVI-alone and GP ablation-alone groups could be explained by the fact that conventional PVI lesions are likely to coincidently eliminate at least some GP located near the pulmonary veins, but PVI covers a larger area of the LA and completely isolates the pulmonary veins so that pulmonary vein triggers unrelated to GP activity cannot initiate AF. 90 It is also possible that targeting GP had a minimal effect on cardiac autonomic innervation, but the additional lesions performed to target GP may have resulted in a longer-lasting isolation of the pulmonary veins.91 Although GP may have a role in initiating AF by increasing both the frequency of pulmonary vein triggers and atrial vulnerability to these triggers, the relationship between GP and the mechanisms which sustain AF is much less clear. As previously discussed, autonomic tone can influence ion channel function which may subsequently influence the behavior of rotors or other AF drivers, but a definitive and direct link between GP and AF drivers has not been demonstrated. GP have also been correlated with areas of CFAEs,52,92 but as discussed above, CFAEs are passive manifestations of inter-atrial conduction and are unlikely to be drivers of AF. In animal models, radiofrequency ablation can actually induce new nerve growth,93 and in humans, ablation has been shown to result in elevations in nerve growth factor,94 which may counteract the beneficial effects of GP ablation. Incomplete GP denervation may also be ineffective95 or even proarrhythmic.96 Overall, GP ablation has only been evaluated in a few small studies, and further trials will be required before it can be safely and effectively adopted into standard practice.

Conclusions and Future Directions The totality of data suggests that there is highly organised reentrant activity underlying the seemingly chaotic and random atrial activity in AF. However, confirming whether or not these AF drivers are rotors or other forms of reentry will require carefully executed high-resolution human mapping and ablation studies. The goal of discovering a single mechanism for triggering and/or sustaining AF may also be impossible, as it is likely that variations in pathology will at least partially influence the way in which AF is initiated and sustained.

In fact, AF may have multiple, disparate mechanisms in different patients or even in the same patient at different times. This may at least partially explain why targeting one specific mechanism, such as isolating the pulmonary veins, is often initially is successful but then fails over time. The best therapy for AF ultimately may involve discerning an individual patient’s ‘type’ or mechanism of AF and

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specifically targeting that, rather than relying on a one-size-fits-all approach. Understanding the electrophysiological mechanisms by

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Roles of adrenergic and cholinergic stimulation in spontaneous atrial fibrillation in dogs. J Am Coll Cardiol 2004;43:483–90.

77. Bettoni M, Zimmermann M. Autonomic tone variations before the onset of paroxysmal atrial fibrillation. Circulation 2002;105:2753–9.

78. Coumel P. Paroxysmal atrial fibrillation: a disorder of autonomic tone? Eur Heart J 1994;15(Suppl A):9–16.

79. Armour JA, Murphy DA, Yuan BX, et al. Gross and microscopic anatomy of the human intrinsic cardiac nervous system. Anat Rec 1997;247:289–98.

80. Vaitkevicius R, Saburkina I, Rysevaite K, et al. Nerve supply of the human pulmonary veins: an anatomical study. Heart Rhythm 2009;6:221–8.

81. Hou Y, Scherlag BJ, Lin J, et al. Ganglionated plexi modulate extrinsic cardiac autonomic nerve input: effects on sinus rate, atrioventricular conduction, refractoriness, and inducibility of atrial fibrillation. J Am Coll Cardiol 2007;50:61–8.

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Clinical Arrhythmias 82. Liu L, Nattel S. Differing sympathetic and vagal effects on atrial fibrillation in dogs: role of refractoriness heterogeneity.

Am J Physiol 1997;273(2 Pt 2):H805–16.

83. Lim PB, Malcolme-Lawes LC, Stuber T, et al. Intrinsic cardiac autonomic stimulation induces pulmonary vein ectopy and triggers atrial fibrillation in humans. J Cardiovasc Electrophysiol 2011;22:638–46.

84. Mao J, Yin X, Zhang Y, et al. Ablation of epicardial ganglionated plexi increases atrial vulnerability to arrhythmias in dogs. Circ Arrhythm Electrophysiol 2014; ePub ahead of print. doi:10.1161/CIRCEP.113.000799.

85. Zhou J, Scherlag BJ, Edwards J, et al. Gradients of atrial refractoriness and inducibility of atrial fibrillation due to stimulation of ganglionated plexi. J Cardiovasc Electrophysiol 2007;18:83–90.

86. Scherlag BJ, Yamanashi W, Patel U, et al. Autonomically induced conversion of pulmonary vein focal firing into atrial fibrillation. J Am Coll Cardiol 2005;45:1878–86.

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87. Lu Z, Scherlag BJ, Lin J, et al. Autonomic mechanism for initiation of rapid firing from atria and pulmonary veins: evidence by ablation of ganglionated plexi. Cardiovasc Res 2009;84:245–52.

88. Pappone C, Santinelli V, Manguso F, et al. Pulmonary vein denervation enhances long-term benefit after circumferential ablation for paroxysmal atrial fibrillation. Circulation 2004;109:327–34.

89. Pokushalov E, Romanov A, Shugayev P, et al. Selective ganglionated plexi ablation for paroxysmal atrial fibrillation.

Heart Rhythm 2009;6:1257–64.

90. Katritsis DG, Pokushalov E, Romanov A, et al. Autonomic denervation added to pulmonary vein isolation for paroxysmal atrial fibrillation: a randomized clinical trial. J Am Coll Cardiol 2013;62:2318–25.

91. Chugh A. Ganglionated plexus ablation in patients undergoing pulmonary vein isolation for paroxysmal atrial fibrillation: here we go again. J Am Coll Cardiol 2013;62:2326–8.

92. Katritsis D, Sougiannis D, Batsikas K, et al. Autonomic modulation of complex fractionated atrial electrograms in patients with paroxysmal atrial fibrillation. J Interv Card Electrophysiol 2011;31:217–23.

93. Okuyama Y, Pak HN, Miyauchi Y, et al. Nerve sprouting induced by radiofrequency catheter ablation in dogs. Heart Rhythm 2004;1:712–7.

94. Kangavari S, Oh YS, Zhou S, et al. Radiofrequency catheter ablation and nerve growth factor concentration in humans.

Heart Rhythm 2006;3:1150–5.

95. Lemola K, Chartier D, Yeh YH, et al. Pulmonary vein region ablation in experimental vagal atrial fibrillation: role of pulmonary veins versus autonomic ganglia. Circulation 2008;117:470–7.

96. Hirose M, Leatmanoratn Z, Laurita KR, Carlson MD. Partial vagal denervation increases vulnerability to vagally induced atrial fibrillation. J Cardiovasc Electrophysiol 2002;13:1272–9.

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Limited Ablation for Persistent Atrial Fibrillation Using Preprocedure Reverse Remodelling Da v id S l o t w i n e r 1 a n d J o n a t h a n S t e i n b e r g 2 1. Assistant Professor of Cardiology, Hofstra North Shore-LIJ School of Medicine, and Associate Director – Cardiac Electrophysiology Laboratory, Long Island Jewish Medical Center; 2. Adjunct Professor of Medicine, University of Rochester School of Medicine, and Director, Arrhythmia Institute, The Valley Health System, New York and New Jersey, USA

Abstract Pulmonary vein isolation (PVI) has been demonstrated to be a highly effective treatment option for patients with paroxysmal atrial fibrillation (AF), but less effective for patients with persistent AF. The lower efficacy of PVI alone has been attributed to adverse atrial electrical and structural remodelling in the setting of AF. Strategies to improve efficacy of catheter ablation for persistent AF alter these pathophysiological characteristics of atrial tissue remodelling. Here we will review the physiology of atrial electrical remodelling observed during AF and evidence that it is reversible. Further, we will explore its uses to reduce the amount of atrial tissue that needs to be ablated to successfully treat patients with persistent AF.

Keywords Atrial fibrillation, catheter ablation, reverse electrical remodelling, antiarrhythmic drug therapy Disclosure: The authors have no conflicts of interest to declare.

Received: 1 March 2014 Accepted: 25 July 2014 Citation: Arrhythmia & Electrophysiology Review 2014;3(2):101–6 Access at: www.AERjournal.com Correspondence: David Slotwiner, North Shore-LIJ Health System, 270-05 76th Ave, New Hyde Park, NY 11040, US. E: dslotwin@NSHS.edu

Electrical Remodelling Evidence Supporting Atrial Remodelling The concept of electrical remodelling was first introduced in 1995 simultaneously by Wijffels et al.1 and Morillo et al.2 who demonstrated that once sustained atrial fibrillation (AF) was induced in goats, or rapid atrial pacing was performed in dogs, physiological changes occurred that favoured the maintenance of AF.3 This led to the concept that ‘AF begets AF’.

Several aspects of the cellular and ion channel function changes that occur during persistent AF have been defined. These include: • R educed inward L-type Ca2+ current (ICaL) by up to 70 %, reducing action potential duration (APD) and effective refractory period (ERP).4,5 • Down-regulation of ICaL to prevent Ca2+ overload during rapid atrial rates.6 • Upregulation of acetylcholine-dependent potassium current (IKACh), which may contribute to shortening of the atrial ERP. • Dysregulated connexin function, which plays an important role in electrical propagation during persistent AF.3,7 The rapid rates of AF induce shortening of both the atrial ERP and APD.2 Shortening of the ERP has been attributed to down-regulation of the L-type Ca 2+ current (I CaL) caused by Ca 2+ accumulation within atrial myocytes. 3,6 Spatial heterogeneity of ERP and conduction velocity also contribute to the pro-arrhythmic electrical changes observed in AF.8 The effects of atrial remodelling have been correlated with measurement of the P-wave duration on surface electrocardiogram (ECG) recordings.9,10 The shortened ERP reduces the wavelength of

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atrial impulses that promotes wave break and multiple wavelet re-entry. Structural and mechanical atrial remodelling (which are beyond the scope of this review) along with electrical remodelling increase the frequency of ectopic and re-entrant arrhythmias and provide atrial tissue substrate that favours sustained re-entrant arrhythmias.6,11

Evidence of Reverse Remodelling The electrical components of atrial remodelling have been demonstrated to be reversible. Soon after studies revealed that AF begets AF, a study from Wijffels et al. recorded complete recovery of atrial ERP one week after cardioversion (goat model, AF duration 24 hours prior to cardioversion).1,12 Animal experiments can directly measure various electrophysiological properties indicative of remodelling and reverse remodelling. This is more difficult in the clinical environment, especially without invasive procedures. However, surface ECG measurements of P-wave duration, including the maximum P-wave duration, P-wave dispersion, and highresolution signal-averaged P-wave (SAPW) have proved to be accurate non-invasive reflections of atrial electrical remodelling.9,10,13–16 For example, several studies have demonstrated that reverse electrical remodelling occurs in humans once sinus rhythm is restored. Using SAPW post-cardioversion, two studies revealed significant reduction in SAPW duration at one and three months post-cardioversion, but no reduction for patients who experienced recurrent AF.13,17 Another study demonstrated that patients who maintain sinus rhythm six months post-cardioversion have shorter P-wave duration compared

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Percentage of Patients Free of AF

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Patients with persistent atrial fibrillation who were pre‐treated with dofetilide and then underwent pulmonary vein isolation (PVI) had a similar outcome at six and 12 months as patients with paroxysmal atrial fibrillation (AF) (76 % vs 80 % and 70 % vs 75 %, respectively, P = NS).21

with those with AF recurrence.18 Two studies evaluated invasive measures of electrical remodelling (ERP) four days and one week postcardioversion.19,20 The studies revealed significantly decreased duration of SAPW and prolongation of atrial ERP, elegantly proving both the physiological phenomenon of atrial electrical reverse-remodelling and the fact that surface P-wave characteristics can be used as a noninvasive measure of atrial electrical remodelling.

Evidence Supporting Pre-ablation Procedure Atrial Remodelling Based upon the physiological ability to promote reverse atrial electrical remodelling by restoring sinus rhythm, we and others have hypothesised that successful atrial remodelling by either cardioversion alone, or with the assistance of temporary antiarrhythmic drug (AAD) therapy, would facilitate the performance of pulmonary vein isolation (PVI) as the primary ablation strategy for patients with persistent AF.21–24

Clinical Study Using Pre-ablation Antiarrhythmic Drug Therapy Our study focused on consecutive patients with symptomatic, drugrefractory, persistent AF. To be included, patients had to be: • I n a persistent pattern of AF (≥7 days and ≤1 year) despite prior efforts at control using at least one class I or class III AAD; • Free of contraindications to use dofetilide, a potent class III AAD.21 Patients underwent pre-treatment with dofetilide three months prior to ablation (with electrical cardioversion after six doses, if required), and the drug was continued one to three months after PVI ablation.

Electrical remodelling was evaluated by measuring P-wave duration immediately after electrical cardioversion, and again at the time of presentation for PVI. If AF had recurred by the time the patient presented for ablation, P-wave duration was measured immediately after cardioversion to normal sinus rhythm. P-wave duration was measured in limb lead II, with ECGs in random order, by an observer blinded to the clinical outcome. The difference in P-wave duration (ΔP) between the ECG at the time of cardioversion and at the time of PVI was used as a measure of reverse remodelling.

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We observed that more than 95 % of patients could be converted to nonpersistent AF or consistent sinus rhythm in the three-month interval preceding ablation.

The technique used for pulmonary vein catheter ablation isolation is described in detail in the original manuscript.21 Briefly, real-time 3D left atrial maps were constructed using a non-fluoroscopic navigation system (Carto®, Biosense-Webster Inc., CA, USA). A 20-pole catheter with distal ring configuration (Lasso Catheter®; Biosense-Webster Inc., CA, USA) was positioned within the ostium of each pulmonary vein. Radiofrequency catheter ablation was performed until all left atrial pulmonary vein connections were severed, as verified by the circumferential mapping catheter. All pulmonary vein connections were severed in each study patient. No patient underwent nonpulmonary vein ablation including linear lesions or targeting of complex fractionated atrial electrograms.

A control cohort of patients with symptomatic, paroxysmal AF who were referred for ablation and did not have prior pre-treatment of AF with AAD functioned as a control group for comparison purposes.

P-wave durations at comparable points in time pre-ablation and at ablation were analysed. The treated persistent AF group was largely converted by dofetilide to paroxysmal AF. The control group was matched for age, gender, duration of AF, concomitant cardiovascular conditions, left atrial size and left ventricular function. Paroxysmal AF was defined as lasting less than seven days in duration and terminating spontaneously. Control patients underwent an identical ablation protocol. A sinus rhythm ECG recorded three months prior to ablation was compared with that recorded at ablation.

Patients were seen at one, three, six and 12 months or more frequently following PVI to assess for recurrence of AF. AF burden was evaluated using patient symptoms, 12-lead ECG, 24-hour Holter monitoring, and mobile cardiac outpatient telemetry. Specifically, after hospital discharge, each patient underwent a minimum of four weeks of mobile outpatient telemetry. At each office visit an ECG was recorded and an extended autotrigger transtelephonic monitor and/or 24–48 hour Holter recording was performed as needed to document asymptomatic AF episodes or to clarify symptoms. AAD treatment was discontinued three months post-ablation when complete freedom from AF was achieved.

A total of 71 consecutive patients with persistent AF were included.

The median duration of the persistent AF episodes was six months.

Overall, the group had mild left atrial dilatation and preserved left ventricular function. A median of one AAD had been ineffective in preventing recurrences of AF before initiation of dofetilide and the ablation procedure. Of the 71 study patients, 15 % required an early second PVI procedure. ECG analysis of the P-wave duration was performed on all patients at a median of 85 days prior to PVI and again at the time of PVI. Baseline characteristics for the 35 patients in the control cohort were not significantly different from the study group.

Efficacy of Dofetilide All 71 patients in the treatment group tolerated AAD therapy with dofetilide (768 ± 291 mcg/day) preablation for a median of 85 days.

During dofetilide initiation, all patients were converted to sinus rhythm. Sixty-nine (97 %) successfully transformed from persistent AF to either paroxysmal AF (56 patients, 81 %) or the AF was completely

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suppressed (13 patients, 19 %). The remaining two patients (3 %) remained in persistent AF.

Figure 2: Comparison of P‐wave Duration Changes Over Time in Study and Control Patients 160

Response to PVI

Among the control patients with paroxysmal AF, 80 % had complete response to PVI at six months and 75 % at 12 months. There was no significant difference in the 6-and 12-month PVI response in the study group versus the control group (see Figure 1). During the postablation period there was a single case of sustained left-sided atrial tachycardia, which occurred in the control paroxysmal AF group.

Of the 13 patients whose AF was completely suppressed with dofetilide pretreatment, 12 (92 %) had complete response to PVI at six months. Neither of the two patients who remained in persistent AF despite dofetilide pretreatment responded to PVI. Of those patients

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All patients in both the treatment and control groups underwent successful catheter ablation isolation of all pulmonary vein connections. In the study of patients with persistent AF, 76 % were completely free of AF recurrence on no drug therapy at six months post-PVI, while 70 % were completely free of AF at 12 months post-PVI (responders). At six and 12 months, 24 % and 30 %, respectively, continued to have AF and required continued medical therapy or repeat ablation (nonresponders).

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Figure 3: Comparison of Change in P‐wave Duration Between Responders and Nonresponders 160

137.0±23.1

Change in P-wave Duration

Predictors of Freedom from Recurrent AF Following Ablation Age, gender, hypertension, left atrial size, duration of persistent AF episodes, duration of AF history, dose of dofetilide and clinical response (suppression vs. paroxysmal AF) to dofetilide all failed to predict a complete clinical response to PVI. A decrease in P-wave duration was the only significant predictor of clinical response to PVI (hazard ratio [HR] 0.94, confidence interval [CI] 0.90–0.98; P = 0.009) on univariate analysis. For each decrease in P-wave duration of 1 ms from baseline to ablation, there was a 6 % increase in the likelihood of a complete response to PVI. Similarly, on multivariate analysis a decrease in P-wave duration was again the only significant predictor of clinical response to PVI (HR 0.092, CI 0.86-0.98; P = 0.007).

Clinical Studies Using Cardioversion or Antiarrhythmic Drug Pre-ablation Another study, based upon the same concept of reverse atrial electrical remodelling as a potential tool to limit the extent of catheter

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Paroxysmal AF

In patients with persistent atrial fibrillation (AF) dofetilide treatment was associated with a significant reduction in P‐wave duration; in contrast, the P‐wave duration remained unchanged in control patients with paroxysmal AF. At baseline, the P‐wave duration was significantly longer in the study group when compared with the control group.

PVI = pulmonary vein isolation.21

with persistent AF who responded to pretreatment with dofetilide, 75 % responded to PVI at six months.

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P-wave duration at baseline was significantly longer in the persistent AF group compared with the paroxysmal AF group (p < 0.001). Patients in the treatment group with persistent AF treated with dofetilide demonstrated a statistically significant reduction in the mean P-wave duration by the time they returned for PVI three months later (see Figure 2). In contrast, the cohort patients with paroxysmal AF who were not treated with AAD during the three months prior to PVI experienced no significant change in P-wave duration (see Figure 2). Patients with persistent AF who responded to PVI after pretreatment with dofetilide had a significantly greater decrease in P-wave duration in response to dofetilide (137.0 ± 23.1 to 116.7 ± 21.2 ms [20.3 ± 16.9 ms or 15 % decrease], P < 0.001) compared with nonresponders (132.9 ± 17.2 ms to 124.7 ± 16.6 ms [8.2 ± 12.4 ms or 6 % decrease], P = 0.014), (see Figures 3 and 4).

P=NS 122.6±11.5 121.3±13.7

116.7±21.2

132.9±17.2 124.7±16.6

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In patients with persistent atrial fibrillation, dofetilide therapy was associated with a significant reduction in P‐wave duration in both responders and nonresponders.

PVI = pulmonary vein isolation.21

ablation required for successful treatment of persistent AF, was published by Rivard et al. in 2012.22 This two-group cohort study was conducted from 2007 through 2009 and included patients undergoing a first catheter ablation procedure for persistent and long-standing persistent AF. The study group consisted of 40 consecutive patients from three European centres who underwent electrical cardioversion one month prior to ablation. Patients who did not remain in sinus rhythm were excluded from the study, and all patients were required to have left atrial diameters ≤55 mm. These patients were retrospectively matched 1:1 with contemporary controls (for age, gender, duration of AF) with persistent AF in whom no attempt to restore sinus rhythm was made prior to ablation.

Radiofrequency catheter ablation was performed one month after cardioversion (for the study group), and after four weeks of therapeutic anticoagulation for both study arms. AAD therapy was discontinued

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Diagnostic Electrophysiology & Ablation Figure 4: Comparison of Change in P‐wave Duration Between Responders and Non-responders

Success was defined as the absence of AF or atrial tachycardia lasting 30 seconds or longer off AAD therapy.

Eighty patients were included in the study (40 in each arm). Both groups were similar with the exception of a slightly lower ejection fraction among patients in the control arm (63.9 ± 11.7 vs. 55.7 ± 14.9, P<0.05). AF cycle length was greater among patients who presented for ablation in sinus rhythm (i.e. induced AF in the treatment arm). Termination of AF occurred more frequently during ablation of patients in the treatment arm, with less extensive application of ablation and with less fluoroscopic exposure (see Table 1).

Change in P Wave Duration (msec)

45 40 35 30 25

p= 0.006

20 15

Clinical success without the use of AAD therapy was similar in both groups up to 36 months following ablation (see Figure 5). The need for repeat ablation was similar in both groups, and after the last procedure success rates off AAD therapy were 80 % in the treatment arm vs. 70 % in the control group (P = 0.47). Noninvasive measures of reverse remodelling were not performed.

10 5 0

Responders

Nonresponders

Clinical response was assessed following pulmonary vein isolation (PVI) in patients with persistent atrial fibrillation who were treated with dofetilide. Responders demonstrated a significantly greater decrease in P‐wave duration as compared with nonresponders (20.3±16.9 ms vs 8.2±12.4 ms, P = 0.006).21

Figure 5: Arrhythmia-free Survival After a Single Catheter Ablation Intervention

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Kaplan-Meier recurrence-free survival rates are shown for patients having undergone a single catheter ablation procedure in the sinus rhythm (SR) and control groups.

five half-lives before the ablation procedure, with the exception of amiodarone. Ablation was performed during AF in all patients according to a sequential stepwise approach previously described in detail.25 AF was induced by burst atrial pacing for patients who presented in sinus rhythm due to previous cardioversion. Briefly, left atrial antral PVI was performed using a 3.5 mm irrigated-tip catheter (ThermoCool™; Biosense Webster, Inc., CA, USA) and guided by a circular mapping catheter (LASSO; Biosense Webster, Inc., CA, USA). Next, electrogrambased ablation was performed at right atrial and/or left atrial sites demonstrating features of continuous electrical activity, complex rapid and fractionated electrograms, and a gradient of activation. If AF persisted after this step, linear ablation lesions were created across the left atrium roof between the superior pulmonary veins and then from the left inferior pulmonary vein to the mitral annulus. The endpoint was termination of AF during ablation. However, if AF persisted beyond these ablation lesions, electrical cardioversion was performed.

Patients were evaluated at one, three, six and 12 months postablation with 48-hour Holter monitoring performed at each visit.

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The authors concluded that cardioversion and maintenance of sinus rhythm one month prior to ablation decreased the extent of ablation required to restore and maintain sinus rhythm without compromising efficacy.

Findings from two other independent studies support the hypothesis that pretreatment of persistent AF with AAD therapy and restoration of sinus rhythm improves efficacy of catheter ablation or at least identifies a subset of patients who are more likely to respond favourably to catheter ablation and thus may limit the extent of ablation lesions required for success.23, 24 Igarashi et al. studied 51 consecutive patients with drug-resistant persistent AF who underwent combined AAD therapy with both a class I and III AAD for greater than three months prior to catheter ablation.23 AAD therapy consisted of a class III AAD (amiodarone or bepridil) plus a class I AAD (flecainide, aprindine, pilicainide or propafenone). Thirty three patients (65 %) converted to sinus rhythm during the three-month treatment period with dual AAD therapy (SR group). The sinus rhythm patients demonstrated evidence of mechanical remodelling such as improved left ventricular ejection fraction, reduced left atrial diameter, and reduced brain natriuretic peptide plasma levels. AAD therapy was discontinued five half-lives before the ablation, with the exception of amiodarone which was discontinued ≥2 weeks before catheter ablation.

All 51 patients underwent catheter ablation consisting of PVI and cavotricuspid isthmus ablation. Ten patients (28 %) from the sinus rhythm group and five patients (28 %) from the AF group (p = ns) required further ablation lesions including a left atrial roof line, superior vena cava isolation, and ablation of complex fractionated electrograms. Fourteen months following ablation, patients who converted to sinus rhythm during treatment with dual AAD therapy prior to ablation were significantly more likely to be in sinus rhythm following a single catheter ablation procedure (61 % vs 22 %; HR 2.62, 95 % CI 1.22–5.63; p = 0.013).

A retrospective case-control study of 82 patients with persistent AF examined outcomes according to those who underwent pretreatment with bepridil to restore sinus rhythm prior to ablation.24 Fifteen of the 22 patients (68 %) treated with bepridil for a maximum of four months prior to ablation achieved sinus rhythm prior to ablation. AAD therapy

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was discontinued at least three weeks prior to PVI ablation. Consecutive case-matched control patients (n = 60) underwent PVI ablation with the addition of left atrial linear ablation lesions if AF remained inducible.

At the end of 18 ± 5 months off AAD therapy, the AF-free rate among patients successfully treated with bepridil who converted to sinus rhythm was 87 %, vs. 29 % for patients who failed to convert with AAD pretreatment. Seventy-two percent of case-matched control patients (not pretreated) remained in sinus rhythm (72 % vs 29 %, p=0.02).

Conversion to sinus with bepridil identified a select group of patients with persistent AF who were more likely to respond to PVI. The question of whether restoration of sinus rhythm played a causative role (by reverse remodelling) in the long-term favourable outcome of this group was uncertain.

Discussion Together, these studies confirm that: • P retreatment of patients with persistent AF to restore sinus rhythm prior to catheter ablation, regardless of whether this is accomplished by drug or simple cardioversion, identifies a group of patients who are more likely to respond favourably to PVI catheter ablation.

• Electrical remodelling plays a role in the maintenance of persistent AF. • R estoration of sinus rhythm facilitates pre-ablation reverse remodelling to occur.

• Catheter ablation for patients with persistent AF may at least be less complicated and prolonged if electrical remodelling is allowed to occur first, and is likely more effective.

The physiological evidence for reverse remodelling is demonstrated by the shortening of the P-wave duration and the longer AF cycle length among patients converted first to sinus rhythm. One potential explanation for the difference between studies is the difference duration of sinus rhythm prior to AF ablation. It is possible that one month is insufficient time to allow for full electrical remodelling.

Whether three months is adequate remains unanswered.

of maintenance of sinus rhythm for less than one month prior to ablation of persistent AF remains unknown.

Practical Application of the Reverse Remodelling Concept Catheter ablation for patients with symptomatic AF (paroxysmal or persistent) remains a long-term management strategy. Cardioversion with or without subsequent AAD therapy is often required acutely to alleviate severe symptoms and achieve adequate ventricular rate-control while a more definitive long-term treatment strategy is identified and then performed (e.g. linear lesion ablation strategy, ablation of autonomic ganglia, or rotor mapping/ablation). Even for patients with persistent AF who have only mild to moderate symptoms, elective cardioversion with or without AAD therapy may be viewed as a temporising intervention until a more definitive intervention such as catheter ablation may be viewed favourably by both the patient and physician. In addition to the benefits of atrial electrical remodelling, this period of time allows the patient time to consider the complex treatment options for persistent AF and confirm the symptom that was associated with AF. It also allows time for scheduling the catheter ablation which is resource-intensive and often must be scheduled weeks to months in advance.

Therefore, from a practical standpoint, many patients are already undergoing a period of reverse atrial electrical remodelling prior to catheter ablation of persistent AF, and the application of atrial reverse electrical remodelling may be considered a complementary tool to AF ablation strategies.

While our study utilised dofetilide to assist in maintenance of sinus rhythm prior to ablation of persistent AF, sinus rhythm is the essential component that allows electrical remodelling to occur, not the AAD.1,3,12,22 If dofetilide is not available or not appropriate for an individual patient, evidence suggests that the same benefit of preprocedural electrical remodelling would be achieved with other antiarrhythmic agents that effectively maintain predominant sinus rhythm.

Conclusions Limitations The studies presented are non-randomised and relatively small. It is possible that by identifying patients who could remain in sinus rhythm (with dofetilide or after cardioversion alone or with other AAD therapy), a cohort of patients more likely to respond favourably to ablation was selected.26 A larger multicentre trial is needed to confirm these findings and the long-term benefits of this approach. And finally, a randomised clinical trial is needed to definitively establish the value of the clinical strategy described in these manuscripts with alternative ablation techniques for persistent AF. This paper is not intended to include a comprehensive review of the phenomenon of atrial electrical remodelling associated with AF. Rather, we have focused on aspects that have been demonstrated to be relevant to ablation of persistent AF and for which some clinical data exists. Reverse electrical remodelling begins within minutes to hours following cardioversion, whether cardioversion is performed electrically or pharmacologically. Cardioversion during catheter ablation of AF is often performed to evaluate efficacy if ablation lesions. But we know of no data that evaluate whether restoration of sinus rhythm by cardioversion during ablation affects outcome of catheter ablation of persistent AF. The effect on ablation outcome

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AF, the most common heart rhythm disturbance, represents the end result of complex structural, electrical and mechanical changes of the atrial tissue. Early in the disease process, elimination of pulmonary vein triggers has been demonstrated to be effective therapy for many patients. However, as the disease process progresses, electrical and structural remodelling create conditions that favour continuation of AF. Most ablation techniques for persistent AF are founded upon the theory that atrial tissue substrate modification, in addition to elimination of AF triggers, is required to improve ablation efficacy.

Preprocedure electrical remodelling by restoration and maintenance of sinus rhythm one to three months prior to ablation for persistent AF offers an alternative strategy to improve ablation efficacy without extending the procedure duration and without exposing patients to the associated risks of prolonged procedures and extensive ablation lesions.

Randomised, controlled multicentre studies are needed to further characterise the effectiveness of preprocedure electrical remodelling prior to ablation of persistent AF and to clearly define the optimal duration of sinus rhythm required for electrical remodelling. n

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afforded by verapamil following cardioversion from atrial fibrillation. Pacing Clin Electrophysiol 2006;29:1089–95.

11. A llessie M, Ausma J, Schotten U. Electrical, contractile and structural remodeling during atrial fibrillation. Cardiovasc Res 2002;54:230–46.

12. Delangen CDJ, Tieleman RG, van der Woude HJ, et al. Delayed recovery of atrial refractoriness after atrial tachycardia in the goat. Circulation 1995;92:3629-3629.

13. Chalfoun N, Harnick D, Pe E, et al. Reverse electrical remodeling of the atria post cardioversion in patients who remain in sinus rhythm assessed by signal averaging of the P-wave. Pacing Clin Electrophysiol 2007;30:502–9.

14. Aytemir K, Ozer N, Atalar E, et al. P wave dispersion on 12-lead electrocardiography in patients with paroxysmal atrial fibrillation. Pacing Clin Electrophysiol 2000;23:1109–12.

15. Andrikopoulos GK, Dilaveris PE, Richter DJ, et al. Increased variance of P wave duration on the electrocardiogram distinguishes patients with idiopathic paroxysmal atrial fibrillation. Pacing Clin Electrophysiol 2000;23:1127–32.

16. Budeus M, Wieneke H, Sack S, et al. Long-term outcome after cardioversion of atrial fibrillation: prediction of recurrence with P wave signal averaged ECG and chemoreflexsensitivity.

Int J Cardiol 2006;112:308–15.

17. Healey JS, Theoret-Patrick P, Green MS, et al. Reverse atrial electrical remodelling following atrial defibrillation as determined by signal-averaged ECG. Can J Cardiol 2004;20:311–5.

18. Guo XH, Gallagher MM, Poloniecki J, et al. Prognostic significance of serial P wave signal-averaged electrocardiograms following external electrical cardioversion for persistent atrial fibrillation: a prospective study. Pacing and Clin Electrophysiol 2003;26:299–304.

19. Y u WC, Lee SH, Tai CT, et al. Reversal of atrial electrical remodeling following cardioversion of long-standing atrial fibrillation in man. Cardiovasc Res 1999;42:470–6.

20. Raitt MH, Kusumoto W, Giraud G, McAnulty JH. Reversal of electrical remodeling after cardioversion of persistent atrial fibrillation. J Cardiovasc Electrophysiol 2004;15:507–12.

21. Khan A, Mittal S, Kamath GS, et al. Pulmonary Vein Isolation Alone in Patients with Persistent Atrial Fibrillation: An Ablation Strategy Facilitated by Antiarrhythmic Drug Induced Reverse Remodeling. J Cardiovasc Electrophysiol 2011;22:142–8.

22. Rivard L, Hocini M, Rostock T, et al. Improved outcome following restoration of sinus rhythm prior to catheter ablation of persistent atrial fibrillation: A comparative multicenter study. Heart Rhythm 2012;9:1025–30.

23. Igarashi M, Tada H, Sekiguchi Y, et al. Effect of Restoration of Sinus Rhythm by Extensive Antiarrhythmic Drugs in Predicting Results of Catheter Ablation of Persistent Atrial Fibrillation. Am J Cardiol 2010;106:62–8.

24. Miyazaki S, Kuwahara T, Kobori A, et al. Pharmacological cardioversion preceding left atrial ablation: bepridil predicts the clinical outcome following ablation in patients with persistent atrial fibrillation. Europace 2009;11:1620–3.

25. O’Neill MD, Jais P, Takahashi Y, et al. The stepwise ablation approach for chronic atrial fibrillation--evidence for a cumulative effect. J Interv Card Electrophysiol 2006;16:153–67.

26. Ghanbari H, Oral H. Restoration of sinus rhythm prior to catheter ablation of persistent atrial fibrillation: Reverse remodeling or patient selection? Heart Rhythm 2012;9:1031–2.

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New Ablation Technologies and Techniques S aagar Ma hida , Benja min Bert e, Seig o Ya m a s h i t a , N i c o l a s D e r v a l , A r n a u d D e n i s, A s h o k S h a h , S a na Amrao u i, Meleze Hoc ini, Mic h e l H a i s s a g u e r r e, Pi e r r e Ja i s a n d Fr e d e r i c S a c h e r Hôpital Cardiologique du Haut-Lévêque and Université Victor Segalen Bordeaux II, Bordeaux, France

Abstract Catheter ablation is an established treatment strategy for a range of different cardiac arrhythmias. Over the past decade two major areas of expansion have been ablation of atrial fibrillation (AF) and ventricular tachycardia (VT) in the context of structurally abnormal hearts. In parallel with the expanding role of catheter ablation for AF and VT, multiple novel technologies have been developed which aim to increase safety and procedural success. Areas of development include novel catheter designs, novel navigation technologies and higher resolution imaging techniques. The aim of the present review is to provide an overview of novel developments in AF ablation and VT ablation in patients with of structural cardiac diseases.

Keywords Ablation; atrial fibrillation; ventricular tachycardia Disclosure: The authors have no conflicts of interest to declare.

Received: 25 March 2014 Accepted: 28 July 2014 Citation: Arrhythmia & Electrophysiology Review 2014;3(2):107–12 Access at: www.AERjournal.com Correspondence: Saagar Mahida, Hôpital Haut-Lévêque, Avenue de Magellan, 33604 Pessac, France. E: saagar7m7@yahoo.co.uk

Since the first catheter ablation for cardiac arrhythmia more than three decades ago, ablation technology has continually evolved at a rapid pace. Much of the early progress in the field was made in ablation of supraventricular tachycardias. Following a seminal study from Haïssaguerre et al.1 in 1998, which demonstrated that pulmonary vein triggers are important sources of atrial fibrillation (AF), the approach to management of AF underwent a revolution. Electrical isolation of pulmonary veins (PVs) using catheter ablation became an established therapeutic strategy in patients with paroxysmal AF. During subsequent years, the role of ablation in AF expanded, and more extensive strategies involving ablation of non-pulmonary vein triggers and modification of the left atrial substrate were demonstrated to be effective, even in persistent forms of AF.2 In recent years catheter ablation has also emerged as an effective treatment strategy for patients with ventricular tachycardia (VT).

An important area of expansion is the use of catheter ablation for treatment of recurrent VT in the context of ischaemic cardiomyopathy (ICM) or non-ischaemic cardiomyopathy (NICM).

VT ablation is commonly used in ICM and NICM patients who have recurrent defibrillator shocks due to drug-refractory VT. Many of the technological advances in AF ablation have been used to develop ablation techniques for scar-related VT. In parallel with the expanding role of catheter ablation for AF and VT, multiple novel technologies have been developed to simplify the procedures while at the same time aiming to increase safety and procedural success. The aim of the present review is to provide an overview of novel developments in AF ablation and VT ablation in the context of structural cardiac diseases. Ablation of other supraventricular tachycardias and VT in the context of structurally normal hearts has previously been reviewed extensively and is not discussed here.

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New Technologies and Techniques for AF Ablation Currently, the most widely used technique for PV isolation involves delivery of point-by-point ablation lesions around the circumference of the vein. A number of different variations to the approach have been developed. During the early stages of PV isolation, a ‘segmental approach’ which involved targeting the earliest PV potentials at the ostium of the PV was commonly used. Due to high reconnection rates and the risk of PV stenosis, the technique has progressively been modified and the prevailing technique involves circumferential antral ablation to achieve PV isolation.3 Techniques for modification of the left atrial substrate for AF include linear ablation and ablation of complex fractionated electrograms.

These techniques are more widely used in patients with persistent AF as an adjuvant strategy to PV isolation.3 Both techniques conventionally involve point-by-point ablation. The aim of linear ablation is to divide the atrium into smaller segments which are less likely to sustain macroreentrant arrhythmias.3 The most common sites of linear ablation are the left atrial roof and the mitral isthmus region. Ablation of complex fractionated electrograms, which may be representative of ´rotors´ that drive AF, involves targeting fractionated areas with short cycle lengths. It is important to note that the relationship between fractionated regions and rotors remains speculative.

Advances in Catheter Design for AF Ablation A point-by-point approach for AF ablation is associated with a number of limitations, including prolonged procedural times. Therefore novel catheter designs, which allow simultaneous application of multiple ablation lesions around the circumference of the PVs or in the left atrium, have been developed. Examples include balloon-mounted ablation techniques and multi-electrode catheters.

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Diagnostic Electrophysiology & Ablation Figure 1: 3D Reconstruction of Left Ventricular and Pulmonary Vein Anatomy from Rotational Angiography

isthmus lines.8 The TVAC has previously been reported to have comparable outcomes to conventional ablation for cavotricuspid isthmus lines with reduced procedure times.8 There are currently no randomised studies comparing conventional ablation with TVAC for roof and mitral lines.

One of the most important recent developments in AF ablation is the design of catheters that provide feedback on contact force during ablation. These catheters have sensors integrated into the tip which provide real-time information on the force of contact. A number of studies have convincingly demonstrated that catheter contact force correlates with the delivery of effective ablation lesions and durable PV isolation.9–12 Further, clinical outcomes have been reported to be superior in patients undergoing AF ablation with contact force catheters as compared with conventional ablation catheters.13 The two main contact force catheters currently in use for AF ablation are the ThermoCool© SmartTOUCH™ catheter (Biosense Webster, CA, USA) and the TactiCath™ catheter (Endosense, Inc., Geneva, Switzerland).

Remote Navigation Technologies for AF Ablation

The 3D reconstruction is superimposed on a live radiographic image. The reconstruction is used to guide manipulation of a circular multi-electrode catheter which is positioned at the ostium of the left inferior pulmonary vein.

Balloon-mounted technologies focus on PV-trigger dependent AF which is mostly observed in patients at early stages of paroxysmal AF. Three different balloon-based technologies have been used to ablate PV ostia; cryoablation, high intensity ultrasound and laser.2 These ablation systems are designed to either ablate the entire ostium of the pulmonary vein or certain arcs of the pulmonary vein circumference.2 Initially there were reports of limited success with balloon-based techniques due to their inability to ablate non-PV sites and technical challenges associated with isolation of the right inferior pulmonary vein. However, more recent studies have reported that these techniques have comparable success rates with RF ablation for PV isolation and shorter procedure times.4–7 Multi-electrode ablation catheters are another technology for simultaneous delivery of multiple ablation lesions during AF ablation.

Early multi-electrode designs include the MESH® catheter (Bard Electrophysiology, MA, USA) and the Pulmonary Vein Ablation Catheter® (PVAC) (Medtronic Ablation Frontiers, CA, USA). The MESH catheter is an expandable non-steerable circular catheter with 36 electrodes.2 The PVAC is a circular deflectable catheter with 10 poles capable of delivering RF energy in unipolar and bipolar modes.2 One of the major limitations of these catheter designs is the lack of irrigation.

In an attempt to overcome this limitation, the nMARQ™ catheter (Biosense Webster, CA, USA), which is an irrigated multipolar catheter, has recently been developed. Studies are ongoing to determine longterm outcomes following ablation with the nMARQ catheter (see Figure 1).4 In addition to their role in PV isolation, multi-electrode catheters have been developed for substrate-based ablation in the left atrium. The Tip-Versatile Ablation Catheter (TVAC; Medtronic Ablation Frontiers, CA, USA) has been designed to create simultaneous linear lesions in the left atrium e.g. roof lines, mitral isthmus lines and cavotricuspid

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Remote navigation technologies have been developed in recent years to simplify catheter manipulation during AF ablation.4 The three main remote navigation technologies include the Niobe® magnetic navigation system (Stereotaxis Inc., MO, USA), the Sensei™ robotic navigation system (Hansen Medical, CA, USA) and the Amigo™ remote catheter system (Catheter Robotics Inc., NJ, USA). The three systems use different technologies to allow remote navigation. While the Niobe system uses a remote magnetic system, the other two systems use remote catheter manipulators. The overall effect is that operators can manipulate catheters from a distance using a 3D navigation handle.14 Potential advantages of these technologies include increased safety, more precise catheter manipulation and increased stability. 15 A number of studies have demonstrated that the results of PV isolation with remote navigation are comparable with conventional ablation techniques.16,17 However, they are also associated with drawbacks, the most important of which relate to the cost and logistical aspects of installation of the technology.

Advances in Imaging Techniques for AF Ablation During the early stages of AF ablation, catheter navigation was based solely on fluoroscopic guidance and intracardiac signals.

AF ablation was therefore associated with significant radiation doses and occasionally difficulty in determining catheter orientation.4 The emergence of electro-anatomical mapping (EAM) techniques has been a major development in the field. EAM systems are designed to create a 3D geometry of the left atrium and PVs and allow precise localisation of the catheter tip within the model.4 Further, these systems allow for identification of scar and provide information on electrical activation relative to the anatomical map. An added advantage is that EAM allows operators to identify areas of incomplete ablation.4,18 The two most commonly used EAM techniques are the Carto® system (Biosense Webster, CA, USA) and the EnSite™ NavX™ system (St Jude Medical, MN, USA). Since their conception, EAM techniques have continued to evolve, and current iterations allow for integration of data from 3D reconstructions from computerised tomography (CT), rotational angiography and magnetic resonance imaging (MRI) scans. As a result, it is possible to delineate complex left atrial and PV anatomy with a high degree of accuracy.2,19,20 More recently, novel mapping systems such as the Rhythmia™ mapping system (Boston

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Scientific Inc., MA, USA) have been demonstrated to rapidly generate high-resolution maps in animal models.21

Figure 2: Phase Mapping Demonstrating a Posterior View of the Left Atrium in a Patient with Persistent Atrial Fibrillation

MRI with late gadolinium enhancement has emerged as a valuable technique for identifying regions of atrial fibrosis and scarring. The degree of fibrosis has been demonstrated to predict outcome in patients undergoing AF ablation.22 In the future, MRI may play a significant role in patient selection for AF ablation. Further, the recent development of MRI-compatible catheters has opened up a new area of research. Early studies have demonstrated that real-time MRI can be used to guide catheter placement.23 Rotational angiography is a potentially valuable tool for real-time imaging in patients undergoing AF ablation. Rotational angiography involves real-time acquisition of left atrial and PV anatomy after injection of contrast in the atrium. Images are then reconstructed superimposed on real-time fluoroscopic images (see Figure 1).19,20,24 It is also possible to integrate rotational angiography images with electroanatomical maps. A number of rotational angiography technologies are currently available including EP Navigator (Philips Healthcare, Best, The Netherlands) and DynaCT Cardiac (Siemens, Forchheim, Germany). Potential advantages of rotational angiography over EAM systems include less anatomical distortion due to more rapid creation of left atrial geometry.4,25

Rotors can be seen in the inferolateral aspect of the left atrium as well as adjacent to the right pulmonary veins. The rotors are indicated in green and turquoise. The rotors adjacent to the right pulmonary vein are stable. Those at the inferolateral aspect of the left atrium are more unstable. The line in peach indicates the trajectory of the unstable rotor.

increasingly prominent. Substrate-based ablation involves targeting late and fractionated electrograms that are suggestive areas of scar and abnormal conduction during sinus rhythm.33 The arrhythmogenic substrate may be endocardial, epicardial or both.

A novel technology that could potentially revolutionise management of AF and especially left atrial tachycardia and flutter is electrocardiographic imaging (ECGI). The technique utilises more than 250 electrodes positioned on the torso to record unipolar electrograms from the atrial epicardial surface. CT scanning is used to determine the atrial anatomy and the positions of the electrodes relative to the atrium.26 The recorded unipolar electrograms are used to derive information on cardiac activation patterns using mathematical modeling. A number of recent studies have demonstrated promising results using ECGI. Shah et al. reported that in 44 patients with atrial tachycardia ECGI (ECVUE mapping system, CardioInsight Technologies Inc., OH, USA) effectively localised the source of atrial tachycardia in 100 % of patients. Further in 92 % of cases, the mechanism of atrial tachycardia was accurately diagnosed.27 In a feasibility study

by Haissaguerre et al., ECGI was demonstrated to identify active sources of AF with high resolution.28 Specifically, they demonstrated active sources in the vicinity of the pulmonary veins in patients with paroxysmal AF and more widespread sources in patients with the more sustained form of the arrhythmia. A number of additional studies have also used non-invasive mapping to identify AF sources which have been targeted for ablation.29,30 An example of rotors identified by ECGI is included in Figure 2. ECGI-based ablation is currently in the investigational phase, and multicentre trials are ongoing to determine the efficacy of the technique.

New Technologies and Techniques for Ablation of Ventricular Arrhythmias During the early stages of VT ablation, the ablation strategies were based primarily on classical techniques such as entrainment and activation mapping to target the critical isthmus of the VT circuit.31,32 While these techniques are effective in a proportion of VT cases, they are associated with significant limitations. Most importantly, they are reliant upon the ability of the operator to induce clinically relevant sustained tachycardias that are haemodynamically tolerated. Due to these limitations, substrate-based ablation techniques have become

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Advances in Imaging Techniques for VT Ablation Scar-related VT ablation is critically dependent upon detailed delineation of ventricular anatomy and localisation of the scar and border zone. EAM is used extensively for these purposes in VT patients.34 As discussed previously, EAM systems create 3D chamber geometry as well as identifying areas of abnormal voltage, and hence scar.4 EAM systems can be used to create both epicardial and endocardial scar maps during VT ablation. It is important to note that while EAM is considered as the standard imaging modality for VT ablation, it is associated with limitations. For instance, single voltage measurements are unlikely to provide accurate representation of complex, 3D intramural scars. Further, EAM is associated with a risk of incorrectly identify areas of low voltage due to poor contact.35,36 Delayed enhancement MRI (DE-MRI) and multidetector CT (MDCT) imaging have emerged as valuable adjunctive techniques that may overcome some of the limitations of using EAM in isolation. As is the case in AF patients, DE-MRI and MDCT images can be integrated with EAM maps. DE-MRI provides high-resolution 3D imaging of scar size, location, heterogeneity and transmurality. Multiple studies have demonstrated that areas of delayed enhancement correlate with low voltage areas on EAM (see Figure 2).37–39 Delayed enhancement is correlated with sites of successful ablation in ICM patients.39 Further, DE-MRI has been reported to identify slow conduction channels that are potentially important regions of VT circuits.40 It is important to note however that, in the majority of centres, DE-MRI is currently restricted to patients who do not have an implantable cardioverter defibrillator (ICD). The development of MRI-compatible ICDs is predicted to significantly expand the role of this imaging technique in VT ablation.

MDCT is associated with high spatial and temporal resolution.41 MDCT is effective for identifying areas of ventricular calcification, fibro-fatty replacement, wall thinning and epicardial fat. Areas of wall thinning have been demonstrated to correlate with low voltage areas identified

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Diagnostic Electrophysiology & Ablation Figure 3: Pre-procedural Imaging in a Patient with Previous Myocarditis Presenting with Ventricular Tachycarida A

C

B

D

A) Endocardial and epicardial substrate maps. Purple demonstrates normal tissue (>1.5 mV bipolar voltage). Endocardial substrate map demonstrates absence of scar. Epicardial map demonstrates a small inferior lateral scar which could potentially have been missed in the absence of pre-procedural imaging. B) Multidetector CT (MDCT) segmentation of left ventricular endocardium and epicardium. Wall thinning is illustrated in green (<4 mm) and orange (<2 mm). Anatomical structures such as the coronary sinus (blue), coronary artery (red) and phrenic nerve (green) are also indicated. C) MDCT and late gadolinium enhancement MRI fusion image with MRI scar demonstrated in yellow. Coronary sinus is depicted in blue, phrenic nerve in green and coronary artery in red.

during EAM (see Figure 2).42 Further, MDCT has been demonstrated to identify areas harbouring local abnormal ventricular activity (LAVA) which, as discussed in subsequent sections, is critical to the VT mechanism.43 A major advantage of MDCT over DE-MRI is that the technique can be used for imaging of patients with an ICD. Additional advantages of MDCT include delineation of the coronary arteries, the phrenic nerve and papillary muscle.44 Pre-procedural annotation of these structures is important for minimising intraprocedural risk.

Further, accurate localisation of epicardial fat using MDCT makes epicardial voltage mapping more reliable. Overall, DE-MRI and MDCT provide complementary information on the arrhythmogenic substrate in patients undergoing VT ablation.44 Recently, ECGI has also been investigated as a potential additional imaging modality for mapping of VT. Wang et al. demonstrated that ECGI accurately identifies the site of origin of VT in more than 90 % of cases when compared with invasive mapping.45 Further, ECGI identified the mechanism of VT with a high degree of accuracy. Therefore, in addition to the expanding role in atrial arrhythmia, ECGI may emerge as an effective tool for mapping of VT. While research into the role of ECGI in VT is at an early stage, the technique has the potential to provide valuable information that can be used for pre-procedural planning of the ablation strategy. It is important to note however that, at this stage, the role of ECGI in patients with scar-related VT is not clear, and further research is necessary to validate its role in this context.

Advances in VT Mapping Techniques As discussed in the previous section, EAM is the most widely used imaging modality during ablation of scar-related VT. EAM commonly involves point-by-point sampling using conventional bipolar catheters.

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However this approach is time consuming, and mapping density is often inadequate. As a result, a number of novel multipolar mapping technologies have been developed to facilitate rapid and highdensity activation mapping. Examples include microelectrode ‘basket’ catheters, non-contact microelectrode arrays and multipolar catheter such as Pentaray and duodecapolar catheters.

Microelectrode ´basket´ catheters have an expandable design with multiple splines, which are designed to conform to the shape of the cardiac chamber. Each spline contains multiple recording electrodes.34 The Constellation® basket catheter (EP Technologies, CA, USA), has previously been reported to significantly reduce mapping times in patients with scar-related VT.46,47 However, these catheters are associated with multiple potential limitations. For instance, inadequate deployment of the splines can result in incomplete mapping. Further the catheter can interfere with ablation catheter manipulation and potentially cause mechanical trauma.34 Overall the use of basket catheters for VT ablation has been limited to small case series.34 Non-contact microelectrode arrays consist of inflatable balloons with multiple unipolar electrodes on the surface. The electrodes are designed to detect far-field electrical potential in addition to the location of a roving standard mapping catheter.34,48 Movement of the roving catheter within the ventricle is used for construction of endocardial geometry. Inverse solution mathematics is used to superimpose numerous reconstructed electrograms on an endocardial model.49 These systems are designed to provide detailed endocardial mapping during a single beat.48 Non-contact mapping is primarily designed for activation mapping and, given that it can map activation with a single beat, it may be of use in patients with poorly tolerated VT. Overall however, while non-contact systems have been used for mapping of scar-related VT, their utility is not widespread.50–52 Steerable multipolar catheters have also been developed for high-density mapping during VT. Examples include the Livewire™ duodecapolar catheter (St Jude Medical, MN, USA) and the PentaRay® catheter (Biosense Webster, CA, USA).33,53 The duodecapolar catheter is a 20 electrode steerable catheter. Two previous studies have demonstrated that the catheter can be used can be used to acquire high-density maps of the epicardial and endocardial surfaces.53,54 The PentaRay catheter consists of five soft and flexible splines with multiple electrodes on each spline. The catheter is designed to minimise traumatic complications during endocardial and epicardial mapping. A major advantage of the PentaRay catheter in the context of VT mapping is that, in addition to endocardial mapping, it can be used to acquire high-density maps of the epicardial surface. Jais et al. demonstrated that the PentaRay catheter produces minimal ectopy during epicardial mapping,33 and is associated with minimal artificial signals. Therefore, during endocardial VT ablation, the PentaRay catheter can be used to monitor transmural response.

Advances in VT Ablation Strategies As discussed previously, VT ablation using activation and entrainment mapping has traditionally been the most widely used strategy for VT ablation.55 However, a major limitation of these approaches is that they depend upon induction of monomorphic VT which is clinically relevant and well tolerated. As a result of these limitations, substrate-based approaches have been used increasingly in VT patients. Strategies for substrate-based ablation include linear ablation across voltage channels, encircling of scars, and homogenisation of regions of heterogenous scar.

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It is important to note that substrate-based approaches are also associated with challenges. One of the major challenges is the definition of the endpoint following ablation. Non-induciblity of VT has been used as an endpoint by many operators. However, this approach is associated with important limitations including non-reproducibility and lack of compelling data to suggest that non-inducibility predicts long-term outcome. Overall, there is currently no general consensus as to the optimal endpoint of substrate-based VT ablation.

Recently, ablation of LAVA has become an increasingly prominent substrate-based ablation technique.33,56–58 The aim of LAVA ablation is the dissociation or isolation of surviving myocardial fibres within scar regions.33 Importantly, the endpoint of LAVA-based ablation is complete LAVA elimination. Therefore, this approach overcomes the aforementioned limitations of non-inducibility of VT as an endpoint.

Jaïs et al. recently demonstrated that complete elimination of LAVA is safe and is associated with a superior clinical outcome.33 More recently, the same group demonstrated that in ICM patients with secondary wall thinning, epicardial LAVA can be eliminated with an endocardial approach, thereby limiting the amount of epicardial ablation.59 Pace-mapping provides valuable information during substrate-based VT ablation. Pace-mapping involves pacing during sinus rhythm at different sites and comparing the activation sequence with that of the clinical VT. Automated algorithms can be used for comparison of QRS morphologies. While pace-mapping is commonly used as an adjunctive technique during scar-related VT ablation, it is associated with important limitations. For instance, in addition to providing pacemaps that match the clinical VT at the VT exit site, normal tissue can also produce matching pace-maps due to large reentry circuits.34 In an interesting recent study however, De Chillou et al. demonstrated that, in patients with ICM, performing high density pace-mapping and annotation using an EAM system can accurately identify the entry and exit points of a VT circuit as well as demonstrating the orientation of the critical isthmus.60 Further, they were able to demonstrate bidirectional block across the isthmus following linear ablation.

Advances in Ablation Techniques for VT One of the major contributors to VT recurrences in patients with scar-related VT is the inability to create adequate lesions in areas critical to the VT circuit. Deep intramural VT circuits are particularly challenging in this context. Intramural VT circuits may be inaccessible to ablate with epicardial and/or endocardial approaches. A number of technologies have therefore been developed in an attempt to overcome these limitations. Examples include transcoronary ethanol injection, bipolar ablation, needle-based catheters and catheters that allow direct visualisation of myocardial tissue. These techniques are discussed in more detail below.

Transcoronary ethanol ablation for VT has been in existence for more than two decades.61 The technique involves identification of the branch of the coronary tree supplying the arrhythmogenic substrate

1. de Jong MM, Niens M, Nolte IM, et al. The human leukocyte antigen region and colorectal cancer risk. Dis Colon Rectum 2005;48:303–6.

2. Andrikopoulos G, Tzeis S, Vardas PE. Invasive therapy for atrial fibrillation: recent developments in ablation, navigation and mapping technology. Heart 2011;97:237–43.

3. Verma A. The techniques for catheter ablation of paroxysmal and persistent atrial fibrillation: a systematic review. Curr Opin Cardiol 2011;26:17–4.

4. Burkhardt JD, Natale A. New technologies in atrial fibrillation

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and injecting ethanol to ablate the substrate. Initial strategies for selection of coronary branches were based primarily on anatomical considerations. Over the years, the procedure has been refined to more accurately define the coronary branches of interest.

For instance, pace mapping with angioplasty guide wires in the coronary circulation has been demonstrated to effectively guide transcoronary ablation. A number of recent studies have demonstrated that, in patients with difficult-to-control VT despite radiofrequency ablation, transcoronary ethanol ablation is an effective alternative strategy. It is important to note however that efficacy of this technique is limited by factors such as unfavourable coronary anatomy and recurrence of modified VT.62 High-power bipolar ablation is a potentially effective technique for ablation of deep intramural VT circuits, particularly circuits arising from within the septum. Bipolar ablation involves positioning two catheters on either side of the septum or endo- and epicardially and delivering high-power radiofrequency energy. In animal infarct models, and more recently in explanted ex vivo human hearts, bipolar ablation has been demonstrated to more effectively create transmural lesions as compared to standard unipolar ablation.63,64 The technique has also been demonstrated to be effective in case reports and small series of patients with VT which is refractory to conventional ablation techniques.65,66 An interesting novel technique designed to reach deep intramyocardial arrhythmogenic substrates is needle-based catheter ablation.67 The catheter design has a needle tip which can be expanded and retracted.

The needle tip is irrigated and can map as well as ablate. The technique involves perforation of the myocardium with the needle and delivery of energy to create deep intramural lesions. In a recent feasibility study, the catheter demonstrated promising results.67 However the technique is currently in the investigational phase and further research is warranted to more clearly define its role in VT ablation.

Finally, catheters that allow direct visualisation during ablation have demonstrated promising results in animal models. Sacher et al. demonstrated that the IRIS™ catheter (Voyage Medical Inc., CA, USA), which allows direct visualisation during ablation, reliably created ablation lesions in 99 % of application sites with minimal complications in a sheep model. Further, the catheter was significantly more effective when compared with a standard open-irrigated tip catheter in creating ablation lesions.68 Once again, this technology is currently in the research phase and studies in humans have not been conducted.

Conclusions Catheter ablation of cardiac arrhythmias is a constantly expanding and evolving field. In recent years, advances in catheter ablation techniques have significantly improved outcomes in patients with AF and VT. However, these techniques remain time consuming and in a proportion of patients, ineffective. Therefore, there remains a need for continual technological advances to improve outcomes. n

ablation. Circulation 2009;120:1533–41.

5. Mugnai G, Chierchia GB, de Asmundis C, et al. Comparison of pulmonary vein isolation using cryoballoon versus conventional radiofrequency for paroxysmal atrial fibrillation.

Am J Cardiol 2014;113:1509–13.

6. Metzner A, Reissmann B, Rausch P, et al. One-year clinical outcome after pulmonary vein isolation using the secondgeneration 28-mm cryoballoon. Circ Arrhythm Electrophysiol 2014;7:288–92.

7. 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;61:1713–23.

8. Erdogan A, Guettler N, Doerr O, et al. Randomized comparison of multipolar, duty-cycled, bipolar-unipolar radiofrequency versus conventional catheter ablation for treatment of common atrial flutter. J Cardiovasc Electrophysiol 2010;21:1109–13.

9. Thiagalingam A, D’Avila A, Foley L, et al. Importance of catheter contact force during irrigated radiofrequency

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Diagnostic Electrophysiology & Ablation ablation: evaluation in a porcine ex vivo model using a forcesensing catheter. J Cardiovasc Electrophysiol 2010;21:806–11.

10. Reddy VY, Shah D, Kautzner J, et al. The relationship between contact force and clinical outcome during radiofrequency catheter ablation of atrial fibrillation in the TOCCATA study.

Heart Rhythm 2012;9:1789–95.

11. Kuck KH, Reddy VY, Schmidt B, et al. A novel radiofrequency ablation catheter using contact force sensing: Toccata study.

Heart Rhythm 2012;9:18–23.

12. Neuzil P, Reddy VY, Kautzner J, et al. Electrical reconnection after pulmonary vein isolation is contingent on contact force during initial treatment: results from the EFFICAS I study.

Circ Arrhythm Electrophysiol 2013;6:327–33.

13. Marijon E, Fazaa S, Narayanan K, et al. Real-Time Contact Force Sensing for Pulmonary Vein Isolation in the Setting of Paroxysmal Atrial Fibrillation: Procedural and 1-Year Results.

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14. Reddy VY, Neuzil P, Malchano ZJ, et al. View-synchronized robotic image-guided therapy for atrial fibrillation ablation: experimental validation and clinical feasibility. Circulation 2007;115:2705–14.

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26. Ramanathan C, Ghanem RN, Jia P, et al. Noninvasive electrocardiographic imaging for cardiac electrophysiology and arrhythmia. Nat Med 2004;10:422–8.

27. Shah AJ, Hocini M, Xhaet O, et al. Validation of novel 3-dimensional electrocardiographic mapping of atrial tachycardias by invasive mapping and ablation: a multicenter study. J Am Coll Cardiol 2013;62:889–97.

28. Haissaguerre M, Hocini M, Shah AJ, et al. Noninvasive panoramic mapping of human atrial fibrillation mechanisms: a feasibility report. J Cardiovasc Electrophysiol 2013;24:711–17.

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30. Narayan SM, Krummen DE, Rappel WJ. Clinical mapping approach to diagnose electrical rotors and focal impulse sources for human atrial fibrillation. J Cardiovasc Electrophysiol 2012;23:447–54.

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33. Jais P, Maury P, Khairy P, et al. Elimination of local abnormal ventricular activities: a new end point for substrate modification in patients with scar-related ventricular tachycardia. Circulation 2012;125:2184–96.

34. Aliot EM, Stevenson WG, Almendral-Garrote JM, et al. EHRA/ HRS Expert Consensus on Catheter Ablation of Ventricular Arrhythmias: developed in a partnership with the European Heart Rhythm Association (EHRA), a Registered Branch of the European Society of Cardiology (ESC), and the Heart Rhythm Society (HRS); in collaboration with the American College of Cardiology (ACC) and the American Heart Association (AHA).

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35. 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.

36. Dickfeld T, Kato R, Zviman M, et al. Characterization of radiofrequency ablation lesions with gadolinium-enhanced cardiovascular magnetic resonance imaging. J Am Coll Cardiol 2006;47:370–8.

37. Reddy VY, Malchano ZJ, Holmvang G, et al. Integration of cardiac magnetic resonance imaging with three-dimensional electroanatomic mapping to guide left ventricular catheter manipulation: feasibility in a porcine model of healed myocardial infarction. J Am Coll Cardiol 2004;44:2202–13.

38. Codreanu A, Odille F, Aliot E, et al. Electroanatomic characterization of post-infarct scars comparison with 3-dimensional myocardial scar reconstruction based on magnetic resonance imaging. J Am Coll Cardiol 2008;52:839–42.

39. Desjardins B, Crawford T, Good E, et al. Infarct architecture and characteristics on delayed enhanced magnetic resonance imaging and electroanatomic mapping in patients with postinfarction ventricular arrhythmia. Heart Rhythm 2009;6:644–51.

40. Perez-David E, Arenal A, Rubio-Guivernau JL, et al. Noninvasive identification of ventricular tachycardia-related conducting channels using contrast-enhanced magnetic resonance imaging in patients with chronic myocardial infarction: comparison of signal intensity scar mapping and endocardial voltage mapping. J Am Coll Cardiol 2011;57:184–94.

41. Bardo DM, Brown P. Cardiac multidetector computed tomography: basic physics of image acquisition and clinical applications. Curr Cardiol Rev 2008;4:231–43.

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43. Komatsu Y, Cochet H, Jadidi A, et al. Regional myocardial wall thinning at multidetector computed tomography correlates to arrhythmogenic substrate in postinfarction ventricular tachycardia: assessment of structural and electrical substrate.

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44. Cochet H, Komatsu Y, Sacher F, et al. Integration of merged delayed-enhanced magnetic resonance imaging and multidetector computed tomography for the guidance of ventricular tachycardia ablation: a pilot study. J Cardiovasc Electrophysiol 2013;24:419–26.

45. Wang Y, Cuculich PS, Zhang J, et al. Noninvasive electroanatomic mapping of human ventricular arrhythmias with electrocardiographic imaging. Sci Transl Med 2011;3:98ra84.

46. Greenspon AJ, Hsu SS, Datorre S. Successful radiofrequency catheter ablation of sustained ventricular tachycardia postmyocardial infarction in man guided by a multielectrode “basket” catheter. J Cardiovasc Electrophysiol 1997;8:565–70.

47. Schalij MJ, van Rugge FP, Siezenga M, van der Velde ET. Endocardial activation mapping of ventricular tachycardia in patients: first application of a 32-site bipolar mapping electrode catheter. Circulation 1998;98:2168–79.

48. Gornick CC, Adler SW, Pederson B, et al. Validation of a new noncontact catheter system for electroanatomic mapping of left ventricular endocardium. Circulation 1999;99:829–35.

49. Schilling RJ, Peters NS, Davies DW. Simultaneous endocardial mapping in the human left ventricle using a noncontact catheter: comparison of contact and reconstructed electrograms during sinus rhythm. Circulation 1998;98:887–98.

50. Della Bella P, Pappalardo A, Riva S, et al. Non-contact mapping to guide catheter ablation of untolerated ventricular tachycardia. Eur Heart J 2002;23:742–52.

51. Rajappan K, Schilling RJ. Non-contact mapping in the treatment of ventricular tachycardia after myocardial infarction J Interv Card Electrophysiol 2007;19:9–18.

52. Strickberger SA, Knight BP, Michaud GF, et al. Mapping and ablation of ventricular tachycardia guided by virtual electrograms using a noncontact. computerized mapping system J Am Coll Cardiol, 2000;35:414–21.

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Diagnostic Electrophysiology & Ablation

Cardiac Autonomic Denervation for Ablation of Atrial Fibrillation Georg e D Ka t r i t s i s 1 a n d D e m o s t h e n e s G K a t r i t s i s 2 1. Academic Foundation Trainee, John Radcliffe Hospital, The Oxford University Clinical Academic Graduate School, Oxford, UK; 2. Director, Department of Cardiology, Athens Euroclinic, Athens, Greece

Abstract The influence of the autonomic nervous system (ANS) on triggering and perpetuation of atrial fibrillation (AF) is well established.

Ganglionated plexi (GP) ablation achieves autonomic denervation by affecting both the parasympathetic and sympathetic components of the ANS. GP ablation can be accomplished endocardially or epicardially, i.e. during the maze procedure or thoracoscopic approaches.

Recent evidence indicates that anatomic GP ablation at relevant atrial sites appears to be safe and improves the results of pulmonary vein isolation in patients with paroxysmal and persistent AF.

Keywords Atrial fibrillation, ablation, ganglionated plexi, autonomic nervous system Disclosure: The author has no conflicts of interest to declare.

Acknowledgement: Andrew Grace, Section Editor – Arrhythmia Mechanisms/Basic Science acted as Editor for this article.

Received: 20 May 2014 Accepted: 21 July 2014 Citation: Arrhythmia & Electrophysiology Review 2014;3(2):113–5 Access at: www.AERjournal.com Correspondence: Dr D. Katritsis, Athens Euroclinic, 9 Athanassiadou Street, Athens 11521, Greece. E: dkatritsis@euroclinic.gr, dgkatr@otenet.gr

Currently, pulmonary vein isolation (PVI) is the most widely used ablation approach to treat atrial fibrillation (AF). However, even in patients with paroxysmal AF (PAF), there is a five-year success rate <30 % after a single procedure1 and <40 % remain off anti-arrhythmic drugs,2 so PVI alone is clearly not sufficient to maintain sinus rhythm. The influence of the autonomic nervous system (ANS) on triggering and perpetuation of AF is well established. Variations of the autonomic tone have been associated with paroxysms of AF and both sympathetic and parasympathetic activation may be proarrhythmic by shortening of atrial refractoriness.3–5 Vagal reflexes from clusters of autonomic ganglia, so-called ganglionated plexi (GP), at sites around the circumference of the left atrial–pulmonary vein (LA–PV) junction may induce and perpetuate AF through increased spatial heterogeneity of refractoriness.3,6 The anatomic sites of GP are located 1–2 cm outside the pulmonary vein (PV) ostia at the left superolateral area (superior left GP; SLGP), the right superoanterior area (anterior right GP; ARGP), the left inferoposterior area (inferior left GP; ILGP), and the right inferoposterior area (inferior right GP; IRGP) (see Figure 1).7–9 In clinical practice, inadvertent parasympathetic denervation has been proposed as a potential mechanism of circumferential or antral PV ablation for the treatment of AF.10–12 Thus, GP are a reasonable target of both surgical and catheter ablation techniques for the eradication of AF.

Early Experience with Autonomic Denervation Initial studies on partial vagal denervation via epicardial fat pad ablation indicated that such a dedicated approach may prevent AF,13,14 although results have not been consistent.15–17 Most probably the selective nature and partial denervation of this kind of procedure, a recognised potentially proarrhythmic approach,18 is responsible for the inconsistency of results. Ablation of areas with prominent sympathetic innervation has also prevented sympathetic AF. The ligament of Marshall is a left atrial epicardial neuromuscular bundle, rich in sympathetic innervation, which has been associated with the

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genesis of atrial tachyarrhythmias (AT) and AF.19–21 Epicardial ablation of the ligament of Marshall in the canine can terminate spontaneous atrial activity and prevent AF,19 whereas in the human epicardial (through the coronary sinus)20 or endocardial21,22 ablation at the insertion site of the Marshall bundle may terminate AF. We now know that selective parasympathetic or sympathetic denervation may not be feasible. Both sympathetic and parasympathetic elements reside in all four major left atrial GP,7–9 and ablation lesions may unavoidably affect both components of the ANS. The area around the ligament of Marshall that had been previously thought to represent an area of predominantly sympathetic innervation has been shown to contain parasympathetic fibres as well.23 Thus, pure parasympathetic or sympathetic denervation is difficult to achieve. Ablation of atrial areas containing autonomic innervation, such as GP, unavoidably results in autonomic denervation.

Techniques of GP Ablation In the electrophysiology laboratory and the operating theatre, identification of major GP has been mainly accomplished through highfrequency stimulation (HFS) and induction of vagal responses in the atria.24,25 HFS is delivered at 1,200 bpm (20 Hz) with a pulse width of 10 ms at 12–24 V.26 A predominant efferent vagal response is defined as induction of AV block (>2 sec) and hypotension or prolongation of the R–R interval by >50 % during AF, following a five-second application of high-frequency stimulation. During these studies the anatomic locations of these plexi in the human have been well characterised. However, although the HFS setting is variable from institution to institution, the method usually entails the discomfort of general anaesthesia, since conscious patients may not tolerate more than 15 V. Furthermore, it has been recently shown that that anatomic ablation, i.e. targeting the areas known to host GP in the left atrium (see Figure 1) without previous identification of GP (see Figure 1), yields superior clinical results to HFS identification and ablation of GP in patients with paroxysmal AF.27

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Diagnostic Electrophysiology & Ablation Figure 1: Anatomic Position of the Major Ganglionated Plexi Targeted for Catheter Ablation

RSPV RSPV

SLGP

LSPV SLGP

LIPV RIPV

LIPV

RIPV

ILGP IRGP IRGP

ILGP

RSPV

LSPV RSPV

SLGP

ARGP

RIPV

ARGP

RIPV IRGP

Presumed ganglionated plexi (GP) clusters are ablated 1–2 cm outside the pulmonary vein–left atrial junctions at the following sites: left superolateral area (superior left GP; SLGP), right superoanterior area (anterior right GP; ARGP), left inferoposterior area (inferior left GP; ILGP), and right inferoposterior area (inferior right GP; IRGP). Another GP (crux GP) the inferoposterior area between the ILGP and IRGP is not indicated. Reproduced with kind permission from Katritsis et al.34

Clinical Experience Endocardial Catheter Ablation Isolated GP ablation has been employed for both paroxysmal and persistent AF with variable success. In paroxysmal AF, arrhythmia-free survival within the first year after the procedure ranged between 26 and 77 %.27–31 GP ablation in combination with PVI has yielded better results that PVI alone, with reported success rates up to 80 %.31–36 Katritsis et al. have investigated the potential efficacy of GP ablation in consecutive randomised trials in both paroxysmal and persistent AF. In the first study, which compared the efficacy of PVI with PVI plus GP ablation in 67 patients with PAF, at the end of follow-up 20 (60.6 %) patients in the PVI group and 29 (85.3 %) patients in the GP+PVI group remained arrhythmia free (log rank test, P = 0.019).34 In the second trial on 242 patients with PAF, freedom from AF or AT was achieved in 44 (56 %), 39 (48 %), and 61 (74 %) patients in the PVI, GP and PVI+GP groups, respectively (p=0.0036 by log-rank test). PVI+GP ablation strategy as compared with PVI alone yielded a hazard ratio (HR) of 0.53 (95 % confidence interval [CI] 0.31–0.91; p=0.022) for the recurrence of AF or AT. Post-ablation atrial flutter was not different between groups: 5.1 % in PVI, 4.9 % in GP, and 6.1 % in PVI plus GP.36 Success rates of <40 % have been reported for persistent AF after a single procedure.37 We have also compared linear lesion (LL) and GP ablation, in addition to PVI, in 264 patients with persistent AF. At 12 months after a single procedure, 47 % of the patients treated with PVI plus LL were in sinus rhythm compared

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with 54 % of the patients treated with PVI plus GP (P = 0.29). At three years, 34 % of the patients with PVI plus LL and 49 % of the patients with PVI plus GP maintained sinus rhythm (P = 0.035). Atrial flutter was more frequent in the PVI plus LL group than in PVI+GP group (18 % vs 6 %; P = 0.002). After a second procedure in 78 patients of the PVI plus LL group and 55 patients of the PVI plus GP group, the long-term overall success rate was 52 % and 68 %, respectively (P = 0.006). Thus, PVI plus GP ablation confers superior clinical results with less ablation-related left atrial flutter and reduced AF recurrence compared with PVI plus LL in persistent AF.38 Due to the epicardial location of GP, relatively higher energy settings than those used for endocardial ablation may be required.

Intraoperative Ablation The epicardial location of GP argues in favour of a surgical approach, and addition of GP ablation to the conventional maze procedure has produced improved outcomes with success rates 83–93 % over the following year.25,39–42 Although this approach is interesting, it is associated with the risks of open heart surgery, and the maze nowadays is only considered in patients undergoing valve surgery.

Thoracoscopic Approaches Thoracoscopic approaches combine PVI with selective GP ablation, with or without ligament of Marshall ablation or left atrial appendage amputation.43–50 The reported success rates over one year follow-up

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range from 65–86 % , usually in mixed populations of paroxysmal and persistent AF, and the procedure does not appear to have any associated mortality, with pleural effusion, pneumothorax, haemothorax, and phrenic nerve injury the reported complications so far. McClelland et al.43 reported freedom from AF during one year of follow-up in 75 % of patients overall, and 87.5 % of patients with paroxysmal or persistent AF. Han et al.44 reported 65 % freedom from AT at 12 months in a patient cohort of paroxysmal (73 %) and persistent (27 %) AF, while recurrences after surgery were usually responsive to catheter ablation and/or antiarrhythmic drugs. Edgerton et al.46 reported long-term freedom from AT of 86.3 % at six months and 80.8 % at 12 months in patients with paroxysmal AF. Yilmaz et al.45 reported a 77 % freedom from AF during a mean follow-up of 11.6 months in a patient cohort with paroxysmal (63 %), persistent (27 %), and permanent (10 %) AF. Edgerton et al.46 reported long-term freedom from AT of 86.3 % at six months and 80.8 % at 12 months in patients with paroxysmal AF. Beyer et al.50 reported freedom from AF in 87 % of patients (paroxysmal 93 %, persistent 96 %, and permanent 71 %) at 13.6 ± 8.2 months.

There has also been evidence for beneficial effects of adding GP ablation to LA ablation lines and PVI, specifically in patients with persistent AF.47 GP ablation has shown promise in catheter trials and is

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becoming popular among groups adopting surgical ablation. However, no randomised data exist to clearly define its potential benefit.

Complications of GP ablation Ablation-induced atrial or ventricular proarrhythmia has been reported with both endocardial and epicardial (thoracoscopic) approaches,33,49,51 and GP modification was initially considered to carry a higher risk of iatrogenic left ATs than PVI. In our experience, anatomic or HFSmediated GP ablation is complicated by atrial macroreentry in <10 % of patients treated, and this incidence is lower than that of circumferential or, especially, linear ablation.34,36

The Future GP ablation appears to be a safe and efficacious method to improve PVI in patients with AF, and has been used in the electrophysiology laboratory, and during the maze procedure and thoracoscopic approaches. However experience is limited and long-term followup (i.e. more than five years) is still not available. This is particularly important since restoration of autonomic activity may occur as early as four weeks following ablation.52 Additional clinical experience is necessary to accurately assess the clinical usefulness of this promising technique, and the potential of autonomic modification for the treatment of arrhythmias. n

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21. Katritsis D, Ioannidis JP, Anagnostopoulos CE, et al.

Identification and catheter ablation of extracardiac and intracardiac components of ligament of Marshall tissue for treatment of paroxysmal atrial fibrillation. J Cardiovasc Electrophysiol 2001;12:750–8.

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34. Katritsis DG, Giazitzoglou E, Zografos T, et al. Rapid pulmonary vein isolation combined with autonomic ganglia modification: a randomized study. Heart Rhythm 2011;8:672–8.

35. Zhou Q, Hou Y, Yang S. A meta-analysis of the comparative efficacy of ablation for atrial fibrillation with and without ablation of the ganglionated plexi. Pacing Clin Electrophysiol 2011;34:1687–94.

36. Katritsis DG, Pokushalov E, Romanov A, et al. Autonomic denervation added to pulmonary vein isolation for paroxysmal atrial fibrillation: a randomized clinical trial.

J Am Coll Cardiol 2013;62:2318–25.

37. Pokushalov E, Romanov A, Artyomenko S, et al. Ganglionated plexi ablation for longstanding persistent atrial fibrillation.

Europace 2010;12:342–6.

38. Pokushalov E, Romanov A, Katritsis DG, et al. Ganglionated plexus ablation vs linear ablation in patients undergoing pulmonary vein isolation for persistent/long-standing persistent atrial fibrillation: a randomized comparison.

Heart Rhythm 2013;10:1280–6.

39. Doll N, Pritzwald-Stegmann P, Czesla M, et al. Ablation of ganglionic plexi during combined surgery for atrial fibrillation.

Ann Thorac Surg 2008;86:1659–63.

40. Ware AL, Suri RM, Stulak JM, et al. Left atrial ganglion ablation as an adjunct to atrial fibrillation surgery in valvular heart disease. Ann Thorac Surg 2011;91:97–102.

41. Onorati F, Curcio A, Santarpino G, Torella D, et al. Routine ganglionic plexi ablation during Maze procedure improves hospital and early follow-up results of mitral surgery.

J Thorac Cardiovasc Surg 2008;136:408–18.

42. Boersma LV, Castella M, van Boven W, et al. Atrial fibrillation catheter ablation versus surgical ablation treatment (FAST): A 2-center randomized clinical trial. Circulation 2012;125:23–30.

43. McClelland JH, Duke D, Reddy R. Preliminary results of a limited thoracotomy: new approach to treat atrial fibrillation. J Cardiovasc Electrophysiol 2007;18:1289–95.

44. Han FT, Kasirajan V, Kowalski M, et al. Results of a minimally invasive surgical pulmonary vein isolation and ganglionic plexi ablation for atrial fibrillation: single-center experience with 12-month follow-up. Circ Arrhythm Electrophysiol 2009;2:370–7.

45. Yilmaz A, Geuzebroek GS, Van Putte BP, et al. Completely thoracoscopic pulmonary vein isolation with ganglionic plexus ablation and left atrial appendage amputation for treatment of atrial fibrillation. Eur J Cardiothorac Surg 2010;38:356–60.

46. Edgerton JR, Brinkman WT, Weaver T, et al. Pulmonary vein isolation and autonomic denervation for the management of paroxysmal atrial fibrillation by a minimally invasive surgical approach. J Thorac Cardiovasc Surg 2010;140:823–8.

47. Krul SP, Driessen AH, van Boven WJ, et al. Thoracoscopic video-assisted pulmonary vein antrum isolation, ganglionated plexus ablation, and periprocedural confirmation of ablation lesions: first results of a hybrid surgical-electrophysiological approach for atrial fibrillation. Circ Arrhythm Electrophysiol 2011;4:262–70.

48. Lockwood D, Nakagawa H, Peyton MD, et al. Linear left atrial lesions in minimally invasive surgical ablation of persistent atrial fibrillation: Techniques for assessing conduction block across surgical lesions. Heart Rhythm 2009;6:S50–63.

49. Kron J, Kasirajan V, Wood MA, Kowalski M, Han FT, Ellenbogen KA. Management of recurrent atrial arrhythmias after minimally invasive surgical pulmonary vein isolation and ganglionic plexi ablation for atrial fibrillation. Heart Rhythm 2010;7:445–51.

50. Beyer E, Lee R, Lam BK. Point: minimally invasive bipolar radiofrequency ablation of lone atrial fibrillation: early multicenter results. J Thorac Cardiovasc Surg 2009;137:521–6.

51. Osman F, Kundu S, Tuan J, et al. Ganglionic plexus ablation during pulmonary vein isolation - predisposing to ventricular arrhythmias? Indian Pacing Electrophysiol J 2010;10:104–7.

52. Sakamoto S, Schuessler RB, Lee AM, Aziz A, Lall SC, Damiano RJ Jr. Vagal denervation and reinnervation after ablation of ganglionated plexi. J Thorac Cardiovasc Surg 2010;139:444–52.

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Cardiac or Other Implantable Electronic Devices and Sleep-disordered Breathing – Implications for Diagnosis and Therapy H enrik Fox , 1 T homa s Bit ter, 2 K l a u s - J ü r g e n G u t l e b e n , 3 D i e t e r H o r s t k o t t e 4 a n d O l a f O l d e n b urg 5 1. Cardiologist, 2. Pneumologist, 3. Co-chair of Electrophysiology, 4. Head, 5. Senior Cardiologist, Department of Cardiology, Heart and Diabetes Centre North Rhine-Westphalia, Ruhr University Bochum, Bad Oeynhausen, Germany

Abstract Sleep-disordered breathing (SDB) is of growing interest in cardiology because SDB is a highly prevalent comorbidity in patients with a variety of cardiovascular diseases. The prevalence of SDB is particularly high in patients with cardiac dysrhythmias and/or heart failure.

In this setting, many patients now have implantable cardiac devices, such as pacemakers, implantable cardioverter-defibrillators or implanted cardiac resynchronisation therapy devices (CRT). Treatment of SDB using implantable cardiac devices has been studied previously, with atrial pacing and CRT being shown not to bring about satisfactory results in SDB care. The latest generations of these devices have the capacity to determine transthoracic impedance, to detect and quantify breathing efforts and to identify SDB. The capability of implantable cardiac devices to detect SDB is of potential importance for patients with cardiovascular disease, allowing screening for SDB, monitoring of the course of SDB in relation to cardiac status, and documenting of the effects of treatment.

Keywords Implantable cardiac devices, heart failure, Cheyne-Stokes respiration, sleep-disordered breathing; obstructive sleep apnoea, central sleep apnoea Disclosure: The authors have no conflicts of interest to declare.

Acknowledgements: English language medical writing assistance was provided by Nicola Ryan, independent medical writer, on behalf of ResMed. Received: 1 July 2014 Accepted: 1 August 2014 Citation: Arrhythmia & Electrophysiology Review 2014;3(2):116–9 Access at: www.AERjournal.com Correspondence: Henrik Fox, MD, Department of Cardiology, Heart and Diabetes Centre North Rhine – Westphalia, Ruhr University Bochum, Georgstrasse 11, D-32545 Bad Oeynhausen, Germany. E: akleemeyer@hdz-nrw.de

Implantable cardiac devices, such as pacemakers, are used to treat a number of heart conditions, especially those related to the electrical conduction system. Cardiac pacemakers are a well-established and effective therapy, and have been in use for more than 50 years.

The first pacemaker was implanted in a patient in October 1958 by Åke Senning in Stockholm, in cooperation with engineer Rune Elmqvist from Siemens. This pioneer work formed the basis of further developments in implantable cardiac device technology, resulting in the devices available today, including implantable cardioverterdefibrillators (ICDs) and biventricular stimulating implanted cardiac resynchronisation therapy (CRT). These newer devices have better effectiveness and a positive impact on patient quality of life (QoL), and are important cardiology treatment strategies.

The idea of treating sleep-disordered breathing (SDB) using implantable cardiac devices is not new. In 2002 Garrigue et al. investigated 15 patients with SDB and permanent atrial-synchronous ventricular pacemakers for symptomatic sinus bradycardia using polysomnographic evaluations on consecutive nights. On the basis of one night of treatment, given in a random order, dual-chamber atrial overdrive pacing reduced the apnoea–hypopnoea index (AHI) to 11 ± 14, compared with 28 ± 22 in spontaneous rhythm (p<0.001).1 Initially it had been suggested that atrial pacing would improve SDB in patients with bradycardia, but this hypothesis has not been supported by the results of recent studies.2,3

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In addition to their treatment capability, there are a number of algorithms available for today’s implantable cardiac devices that allow them to also be used as diagnostic tools. For example, detection of transthoracic impedance has been used to measure respiratory efforts for many years. In addition, for more than a decade many pacemakers have included integrated respiratory minute volume sensors as part of a basic algorithm to adapt the heart rate.4 Recently, this capability was enhanced to allow detection of cardiac decompensations by measuring changes in intrathoracic fluids.5 A growing number of implantable cardiac devices also now have the ability to detect SDB.6–8

Sleep-disordered Breathing Interest in SDB among cardiologists is increasing rapidly due to the high prevalence of SDB in patients with cardiovascular disease.

The prevalence of SDB in cardiovascular patients is particularly high in those with cardiac dysrhythmias and heart failure (HF; see Figure 1).9 There are two main types of SDB: obstructive sleep apnoea (OSA) and central sleep apnoea (CSA). OSA is characterised by repetitive interruptions of ventilation during sleep caused by collapse of the pharyngeal airway. An obstructive apnoea is a 10-second pause in respiration associated with ongoing ventilatory effort, combined with a decrease in oxygen saturation and/or arousal. A diagnosis of OSA syndrome is made when the number of respiratory events (AHI per hour) is five or more per hour and the patient has symptoms of

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excessive daytime sleepiness.10,11 CSA is characterised by repetitive cessation of ventilation during sleep resulting from a loss of ventilatory drive. A central apnoea is a 10-second pause in ventilation with no associated respiratory effort. CSA is present when a patient has five or more central apnoeas or hypopnoeas per hour.10,12

Figure 1: Prevalence of Sleep-disordered Breathing in Cardiovascular Patients with Cardiac Dysrhythmias and Heart Failure

Implantable Cardiac Electronic Devices and SDB Diagnosis The ability of current implantable cardiac devices (pacemakers, ICDs and CRT) to determine transthoracic impedance, and therefore detect and quantify breathing efforts, makes them capable of detecting SDB. Multichannel polysomnography (PSG) is the gold standard tool for the detection and quantification of SDB.13 However, PSG is costly and needs to be undertaken at specialist clinics. As a result, alternative, less expensive and more convenient options that can offer good reliability are becoming increasingly attractive, particularly for the detection and monitoring of SDB in cardiac patients and for monitoring the effects of therapy.

CSA OSA

ability to do so has been validated in comparisons with multichannel polysomnography (PSG) recordings, the gold standard for diagnosing SDB.7,8,14–20 Recently, the internal SDB detection algorithm of an implanted pacemaker device documented a high prevalence of SDB (up to 75 %) in a cohort of 32 unselected cardiac patients.21 SDB definition varies between different devices. The algorithm of a pacemaker by Sorin (Paris, France) records an apnoea when there is breathing cessation of >10 seconds, and a hypopnoea when the breathing amplitude is reduced by ≥50 % for >10 seconds; the number of events per hour is used to calculate the respiratory disturbance index (RDI).22 In devices from Boston Scientific (St. Paul, Minnesota, USA), the SDB detection algorithm also registers apnoeas as breathing cessation of >10 seconds, but hypopnoeas as a ≥26 % decrease in transthoracic impedance amplitude for >10 seconds and the AHI is calculated as a reflection of the RDI. The algorithms of devices from both companies have been validated against multichannel PSG, with the Sorin algorithm in Talent™-3 pacemakers (ELA Medical, Montrouge, France) identifying severe SDB with sensitivity of 75 % and specificity of 94 %.22 In another study utilising Boston Scientific (Guidant) pacemakers, there was a good correlation between the calculated RDI and the AHI measured using PSG (r = 0.8), with sensitivity of 82 % and specificity of 88 % for detecting severe SDB.23 Newer generations of implantable devices include updated SDB detection algorithms. The novel sleep monitoring algorithm of Sorin pacemakers from the Reply™ 200 family (Sleep Apnoea Monitoring) was investigated in 31 patients and data compared with multichannel PSG 30–90 days after device implantation. Severe SDB was detected with sensitivity of 89 % and specificity of 85 %.24 Boston Scientific has a new SDB detection algorithm in their ICD and CRT devices, called ApneaScan™, and a validation study of Boston’s Incepta™ ICD family of devices compared with polygraphy in the outpatient setting is ongoing (NCT01979120).

To date there are no randomised controlled clinical trials of the new implantable device technologies, but the ability of this approach to

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no SDB

Data derived from Fox H et al. [2014] showing the high prevalence and distribution of sleepdisordered breathing in a population of cardiovascular patients with cardiac dysrhythmias and heart failure9. CSA = central sleep apnoea; OSA = obstructive sleep apnoea; SDB = sleep-disordered breathing.

Figure 2: Improvements of Sleep-disordered Breathing after Cardiac Resynchronisation Therapy Implantation in Patients with Heart Failure and Central Sleep Apnoea 50 45 40 35 AHI/h

Thoracic impedance is determined by the relation of air to fluids between the measurement locations. Implantable pacemakers measure transthoracic impedance between an endocardial implanted lead and the pectoral aggregate. Thoracic impedance rises with inspirational efforts and falls during expiration.4 Implantable cardiac devices have been used to detect SDB for at least a decade, and their

30 25 20 15 10 5 0 pre CRT

post CRT

Data derived from Oldenburg et al [2007]; 77 patients with heart failure (19 females; 62.6 ± 10 years) eligible for CRT were screened for the presence, type and severity of sleep-disordered breathing (SDB) before and after CRT initiation (5.3 ± 3 months) using multichannel cardiorespiratory polygraphy. SDB parameters only improved in CSA patients [AHI decrease from 31.2 ± 15.5/h to 17.3 ± 13.7/h, p<0.001]26; CSA = central sleep apnoea; AHI = apnoea hypopnea index; CRT = cardiac resynchronisation therapy.

overcome the limitations of PSG and polygraphy appears promising.

In addition, ability to continuously monitor SDB means that patient monitoring can be improved, with the possibility of detecting deterioration early and therefore initiating appropriate changes in therapy.25–27

Implantable Cardiac Electronic Devices and SDB Therapy Patients with relevant SDB and symptomatic HF need to be treated with optimal medical therapy according to current local guidelines. When left ventricular function is severely impaired (≤35 %) and in the presence of left bundle branch block, CRT implantation is indicated.28 In addition to beneficial cardiovascular effects, CRT implantation has been shown to also be associated with a significant improvement in

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B

(A) The left X-ray shows an implanted phrenic nerve stimulator (Remedē®, Respicardia Inc., Minnesota, USA) in the right pectoral area. The system comes with a stimulation lead and a sensing lead and the aggregate itself. A guidance catheter was introduced into the left brachiocephalic vein (the site of epicardiophrenic vein discharge). This vein follows the left phrenic nerve, and use of this close anatomy allows phrenic nerve stimulation via the transvenous stimulation device. The arrow marks the stimulation lead placed into the epicardiophrenic vein.

The stimulation lead is introduced by selective contrast dye exploration using an ‘over-the-wire’ technique. (B) As shown on the right X-ray, a stimulation lead can also be placed into the right vena brachiocephalica to stimulate the right phrenic nerve. Placement of the sensing electrode is similar; after selective exploration with a suitable catheter it is positioned into the azygos vein, as close to the diaphragm as possible. When the guidance catheters are removed, electrode fixation follows and the aggregate is placed into a prepared subfascial pouch. The arrow on the right marks the stimulation lead placed into the right vena brachiocephalica.

CSA.26 Sinha et al. reported a beneficial effect of CRT on CSA and CSR

lead is introduced by selective contrast dye exploration using an ‘over-

in 24 patients with chronic HF. There was a significant decrease in AHI (from 19.2 ± 10.3 per hour to 4.6 ± 4.4 per hour, p<0.001) and in subjective sleep quality assessed using the Pittsburgh Sleep Quality Index (from 10.4 ± 1.6 to 3.9 ± 2.4, p<0.001); no significant changes were documented in patients without CSA.29 In a larger study, Oldenburg et al. investigated the influence of CRT on SDB in 77 patients with severe HF before and five months after device implantation. CRT improved clinical and haemodynamic parameters, but only had a significant effect on SDB parameters in patients with CSA (AHI decreased from 31.2 ± 15.5 per hour to 17.3 ± 13.7 per hour, p<0.001). In addition, improvements in CSA were only documented in responders to CRT (see Figure 2).26

the-wire’ technique. Alternatively a stimulation lead can also be placed into the right vena brachiocephalica to stimulate the right phrenic nerve (see Figure 3). Placement of the sensing electrode is similar; after selective exploration with a suitable catheter it is positioned into the azygos vein, as close to the diaphragm as possible. When the guidance catheters are removed, electrode fixation follows and the aggregate is placed into a prepared subfascial pouch. After implantation, the device is tested by a programmer.

Current first-line therapy for sleep apnoea consists of positive airway pressure. The specific treatment used depends on the underlying type of SDB – continuous positive airway pressure (CPAP) for OSA and adaptive servo-ventilation (ASV) for CSA/CSR. However, although there are a variety of devices and patient interfaces, not all patients are able to tolerate positive airway pressure therapy. Most current literature suggests that about 15 % of patients are unable or unwilling to tolerate masks and ventilation therapy, and another 15 % quit ventilation therapy within the first six months of treatment.30–33 These patients could potentially benefit from implantable devices to treat SDB. A new implantable device (Remedē®, Respicardia Inc., Minnesota, USA) is currently undergoing clinical testing. Treatment of CSA is thought to be achieved by nocturnal unilateral phrenic nerve stimulation.

The system comes with a stimulation lead and a sensing lead and the aggregate itself. Programming can be modified by an external programmer, which allows readouts of diagnostic parameters and programming of stimulation therapy. The device is implanted under local anaesthesia, preferably in the right pectoral area, similar to basic pacemaker implantation. After puncturing the subclavian vein, a guidance catheter is introduced into the left brachiocephalic vein (the site of epicardiophrenic vein discharge). This vein follows the left phrenic nerve, and use of this close anatomy allows phrenic nerve stimulation via the transvenous stimulation device (see Figure 3). The stimulation

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Initial experience with this phrenic nerve stimulation device is positive.

Patients tolerated stimulation well and PSG recordings showed good suppression of CSA. An initial first multicentre clinical trial in 31 patients reported statistically significant reductions in CSA with the phrenic nerve stimulation device compared with no treatment (control night prior to device implantation).34 Longer term six-month followup data are available for a cohort of 47 patients, 70 % of whom had symptomatic HF with reduced systolic left ventricular ejection fraction (LVEF, 31 ± 12 %) and severe CSA (mean AHI 50±15 per hour and mean central apnoea index [CAI] 28 ± 14 per hour). PSG performed after three and six months documented significant reductions in CSA (baseline to three months: AHI from 50 ± 15 per hour to 22 ± 14 per hour, p<0.0001; CAI from 28 ± 14 per hour to 5 ± 9 per hour, p<0.0001). This study also reported significant improvements in QoL, assessed using the Minnesota Living with Heart Failure questionnaire (p = 0.0012), and New York Heart Association functional class (p<0.0001).35–37 AHI was reduced, but not to normal levels, and there was no data on the effects of therapy on cardiac performance and patient prognosis.

There is also an implantable device available for patients with OSA. This stimulates the hypoglossus nerve to prevent upper airway collapse. Implantation of the electrodes for this device is more complex and requires surgery on the neck because direct access and preparation of the nerve are necessary. Furthermore, video endoscopic sleep examination is mandatory to identify appropriate candidates for this procedure. As such, this device has limited clinical application38 but the first clinical data are promising. Over 12 months

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of follow-up in 31 patients, respiratory events and clinical parameters were improved.39 Final validation and clinical endpoint studies for this implantable device are not yet available, but initial data from a multicentre, prospective, cohort study, the Stimulation Therapy for Apnoea Reduction (STAR) trial, show that use of an upper-airway stimulation device in 126 patients with OSA who had difficulty either accepting or adhering to CPAP therapy, decreased median AHI at 12 months by 68 % (from 29.3 to 9.0 per hour, p<0.001). Participants with a response to therapy were then included in a randomised, controlled trial of therapy withdrawal, which showed a rebound increase in the AHI when upper airway stimulation was withdrawn (to 25.8 per hour from 7.6 per hour, p<0.001). The rate of procedurerelated serious adverse events was <2 %.40

Conclusions, Outlook and Clinical Perspective SDB is a highly prevalent comorbidity in patients with cardiac dysrhythmia, HF and in those with implanted cardiac devices.

Today’s pacemaker, ICD or CRT devices have the ability to constantly monitor transthoracic impedance making them capable of detecting and quantifying SDB. Results from the first studies of new devices are promising and they reveal the potential of this technology.

1. Garrigue S, Bordier P, Jais P, et al. Benefit of atrial pacing in sleep apnea syndrome. N Engl J Med 2002;346:404–12.

2. Krahn AD, Yee R, Erickson MK, et al. Physiologic pacing in patients with obstructive sleep apnea: a prospective, randomized crossover trial. J Am Coll Cardiol 2006;47:379–83.

3. Pepin JL, Defaye P, Garrigue S, et al. Overdrive atrial pacing does not improve obstructive sleep apnoea syndrome.

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4. Bonnet JL, Ritter P, Pioger G. Measurement of minute ventilation with different DDDR pacemaker electrode configurations. Investigators of a Multicenter Study Evaluating the Chorus RM and Opus RM Pacemakers.

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8. Fox H, Nolker G, Gutleben KJ, et al. Reliability and accuracy of sleep apnea scans in novel cardiac resynchronization therapy devices: an independent report of two cases.

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10. Somers VK, White DP, Amin R, et al. Sleep apnea and cardiovascular disease: an American Heart Association/American College Of Cardiology Foundation Scientific Statement from the American Heart Association Council for High Blood Pressure Research Professional Education Committee, Council on Clinical Cardiology, Stroke Council, and Council On Cardiovascular Nursing. In collaboration with the National Heart, Lung, and Blood Institute National Center on Sleep Disorders Research (National Institutes of Health). Circulation 2008;118:1080–11.

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12. Berry RB, Budhiraja R, Gottlieb DJ, et al. Rules for scoring respiratory events in sleep: update of the 2007 AASM Manual for the Scoring of Sleep and Associated Events. Deliberations of the Sleep Apnea Definitions Task Force of the American Academy of Sleep Medicine. J Clin Sleep Med 2012;8:597–619.

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Detected SDB events and severity show good correlation with PSG, the gold standard for diagnosing SDB. The latest implantable device technology even allows treatment of SDB, via selective stimulation of the hypoglossus nerve for OSA and via phrenic nerve stimulation for CSA. Clinical studies are underway to determine the usefulness of the latter approach for the treatment of CSA and the suppression of CSR. One of the benefits of the new phrenic nerve stimulation device is that it is inserted using a well-known transvenous implantation procedure.

The main limitation of the new implantable devices is that they do not record oximetry or sleep and breathing parameters. Nevertheless, the ability of implantable cardiac devices to detect SDB could have clinical utility, not only for SDB screening but also to monitor SDB severity and document the effectiveness of SDB treatment. Implantable devices are also able to measure additional parameters, including intrathoracic fluids, heart rate variability, and activity parameters. This type of information may allow early detection of worsening of HF and facilitate the prevention of clinical events. There are currently no randomised, controlled clinical trials looking at this utility, but this is an area for future research. n

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14. Thackray SD, Witte KK, Nikitin NP, et al. The prevalence of heart failure and asymptomatic left ventricular systolic dysfunction in a typical regional pacemaker population.

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15. Oldenburg O, Lamp B, Faber L, et al. Sleep-disordered breathing in patients with symptomatic heart failure: a contemporary study of prevalence in and characteristics of 700 patients. Eur J Heart Fail 2007;9:251–7.

16. Javaheri S, Shukla R, Zeigler H, Wexler L. Central sleep apnea, right ventricular dysfunction, and low diastolic blood pressure are predictors of mortality in systolic heart failure.

J Am Coll Cardiol 2007;49:2028–34.

17. Bitter T, Langer C, Vogt J, et al. Sleep-disordered breathing in patients with atrial fibrillation and normal systolic left ventricular function. Dtsch Arztebl Int 2009;106:164–70.

18. Bitter T, Westerheide N, Prinz C, et al. Cheyne-Stokes respiration and obstructive sleep apnoea are independent risk factors for malignant ventricular arrhythmias requiring appropriate cardioverter-defibrillator therapies in patients with congestive heart failure. Eur Heart J 2011;32:61–74.

19. Leung RS. Sleep-disordered breathing: autonomic mechanisms and arrhythmias. Prog Cardiovasc Dis 2009;51:324–38.

20. Leung RS, Huber MA, Rogge T, et al. Association between atrial fibrillation and central sleep apnea. Sleep 2005;28:1543–6.

21. Liu T, Korantzopoulos P, Li L, et al. Poster session 5. Europace 2013;15:ii171–215.

22. Defaye P, Pepin JL, Poezevara Y, et al. Automatic recognition of abnormal respiratory events during sleep by a pacemaker transthoracic impedance sensor. J Cardiovasc Electrophysiol 2004;15:1034–40.

23. Shalaby A, Atwood C, Hansen C, et al. Feasibility of automated detection of advanced sleep disordered breathing utilizing an implantable pacemaker ventilation sensor. Pacing Clin Electrophysiol 2006;29:1036–43.

24. Defaye P, de la Cruz I, Marti-Almor J, et al. A pacemaker transthoracic impedance sensor with an advanced algorithm to identify severe sleep apnea: the DREAM European study.

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25. Efken C, Bitter T, Prib N, et al. Obstructive sleep apnoea: longer respiratory event lengths in patients with heart failure.

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26. Oldenburg O, Faber L, Vogt J, et al. Influence of cardiac resynchronisation therapy on different types of sleep disordered breathing. Eur J Heart Fail 2007;9:820–6.

27. Wedewardt J, Bitter T, Prinz C, et al. Cheyne-Stokes respiration in heart failure: cycle length is dependent on left ventricular ejection fraction. Sleep Med 2010;11:137–42.

28. Brignole M, Auricchio A, Baron-Esquivias G, et al.

2013 ESC Guidelines on cardiac pacing and cardiac resynchronization therapy: the Task Force on cardiac pacing and resynchronization therapy of the European Society of Cardiology (ESC). Developed in collaboration with the European Heart Rhythm Association (EHRA). Eur Heart J 2013;34:2281–329.

29. Sinha AM, Skobel EC, Breithardt OA, et al. Cardiac resynchronization therapy improves central sleep apnea and Cheyne-Stokes respiration in patients with chronic heart failure. J Am Coll Cardiol 2004;44:68–71.

30. Engleman HM, Martin SE, Douglas NJ. Compliance with CPAP therapy in patients with the sleep apnoea/hypopnoea syndrome. Thorax 1994;49:263–6.

31. Philippe C, Stoica-Herman M, Drouot X, et al. Compliance with and effectiveness of adaptive servoventilation versus continuous positive airway pressure in the treatment of Cheyne-Stokes respiration in heart failure over a six month period. Heart 2006;92:337–42.

32. Oldenburg O, Schmidt A, Lamp B, et al. Adaptive servoventilation improves cardiac function in patients with chronic heart failure and Cheyne-Stokes respiration.

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33. Bitter T, Westerheide N, Faber L, et al. Adaptive servoventilation in diastolic heart failure and Cheyne-Stokes respiration. Eur Respir J 2010;36:385–92.

34. Ponikowski P, Javaheri S, Michalkiewicz D, et al. Transvenous phrenic nerve stimulation for the treatment of central sleep apnoea in heart failure. Eur Heart J 2012;33:889–94.

35. Ponikowski P, Ponikowski P, Jagielski D, et al. TCT-134 Transvenous Phrenic Nerve Stimulation in the Treatment of Central Sleep Apnea in Patients with Reduced Ejection Fraction: A Report from the remede(r) System Pilot Study.

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36. Oldenburg O, Abraham WT, Ponikowski P, et al. Phrenic nerve stimulation improves acute circulatory delay in patients with heart failure and central sleep apnea. Clin Res Cardiol 2012;101(Suppl 2):P477.

37. Oldenburg O, Gutleben KJ, Jagielski D, et al. The effects of chronic implanted transvenous phrenic nerve stimulation in central sleep apnea: the Remede® System Pilot Study. Clin Res Cardiol 2013;102(Suppl 2):P518.

38. Vanderveken OM, Maurer JT, Hohenhorst W, et al. Evaluation of drug-induced sleep endoscopy as a patient selection tool for implanted upper airway stimulation for obstructive sleep apnea. J Clin Sleep Med 2013;9:433–8.

39. Kezirian EJ, Goding GS, Jr., Malhotra A, et al. Hypoglossal nerve stimulation improves obstructive sleep apnea: 12-month outcomes. J Sleep Res 2014;23:77–83.

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Can we Modulate the Autonomic Nervous System to Improve the Life of Patients with Heart Failure? The Case of Vagal Stimulation Pe t e r J S c h w a r t z Professor and Head, Centre for Cardiac Arrhythmias of Genetic Origin, IRCCS Istituto Auxologico Italiano, Milan, Italy

Abstract An imbalance of the autonomic nervous system, with reduced vagal and increased sympathetic activity, contributes to pathogenesis and clinical deterioration in heart failure (HF). Experimental studies have demonstrated that vagal stimulation (VS) has an antifibrillatory effect that has proved beneficial in animal models of HF. The potential value of chronic VS in man was first investigated with an implantable neuro-stimulator capable of delivering low current pulses with adjustable parameters to stimulate the right vagus. The results of a pilot study and a small multicentre clinical trial of VS in HF patients appeared to show a favourable clinical effect, and feasibility and safety data were encouraging. An ongoing pivotal clinical trial will provide a definitive assessment of the efficacy and usefulness of chronic VS in HF patients.This approach represents a new and exciting possibility for the management of HF that will provide clinicians with a novel tool to modulate non-pharmacologically the autonomic nervous system in patients with moderate-to-advanced HF.

Keywords Heart failure, autonomic nervous system, vagal stimulation Disclosure: Peter Schwartz is a consultant for BioControl Medical Ltd. Acknowledgement: The Author is grateful to Pinuccia De Tomasi for her expert editorial support.

Received: 27 June 2014 Accepted: 29 July 2014 Citation: Arrhythmia & Electrophysiology Review 2014;3(2):120–2 Access at: www.AERjournal.com Correspondence: Peter J Schwartz, Professor and Head, Centre for Cardiac Arrhythmias of Genetic Origin, IRCCS Istituto Auxologico Italiano, Casa di Cura San Carlo, Via Pier Lombardo, 22, 20135 Milan, Italy. E: peter.schwartz@unipv.it

Despite the clear improvements in clinical outcomes brought about by medical therapy with ß-blockers, ACE inhibitors and aldosterone antagonists, as well as by device therapy with cardiac resynchronisation, many patients with chronic heart failure (HF) remain symptomatic despite optimal medical therapy. Symptomatic HF can have devastating consequences for the quality of life of individuals, and impacts on their families as well as the wider community. HF represents a major socio-economic burden due to the huge number of individuals affected worldwide.

The first clinical report demonstrating the feasibility of performing chronic stimulation of the vagus in patients with severe HF7 gave the green light for a series of clinical endeavours to modulate the autonomic nervous system. These are still in their infancy but appear full of promise. The first-in-man-study and its continuation in the first multicentre clinical trial of chronic vagal stimulation (VS)7,8 have paved the way for a diversity of clinical approaches that all seek to address autonomic imbalance by modulating the autonomic nervous system both to decrease sympathetic and increase vagal activity.9

Whenever situations like this occur in medicine, the medical community is keen to explore novel means of treatment, and one such approach has attracted widespread interest. Although original, its background goes back 30 years to the recognition that the autonomic nervous system can be dysfunctional in HF1,2 and that this dysfunction is characterised by an autonomic imbalance, with reduced vagal and increased sympathetic activity.3 Initially, the augmented cardiac adrenergic drive supports the performance of the failing heart. However, long-term activation of the sympathetic nervous system is deleterious and ß-adrenergic blocker treatment is beneficial.4 The realisation that decreased vagal activity could be as important as increased sympathetic activity in causing cardiovascular morbidity and mortality5,6 focused interest toward the possibility of producing benefit also by augmenting vagal tone and reflexes. Eventually clinical cardiologists realised the potential inherent in approaches that modulate the autonomic nervous system to obtain a higher vagal and a lower sympathetic activity.3

Initial work with VS7,8 has been followed by other approaches, all interesting and potentially useful. They include spinal cord stimulation, baroreceptor activation and renal denervation.10,11 This article will provide a succinct review of the rationale behind VS, results of the firstin-man study, its evolution, and the current situation.

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Experimental Background A number of experimental studies laid the foundation for the current translational attempts. Evidence was obtained from postmyocardial infarction (MI) dogs 5 and then from post-MI humans, 12 that depressed baroreflex sensitivity (BRS) is associated with higher risk for sudden cardiac death. As BRS is largely a marker of vagal activity, this implied that conditions associated primarily with impaired vagal reflexes, but also with increased sympathetic reflexes, can predispose to life-threatening arrhythmias. Direct right VS performed in conscious dogs with a healed MI during a transient

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Modulation of the Autonomic Nervous System in Patients with Heart Failure

coronary occlusion performed in an exercise stress test13 was found to reduce the occurrence of ventricular fibrillation from 100 % to 10 % (p<0.001). 14 The transition towards HF was provided by two large studies that demonstrated an inverse relationship between New York Heart Association (NYHA) class and BRS, with a higher mortality in HF patients with depressed BRS.15 This predictive value of impaired vagal reflexes was present also among patients treated with ß-blockers. 16 When experimental studies on the effect of VS in animals with HF began to be published,17-19 there was no reason to delay initiation of VS studies in man.

In constrast with the wide experience of VS in epilepsy, which is conducted through stimulation of the left vagus, the right vagus would be the natural choice for stimulation when targeting the heart itself. As one has to stimulate the intact vagus, the electrical stimulation will activate both efferent and afferent fibres. But what are the consequences of activating the afferent vagal fibres? The answer to this question was provided 40 years ago when it was demonstrated, by recording single vagal and sympathetic fibres directed to the heart, that stimulation of vagal afferent fibres produces a reflex increase in the activity of the contralateral vagus and a reflex inhibition of cardiac sympathetic efferent activity.20 Thus, at clinical level we can expect stimulation of the right vagus to result not only in the direct and reflex activation of vagal efferent fibres but also in the reflex inhibition of cardiac sympathetic efferent traffic.

This synergistic effect is likely to contribute significantly to the results observed clinically.

Additional considerations are relevant. In HF there is an increased density of cardiac muscarinic receptors, likely to be secondary to reduced tonic vagal activity.21 While postganglionic vagal nerve transmission seems to be intact in HF, pre- to post-ganglionic parasympathetic efferent neurotransmission via nicotinergic acetylcholine receptors seems to be impaired.21 These nicotinergic receptors are agonist-dependent and chronic exposure to a nicotinic agonist during HF can re-establish efferent parasympathetic neural control of the sinus node.22 These data enhance the pathophysiological rationale for the use of electrical preganglionic cervical vagal nerve stimulation to re-establish the diminished cardiac vagal tone in chronic HF.

Clinical Translation Based on the experimental background and rationale, we moved into the clinical arena with a single centre study involving eight severely diseased patients, as appropriate for a non-traditional approach. This was the first-in-man study with chronic vagal stimulation for heart failure.7 The encouraging preliminary results showed the technique to be safe and achievable, and possibly beneficial. It was logical to continue with a multicentre single-arm open-label interventional phase II study.8 The pilot study enrolled 32 patients in total (94 % men; mean age 56 ± 11 years) with a history of chronic HF in symptomatic NYHA class II–IV and average left ventricular ejection fraction (LVEF) of 23 ± 8 %. The patients were on optimal medical therapy; and 19 had an implantable cardioverter-defibrillator (ICD).

These patients underwent implantation of the CardioFit 5000 system (BioControl Medical Ltd, Yehud, Israel), including; an implantable neurostimulator capable of delivering low-current electrical pulses (with adjustable parameters); a proprietary cuff with a bipolar electrode placed over the right vagus nerve; and an intracardiac sensing electrode placed in the right ventricle. This enables suppression of

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nerve stimulation when heart rate falls below a pre-determined value.

The stimulator is designed to sense the heart rate (via an intracardiac implanted electrode) and to deliver stimulation at preset delays from the R wave.

Following an up-titration phase, the stimulation intensity reached 4.1±1.2 mA and was limited by discomfort or pain. Adverse events were limited, and as a rule, disappeared by lowering stimulation intensity. The heart rate changes observed during VS were modest but baseline resting heart rate decreased significantly during the study from 82 ± 13 to 76 ± 13 beats per minute. Most patients (59 %) improved by at least one NYHA class at six months. Quality of life markedly improved at six months (from 49 ± 17 to 32 ± 19 on the Minnesota Living with Heart Failure Questionnaire). The same was found for the six-minute walk test with an increase at three months from 411 ± 76 to 470 ± 99 m and subsequent stability. The blinded echocardiogram analysis disclosed a significant reduction in LV endsystolic volume, and a significant increase in LVEF (from 22 ± 7 % to 29 ± 8 %). A group of 23 patients continued their follow-up with active VS revealing significant maintenance and even magnification of the favourable effects of VS at one year (especially LVEF, from 21–34 %).

This first human experience of chronic VS in patients with HF suggested that the treatment is feasible, safe and tolerable and leads to a subjective clinical improvement. The continuation of data collection in a subset of 19 patients has proved that these effects are preserved at two-year follow-up, a strong argument against a major role for a possible placebo effect. As of today, this represents a major difference from other approaches, be they spinal cord stimulation, baroreceptor activation or renal denervation.

These two clinical studies7,8 were ground-breaking as they represented the first attempt to modify the autonomic control of the heart in man with the objective of altering the downhill course of heart failure. Their encouraging results stimulated the design of a formal, randomised clinical trial. The INOVATE-HF (INcrease Of VAgal TonE in CHF) study (NCT01303718) is an international, multicentre, randomised clinical trial designed to assess safety and efficacy of vagus nerve stimulation using the CardioFit System in patients with symptomatic HF who are on optimal medical therapy.23 This ongoing study is enrolling patients with NYHA Class III symptoms, LVEF ≤ 40 % and end-diastolic dimensions between 50 and 80 mm. Patients are randomised in a 3:2 ratio to either active treatment (implanted) or continuation of medical therapy (not implanted). The primary efficacy end point of the study is the composite of all-cause mortality or unplanned HF hospitalisation equivalent, using a time to first event analysis. The study will continue until a pre-specified number of clinical and safety events have been accumulated and the 500th enrolled patient has been followed for at least one year or for a maximum of 4.5 years. There are two co-primary safety end points: freedom from procedure and system-related complication events at 90 days; and the number or patients with allcause death or complications at 12 months. After the randomisation and optimisation period, the clinical status of all subjects is evaluated at three-monthly intervals during 18 months post-implant and every six months thereafter. At the time of writing the number of enrolled patients exceeds 460.

Other clinical studies based on vagal stimulation include the Neurocardiac Therapy for Heart Failure study (NECTAR-HF) 24 and the Autonomic Neural Regulation Therapy to Enhance Myocardial

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Device Therapy Function in Heart Failure (ANTHEM-HF) study. 25 Preliminary results from these two trials will be presented in September 2014.

Conclusion It is evident that management of HF has entered a new phase of hope. As yet nobody can say whether or not the novel approach to

1. Eckberg DL, Drabinsky M, Braunwald E, Defective cardiac parasympathetic control in patients with heart disease, N Engl J Med, 1971;285:877–883.

2. Cohn JN, Levine TB, Olivari MT, et al., Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure, N Engl J Med, 1984;311:819–23.

3. Schwartz PJ, De Ferrari GM, Sympathetic-parasympathetic interaction in health and disease: abnormalities and relevance in heart failure, Heart Fail Rev 2011;16:101–7.

4. Hunt SA, Abraham WT, Chin MH,et al.; American College of Cardiology Foundation; American Heart Association.

2009 focused update incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the International Society for Heart and Lung Transplantation.

Circulation 2009;119:e391-479.

5. Schwartz PJ, Vanoli E, Stramba-Badiale M, et al., Autonomic mechanisms and sudden death: New insights from analysis of baroreceptor reflexes in conscious dogs with and without a myocardial infarction, Circulation, 1988;78:969–79.

6. Schwartz PJ, Cardiac innervation and sudden death: New strategies for prevention. In: Rosen MR and Palti Y, Eds., Lethal Arrhythmias Resulting From Myocardial Ischemia and Infarction, Boston, Kluwer, 1989;293–09.

7. Schwartz PJ, De Ferrari GM, Sanzo A, et al., Long term vagal stimulation in patients with advanced heart failure. First experience in man, Eur J Heart Fail, 2008;10:884–91.

8. De Ferrari GM, Crijns HJGM, Borggrefe M, et al., CardioFit multicenter trial investigators. Chronic vagus nerve stimulation: a new and promising therapeutic approach for

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modulate the autonomic nervous system by increasing vagal and decreasing cardiac-bound sympathetic activity will be successful.

However, there is undoubtedly merit in exploring this physiologicallybased attempt to improve the life of patients with heart failure. Within the next few years INOVATE-HF and the other ongoing studies will provide a clear answer. n

chronic heart failure, Eur Heart J, 2011;32:847–55.

9. Schwartz PJ, La Rovere MT, Vanoli E, Autonomic nervous system and sudden cardiac death. Experimental basis and clinical observations for post-myocardial infarction risk stratification, Circulation, 1992;85(Suppl. I):I77–91.

10. Kuck KH, Bordachar P, Borggrefe M, et al., New devices in heart failure: an European Heart Rhythm Association report: developed by the European Heart Rhythm Association; endorsed by the Heart Failure Association, Europace, 2014;16:109–28.

11. Schwartz PJ, La Rovere MT, De Ferrari GM, Mann D, Autonomic modulation for the management of patients with chronic heart failure. (Submitted for publication).

12. La Rovere MT, Bigger JT Jr, Marcus FI, et al., for the ATRAMI Investigators. Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarction, Lancet, 1998;351:478–84.

13. Schwartz PJ, Billman GE, Stone HL, Autonomic mechanisms in ventricular fibrillation induced by myocardial ischemia during exercise in dogs with healed myocardial infarction.

An experimental preparation for sudden cardiac death, Circulation, 1984;69:790–800.

14. Vanoli E, De Ferrari GM, Stramba-Badiale M,et al., Vagal stimulation and prevention of sudden death in conscious dogs with a healed myocardial infarction, Circ Res, 1991;68:1471–81.

15. Mortara A, La Rovere MT, Pinna GD, et al., Arterial baroreflex modulation of heart rate in chronic heart failure: Clinical and hemodynamic correlates and prognostic implications, Circulation, 1997;96:3450–8.

16. La Rovere MT, Pinna GD, Maestri R, et al., Prognostic implications of baroreflex sensitivity in heart failure patients

in the β-blocking era, J Am Coll Cardiol, 2009;53:193–9.

17. Li M, Zheng C, Sato T, Kawada T, et al., Vagal nerve stimulation markedly improves long-term survival after chronic heart failure in rats, Circulation, 2004;109:120–4.

18. Sabbah HN, Rastogi S, Mishra S, et al., Long-term therapy with neuroselective electric vagus nerve stimulation improves LV function and attenuates global LV remodelling in dogs with chronic heart failure (abstr), Eur J Heart Fail, 2005:4(Suppl):166.

19. Zhang Y, Popovic ZB, Bibevski S, et al., Chronic vagus nerve stimulation improves autonomic control and attenuates systemic inflammation and heart failure progression in a canine high-rate pacing model, Circ Heart Fail, 2009;2:692–9.

20. Schwartz PJ, Pagani M, Lombardi F, et al., A cardio-cardiac sympatho-vagal reflex in the cat, Circ Res, 1973;32:215–20.

21. Bibevski S, Dunlap ME, Ganglionic mechanisms contribute to diminished vagal control in heart failure, Circulation, 1999;99:2958–63.

22. Bibevski S, Dunlap ME, Prevention of diminished parasympathetic control of the heart in experimental heart failure, Am J Physiol Heart Circ Physiol, 2004;287:H1780–5.

23. Hauptman PJ, Schwartz PJ, Gold MR, et al., Rationale and study design of the increase of vagal tone in heart failure study: INOVATE-HF, Am Heart J, 2012;163:954–62.

24. De Ferrari GM, Tuinenburg AE, Ruble S, et al., Rationale and study design of the NEuroCardiac TherApy foR Heart Failure study: NECTAR-HF, Eur J Heart Fail, 2014;16:692–9.

25. DiCarlo L, Libbus I, Amurthur B, et al., Autonomic regulation therapy for the improvement of left ventricular function and heart failure symptoms: the ANTHEM-HF study, J Card Fail, 2013;19:655–60.

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Device Therapy

Remote Monitoring for Follow-up of Patients with Cardiac Implantable Electronic Devices R ena t o P iet ro R i c c i , 1 L o r e d a n a M o r i c h e l l i 1 a n d N i ra j Va r m a 2 1. Department of Cardiology, San Filippo Neri Hospital, Rome, Italy; 2. Cardiac Pacing and Electrophysiology, Cleveland Clinic, Cleveland, Ohio, US

Abstract Follow-up of patients with cardiac implantable electronic devices is challenging due to the increasing number and technical complexity of devices coupled to increasing clinical complexity of patients. Remote monitoring (RM) offers the opportunity to optimise clinic workflow and to improve device monitoring and patient management. Several randomised clinical trials and registries have demonstrated that RM may reduce number of hospital visits, time required for patient follow-up, physician and nurse time, hospital and social costs. Furthermore, patient retention and adherence to follow-up schedule are significantly improved by RM. Continuous wireless monitoring of data stored in the device memory with automatic alerts allows early detection of device malfunctions and of events requiring clinical reaction, such as atrial fibrillation, ventricular arrhythmias and heart failure. Early reaction may improve patient outcome. RM is easy to use and patients showed a high level of acceptance and satisfaction. Implementing RM in daily practice may require changes in clinic workflow. To this purpose, new organisational models have been introduced. In spite of a favourable cost:benefit ratio, RM reimbursement still represents an issue in several European countries.

Keywords Cardiac implantable electronic devices, implantable cardioverter defibrillator, remote monitoring, follow-up, recall management, atrial fibrillation, ventricular arrhythmias, heart failure Disclosure: Renato Pietro Ricci has received minor consultancy fees from Medtronic and Biotronik; Loredana Morichelli has received minor consultancy fees from Medtronic; Niraj Varma was a consultant to Biotronik for and principal investigator of the TRUST Trial and has received minor consultancy fees from St Jude, Medtronic, Boston Scientific and Sorin.

Received: 24 July 2014 Accepted: 7 August 2014 Citation: Arrhythmia & Electrophysiology Review 2014;3(2):123–8 Access at: www.AERjournal.com Correspondence: Renato Pietro Ricci, Department of Cardiology, San Filippo Neri Hospital, Via Martinotti, 20 00135 Rome, Italy; El: renatopietroricci@tin.it

Monitoring after implant of patients with cardiac implantable electronic devices (CIED) forms a part of both device and patient care, and is the responsibility of the implanting centre. Monitoring is challenged by the increasing number and technical complexity of implanted devices coupled with the increasing clinical complexity of the patient population. Current practice is based on quarterly to yearly in-office visits with an increased rate when the device approaches its end of service, or in case of advisories.1–3 In this model, download of data stored in the device memory, potentially useful for patient management, is delayed. Telemedicine offers a unique opportunity to optimise clinic workflow and to improve device monitoring and patient management.

Technology All major CIED manufacturers have introduced remote monitoring (RM) systems.4 All of them are based on a patient unit capable of interrogating the device and downloading the programmed parameters and the diagnostic data. Information is transmitted to a central database where it is decrypted and stored on a secure website on which it can be viewed by the clinical staff. Early wand-based systems required patient-driven downloads relayed via telephone connections to following facilities. Currently available systems are based on automatic transmission mechanisms that are fully independent of patient or physician interaction. A distinction has to be made between ‘remote interrogation’ and ‘remote monitoring’. In

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the first, device interrogation is performed periodically at home either by the patient manually or by the monitoring system automatically at predefined intervals. In the second, continuous device monitoring may trigger unplanned transmissions in case of programmable alerts.

In spite of major commonalities, different proprietary systems may differ substantially in connectivity, patient involvement, transmission scheduling and alert availability and programming.

Impact on Out-patient Clinic Workload The Lumos-T Safely Reduces Routine Office Device Follow-up Trial (TRUST)5 was the first large randomised trial which demonstrated that RM may safely reduce the number of in-hospital visits by nearly 50 %. The reduction primarily occurred in scheduled encounters involving collection of routine measurements and requiring no clinical intervention. Unscheduled visits slightly increased in the remote arm.

The overall reduction in face-to-face visits was obtained safely, with no difference between the two study arms in mortality, incidence of strokes and events requiring surgical interventions. Furthermore, detection of arrhythmia onset was anticipated by more than 30 days.

Regarding patient adherence to follow-up, the TRUST results6 showed that patients in the RM arm more effectively and durably attained follow-up goals of punctual scheduled follow-up and patient retention compared with conventional methods. Several studies have confirmed such results and there is now strong evidence that RM significantly reduces in-hospital visit numbers, time required for patient follow-up,

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Device Therapy Figure 1: Early Detection of High Voltage Lead Failure

by Continuous Remote Monitoring

Top: intermittent sudden drop in right ventricular (RV) pacing impedance. Bottom: inappropriate detection of self-limited ventricular fibrillation (VF) due to oversensing of spurious signals (noise). Combined data allowed lead replacement before any symptom experienced by the patient. Marker channel: VF = ventricular event sensed in the VF detection window; VS = ventricular sensed event; AS = atrial sensed event. FU = in-person follow-up.

Figure 2: Alert for Newly Detected Atrial Fibrillation – Internal Atrial Electrogram Confirms Appropriate Detection

AS = atrial sensed event; AP = atrial paced event; VS = ventricular sensed event; VP = ventricular paced event; AMS = automatic mode switch.

physician and nurse time and hospital costs.7–11 Furthermore, social costs for patients and caregivers which include travelling, missed work and social activities may be reduced by RM.12,13

Device Management Lead and device performance monitoring is a physician responsibility and represents a challenge due to the number and complexity of

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implanted systems and the increased number of advisories during the last 10 years. A strategy based on frequent in-hospital follow-up visits is unsuitable as it places a huge work burden on out-patient clinics. It is also inefficient since malfunctions are rare and likely to be missed when developing suddenly in the interval between visits, with the possibility of causing potentially life-threatening complications.14 RM allows continuous monitoring, with automatic alerts of battery voltage and impedance, circuit status, charging time, low- and highvoltage lead impedances, sensing and pacing threshold values, external interferences, inappropriate detection of arrhythmias due to noise and double counting or T-wave oversensing (see Figure 1). Clinical studies have demonstrated that malfunctions are usually asymptomatic and that RM is superior to a standard strategy for early detection.15–18 Impact of RM on device longevity is a matter of debate. Concerns have been raised about the potential negative impact of monitoring itself on battery drain. On the other hand, continuous monitoring may allow device programming optimisation with reduction of battery drain. Reduction of capacitor charges by 75 % in implantable cardioverter defibrillator (ICD) patients randomised to RM has been demonstrated in the Effectiveness and Cost of ICD Follow-up Schedule with Telecardiology (ECOST) trial with a potential major impact on battery longevity.19

Disease Management Atrial Fibrillation Expected benefits of RM in patients with CIED and atrial fibrillation (AF) are mainly represented by early arrhythmia detection and patient continuous monitoring. Early detection of AF may induce prompt clinical reaction aimed at preventing severe adverse events such as stroke and heart failure.20 Continuous monitoring allows individual tailoring of patient treatment and continuous updating of therapeutic strategy. AF is very common in CIED patients even in those without any history before implant. Furthermore the majority of events are asymptomatic.21 CIEDs keep detailed information about AF episodes, including number and duration, arrhythmia recurrences and burden, mean and maximum ventricular rate and intracardiac electrogram strips (see Figure 2).22 RM allows continuous access to stored data, and alerts may be programmed for specific events. Early detection of AF by RM has been demonstrated by several trials (for instance five days versus 31 days in the TRUST trial).5 Clinical evidence for stroke risk reduction by RM is still awaited. Preliminary studies estimated that daily monitoring may reduce the two-year stroke risk by 9–18 % with an absolute reduction of 0.2–0.6 %, compared with conventional inter-visit intervals of 6–12 months.23,24 In the Comparative Followup Schedule with Home Monitoring (COMPAS) trial, stroke rate was significantly higher in the control group than in the RM group (3.3 % vs 0.8 %).8 In the recent Anticoagulation Guided by Remote Rhythm Monitoring in Patients With Implanted Cardioverter-Defibrillator and Resynchronisation Devices (IMPACT) study25 of oral anticoagulation therapy for AF guided by RM (started in the case of AF detection, stopped in the case of no recurrences), there was no difference in the outcomes of stroke or all-cause mortality between the intervention group and controls. As a matter of fact, 92 % of patients who experienced stroke in the study group were either not anticoagulated at all or had an international normalised ratio (INR) < 2 at the moment of the event.

Considering that several trials have demonstrated no temporal relationship between AF episodes and stroke it should be recommended that, once started for AF, anticoagulation is not discontinued in the absence of device-detected AF.26,27

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Remote Monitoring for Follow-up of Patients with Cardiac Implantable Electronic Devices

Figure 3: Ventricular Fibrillation Appropriately Detected and Treated at Night During Sleep

Shock delivery restored sinus rhythm. The patient did not perceive the shock. Automatic transmission alerted the clinical staff who called the patient for an unscheduled visit.

AR = atrial event sensed in the refractory period; AP = atrial paced event; VS=ventricular sensed event; VP=ventricular paced event; VF = ventricular event sensed in the ventricular fibrillation detection window; VT = ventricular event sensed in the ventricular tachycardia detection window; FD = ventricular fibrillation detection; CE = charge end; CD = charge delivery.

Ventricular Arrhythmias The significant advantage of RM is the prompt evaluation of appropriateness of detection and efficacy of therapy delivered (see Figure 3). Wireless devices send a virtually immediate transmission for review. The physician can evaluate the episode detail on the website, including internal electrograms and marker chain. With inductive systems, patients may manually send a transmission to the service centre and inform the referring physician by phone in case of perceived shock and/or palpitations or syncope. Ability of RM to early detect ventricular tachyarrhythmias has been demonstrated by the TRUST trial5 (one day vs 36 days for ventricular fibrillation and one day vs 28 days for ventricular tachycardia). Another potential benefit of RM is prevention of inappropriate shocks and also of appropriate but unnecessary shocks. Early reprogramming after inappropriate detection and therapy modulation in the case of slow, well-tolerated arrhythmias may represent the mechanisms for reaching this goal.

The ECOST trial demonstrated that RM significantly reduced the number of actual delivered shocks (-72 %), the number of charged shocks (-76 %) and the rate of inappropriate shocks (-52 %).19,28

Heart Failure In addition to providing necessary therapies for cardiac arrhythmias and heart failure (HF), modern implantable devices also provide diagnostic information that may be useful in monitoring disease progression and in early detection of deterioration of HF, such as rest and night heart rate, heart rate variability, patient daily activity, percentage of right ventricular pacing in single and dual chamber devices, percentage of actual biventricular pacing in cardiac resynchronisation therapy (CRT) devices, intrathoracic impedance or hemodynamic sensors (see Figure 4). A periodic internal electrogram is available to check actual left ventricular capture (see Figure 5).

A drop in impedance is related to pulmonary congestion and it may trigger an alert if it reaches a critical threshold. Continuous monitoring of device diagnostics may allow early identification of HF

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Figure 4: Multiparametric Heart Failure Monitoring in Cardiac Resynchronisation Therapy Patient

Deterioration of heart failure is clearly documented by very low cardiac resynchronisation therapy (CRT) delivery percentage and sudden drop-in thoracic impedance (arrows). CRT = cardiac resynchronisation therapy; BIV = biventricular pacing; VAR PP = heart rate variability; Brd.A = atrial fibrillation burden; IT= thoracic impedance.

progression in the phase in which the patient is still asymptomatic, but in which filling pressures increase and sympathetic activation starts. The ultimate goal is to switch clinical reaction from a ‘reactive phase’, delivered when symptoms worsen and weight increases or when the patient has a pulmonary oedema, to a ‘proactive phase’ delivered when the patient is asymptomatic, typically two to three weeks in advance. The expected results of this strategy are prevention of hospitalisations for heart failure and of disease progression and improvement of patient quality of life (QoL).

Algorithms based on impedance alone showed good sensitivity in HF early detection, on average two weeks in advance, but specificity was poor.29–32 The PARTNERS HF (Program to Access and Review Trending Information and Evaluate Correlation to Symptoms in Patients with Heart Failure) trial demonstrated that patients with a combined HF diagnostic algorithm had a 5.5-fold higher risk of HF event within 30 days.33 RM strategies have been associated with reduced unplanned device-related or cardiac in-hospital visits and reduced emergency visits for cardiac or device-related events (Evolution of Management Strategies of Heart Failure Patients with Implantable Defibrillators [EVOLVO] trial).34 Studies are ongoing to identify a combined score from device diagnostics with the greatest sensitivity and specificity for predicting HF events. Pressure-based technologies have been introduced to improve HF monitoring. Among them, a wireless implantable pulmonary artery haemodynamic monitoring system, the CardioMEMS™ (St Jude Medical, MN, US), has been recently approved by the US Food and Drug Administration (FDA). Pulmonary arterial pressure is continuously monitored and data may be reviewed by the physicians via a RM system. In the CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Heart Failure Patients (CHAMPION) trial35 (550 patients), patients randomised to CardioMEMS guided treatment had a 37 % significant reduction in HF hospitalisation when compared with the control group.

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Device Therapy Figure 5: Periodic Internal Electrogram in a Nonresponder to Cardiac Resynchronisation Therapy

The strip shows intermittent loss of left ventricular capture in the 2nd, 3rd, 6th beat (arrows).

VD = right ventricular channel; VS = left ventricular channel; VP = right ventricular pacing; VSP = left ventricular pacing.

Survival Evidence is emerging that RM may improve survival. The ALTITUDE database (a large observational retrospective, non-randomised, post-market analysis of real-world data) enrolled about 200,000 patients,36 of whom 30 % were remotely monitored. In the RM group risk of death was reduced by 50 % both in patients with single/ dual chamber ICDs and in those with CRT defibrillators (CRT-D).

In the prospective randomised IN-TIME (The Influence of ImplantBased Home Monitoring on the Clinical Management of Heart Failure Patients with an Impaired Left Ventricular Function) trial,37 after one year patients in the RM arm, further to a significant improvement in the composite clinical Packer score (mortality plus HF hospitalisations plus New York Heart Association [NYHA] class), showed a 60 % reduction in cardiovascular mortality.

Implementing Remote Monitoring in Daily Practice – The Organisational Model In spite of the documented benefits, implementing RM in daily clinical practice is challenging and is currently offered only to a minority of potential candidates.38 Reasons for that include reluctance to accept new technology, concern for legal issues, reimbursement issues, concern for increased work burden in the transition phase, and the need to develop new organisational models. Promising results have been demonstrated by a new model based on ‘Primary Nursing’ in which each patient is assigned to a nurse responsible for continuity of care.39 The model is essentially based on a cooperative interaction between the roles of an expert reference nurse and a responsible physician with an agreed list of respective tasks and responsibilities. The model includes strict definition of workflow, early reaction, traceability, continuity of care and maintaining human relationship with the patient. Nurse duties primarily include patient training and education, website data entering, data and alert reviewing, data screening, critical case submission to the physician for clinical judgement, contacts with the patients, monitoring of patient compliance and therapy benefits. Written protocols are established in order to guide nurse reaction to findings and alerts. Physician duties include obtaining patient consent, analysis of submitted critical events and medical decisions, and communicating with general practitioners or other specialists. This model performed remarkably well in the wide Home Guide Registry which enrolled 1,650 patients.40,41 Sensitivity of RM in detecting major cardiovascular events was 84 % with a positive predictive value of 97%. RM required a median manpower less than one hour per health personnel per month for every 100 patients.

A centralised ‘hub and spoke’ model, in which one monitoring centre (hub) screened and filtered daily automatic data in pacemaker and ICD

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patients from several satellite clinics (spokes), has been suggested to help smaller centres fully utilise RM technology despite limited workforce and low patient numbers that may hamper development of dedicated, experienced, single-centre RM teams.42 The use of external centralised call centres has been suggested to reduce the work burden of the hospitals and to avoid the need for on-site dedicated expert teams.43 Personnel at the call centre usually include expert technicians on duty 24 hours a day, seven days a week, with electrophysiologists available on call. Potential advantages of this model may be represented by the 24-hour service and by the possibility of following thousands of patients in a centralised station.

The main limits are represented by the loss of human relationship with the patient and potentially decreased patient compliance and satisfaction. Cost and effectiveness of this strategy could be unfavourable due to call centre costs and to the risk of repetitious alerts and duplication of clinical interventions.

Patient Acceptance and Satisfaction Several studies have shown high patient satisfaction rates, ease of use and compliance with the use of RM systems, even when manual transmission of the data in non-wireless devices is requested.44–46 In spite of some initial concerns, RM has been demonstrated to be easy to use and well accepted even for elderly people and for patients with a low level of education.47 A few patients do not accept RM mainly due to concerns about technology and about the risk of losing the human contact with nurses and physicians. Patient education is critical to overcoming their concerns.48 Poor patient compliance may complicate workflow efficiency, mainly because of missed scheduled remote transmissions or duplicate transmissions. Phonecall burden due to patient noncompliance may negatively impact on personnel work load.49 Automaticity and reliability of the remote technology used is important. In the TRUST trial, no patient assigned to RM crossed over during the study and 98 % elected to retain this follow-up mode on trial conclusion, indicating patient acceptance and confidence in follow-up with this technology.50

Legal Issues RM changes the paradigm of face-to-face visits by gathering electronic data into a data repository that is remote from the health facility, yet readily accessed and shared with various healthcare providers involved in a patient’s care or for research or educational purposes.

There are challenges to maintaining the privacy of patient health information and potential issues related to liability for RM-related services. Telemedicine is still a medical act and the patient has to be appropriately informed about the service and must sign an informed consent document. In order to ensure privacy, patients have to sign a ‘Declaration of Privacy Principles’, written according to the local privacy laws. Responsibility for the data management process lies with the device manufacturer and RM service provider (usually the same), hospitals, telecommunication technology and service providers, physicians and allied professionals and patients. In this scenario the patient is proactive and asked for their compliance with guidelines and physician’s prescriptions. Patient compliance is critical for a good result, and in some cases RM should be denied or withdrawn.

The relationship between the patients and the clinical staff is based on an atypical contract, reported in the informed consent document signed by the patient and the physician, in which general rules for patient RM are defined. In particular, scheduling for alert and transmission

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revision, including the maximum reaction time, and the hospital service level agreement have to be understood and signed by the patient.

The patient has to be informed that currently RM is not an emergency system, but only a tool to improve device surveillance and patient management. Clear instructions have to be given for emergency management. The technology provider is asked to respect the privacy statement and local laws, and to support the hospital centre in all aspects relating to providing patients with a RM service. Hospital duties are mainly to define and make available the facilities needed for RM.

Costs and Reimbursement Issues Economical analyses have consistently demonstrated CIED RM to be cost effective.8,10,12,51–55 Mechanisms involved in savings include reduction of in-hospital visits, reduction of follow-up duration and physician and nurse time, and a reduction in patient costs related to travelling and missed work. Further economic benefits may come from increased device longevity, reduction of hospitalisations and prevention of clinical adverse events such as stroke. In the US since 2006 Medicare and Medicaid defined reimbursement codes for remote follow-up of pacemakers and defibrillators. Reimbursement policies for RM by healthcare systems and insurances vary widely among different countries in Europe.56 This limits adoption. Some form of reimbursement does exist in Germany, UK, Netherlands, Norway, Sweden, Finland, Denmark and Portugal. Although actual fee delivery to hospitals, doctors and manufacturers differs significantly. The fee-for-service payment approach and disease management global budget are the most common systems applied. No reimbursement exists in Switzerland, Belgium, Greece, Baltic States, Italy and Austria.

This situation is rapidly evolving and soon hopefully homogeneous reimbursement rules will be established in Europe.

Current Guidelines Since 2006, the Heart Rhythm Society (HRS)2 recommended that CIED manufacturers developed and implemented wireless and RM

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Carlson MD, Wilkoff BL, Maisel WH, et al. Recommendations from the Heart Rhythm Society Task Force on Device Performance Policies and Guidelines Endorsed by the American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA) and the International Coalition of Pacing and Electrophysiology Organizations (COPE). Heart Rhythm 2006;3:1250–73.

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Varma N, Michalski J, Stambler B, Pavri BB; TRUST Investigators. Superiority of automatic remote monitoring compared with in-person evaluation for scheduled ICD follow-up in the TRUST trial – testing execution of the recommendations. Eur Heart J 2014;35:1345–52.

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technologies to early identify abnormal device behaviour and to reduce under-reporting of device malfunctions. In 2008, the HRS/ European Heart Rhythm Association (EHRA) Expert Consensus on the Monitoring of Cardiovascular Implantable Electronic Devices1 stated that the majority of in-person follow-up could be replaced by RM. The document suggested to maintain face-to-face visits at predischarge visits, at one-month follow-up and at least once a year. Detail on CIED RM management recommendations has been published by a joint committee of the International Society for Holter and Noninvasive Electrocardiology (ISHNE) and EHRA4 in 2012 and by some national societies.57–59 In the 2013 European Society of Cardiology Guidelines on cardiac pacing and cardiac resynchronisation therapy it was stated that “Device-based RM should be considered in order to provide earlier detection of clinical problems and technical issues” (Recommendation class IIa, level of evidence A).60 n

Clinical Perspective • R emote monitoring is rapidly becoming the new standard of care for patients with cardiac implantable electronic devices.

The challenge is to implement remote monitoring in daily practice.

• T he key to the success is from one side to invest on human resource (continuous education of personnel and development of the organisational model) and from the other to use technology progress for better interconnectivity and integration of data in the hospital electronic systems.

• R emote reprogramming which is not currently available, but technically feasible, will require great attention to patient safety prior to implementation.

• A clear reimbursement policy is mandatory to dedicate appropriate resource for a remote monitoring service.

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25. Martin DT, et al. Randomized trial of anticoagulation guided by remote rhythm monitoring in patients with implanted cardioverter-defibrillator and resynchronization devices. American College of Cardiology Scientific Session, Washington, DC, March 29, 2014.

26. Glotzer TV, Daoud EG, Wyse DG, et al., on behalf of the TRENDS Investigators. The relationship between daily atrial tachyarrhythmia burden from implantable device diagnostics and stroke risk: The TRENDS Study. Circ Arrhythmia Electrophysiol 2009;2:474–80.

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28. Guédon-Moreau L, Kouakam C, Klug D, et al. Decreased delivery of inappropriate shocks achieved by remote monitoring of ICD: a substudy of the ECOST trial. J Cardiovasc Electrophysiol 2014; ePub ahead of print. doi: 10.1111/ jce.12405.

29. Yu CM, Wang L, Chau E, et al. Intrathoracic impedance monitoring in patients with heart failure: correlation with fluid status and feasibility of early warning preceding hospitalization. Circulation 2005;112:84–8.

30. Conraads VM1, Tavazzi L, Santini M, et al. Sensitivity and positive predictive value of implantable intrathoracic impedance monitoring as a predictor of heart failure hospitalizations: the SENSE-HF trial. Eur Heart J 2011;32:2266–73.

31. Catanzariti D, Lunati M, Landolina M, et al. Italian Clinical Service Optivol-CRT Group. Monitoring intrathoracic impedance with an implantable defibrillator reduces hospitalizations in patients with heart failure. Pacing Clin Electrophysiol 2009;32:363–70.

32. van Veldhuisen DJ, Braunschweig F, Conraads V, et al. DOT-HF Investigators. Intrathoracic impedance monitoring, audible patient alerts, and outcome in patients with heart failure.

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33. Whellan DJ, Ousdigian KT, Al-Khatib SM, et al. PARTNERS Study Investigators. Combined heart failure device diagnostics identify patients at higher risk of subsequent heart failure hospitalizations: results from PARTNERS HF (Program to Access and Review Trending Information and Evaluate Correlation to Symptoms in Patients With Heart Failure) study.

J Am Coll Cardiol 2010;55:1803–10.

34. Landolina M, Perego GB, Lunati M, et al. Remote monitoring reduces healthcare use and improves quality of care in heart failure patients with implantable defibrillators: the evolution of management strategies of heart failure patients with implantable defibrillators (EVOLVO) study. Circulation 2012;125:2985–92.

35. Abraham WT1, Adamson PB, Bourge RC, et al. CHAMPION Trial Study Group. Wireless pulmonary artery haemodynamic monitoring in chronic heart failure: a randomised controlled trial. Lancet 2011;377:658–66.

36. Saxon LA, Hayes DL, Gilliam FR, et al. Long-term outcome after ICD and CRT implantation and influence of remote device follow-up: the ALTITUDE survival study. Circulation 2010;122:2359–67.

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53. Guédon-Moreau L, Lacroix D, Sadoul N, et al. on behalf of the ECOST trial Investigators. Costs of remote monitoring vs. ambulatory follow-ups of implanted cardioverter defibrillators in the randomized ECOST study. Europace 2014; Epub ahead of print. doi:10.1093/europace/euu012.

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2014

info@heartrhythmcongress.org.uk

International Convention Centre (ICC), Birmingham, UK

www.heartrhythmcongress.org

5th - 8th October

Heart Rhythm Congress

“I love my life.

Now it beats to the right rhythm.”

Michael T. (67), GER, Inventra HF-T QP BIOTRONIK CRT Bringing quality to life

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