AER 3.3

Arrhythmia & Electrophysiology Review Volume 3 • Issue 3 • Winter 2014

www.AERjournal.com

Volume 3 • Issue 3 • Winter 2014

The Burden of Ventricular Arrhythmias Following Left Ventricular Assist Device Implantation Jan M Griffin and Jason N Katz

Management of Cardiac Implantable Electronic Device Infection Cristian Podoleanu and Jean-Claude Deharo

The Use of Gene Therapy for Ablation of Atrial Fibrillation Zhao Liu and J Kevin Donahue

Sudden Unexplained Death – Treating the Family Greg Mellor and Elijah R Behr

Gene delivery to right and left atrium for sinus rhythm restoration: 1. Local myocardial injection with or without electroporation 2. Epicardial gene painting Gene delivery to atrioventricular node for rate control: 1. Intracoronary perfusion and catheterisation 2. Myocardial injection with or without electroporation

ISSN - 2050-3369

Echocardiographic Evidence of an Left Ventricular Assist Devices Suction Event

Temporary Pacing Using a Right Ventricular Screw-in Lead

Gene Delivery Methods for Therapeutic Targets Relevant To Atrial Fibrillation

Radcliffe Cardiology

Lifelong Learning for Cardiovascular Professionals

AER3.3_FC+spine.indd All Pages

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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 ▼ Xarelto® 15 and 20 mg film-coated tablets (rivaroxaban) Prescribing Information (Refer to full Summary of Product Characteristics (SmPC) before prescribing) Presentation: 15mg/20mg rivaroxaban tablet Indication(s): 1. Prevention of stroke & systemic embolism in adult patients with nonvalvular 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: Dosage 1 (SPAF): 20 mg orally o.d. with food. Dosage 2 (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. 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; moderate (creatinine clearance 30-49 ml/min) & severe (creatinine clearance 15-29 ml/min) - limited data indicate 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; 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. Contraindications: 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 under specific circumstances of switching anticoagulant therapy 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: Clinical surveillance in line with anticoagulant practice is recommended throughout the treatment period. 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.

BAYER_NOVEMBER_AER.indd 1

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. 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 co-administration 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: 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): 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: August 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):249-255.

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

November 2014

L.GB.11.2014.8740

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Volume 3 • Issue 3 • Winter 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 •

•

Douglas P Zipes Krannert Institute of Cardiology, Indianapolis, US

In partnership with

•

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

Radcliffe Cardiology Radcliffe Cardiology

Lifelong Learning for Cardiovascular Professionals

Published by Radcliffe Cardiology.

All information obtained by Radcliffe Cardiology and each of the contributors from various sources is as current and accurate as possible. However, due to human or mechanical errors, Radcliffe Cardiology and the contributors cannot guarantee the accuracy, adequacy or completeness of any information, and cannot be held responsible for any errors or omissions, or for the results obtained from the use there of. Where opinion is expressed, it is that of the authors and does not necessarily coincide with the editorial views of Radcliffe Cardiology.

Statistical and financial data in this publication have been compiled on the basis of factual information and do not constitute any investment advertisement or investment advice.

Radcliffe Cardiology, 7/8 Woodlands Farm, Cookham Dean, Berks, SL6 9PN. © 2014 All rights reserved © RADCLIFFE CARDIOLOGY 2014

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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: Winter 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

Editorial Expertise

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

Reprints

Abstracting and Indexing Arrhythmia & Electrophysiology Review is abstracted, indexed and listed in Embase, Scopus, Google Scholar and Summon by Serial Solutions.

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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22/11/2014 11:42

MitraClip

Percutaneous Mitral Valve Repair

From beyond hope…

…to a renewed life

Early referrals to treat mitral regurgitation change lives, leading to improved patient survivability and quality of life.1,2 Percutaneous mitral valve repair, included in 2012 ESC and ESC/EACTS guidelines,3,4 offers high-surgical-risk heart failure patients a new treatment option with an excellent safety profile.3 Referrals for MitraClip percutaneous mitral valve repair could change your patients’ lives.1,2 Locate your nearest MitraClip center at www.abbottvascular.com/int/PMVR References: 1. Schillinger W. ACCESS-EUROPE Phase I: A Post Market Study of the MitraClip System for the Treatment of Significant Mitral Regurgitation in Europe: Analysis of Outcomes at 1 Year. Presented at: ESC 2012; August 25–29, 2012; Munich, Germany. 2. Enriquez-Sarano M, Avierinos JF, Messika-Zeitoun D et al. N Engl J Med 2005;352:875–883.

3. McMurray JJ, Adamopoulos S, Anker SD et al. Eur Heart J 2012;33(14):1787–1847. 4. Vahanian A, Alfieri O, Andreotti F et al. Eur Heart J 2012;33(19):2451–2496.

Abbott Vascular International BVBA. Park Lane, Culliganlaan 2B, B-1831 Diegem, Belgium, Tel: +32 2 714 14 11 Product is subject to prior training requirement as per the Instruction for Use. This product is intended for use by or under the direction of a physician. Prior to use, it is important to read the package insert thoroughly for instructions for use, warnings and potential complications associated with the use of this device. Information contained herein is for distribution for Europe, Middle East and Africa ONLY. Please check with the regulatory status of the device before distribution in areas where CE marking is not the regulation in force. All drawings are artist’s representations only and should not be considered as an engineering drawing or photograph. Photo(s) on file at Abbott Vascular.

For more information, visit our web site at www.abbottvascular.com. MitraClip is a trademark of the Abbott Group of Companies. © 2014 Abbott. All rights reserved. PML04119 Rev A / 9-EH-2-4800-01 10-2014

MitraClip(Abbott).indd 131

Valves repaired. Lives improved.

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ELIQUIS® (apixaban): An oral, direct factor Xa inhibitor indicated for prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation (NVAF), with one or more risk factors, such as prior stroke or transient ischaemic attack (TIA); age ≥75 years; hypertension; diabetes mellitus; symptomatic heart failure (NYHA Class ≥II).2

SUPERIORITY demonstrated on

STROKE OR SYSTEMIC EMBOLISM vs. warfarin1*

* 21% RRR; 0.33% ARR; p=0.01. † 31% RRR; 0.96% ARR; p<0.001.

ELIQUIS®

(apixaban) 2.5 mg & 5 mg Film-coated Tablets Prescribing Information

Consult summary of product characteristics (SmPC) prior to prescribing and for full list of adverse events. PRESENTATION: Film-coated tablets; 2.5mg and 5mg apixaban. INDICATION: Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation (NVAF) with one or more risk factors, such as prior stroke or transient ischaemic attack (TIA), age ≥ 75 years, hypertension, diabetes mellitus or symptomatic heart failure (NYHA Class ≥ II). DOSAGE AND ADMINISTRATION: Oral. The recommended dose is 5mg taken twice a day with water, with or without food.

Patients who meet at least two of the following criteria: serum creatinine ≥ 1.5 mg/dL (133 micromole/l), age ≥ 80 years, or body weight ≤ 60 kg should receive the lower dose of Eliquis, 2.5 mg twice daily. All patients with severe renal impairment (creatinine clearance 15-29 ml/min) should receive the lower dose of Eliquis 2.5 mg twice daily. Therapy should be continued long term. If a dose is missed, Eliquis should be taken immediately and then continue with twice daily dose as before. Switching treatment from parenteral anticoagulants to Eliquis (and vice versa) can be done at the next scheduled dose. Switching treatment from VK A therapy to Eliquis, discontinue warfarin or other VKA therapy and start Eliquis when the international normalized ratio (INR) is < 2.0. Switching treatment from Eliquis to VKA therapy, continue administration of Eliquis for at least 2 days after beginning VKA therapy. After 2 days of co-administration of Eliquis with VKA therapy, obtain an INR prior to next scheduled dose of Eliquis. Continue co-administration of Eliquis and VKA therapy until the INR is ≥ 2.0. Eliquis is not recommended in children and adolescents below the age of 18. See contraindications, and special warnings and precautions section for information on use in patients with hepatic and renal impairment.

CONTRAINDICATIONS: Hypersensitivity to the active substance or to any of the excipients listed in SmPC, active clinically significant bleeding, hepatic disease associated with coagulopathy and clinically relevant bleeding risk, lesion or condition if considered a significant risk factor for major bleeding (refer to SmPC). Concomitant treatment with any other anticoagulant except

Pfizer_doublespread.indd 132

under the circumstances of switching therapy to or from Eliquis or when unfractionated heparin is given at doses necessary to maintain an open central venous or arterial catheter (refer to SmPC). SPECIAL WARNINGS AND PRECAUTIONS: Haemorrhage risk: Carefully observe for signs of bleeding.

Use with caution in conditions with increased risk of haemorrhage.

Discontinue administration if severe haemorrhage occurs. Interaction with other medicinal products affecting haemostasis: Concomitant treatment with any other anticoagulant is contraindicated (see contraindications). The concomitant use of Eliquis with antiplatelet agents increases the risk of bleeding. Care is to be taken if patients are treated concomitantly with nonsteroidal anti-infl ammatory drugs (NSAIDs), including acetylsalicylic acid.

Following surger y, other platelet aggregation inhibitors are not recommended concomitantly with Eliquis. In patients with atrial fibrillation and conditions that warrant mono or dual antiplatelet therapy, a careful assessment of the potential benefi ts against the potential risks should be made before combining this therapy with Eliquis. Renal impairment: No dose adjustment in mild or moderate renal impairment. Lower dose of 2.5mg twice daily in severe renal impairment. Not recommended in patients with creatinine clearance < 15ml/min or in patients undergoing dialysis. Patients with serum creatinine ≥ 1.5 mg/dL (133 micromole/l) associated with age ≥ 80 years or body weight ≤ 60 kg should receive the lower dose of Eliquis, 2.5 mg twice daily. Elderly Patients; The co-administration of Eliquis with acetylsalicylic acid in elderly patients should be used cautiously because of a potentially higher bleeding risk. Hepatic impairment: Eliquis is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk. Not recommended in severe hepatic impairment. Use with caution in mild or moderate hepatic impairment. No dose adjustment is required in patients with mild or moderate hepatic impairment. Eliquis should be used with caution in patients with elevated liver enzymes ALT/AST > 2 x ULN or total bilirubin ≥ 1.5 X ULN. Prior to initiating Eliquis, liver function testing should be

performed. Interaction with inhibitors of CYP3A4 and P-gp: Eliquis is not recommended in patients receiving concomitant strong inhibitors of both CYP3A4 and P-gp. Interaction with inducers of CYP3A4 and P-gp: Strong inducers of both CYP3A4 and P-gp should be co-administered with caution.

Patients with prosthetic heart valves: Safety and efficacy of Eliquis have not been studied in patients with prosthetic heart valves, with or without atrial fibrillation. Therefore, the use of Eliquis is not recommended in this setting.

Surgery and invasive procedures: Eliquis should be discontinued at least 48 hours prior to elective surgery or invasive procedures with a moderate or high risk of bleeding. This includes interventions for which the probability of clinically signifi cant bleeding cannot be excluded or for which the risk of bleeding would be unacceptable. Eliquis should be discontinued at least 24 hours prior to elective surgery or invasive procedures with a low risk of bleeding. This includes interventions for which any bleeding that occurs is expected to be minimal, non-critical in its location or easily controlled. If surgery or invasive procedures cannot be delayed, appropriate caution should be exercised, taking into consideration an increased risk of bleeding. This risk of bleeding should be weighed against the urgency of intervention.

Temporary discontinuation: Discontinuing anticoagulants, including Eliquis, for active bleeding, elective surgery, or invasive procedures places patients at an increased risk of thrombosis. Lapses in therapy should be avoided and if anticoagulation with Eliquis must be temporarily discontinued for any reason, therapy should be restarted as soon as possible provided the clinical situation allows and adequate haemostasis has been established. Spinal/ epidural anaesthesia or puncture: Special care should be taken when neuraxial anaesthesia or spinal/epidural puncture is employed due to risk of epidural or spinal haematoma with potential neurologic complications. The risk of these events may be increased by the post-operative use of indwelling epidural catheters or the concomitant use of medicinal products affecting haemostasis. Indwelling epidural or intrathecal catheters must be removed at least 5 hours prior to the first dose of Eliquis. The risk may also be

22/11/2014 10:40

inc to imp pot be wit Ple Ext neu are Inf gal ma ass Eliq thie Adm con Sm inte Pre bre Com hae hae gin hyp oed (inc hae hae

not oth ong ion. not rial ing.

48 igh y of k of 24 k of s is d. If uld risk on. uis, nts and any cal nal/ hen k of The ing ing ved be

ONLY ELIQUIS® CONNECTS BOTH Choose ELIQUIS®, the only factor Xa inhibitor that demonstrated superior risk reduction in stroke or systemic embolism with significantly less major bleeding vs. warfarin.1

SUPERIORITY demonstrated on

MAJOR BLEEDING vs. warfarin1†

increased by traumatic or repeated epidural or spinal puncture. Patients are to be frequently monitored for signs and symptoms of neurological impairment. Prior to neuraxial intervention the physician should consider the potential benefit versus the risk in anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis. There is no clinical experience with the use of Eliquis with indwelling intrathecal or epidural catheters.

Please refer to SmPC for further information in case there is such a need.

Extreme caution is recommended when using Eliquis in the presence of neuraxial blockade. Laboratory parameters: Clotting tests (PT, INR, and aPTT) are not recommended to assess the pharmacodynamic effects of Eliquis.

Information about excipients: Eliquis contains lactose. Patients with galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take Eliquis. DRUG INTERACTIONS: Agents associated with serious bleeding are not recommended concomitantly with Eliquis, such as: thrombolytic agents, GPIIb/IIIa receptor antagonists, thienopyridines (e.g., clopidogrel), dipyridamole, dextran and sulfinpyrazone.

Administration of activated charcoal reduces Eliquis exposure. Also see contraindications, and special warnings and precautions section; Consult SmPC (contraindications, special warnings and precautions, and drug interactions) for full details on interactions. PREGNANCY AND LACTATION: Pregnancy: Not recommended during pregnancy. Breastfeeding: Discontinue breastfeeding or discontinue Eliquis therapy. UNDESIRABLE EFFECTS: Common (≥ 1/100 to < 1/10): Eye haemorrhage (including conjunctival haemorrhage), other haemorrhage, haematoma, epistaxis, gastrointestinal haemorrhage (including haematemesis and melaena), rectal haemorrhage, gingival bleeding, haematuria, contusion. Uncommon (≥ 1/1,000 to < 1/100): hypersensitivity (including skin rash, anaphylactic reaction and allergic oedema), brain haemorrhage, other intracranial or intraspinal haemorrhage (including subdural haematoma, subarachnoid haemorrhage, and spinal haematoma), intra-abdominal haemorrhage, haemoptysis, haemorrhoidal haemorrhage, haematochezia, mouth haemorrhage, abnormal vaginal

Pfizer_doublespread.indd 133

haemorrhage, urogenital haemorrhage, application site bleeding, occult blood positive, traumatic haemorrhage, post procedural haemorrhage, incision site haemorrhage. Rare (≥ 1/10,000 to < 1/1,000): Respiratory tract haemorrhage (including pulmonary alveolar haemorrhage, laryngeal haemorrhage and pharyngeal haemorrhage), retroperitoneal haemorrhage. LEGAL CATEGORY: POM. PACKAGE QUANTITIES AND BASIC NHS PRICE: Carton of 10 film-coated tablets 2.5mg £10.98, 20 film-coated tablets 2.5mg £21.96, 60 film-coated tablets 2.5mg £65.90, 56 film-coated tablets 5mg £61.50. MARKETING AUTHORISATION NUMBERS: EU/1/11/691/001 - EU/1/11/691/003 and EU/1/11/691/008. MARKETING AUTHORISATION HOLDER: BristolMyers Squibb/Pfizer EEIG, BMS House, Uxbridge Business Park, Sanderson Road, Uxbridge, Middlesex. UB8 1DH. Telephone: 0800-7311736 . DAT E OF PI PRE PA R AT ION: S ep t emb er 2013.

432UK13PR08849-01; ELQ365

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 Bristol-Myers Squibb Pharmaceuticals Ltd Medical Information on 0800 731 1736 or medical.information@bms.com ARR = Absolute Risk Reduction RRR = Relative Risk Reduction References: 1. Granger CB et al. N Engl J Med 2011; 365: 981–992.

2. ELIQUIS ® (apixaban) Summary of Product Characteristics. 19 September 2013. Available at http://www.medicines.org.uk. Last accessed 11 July 2014.

Date of preparation: July 2014 Job code: ELQ567

22/11/2014 10:40

Contents

Foreword

138

Arrhythmia & Electrophysiology Review – Time to Reflect

Demosthenes Katritsis, Editor-in-Chief

Director, Department of Cardiology, Athens Euroclinic, Greece and Honorary Consultant Cardiologist,

St Thomas’ Hospital, London, UK

139

Arrhythmia Mechanisms

The Use of Gene Therapy for Ablation of Atrial Fibrillation

Zhao Liu 1 and J Kevin Donahue 1,2

1. Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio; 2. Department of Cardiovascular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, US

Clinical Arrhythmias

145

The Burden of Ventricular Arrhythmias Following Left Ventricular Assist Device Implantation

Jan M Griffin 1 and Jason N Katz 2

1. Department of Internal Medicine, University of North Carolina; 2. Division of Cardiology, Center for Heart and Vascular Care, University of North Carolina, US

149

Arrhythmias in the Heart Transplant Patient

David Hamon, 1 Jane Taleski, 2 Marmar Vaseghi, 1 Kalyanam Shivkumar 1 and Noel G Boyle 1

1. UCLA Cardiac Arrhythmia Center, UCLA Health System, David Geffen School of Medicine at UCLA, Los Angeles, US; 2. Department of Cardiac Electrophysiology, University Clinic of Cardiology, University of St. Cyril and Methodius, Skopje, Former Yugoslav Republic of Macedonia

156

Greg Mellor 1 and Elijah R Behr 2

161

Sudden Unexplained Death – Treating the Family 1. Clinical Research Fellow & Specialist Registrar Cardiology; 2. Reader in Cardiovascular Medicine & Honorary Consultant Cardiologist & Electrophysiologist Cardiac Research Centre, Institute of Cardiovascular and Cell Sciences, St. George’s University of London, London

Ventricular Tachycardia Ablation – The Right Approach for the Right Patient

Mouhannad M Sadek, Robert D Schaller, Gregory E Supple, David S Frankel, Michael P Riley, Mathew D Hutchinson, Fermin C Garcia, David Lin, Sanjay Dixit,

Erica S Zado, David J Callans, Francis E Marchlinski

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Section of Cardiac Electrophysiology, Cardiovascular Division, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, US

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Contents

168

Pathophysiology and Management of Arrhythmias Associated with Atrial Septal Defect and Patent Foramen Ovale

Henry Chubb, 1,2 John Whitaker, 1 Steven E Williams, 1,3 Catherine E Head, 3 Natali AY Chung, 3 Matthew J Wright 1 and Mark O’Neill 1,3

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

Diagnostic Electrophysiology & Ablation

173

Three-dimensional Rotational Angiography as a Periprocedural Imaging Tool in Atrial Fibrillation Ablation

Tom JR De Potter, Gazmend Bardhaj, Aniello Viggiano, Keith Morrice a nd Peter Geelen

Arrhythmia Unit, Cardiovascular Center, OLV Hospital, Aalst, Belgium

177

Evaluating the Cost-effectiveness of Catheter Ablation of A trial Fibrillation

Andrew Y Chang, 1 Daniel Kaiser, 1 Aditya Ullal, 2 Alexander C Perino, 1,2 Paul A Heidenreich 1,2 and Mintu P Turakhia 1,2

1. Department of Medicine, Stanford University School of Medicine, Stanford, California; 2. Veterans Affairs Palo Alto Health Care System, California, US

Device Therapy

184

Management of Cardiac Implantable Electronic Device Infection

Cristian Podoleanu 1 and Jean-Claude Deharo 2

1. Cardiology Department, University of Medicine and Pharmacy Tîrgu Mures, Tîrgu Mures, Romania; 2. Cardiology Department, CHU La Timone, Marseille, France

190

Cardiac Resynchronisation Therapy or MitraClip® Implantation f or Patients with Severe Mitral Regurgitation and Left Bundle Branch Block?

Jens Kienemund, Karl-Heinz-Kuck and Christian Frerker

Department of Cardiology, Asklepios Clinic St. Georg, Hamburg, Germany

Supported Contribution

194

Stroke Prevention in Atrial Fibrillation – Outcomes and F uture Directions

Katrina Mountfort, Medical Writer, Radcliffe Cardiology Reviewed for accuracy by: John Camm, 1 Gregory Lip, 2 Andreas Goette 3 and Jean-Yves LeHeuzey 4

1. St. George’s University Hospital, London, UK; 2. University of Birmingham, Birmingham, UK; 3. St Vincenz-Hospital, Paderborn, Germany; 4. Georges Pompidou European Hospital and Paris Descartes University, Paris, France

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Foreword

Arrhythmia & Electrophysiology Review – Time to Reflect

A

s this year draws to a close, it seems an appropriate time to reflect on the progress of Arrhythmia & Electrophysiology Review during 2014.

An increased issue frequency compared with previous years has meant a rise in the number of manuscripts published, from 11 in 2012, to 23 in 2013, and rising to 32 in 2014.

All of the review articles that have appeared in the journal have passed through at least one round of double-blind peer review, with the average time from initial submission to first decision of 26 days. Most papers then undergo minor or major revision and at least one further round of peer review (just four papers were accepted without revision). I then conduct a final review of all papers myself before their final acceptance and publication. The average time from submission to acceptance of published papers in 2014 has been 10 weeks.

The support of the journal’s peer review board and members of the wider cardiology community who have been called on to review papers in their specialist areas, and the authors who have worked with them to develop and refine their papers, have been integral to the success of the peer-review process.

Three issues of Arrhythmia & Electrophysiology Review are planned next year – to be published in April, August and November 2015. We hope to publish an increasing number of articles online first, to create a steady flow of new, relevant content to the journal’s website, www.aerjournal.com.

Thank you for your contribution as readers, reviewers and authors, which has been essential to the success of the journal in 2014. We look forward to your continuing support over the coming year.

Dr Demosthenes Katritsis, Editor-in-Chief Director, Department of Cardiology, Athens Euroclinic, Greece and Honorary Consultant Cardiologist, St Thomas’ Hospital, London, UK

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Arrhythmia Mechanisms

The Use of Gene Therapy for Ablation of Atrial Fibrillation Zhao Liu1 and J Kevin Donahue1,2 1. Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio; 2. Department of Cardiovascular Medicine, University of Massachusetts Medical School. Worcester, Massachusetts, US

Abstract Atrial fibrillation is the most common clinically significant cardiac arrhythmia, increasing the risk of stroke, heart failure and morbidity and mortality. Current therapies, including rate control and rhythm control by antiarrhythmic drugs or ablation therapy, are moderately effective but far from optimal. Gene therapy has the potential to become an attractive alternative to currently available therapies for atrial fibrillation. Various gene transfer vectors have been developed for cardiovascular disease with viral vectors being most widely used due to their high efficiency. Several gene delivery methods have been employed on different therapeutic targets. With increasing understanding of arrhythmia mechanisms, novel therapeutic targets have been discovered. This review will evaluate state-of-art gene therapy strategies and approaches including sinus rhythm restoration and ventricular rate control that could eventually prevent or eliminate atrial fibrillation in patients.

Keywords Atrial fibrillation, arrhythmia, heart, gene therapy, vector Disclosure: Zhao Liu has no conflicts of interest to declare. J Kevin Donahue is inventor on gene therapy patents issued to Johns Hopkins University. Otherwise JKD has no conflicts to declare.

Received: 5 September 2014 Accepted: 17 October 2014 Citation: Arrhythmia & Electrophysiology Review, 2014;3(3):139–44 Access at: www.AERjournal.com Correspondence: J. Kevin Donahue, MD, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, 01605. E: donahuelab@gmail.com

In the United States, atrial fibrillation (AF) is the most common sustained cardiac arrhythmia affecting approximately six million patients and contributing to a greatly increased risk of stroke, heart failure (HF) and overall morbidity and mortality.1,2 The prevalence of AF is increasing as the average age of the population increases.3,4 Currently available therapies for AF are suboptimal. Therapeutic options include sinus rhythm restoration and/or ventricular rate control. Both are achieved by pharmacological or ablation therapy.

Efficacy is limited, and the risk of adverse effects to therapy is increased in patients with long-standing persistent AF and comorbidities

Clinical Perspective • A t the current time, gene transfer in several preclinical models has been shown to successfully control ventricular rate or restored sinus rhythm during atrial fibrillation (AF), strengthening the rationale for future use of gene therapy to treat atrial fibrillation.

• Continuing advances in vector technology with clinically favourable attributes, development of minimally invasive gene delivery methods, and novel gene therapy targets increases the likelihood of successful, future translation of AF gene therapy to the clinic.

• Gene therapy for AF has the potential for tremendous patient benefit, but it is not without potential risks. Formal preclinical testing and well thought out clinical trials are prerequisite before clinical release of a gene therapeutic.

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that commonly accompany AF, such as HF or lung disease. 5 Antiarrhythmic drug use has potential risks such as pro-arrhythmia and non-cardiovascular toxicities.6–8 AF ablation therapy has become increasingly popular, but efficacy is limited, with high recurrence rates requiring repeated procedures.9,10 Severe complications (including mortality of 0.1 % in a recent survey) remain a persistent problem for AF ablation.11 Limitations in currently available therapies dictate a need for novel and more effective therapies.

Cardiovascular gene therapy has the potential to expand treatment options for AF. Recent improvements in gene transfer vectors and delivery methods and a deeper understanding of molecular mechanisms of AF increase the probability that gene therapy will successfully translate to a clinically viable therapy over the next few years. In this review, we will analyse the available vectors and delivery methods for myocardial gene therapy and evaluate the current stateof-the-art for AF gene therapy.

General Principles of Myocardial Gene Transfer Gene therapy is the delivery of functional genes into a target cell or tissue for the treatment or prevention of disease. Three major components for successful gene therapy are the selection of a gene transfer vector, a delivery method and a therapeutic gene target.

Vectors Generally, vectors for gene delivery fall into one of two different kinds: viral or nonviral vectors. Nonviral vectors are DNA plasmids, alone or in combination with adjuncts that improve delivery.12,13 The advantage of naked DNA (plasmid with no complexing agent) is its

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Arrhythmia Mechanisms Table 1: Gene Therapy Targets and Strategies for Ablation of Atrial Fibrillation Study

Type of Transgene or Strategy Target

Findings

Species

Vector Delivery Method

Kikuchi et al. 200533

Reentry-disrupting

Human

Atrial APD prolongation. No ventricular

Swine

Ad

Epicardial painting

interventions by

KCNH2-G628S

effects. Arrhythmia suppression not tested.

prolongation

Atrial APD prolongation eliminated burst

Swine

Ad

Epicardial painting

of APD

pacing-induced AF Swine

Ad

Myocardial injection

Rhythm Control

Amit et al.201063

Canine

Soucek et al.201246

KCNH2-G627S

Igarashi et al. 201264 Reentry-disrupting

GJA1, GJA5

Bikou et al. 201134

interventions by

GJA1

improvement of atrial

conduction velocity

Improved atrial conduction and prevented AF

Ad

Epicardial painting

Swine

Ad

Myocardial injection

Liu et al. 200873

HDAC class I

HDAC inhibition reduced atrial arrhythmia

Transgenic

and II inhibitor

inducibility and atrial fibrosis

mice

Trappe et al. 201347

CASP3 inhibitor

Knockdown of caspase 3 suppressed or

Swine

and electroporation

NA Ad

delayed sustained AF by reducing atrial

cardiomyocyte apoptosis

Li et al. 201276

Trigger-disruption by CAMK2D inhibitor Inhibition of CaMKII phosphorylation of

Transgenic

and 201493

preventing Ca2+

mice

leak from SR

RyR2 prevented AF induction

and electroporation

Swine

Myocardial injection and electroporation NA

Rate Control Donahue

Modification

et al. 200031

of AV node

GNAI2

ventricular rate by 20 % in anesthetised

perfusion and

animals

catheterisation

Bauer

Suppressed AV conduction and reduced

Intracoronary

GNAI2-Q205L

et al. 200480

Suppressed AV conduction and reduced

Swine

Swine

Ad

Ad

ventricular rate ~20 % in alert animals

GNAS siRNA

Suppression of Gαs protein expression

Modification of

et al. 201282

SA node

reduced ventricular rate by 8–17 % during SR

and electroporation,

Murata

Suppress L-type

Gem gene transfer to AV node reduced the

Intracoronary

et al. 200481

Calcium channel

Swine

Ad

perfusion and catheterisation

Lugenbiel

GEM

Swine

Intracoronary

Ad

heart rate by 20 % during AF

Myocardial injection

catheterisation

AF = atrial fibrillation; SR = sinus rhythm, Ad = Adenovirus; AV = atrioventricular; APD = action potential duration; NA = not available.

Figure 1: Gene Delivery Methods for Therapeutic Targets Relevant To Atrial Fibrillation

Gene delivery to right and left atrium for sinus rhythm restoration: 1. Local myocardial injection with or without electroporation 2. Epicardial gene painting Gene delivery to atrioventricular node for rate control: 1. Intracoronary perfusion and catheterisation 2. Myocardial injection with or without electroporation

inherent simplicity. DNA in the form of a plasmid is relatively easy to grow, purify and use, and it has documented acceptance by regulatory bodies. The major problem with nonviral vectors is inadequate transfection efficiency.14 Most studies that have assessed in vivo gene delivery with nonviral vectors have shown very limited uptake

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by target cells, with at most a few percent of target cells expressing the transgene. Complexing agents (lipid, carbohydrate or protein coatings) increase delivery to a limited degree, but these agents also increase toxicity. Some physical methods (electroporation, ultrasound disruption of microbubbles) have been developed to enhance gene transfer, but the efficiency in vivo still remains low.14–18 Viral vectors are more frequently used for cardiovascular diseases due to their superior efficiency in cellular uptake and gene expression compared with nonviral vectors. The viral vector genome is altered by removing genes essential for virus replication so that viral vectors can only grow under special, supported circumstances and not in the target tissue (except conditionally replicating adenoviruses used in cancer gene therapy that are not relevant to this AF discussion). The three most commonly used viruses for cardiovascular applications are adenoviruses (Ad), adeno-associated viruses (AAV) and lentiviruses.

Ad are double-stranded DNA viruses with a 35 kb genome. First generation Ad have deletions of a limited number of viral genes, preventing virus replication and creating space for gene insertions up to 10 kb. Helper-dependent Ad vectors have the entire viral genome removed. Ad vectors have been widely used in the myocardial gene transfer literature, mainly due to their high transduction efficiency in cardiac myocytes and capability of generating peak expression over a short time period. The main disadvantage of Ad is the ability to elicit a profound immune response from the recipient. This immune

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response limits duration of gene expression to 2–4 weeks in vivo, depending on the target organ and transgene.19 Immune responses to Ad can cause organ damage and systemic inflammatory responses.20 Ad vectors have been used in a number of myocardial gene therapy clinical trials that have not yet shown efficacy (due in large part to limitations in delivery) but that also have not shown any detectable toxicity.21–23 AAV is a small virus with a linear 5 kb single-stranded DNA genome containing two genes: rep and cap.24 Recombinant AAVs have many desirable properties for cardiac gene transfer, including long-term (potentially permanent) gene expression and a relatively limited immune or inflammatory response by the host organism.25 Among the reported AAV serotypes, AAV1, 6, 8 and 9 are most commonly used for cardiac gene therapy.26,27 AAV gene therapy was initially tested on rodents, where dense cardiac delivery was demonstrated.

It is not nearly as effective in large mammals as it is in mice, but it appears sufficient to alter the phenotype in large mammalian models of disease.28,29 The principal advantage of AAV is the possibility of permanent gene expression. Cardiac studies have been limited, but gene expression in skeletal muscle persisted over one year after injection in a haemophilia clinical trial.30 Preclinical large mammalian models with various targets, delivery techniques and transgenes have reported stable expression persisting for several years after gene transfer.31–33 The principal disadvantage of AAV vectors is the limited insert size, preventing use with some ion channels or other large genes. Recent cardiac studies have shown efficacy of AAV gene therapy in large mammalian models and in a human HF clinical trial.28,34 Lentiviruses are human immunodeficiency virus-based members of the retrovirus family. They are enveloped RNA viruses capable of packaging approximately 10 kb of genetic information. Unlike other retroviruses, lentivirus can transduce non-dividing cells, including cardiomyocytes.

Transfection efficiency for lentivirus vectors is similar to AAV.30 Longterm stable gene expression is another similarity between lentiviruses and AAV, although by a different mechanism. Lentiviruses actually integrate into the host genome allowing permanent expression. A potential risk for lentiviruses is the possibility of mutagenesis related to the insertion site. Another significant limitation is the inability of current technology to concentrate them to levels necessary for intracoronary delivery. Lentivirus vectors have been used for intramyocardial injection in large mammalian models of cardiac disease. The feasibility of using lentivirus vectors in situations needing widespread cardiac delivery has not yet been verified and no clinical trials using lentivirus vectors for cardiac disease have been attempted to date.

Gene Delivery Methods Several gene delivery strategies have been developed and verified for the large mammalian heart (see Figure 1). For AF therapy, the areas of therapeutic interest are primarily broad atrial delivery for sinus rhythm restoration and atrioventricular (AV) nodal delivery for rate control. Methods to deliver a gene transfer vector to these regions reported in preclinical AF models include direct myocardial injection followed by electroporation, epicardial gene painting and intracoronary catheterisation.31–34 Some methods such as intravenous injection and tail vein injection have been reported in mice, but these have not shown viability in large mammals.35,36 Direct myocardial injection is one of the simplest methods for effective cardiac gene delivery. Both naked DNA plasmids and viral vectors

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have been tested with this method.37,38 Intramyocardial injection leads to focused, high-density gene expression, but gene delivery is limited to the tissue volume within a few millimetres of the needle track.39,40 Thus, multiple injection sites would be required to achieve sufficient gene delivery in the large mammalian heart, which increases both the risk of adverse events during the procedure and the probability of heterogeneous gene expression. Injection-related tissue damage also has a risk of triggering an acute inflammatory response.41,42 In order to enhance efficiency, electroporation has been used immediately after plasmid or virus injection. Since its initial trial on skeletal muscle, electroporation-mediated nonviral gene therapy has improved efficiency in both small and large mammalian hearts in vivo.15,43–45 Thomas et al. and Aistrup et al. have demonstrated viability of direct myocardial injection with epicardial electroporation for gene delivery to the atria.34,46-48 In their studies, epicardial electroporation increased the efficiency from ~10 % to ~50 % in both atria. The drawbacks of this hybrid injection/electroporation approach include possible fibrillation of the heart if the pulse is not synchronised and challenges to coordinate the injection with the placement of the electrodes for routine clinical use.15 Targeting for direct injection has been reported with various imaging modalities, such as magnetic resonance imaging (MRI), cardiac CARTO-NOGA mapping (Biosense Webster Inc, CA, US) and ultrasound. These have not yet been reported in AF studies, but they could potentially be adapted for atrial or AV nodal gene delivery.49–52 To date, the atrial epicardial gene painting method is the only reported widespread atrial gene transfer method that achieves dense, transmural, homogenous atrial expression without affecting ventricular cardiomyocytes.33 Gene painting involves applying a mixture of poloxamer gel, dilute trypsin and gene transfer vector to the atrial epicardial surface. Poloxamer gel is used to increase virus contact time with the atria and trypsin increases virus penetration.

The main technical difficulty to translating painting is the current need for open access to the atrial epicardial surface. In clinical settings, this delivery method could potentially be performed during open cardiac surgery or cardiac allografting.53 Modifications to create a minimally invasive method for this technique have not yet been reported.

Intracoronary perfusion is an attractive method for either whole heart or targeted AV nodal gene delivery, but it is not effective for isolated atrial gene delivery due to the lack of sufficient atrial vasculature.54 The advantages of this approach include minimal invasiveness and delivery of vectors using clinically standard equipment. The main disadvantage of delivery by intracoronary perfusion is the limited efficacy of whole heart delivery in spite of several reports that have outlined various parameters that can optimise gene transfer.55–59 To date, the best available method requires nitroglycerin, adenosine, vascular endothelial growth factor and low calcium administration to increase transvascular access, and simultaneous coronary arterial and venous delivery to increase target area. Sasano et al. used these methods with Ad vectors and achieved 80 % transfer to the anterior-septal left ventricle.32 A modification to achieve dense, whole heart delivery has not yet been reported.

Gene delivery methods are arguably the principal limitation to clinical translation of AF gene therapy. Myocardial injection and intracoronary infusion have been used in angiogenesis and heart failure clinical trials.60,61 As noted above, these methods would be

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Arrhythmia Mechanisms limited for widespread, specific atrial delivery in the clinical setting.

The epicardial painting method has potential for clinical application during cardiac surgery, and the development of a minimally invasive version could potentially lead to use in non-surgical AF therapy.

Gene Therapy Targets and Strategies for Ablation of Atrial Fibrillation A key consideration for developing AF therapies is the arrhythmia mechanism. Both triggered activity and reentry have been implicated for provoking AF onset. Multiple lines of evidence support reentry as the dominant mechanism for sustaining AF.5,62 Approaches for sinus rhythm restoration include reentry-disrupting interventions such as prolongation of atrial action potential duration (APD), improvement of atrial conduction and trigger disruption by prevention of calcium leak from the sarcoplasmic reticulum. Rate control has targeted the AV node with overexpression of inhibitory G proteins, suppression of stimulatory G proteins, or introduction of a calcium channel inhibiting protein.

Table 1 presents various gene targets and strategies for AF therapy.

Restoration of Sinus Rhythm A principal element of AF electrical remodelling is the shortening of APD, which favours the maintenance of reentrant circuits. A logical approach would be to prevent AF by increasing the reentrant path length to prolong APD. Kikuchi et al. and Amit et al. demonstrated that gene transfer of the dominant negative mutation KCNH2 (G628S) blocked the IKr current and prolonged atrial APD.33 Animals receiving this gene by the epicardial gene painting method were resistant to atrial burst pacing-induced AF.63 The extent of APD prolongation and AF resistance correlated with gene expression. The dominant negative character of the mutation allowed it to suppress the endogenous, presumably normal, KCNH2 expressed in the atria.

Soucek et al. performed a comparable study confirming that inhibition of KCNH2 function could prevent AF. They used the canine analogue of the channel (CERG-G627S) delivered to pigs using the injection/ electroporation method.46

AF is also linked to cardiomyocyte apoptosis, which leads to a reduction in conduction velocity. In vivo gene transfer with Ad-siRNA-Cas3 to knockdown caspase 3 has suppressed apoptosis, improved conduction velocity and delayed onset of AF, but didn’t alter myocardial fibrosis significantly.47 Calcium leak from the sarcoplasmic reticulum (SR) through ryanodine receptors (RYRs) potentially plays an important role in triggered activity that initiates AF.74 One strategy to target calcium leak from the SR is to reduce calcium/calmodulin-dependent protein kinase II (CaMKII) activity.75 Inhibition of CaMKII decreased phosphorylation of RyR2 and prevented induction of AF in FKBP12.6 knockout mice.76 Long-term inhibition of CaMKII prevented AF in CREM mice.77 A limitation of these data is that they are all from various transgenic mouse models.

AF mechanisms are likely to differ in mice where triggered activity may play a more prominent role. Further investigations in preclinical models are required for a thorough understanding of the various roles of triggering and sustaining mechanisms in maintaining AF. A strategy explored for protection against vagal-induced AF was administration of genes encoding the C-terminal fragment of Gαi and Gαo. The strategy competitively inhibited interaction between endogenous Gαi and Gαo with the muscarinic receptor, attenuating the effects of parasympathetic stimulation. Investigators delivered plasmids by direction injection followed by electroporation. Afterwards, they checked AF inducibility with vagal stimulation or carbachol administration. The combination of Gαi plus Gαo had similar effects on APD shortening when compared with Gαi alone, but had improved AF prevention effects suggesting a mechanism that involved more than the observed APD effects.18

Rate Control

A potentially complementary strategy is to prevent or reverse impaired intra-atrial conduction associated with AF or other diseases affecting the atria. One method to improve conduction is to target disease-related gap junction remodelling. Igarashi et al. found that atrial conduction impairment correlated with connexin (Cx) expression, phosphorylation and intercalated disk localisation. Using the atrial epicardial painting method, they showed not only that Cx43 gene transfer could reverse the conduction defect, but also that Cx40 gene transfer could replace the lost Cx43 and prevent AF.64 Bikou et al. additionally showed that Cx43 gene transfer using the injection/electroporation method improved atrial conduction and prevented AF.34

AF normally results in an elevated ventricular rate. Rate controlling drugs are largely successful mainstays of therapy, but their use is limited in some patients by inadequate efficacy or intolerable side effects.78,79 Patients with AV node ablation are permanently dependent on pacemaker, and they have loss of synchronous left ventricular contraction that can be partially relieved by biventricular pacing, again requiring more implanted hardware. As a proof-of-concept, the inhibitory G-protein α-subunit (Gαi2) was incorporated into Ad and transferred to porcine AV node. The heart rate during AF after Gαi2 gene transfer reduced 20 %.31 In a follow-up study, the heart rate reduction with wild-type Gαi2 was lost when the animals were awake. A constitutively active Gαi2 mutation (cGi) caused a similar rate reduction that was impervious to animal arousal.80 A similar approach introduced Gem, an L-type calcium channel blocking G protein into the pig AV node and reduced ventricular rate.81

A possible approach to suppress conduction heterogeneity is to target atrial structural remodelling. Atrial apoptosis, inflammation and fibrosis are near universal findings, not only in AF, but also in diseases that support development of AF (e.g. HF, hypertension).65–67 Experimental studies indicate that AF can be prevented by suppression of fibrotic pathways including the renin–angiotensin system, transforming growth factor-β1, and other pathways relevant to inflammation and oxidative stress.68–72 As an example, histone deacetylase inhibition inhibited atrial fibrosis and reduced AF vulnerability in transgenic mice.73 No studies with gene therapy in clinically relevant models have yet been reported for prevention or reversal of atrial fibrosis, but this area holds promise.

An alternative approach for AV nodal therapy is down-regulation of the stimulatory G protein α subunit. Lugenbeil et al. found that RNA interference-mediated inhibition of Gαs expression decreased ventricular rate by 20 %.82 In a separate study, they transferred this gene to the sinoatrial node and achieved an 8–17 % decrease in sinus rate.48 This strategy may well be complementary with the reported Gαi approach since the two proteins relay opposite signalling pathways in AV nodal cells. Gαs transmits β adrenergic signalling by increasing adenylate cyclase activity and downstream effects through protein kinase A. Gαi transmits cholinergic and purinergic signalling that decrease adenylate cyclase activity, antagonising the β-adrenergic effects in the AV node.

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RNA interference is evolving to be a promising method for therapeutic silencing of protein-coding genes.83 MicroRNAs (MiRs) that inhibit expression of several proteins have been described. MiRs have been proven in various systems to be critical contributors to the pathophysiology of AF, either directly by modulation of ion channels and connexins, or indirectly by affecting fibrosis.84 MiR-1 is related to potassium channel and conduction velocity.85 MiR-21 and MiR-101 are associated with cardiac fibrosis.86,87 MiR-26 and MiR-328 contribute to the electrical remodelling of AF.88,89 MiRs are a potential gene therapy target for AF. This area is developing rapidly although it is still in an early stage.

Conclusions Gene therapy approaches for AF are all currently at the preclinical development stage. Translation to clinical trial and practice is a long and difficult process. Clinical trials have demonstrated excellent long-

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term safety but limited efficacy for gene therapy in other cardiovascular diseases.22,23,60,61,90 The existing obstacles include lack of efficient, safe and clinically relevant delivery approaches and lack of vectors with high transfer efficiency and long-term regulated expression.91,92 Improvements in gene transfer vectors and delivery methods (including development of minimally invasive delivery methods) will further increase the likelihood of successful transfer of animal studies to clinical science. A better understanding of AF mechanisms in humans (particularly those with persistent AF complicated by heart failure or other cardiac diseases) is needed to refine therapeutic targets.

Appropriate animal models with established AF need to be developed to study for longer time to insure effectiveness and durability of gene therapy. Overall, gene therapy for atrial fibrillation holds the potential to become the paradigm for clinical treatment but extensive further development is needed to reach this goal. n

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48. Lugenbiel P, Bauer A, Kelemen K, et al. Biological Heart Rate Reduction Through Genetic Suppression of G alpha(s) Protein in the Sinoatrial Node. J Am Heart Assoc 2012;1.

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50. Banovic M, Ostojic MC, Bartunek J, et al. Brachial approach to NOGA-guided procedures: electromechanical mapping and transendocardial stem-cell injections. Texas Heart Institute journal / from the Texas Heart Institute of St. Luke’s Episcopal Hospital, Texas Children’s Hospital 2011;38:179–82.

51. David AL, Peebles DM, Gregory L, et al. Clinically applicable procedure for gene delivery to fetal gut by ultrasound-guided gastric injection: toward prenatal prevention of early-onset intestinal diseases. Hum Gene Ther 2006;17:767–79.

52. Voges J, Reszka R, Gossmann A, et al. Imaging-guided convection-enhanced delivery and gene therapy of glioblastoma. Annals of neurology 2003;54:479–87.

53. Ly H, Kawase Y, Yoneyama R, et al. Gene therapy in the treatment of heart failure. Physiology 2007;22:81–96.

54. Greener I, Donahue JK. Gene therapy strategies for cardiac electrical dysfunction. J Mol Cell Cardiol 2011;50:759–65.

55. Donahue JK, Kikkawa K, Johns DC, et al. Ultrarapid, highly efficient viral gene transfer to the heart. Proc Natl Acad Sci USA 1997;94:4664–8.

56. Boekstegers P, von Degenfeld G, Giehrl W, et al. Myocardial gene transfer by selective pressure-regulated retroinfusion of coronary veins. Gene Ther 2000;7:232–40.

57. Bridges CR, Burkman JM, Malekan R, et al. Global cardiacspecific transgene expression using cardiopulmonary bypass with cardiac isolation. Ann Thorac Surg 2002;73:1939–46.

58. Breil I, Koch T, Belz M, et al. Effects of bradykinin, histamine and serotonin on pulmonary vascular resistance and permeability. Acta Physiol Scand 1997;159:189–98.

59. Hajjar RJ, Schmidt U, Matsui T, et al. Modulation of ventricular function through gene transfer in vivo. Proc Natl Acad Sci U S A 1998;95:5251–56.

60. Penn MS, Mendelsohn FO, Schaer GL, et al. An open-label dose escalation study to evaluate the safety of administration of nonviral stromal cell-derived factor-1 plasmid to treat symptomatic ischemic heart failure. Circ Res 2013;112:816–25.

61. Jessup M, Greenberg B, Mancini D, et al. Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID): a phase 2 trial of intracoronary gene therapy of sarcoplasmic reticulum Ca2+ATPase in patients with advanced heart failure. Circulation 2011;124:304–13.

62. Mandapati R, Skanes A, Chen J, et al. Stable microreentrant sources as a mechanism of atrial fibrillation in the isolated sheep heart. Circulation 2000;101:194–99.

63. Amit G, Kikuchi K, Greener ID, et al. Selective Molecular Potassium Channel Blockade Prevents Atrial Fibrillation.

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64. Igarashi T, Finet JE, Takeuchi A, et al. Connexin Gene Transfer Preserves Conduction Velocity and Prevents Atrial Fibrillation.

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65. Lee KW, Everett TH, Rahmutula D, et al. Pirfenidone prevents the development of a vulnerable substrate for atrial fibrillation in a canine model of heart failure. Circulation 2006;114:1703–12.

66. Anyukhovsky EP, Sosunov EA, Plotnikov A, et al. Cellular electrophysiologic properties of old canine atria provide a substrate for arrhythmogenesis. Cardiovascular research 2002;54:462–69.

67. Li DS, Fareh S, Leung TK, et al. Promotion of atrial fibrillation by heart failure in dogs - Atrial remodeling of a different sort.

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69. Burstein B, Nattel S. Atrial fibrosis: Mechanisms and clinical relevance in atrial fibrillation. J Am Coll Cardiol 2008;51:802–09.

70. Verheule S, Sato T, Everett T, et al. Increased vulnerability to atrial fibrillation in transgenic mice with selective atrial fibrosis caused by overexpression of TGF-beta 1. Circ Res 2004;94:1458–65.

71. Freestone B, Beevers DG, Lip GYH. The renin-angiotensinaldosterone system in atrial fibrillation: a new therapeutic target? J Hum Hypertens 2004;18:461–65.

72. Van Wagoner DR. Oxidative Stress and Inflammation in Atrial Fibrillation: Role in Pathogenesis and Potential as a Therapeutic Target. J Cardiovasc Pharmacol 2008;52:306–13.

73. Liu F, Levin MD, Petrenko NB, et al. Histone-deacetylase inhibition reverses atrial arrhythmia inducibility and fibrosis in cardiac hypertrophy independent of angiotensin. J Mol Cell Cardiol 2008;45:715–23.

74. Dobrev D, Voigt N, Wehrens XHT. The ryanodine receptor channel as a molecular motif in atrial fibrillation: pathophysiological and therapeutic implications. Cardiovasc Res 2011;89:734–43.

75. Rokita AG, Anderson ME. New Therapeutic Targets in Cardiology Arrhythmias and Ca2+/Calmodulin-Dependent Kinase II (CaMKII). Circulation 2012;126:2125–39.

76. Li N, Wang TN, Wang W, et al. Inhibition of CaMKII Phosphorylation of RyR2 Prevents Induction of Atrial Fibrillation in FKBP12.6 Knockout Mice. Circ Res

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77. Heijman J, Voigt N, Wehrens XH, et al. Calcium dysregulation in atrial fibrillation: the role of CaMKII. Front Pharmacol 2014;5:30.

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79. Boriani G, Biffi M, Diemberger I, et al. Rate control in atrial fibrillation: choice of treatment and assessment of efficacy.

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80. Bauer A, McDonald AD, Nasir K, et al. Inhibitory G protein overexpression provides physiologically relevant heart rate control in persistent atrial fibrillation. Circulation 2004;110:3115–20.

81. Murata M, Cingolani E, McDonald AD, et al. Creation of a genetic calcium channel blocker by targeted gem gene transfer in the heart. Circ Res 2004;95:398–405.

82. Lugenbiel P, Thomas D, Kelemen K, et al. Genetic suppression of Galphas protein provides rate control in atrial fibrillation. Basic Res Cardiol 2012;107:265.

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Clinical Arrhythmias

The Burden of Ventricular Arrhythmias Following Left Ventricular Assist Device Implantation Ja n M G r i f f i n 1 a n d Ja s o n N K a t z 2 1. Department of Internal Medicine, University of North Carolina; 2. Division of Cardiology, Center for Heart and Vascular Care, University of North Carolina, US

Abstract Few innovations in medicine have so convincingly and expeditiously improved patient outcomes more than the development of the left ventricular assist device (LVAD). Where optimal pharmacotherapy once routinely failed those with end-stage disease, the LVAD now offers considerable hope for the growing advanced heart failure population. Despite improvements in mortality, however, mechanical circulatory support is not without its limitations. Those supported with an LVAD are at increased risk of several complications, including infection, bleeding, stroke and arrhythmic events. While once considered benign, ventricular arrhythmias in the LVAD patient are being increasingly recognised for their deleterious influence on patient morbidity and quality of life. In addition, the often multifactorial aetiology to these episodes makes treatment difficult and optimal therapeutic management controversial. Novel strategies are clearly needed to better predict, prevent, and eradicate these arrhythmias in order to allow future generations of heart failure patients to reap the full benefits of LVAD implantation.

Keywords Ventricular assist device, ventricular arrhythmias, treatment Disclosure: Dr Griffin has no conflicts of interest to declare. Dr Katz receives research support from the Thoratec Corporation.

Received:28 July 2014 Accepted: 29 October 2014 Citation: Arrhythmia & Electrophysiology Review, 2014;3(3):145–8 Access at: www.AERjournal.com Correspondence: Jason N Katz, 160 Dental Circle, CB #7075, 6th Floor Burnett Womack Building, Chapel Hill, NC 27599-7075. E: katzj@med.unc.edu

Prior to the widespread availability of left ventricular assist devices (LVADs), many end-stage heart failure patients were forced to fight over scarce transplant resources or face the reality of impending death. For those considered transplant-ineligible, due to medical or psychosocial factors, symptom palliation and end-of-life care were the only available options. This all changed dramatically following the publication of the landmark Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) trial,1 a multicentre investigation designed to determine the impact of a pulsatile LVAD compared with optimal pharmacotherapy in a high-risk cohort of patients with advanced disease. Boasting a remarkable 48 % reduction in mortality with LVAD support,1 the results of this study promptly ushered in a historic evolution in mechanical circulatory support. Now, little more than a decade after REMATCH was presented, more than 10,000 patients have been implanted with a durable LVAD.2 Novel design changes have ensued, such that modern devices are substantially smaller and no longer pulsatile. By embracing continuous-flow technology, the field has seen incremental gains in patient survival and quality of life. Currently, over 80 % of patients are alive at one year, while two-year survival following device implantation now exceeds 70 per cent.2 Despite enhanced durability and improved long-term outcomes, the LVAD remains susceptible to complications. While untoward sequelae such as bleeding and thrombosis are being increasingly recognised and reported, the influence of cardiac arrhythmia in individuals with an LVAD cannot be overlooked. Rhythm disturbances are, in fact, some of the most common complications. Recent estimates suggest an incidence of 4.66 events per patient year – a figure that would

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put arrhythmia behind only haemorrhage and infection in terms of magnitude of risk.3 Of particular concern is the development of ventricular arrhythmias during mechanical support. What were once thought to be well tolerated and of little clinical consequence, have now become the focus of intensified basic and clinical investigation.

With this in mind, the following review will highlight the epidemiology, symptomatology, complications and management goals for ventricular arrhythmias in the contemporary LVAD era.

Evolution of Ventricular Assist Device Therapy From a historical perspective, LVADs have evolved considerably in a relatively short period of time. Initial first-generation LVADs were designed to be volume-displacement pumps. They provided pulsatile flow, as a blood-containing chamber would fill and then empty in concert with the heart’s native contraction. These pumps were relatively large and required a number of moving parts in order to function optimally.

As a result, they were difficult to implant in smaller patients and were prone to wear over time. In order to overcome some of these limitations, second generation LVADs employed continuous-flow technology through the use of an axial rotor. These devices were considerably smaller, could be implanted in a broader population of patients, and demonstrated enhanced durability. In addition, systemic pulsatility was abandoned in exchange for continuous ventricular unloading. Newer third-generation devices – designed with either hydrodynamically- or magnetically-elevated rotors – now provide cardiac support to advanced heart failure patients via centrifugal flow. Though they have only recently been introduced into the marketplace, and are currently the subject of ongoing investigation, implant volumes for these novel LVADs have been

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Clinical Arrhythmias Table 1: Device Characteristics of First- Through Thirdgeneration Left Ventricular Assist Devices

Flow Type

First Generation Pulsatile

Second Generation Third Generation Axial – Continuous Centrifugal –

Continuous

Power Source

Pneumatic

Electric

Electric

Implant Site

Abdomen

Abdomen/Chest

Pericardium

Indication

BTT or DT

BTT or DT

BTT

Example

HeartMate XVE

HeartMate II

HeartWare HVAD

or Electric

BTT – Bridge-to-Transplantation, DT – Destination Therapy

Table 2: Potential Mechanisms for Ventricular Arrhythmia Generation During Left Ventricular Assist Devices Support Mechanism Description “Suction” Events Caused by excessive LVAD unloading in the setting of suboptimal left ventricular preload. Contact between LVAD inflow cannula and opposing myocardial wall during ventricular collapse may incite arrhythmia.

Fast onset and offset is typical of these events.

Myocardial Electrolyte

Initiation of LVAD support rapidly reverts perturbed

Shifts electrolyte imbalance of failing heart to more “normal” physiological state. This abrupt change may lead to alterations in electrochemical gradients enhancing early post-implantation arrhythmogenesis.

Repolarisation

Early prolongation of the QT interval following LVAD

Abnormalities

placement can trigger early arrhythmic events.

Myocardial Scar Chronic ventricular scar, as well as new scar at the LVAD inflow cannulation site, are both potential substrates for re-entrant arrhythmia.

Systemic Electrolyte

Electrolyte disturbances (e.g. hypokalaemia)

Imbalance secondary to ongoing diuresis, changes in renal function, and additional pharmacotherapies may increase the risk of ventricular arrhythmias during LVAD support.

Figure 1: Echocardiographic Evidence of an Left Ventricular Assist Devices Suction Event

Echocardiographic image showing LVAD suction event. In the first panel, solid arrows indicate typical path of blood flow into the apical LVAD inflow cannula. In the second panel, a dashed circle reveals near complete occlusion of the inflow cannula by the ventricular septum during cavitary collapse (in this case, the result of excessive unloading during severe hypovolaemia).

escalating rapidly. Table 1 highlights some of the important similarities and differences among first- through third-generation devices.

Epidemiology and Aetiology of Ventricular Arrhythmias During LVAD Support In spite of the technological improvements described previously, device complications still plague LVAD populations. As mentioned, ventricular

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arrhythmias are among the most common, occurring in 20–50 % of supported patients.4–9 While the greatest risk tends to be in the first month following device implantation,8 there is a growing body of evidence to suggest that later arrhythmic events are still important. In addition, recurrence following an initial episode is common,9 making care of affected patients an ongoing and laborious challenge.

There have been very few baseline patient or device characteristics that have been shown to be associated with the development of ventricular arrhythmias, and most of these associations have been of limited statistical rigor. Some investigators have demonstrated greater rates of arrhythmic events among patients with ischaemic heart disease,10,11 while others have suggested that non-ischaemic patients are at higher risk.8 The absence of postoperative beta-blocker therapy,12 prolongation of the baseline QT interval,13 and deranged serum electrolytes have all been touted as risk factors as well,11 but none of these have been well validated. In fact, only the presence of pre-implantation ventricular tachycardia (VT) has been repeatedly shown to be a powerful predictor of future episodes of VT after LVAD.4,6,8,9

Mechanisms of Ventricular Arrhythmias in the LVAD Patient Table 2 lists proposed mechanisms for the provocation of arrhythmias during LVAD support. It is not only plausible, but also quite probable that the majority of these conditions do not exist in isolation, but rather may conspire together to trigger an arrhythmic event. Nonetheless, a careful examination of each of these potential mechanisms should be conducted when considering an optimal therapeutic approach to patient management.

Continuous-flow LVADs, with either axial- or centrifugal-flow designs, maintain constant unloading of the left ventricle throughout the entire cardiac cycle. As a result, these devices are considerably more susceptible to preload and afterload changes than their pulsatile-flow predecessors. Suction events occur when the LVAD unloading exceeds the capacity of the left ventricular preload. In such cases, the ventricular chamber collapses and the inflow cannula can then make direct contact with the opposing ventricular wall, resulting in a so-called “suction” episode (see Figure 1). This most commonly occurs during periods of hypovolaemia, but may complicate any clinical situation resulting in diminished LV filling, including cardiac tamponade, right ventricular failure, and severe pulmonary hypertension. These “suction” events are one proposed mechanism for the development of ventricular arrhythmias, particular the instigation of monomorphic ventricular tachycardia (VT).14 Importantly, the development of suction-related VT is usually considered acute in both onset and offset. Recovery of LV preload, or a reduction in LVAD unloading, can often eradicate these episodes.

Electrolyte shifts associated with device implantation and continuousflow support have also been implicated in the development of ventricular arrhythmias after LVAD. Abnormalities in electrophysiological homeostasis are hallmark characteristics of chronic heart failure.15 While the Na/K-ATPase pump maintains a normal potassium gradient in healthy human hearts, this is not often the case in the failing heart.

As a result, myocyte ionic gradients are frequently perturbed, and therefore highly susceptible to sudden depolarisation and arrhythmia formation. At the same time, implantation of an LVAD has been shown to rapidly reverse the electrolyte imbalance of the failing heart, restoring a state of more “normal” physiology. This acute shift in

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Burden of Ventricular Arrhythmias Following Left Ventricular Assist Device Implantation

myocardial electrolyte composition, however, has also been shown to enhance arrhythmogenic vulnerability.16 Patients with chronic heart failure also commonly exhibit several characteristic electrophysiological abnormalities including prolongation of the myocyte action potential, increases in the QT interval and diminished heart rate variability.15 While some studies have shown that after sustained LVAD support there is a shortening of the action potential duration and reduction in the QT interval, occurring in parallel with phenotypic ventricular reverse-remodelling, others have demonstrated a paradoxical QT prolongation in the first week following LVAD implantation, and have suggested that these acute repolarisation abnormalities may trigger early ventricular arrhythmias in the LVAD patient.13 Finally, the influence of myocardial scar has also received considerable attention as a substrate for post-device ventricular arrhythmias. The resulting re-entrant VT is a common cause of morbidity and mortality in patients with advanced heart failure, and remains a potent mechanism for VT even after LVAD placement. Additionally, new scar at the apical inflow cannulation site has been shown to be a viable, though less common source of arrhythmia propagation.17

LVAD Outcomes after Ventricular Arrhythmia Although in the unsupported heart failure patient ventricular arrhythmias can be life threatening, a number of case reports have highlighted their improved tolerability after LVAD implantation. As a result of continuous ventricular unloading, the literature is now replete with cases of LVAD patients maintaining adequate functionality despite weeks or even months of ongoing arrhythmia.18–20 Furthermore, implantable cardioverter defibrillator (ICD) interrogations in LVAD individuals have shown that many patients are experiencing a substantial burden of asymptomatic arrhythmic events.21 Despite these findings, it is anticipated that the majority of individuals will ultimately be affected by their ventricular arrhythmias.9 Most symptoms result from the influence of the arrhythmia on the right ventricle (RV), and the subsequent reduction in right ventricular stroke volume. Manifestations of this can include peripheral oedema, nausea, emesis, hepatic congestion and renal dysfunction, to name a few. Additionally, the reduction in RV stroke volume limits LV filling (and thus LVAD unloading) and can lead to symptoms of low cardiac output, including pre-syncope, syncope, exertional dyspnoea and fatigue.

While it is not clear if the development of ventricular arrhythmias is associated with worsened survival in LVAD cohorts,22 these events do appear to be negatively impacting patient quality-of-life. In a group of patients who routinely value quality over quantity,23 this is an important consideration. Not only are patients challenged physically by the symptoms that may develop, but they are also at much greater risk for re-hospitalisation. In addition, due to the often refractory nature of these rhythm disturbances, management can commonly require multiple pharmacotherapies and even invasive procedures.9

Arrhythmia Management Several methods for managing ventricular arrhythmias in the LVAD population have been employed with modest success. Medications

1. Rose EA, Gelijns AC, Moskowitz AJ, et al. Long-term mechanical left ventricular assistance for end-stage heart failure. N Engl J Med 2001:345:1435–43.

2. Kirklin JK, Naftel DC, Pagani FD, et al. Sixth INTERMACS annual report: a 10,000-patient database. J Heart Lung Transplant

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such as anti-arrhythmic agents and beta-blockers should be utilised when possible in an effort to eliminate the need for more invasive therapies. Both oral and intravenous amiodarone have been previously shown to be the most effective anti-arrhythmic drugs for the secondary prevention of ventricular arrhythmias,9 though the evidence-base supporting this is admittedly thin. Due to the aforementioned refractory nature of many of these events, combination anti-arrhythmic pharmacological strategies are commonly used with varying results.9 In many cases, arrhythmia termination may ultimately require electrical cardioversion. In addition, catheter-based approaches for managing ventricular tachyarrhythmias have been used more frequently. While limited outcome data exist, ablation appears to be safe and feasible.24,25 Though it may not eradicate all rhythm disturbances, this technique seems to reliably reduce arrhythmic burden in the majority of cases.

Future prospective study is clearly warranted to address the role of ablation in LVAD arrhythmia management.

Implantable Cardioverter Defibrillators in LVAD Patients While clearly indicated to reduce sudden death in advanced heart failure populations,26 greater controversy exists regarding the use of ICD therapies in LVAD-supported individuals – particularly those with contemporary continuous-flow devices. Though some investigators have reported survival benefits with ICDs in these patients, and hence advocate ICD implantation in all individuals,6,8 others have shown no demonstrable improvements in mortality.4,21 At this point it is unclear whether everyone with an LVAD should receive an ICD. Given the known adverse impact of ICD shocks on quality of life, the risk of ICD infection and haematogenous seeding of the LVAD pump, and the challenges with electrical interference between some devices, perhaps a more tailored approach to ICD implantation should be considered. In fact, some have advocated the implantation of an ICD only for those with a substantial burden of pre-LVAD arrhythmias.4,8 Additional study will be needed to clarify this ICD debate.

How best to program an ICD during LVAD support also remains uncertain at this time. Given the improved tolerability of ventricular arrhythmias with continuous LVAD unloading, a more restrictive therapeutic strategy is often employed so that only arrhythmic events that are sustained or that result in haemodynamic instability are targeted for ICD intervention. More than likely, novel programming strategies utilising more aggressive anti-tachycardic pacing while limiting ICD discharge will be the goal for future arrhythmia treatment.

Conclusion The implantation of an LVAD can enhance the functional status and survival of patients with end-stage heart failure. While improvements in pump design have led to greater durability and broader patient applicability, complications of these mechanical devices still exist.

Among these are the development of ventricular arrhythmias. Though better tolerated than in unsupported individuals, ventricular arrhythmias can lead to worsening symptoms, increased hospitalisations and diminished quality of life among LVAD patients. Novel strategies for predicting, preventing and treating these common events are needed so that patients may continue to prosper from LVAD support. n

20014;33:555–64.

3. Kirklin JK, Naftel DC, Kormos RL, et al. Fifth INTERMACS annual report: risk factor analysis from more than 6,000 mechanical circulatory support patients. J Heart Lung Transplant 2013;32:141–56.

4. Garan A, Yuzefpolskaya M, Colombo P, et al. Ventricular arrhythmias and implantable cardioverter-defibrillator therapy in patients with continuous-flow left ventricular assist devices. J Am Coll Cardiol 2013;61:2542–50.

5. Genovese E, Dew M, Teuteberg J, et al. Incidence and

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Clinical Arrhythmias patterns of adverse event onset during the first 60 days after ventricular assist device implantation. Ann Thorac Surg 2009;88:1162–70.

6. Cantillon D, Tarakji K, Kumbhani D, et al. Improved survival among ventricular assist device recipients with a concomitant implantable cardioverter-defibrillator. Heart Rhythm 2010;7:466–71.

7. Anderson M, Videbaek R, Boesgaard S, et al. Incidence of ventricular arrhythmias in patients on long-term support with a continuous-flow assist device (HeartMate II). J Heart Lung Transplant 2009;28:733–5.

8. Oswald H, Schultz-Wildelau C, Gardiwal A, et al. Implantable defibrillator therapy for ventricular tachyarrhythmia in left ventricular assist device patients. Eur J Heart Fail 2010;12:593–9.

9. Raasch H, Jensen BC, Chang PP, et al. Epidemiology, management, and outcomes of sustained ventricular arrhythmias after continuous-flow left ventricular assist device implantation. Am Heart J 2012;164:373–8.

10. Bedi M, Kormos R, Winowich S, et al. Ventricular arrhythmias during left ventricular assist device support. Am J Cardiol 2007;99:1151–3.

11. Ziv O, Dizon J, Thosani A, et al. Effects of left ventricular assist device therapy on ventricular arrhythmias. J Am Coll Cardiol 2005;45:1428–34.

12. Refaat M, Chemaly E, Lebeche D, et al. Ventricular arrhythmias after left ventricular assist device implantation.

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Pacing Clin Electrophysiol 2008;31:1246–52.

13. Harding J, Piacentino V, Rothman S, et al. Prolonged repolarization after ventricular assist device support is associated with arrhythmias in humans with congestive heart failure. J Card Fail 2005;11:227–32.

14. Vollkron M, Voitl P, Ta J, et al. Suction events during left ventricular support and ventricular arrhythmias. J Heart Lung Transplant 2007;26:819–25.

15. Tomasselli GF, Beuckelmann DJ, Calkins HG, et al. Sudden death in cardiac failure: the role of abnormal repolarization.

Circulation 1994;90:2534–9.

16. Monreal G, Gerhardt M. Left ventricular assist device support induces acute changes in myocardial electrolytes in heart failure. ASAIO Journal 2007;53:152–8.

17. Cantillon DJ, Bianco C, Wazni OM, et al. Electrophysiologic characteristics and catheter ablation of ventricular arrhythmias among patients with heart failure on ventricular assist device support. Heart Rhythm 2012;9:859–64.

18. Boilson BA, Durham LA, Park SJ. Ventricular fibrillation in an ambulatory patient supported by a left ventricular assist device: highlighting the ICD controversy. ASAIO J 2012;58:170–3.

19. Patel P, Williams JG, Brice JH. Sustained ventricular fibrillation in an alert patient: preserved hemodynamics with a left ventricular assist device. Prehosp Emerg Care 2011;15:533–6.

20. Sims DB, Rosner G, Uriel N, et al. Twelve hours of sustained

ventricular fibrillation supported by a continuous-flow left ventricular assist device. Pacing Clin Electrophysiol 2012:35:e144–8.

21. Enriquez AD, Calenda B, Miller MA, et al. The role of implantable cardioverter-defibrillators in patients with continuous flow left ventricular assist devices. Circ Arrhythm Electrophysiol 2013;6:668–74.

22. Refaat M, Tanaka T, Kormos R, et al. Survival benefit of implantable cardioverter-defibrillators in left ventricular assist device-supported heart failure patients. J Card Fail 2012;18:140–5.

23. Stewart GC, Brooks K, Pratibhu PP, et al. Thresholds of physical activity and life expectancy for patients considering destination ventricular assist devices. J Heart Lung Transplant 2009;28:863–9.

24. Garan A, Iyer V, Whang W, et al. Catheter ablation for ventricular tachyarrhythmias in patients supported by continuous flow left ventricular assist devices. ASAIO Journal 2014;60:311–6.

25. Herweg B, Ilercil A, Kristof-Kuteyeva O, et al. Clinical observations and outcome of ventricular tachycardia ablation in patients with left ventricular assist devices. PACE 2012;35:1377–83.

26. Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 2005;352:225–37.

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Clinical Arrhythmias

Arrhythmias in the Heart Transplant Patient Da v id Ha mon, 1 Ja ne T a lesk i, 2 M a r m a r V a s e g h i , 1 Ka l y a n a m S h i v k u m a r 1 a n d N o e l G B o y l e 1 1. UCLA Cardiac Arrhythmia Center, UCLA Health System, David Geffen School of Medicine at UCLA, Los Angeles, US; 2. Department of Cardiac Electrophysiology, University Clinic of Cardiology, University of St. Cyril and Methodius, Skopje, Former Yugoslav Republic of Macedonia

Abstract Orthotopic heart transplantation (OHT) is currently the most effective long-term therapy for patients with end-stage cardiac disease, even as left ventricular devices show markedly improved outcomes. As surgical techniques and immunosuppressive regimens have been refined, short-term mortality caused by sepsis has decreased, while morbidity caused by repeated rejection episodes and vasculopathy has increased, and is often manifested by arrhythmias. These chronic transplant complications require early and aggressive multidisciplinary treatment. Understanding the relationship between arrhythmias and these complications in the acute and chronic stages following OHT is critical in improving patient prognosis, as arrhythmias may be the earliest or sole presentation. Finally, decentralised/ denervated hearts represent a unique opportunity to investigate the underlying mechanisms of arrhythmias.

Keywords Orthotopic heart transplantation, arrhythmias, bradyarrhythmia, sudden cardiac death, graft rejection, transplant vasculopathy Disclosure: Authors have no conflicts of interest to declare.

Received: 8 July 2014 Accepted: 7 October 2014 Citation: Arrhythmia & Electrophysiology Review, 2014;3(3):149–55 Access at: www.AERjournal.com Correspondence: Noel G Boyle, David Geffen School of Medicine at UCLA, 100 UCLA Medical Plaza, Suite 660, Los Angeles, CA 90095-1679, US. E: NBoyle@mednet.ucla.edu

Support: Supported by grants from the French Federation of Cardiology (to Dr Hamon) and the NIH/National Heart Lung and Blood Institute R01HL084261 (to Dr Shivkumar).

Orthotopic heart transplantation (OHT) is the most effective long-term therapy for end-stage heart disease, with implanted left ventricular assist devices (‘destination therapy’) as an alternative for selected patients. The denervation of the transplanted heart with complete loss of autonomic nervous system modulation, the use of immunosuppressant drugs, as well as the risk of allograft rejection (AR) and vasculopathy, all change the incidence, prognosis and treatment of tachyarrhythmias and bradyarrhythmias, as well as the mechanisms of sudden cardiac death (SCD).

Arrhythmias post-OHT can be classified according to their underlying mechanisms (see Table 1). Tachyarrhythmias and bradyarrythmias can come from the transplanted heart, be due to the surgery itself or result from AR or vasculopathy. In addition, bradyarrhythmias may be caused by drugs taken by the recipient patient before surgery. This review aims to present the most common causes of arrhythmias in OHT patients, and to highlight the importance of ruling out and treating AR and vasculopathy – transplant coronary artery disease (TCAD), which should always be the first concern. The causative mechanisms represent different risk factors, and overlap is possible, which may increase the occurrence of such arrhythmias.

With the increasing success of radiofrequency (RF) ablation techniques, it is important that cardiologists are familiar with tachycardias and bradycardias in this context, which may benefit from a multidisciplinary approach in the management of the patient starting with the underlying mechanisms.

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Tachyarrhythmias Supraventricular Tachycardia The most common atrial arrhythmia in OHT patients is atrial flutter (AFL) followed by atrial fibrillation (AF) with respective incidences of 2.8 %1 to 30.0 %2 and 0.3 %1 to 24.0 %.2 The discrepancies mostly reflect the fact that those studies have variable follow-up periods and often small cohorts. After 1991, the year of the first report of bicaval OHT, this technique progressively supplanted the prior standard atrial anastomosis OHT. In a small cohort of 66 patients, Grant et al.3 found a significant decrease in atrial arrhythmias in the post-operative period among patients undergoing bicaval OHT (9.7 %) compared with those undergoing standard OHT (37.1 %). Maintenance of atrial conformation with better ventricular filling and a reduced tendency to mitral and tricuspid regurgitation may have contributed to this acute decrease.4 In stable OHT patients, only reentrant atrial tachycardia (AT) linked to surgical scars at atrial suture lines seem decreased withbicaval OHT, but not other ATs.5 The major limitation of such studies is that this group also represents the most recently treated patients, and other factors including advances in medical therapy may contribute to the findings.

The largest and most recent studies report a smaller incidence of supraventricular tachycardias (SVTs) due to improvements in graft preservation, surgical techniques resulting in neural decentralisation and isolation of the posterior left atrial wall in addition to advances in immunosuppressant therapy. Thus, post-operative OHT AF or AFL (POAF, POAFL) is not a common finding compared with other thoracic surgeries. Indeed, Khan et al.1 first compared the incidence of AF, AFL

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Clinical Arrhythmias Table 1: Arrhythmias in Transplanted Hearts and Main Underlying Mechanisms Tachyarrhythmia Mechanism 1 Coming from the

Examples AVRT, AVNRT

transplanted heart

2 Due to surgery

AFL, atrio-atrial reentrant

tachycardia

3 Due to rejection or vasculopathy

Early AFL, AF and most late AF

Bradyarrhythmia Mechanism 1 Coming from the

Examples (SND>>AVB) Older donors with pre-existing

SND

transplanted heart

2 Due to surgery

SAN artery injury, biatrial

surgery, IT

3 Due to rejection or vasculopathy

Rejection involving sometimes

HPS only

4 Recipient prior drug exposure

Amiodarone+++

AF = atrial fibrillation; AFL = atrial flutter; AV = atrioventricular; AVB = atrioventricular block; AVRT = atrioventricular reentrant tachycardia; AVNRT = atrioventricular nodal reentrant tachycardia; HPS = His-Purkinje system; IT = ischaemic time; SAN = sinoatrial nodal; SND = sinus node dysfunction.

and other SVTs in heart transplant versus matched low-risk coronary artery bypass graft (CABG) patients. They demonstrated that the OHT group had uncommon AT (0.3 % AF + 2.8 % AFL) when compared with CABG (25 % AF + 17 % AFL), and interestingly, ‘other SVT’ cases were not so different between two groups (1.3 versus 4.3 %, respectively). Dizon et al.6 compared the incidence of AF and AFL in heart transplant versus double-lung transplant and CABG surgery patients. Consistently, the OHT group had uncommon AT (4.6 % AF + 2.9 % AFL) when compared with the two other thoracic surgeries (18.9 % AF + 7.4 % AFL and 19.8 % AF + 3.8 % AFL, respectively). In a similar study, Noheria et al.7 also found that POAF occurred only in 6.5 % of OHT patients, and was much more frequent after maze (22.7 %) or CBAG (16.4 %) surgery. POAF is usually benign and thought to be secondary to the immediate post-operative inflammatory state.8 The two main factors that may contribute to the lower incidence of AT in OHT compared with other thoracic surgeries are autonomic denervation and the use of steroids in OHT. The common underlying mechanisms, prognosis and therapeutic strategies for each arrhythmia are described below.

Atrial Fibrillation Early and late AF incidences and mechanisms (association with graft rejection), are shown in Table 2. In addition to small cohorts and variable follow-up durations, the definition of AF itself played an important role, as some studies counted brief episodes (33 % <6 minutes), while others included only sustained episodes.2 Moreover, the period used to link AF to acute rejection ranged from one week to one month.

These studies demonstrate that POAF (first month after surgery) is an uncommon finding (6 %), and is associated with AR in about one-third of patients. AF in this period was not associated with a poorer prognosis in OHT patients.

AF after the immediate post-operative period (after one month) was rare (4 %) but was associated with very poor outcomes. Indeed, almost no studies reported AF in stable OHT patients. AF in this context was mostly associated with AR in half of the cases and TCAD in almost one-quarter (and also diabetes).9 The remaining cases of AF in this context were linked to sepsis or multiple organ failure.

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Pavri et al.2 found that AF in OHT was associated with a three-fold increased risk of death (relative risk [RR] 3.15). Detailed analysis revealed that only late AF patients were affected and 100 % of them died. The reason for this is not clear, but it is likely that the more severe AR in this period, the cumulative effect of repeated AR episodes and TCAD may be determinant factors. In the absence of central autonomic factors, which increase dispersion of atrial refractoriness,10 and in the presence of pulmonary vein isolation, AF is more likely to be induced by a disease state of the myocardium (immune, ischaemic), or an abnormal neurohormonal milieu with an increased response to endogenous catecholamines11 and adenosine12 due to denervation. Acute changes caused by AR include oedema, lymphocytes infiltrate and myocardial necrosis; repeat episodes are associated with increased myocardial stiffness and fibrosis,13–15 which is likely to promote atrial heterogeneity and areas of slow conduction, facilitating AF.

Atrial Flutter In the early post-operative period, AFL appeared to be even less common than AF (3 %) but the ratio AFL/AF (1/2) was much higher than after other thoracic surgeries (1/3–1/5)6 (see Table 3). Indeed, AR was more linked to POAFL than POAF (one every two versus one every three patients, respectively). A study by Ahmari et al.16 provided new insights, showing that acute rejection was associated with predominant increased pressure and size in the right rather than in the left atrium. The right ventricle is probably more affected by AR and, as with chronic lung diseases, is likely to increase the AFL/ AF ratio in such circumstances. Interestingly, no study has shown a correlation between left ventricular ejection fraction (LVEF) and SVT occurring in the first month during acute AR. Only myocardial biopsies provide a diagnosis of AR, with the sensitivity depending on the number and site.

On the other hand, AFL after the first month post-OHT is slightly more frequent (7 %) than AF and has not clearly been linked to AR. Vaseghi

Clinical Perspective • A trial tachycardia (AT) is an uncommon finding after orthotopic heart transplantation (OHT) compared with other surgeries, and is highly associated with acute rejection.

• A trial fibrillation (AF) is exceptionally rare in stable OHT patients, so late AF must lead physicians to rule out and treat acute rejection, transplant coronary artery disease (TCAD) or sepsis.

• L ate and stable atrial flutter/AT are amenable to ablation, and good outcomes suggest the therapeutic strategy should not differ from non-OHT patients.

• B radyarrhythmias post-OHT respond to sympathomimetics in 50 % of cases; permanent pacing is indicated for persistent symptomatic bradycardia.

• M ost sudden cardiac death in OHT patients is a consequence of TCAD, with mainly asystolic presentation and almost never ventricular fibrillation in patients with moderately depressed or preserved left ventricular ejection fraction.

Pending randomised trials, any evidence of bradycardia or conduction disease merits very careful patient evaluation and consideration for either a pacemaker or an implantable cardioverter defibrillator.

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Table 2: Atrial Fibrillation Frequency and Significance in Transplanted Patients Author Chang9

Year 2013

patients POAF AR 217

Late AF 11.0 %

AR/TCAD 22.3 % AR 25.0 % TCAD 12.5 % sepsis

∑AF

Noheira7

2013

155

6.5 %

0 %

6.5 %

Dasari19

2010

228

8.0 %

5.0 %

13.0 %

1.7 %

4.6 %

Dizon6

2009

174

2.9 %

Cohn46

2008

498

5.4 %

Total AR

62.5 %

52.0 %

Vaseghi5

2008

657

4.0 %

3.0 %

80.0 % AR 15.0 % TCAD 5.0 % sepsis

Ahmari16

2006

167

9.5 %

HR 2.3

7.0 %

34.8 % AR 6.5 % TCAD

Khan1 2006 857

0.3 %

Cui17

2001

892

7.0 %

32.0 %

11.4 %

Grant3

1995

66

10.6 %

28.6 %

Pavri2

1995

TOTAL

2.0 %

47.0 % AR 24.0 % TCAD

88

18.2 %

5.8 %

24.0 %

3,999

6.2 %

4.0 %

7.2 %

37.5 %

46.0 % AR 21.0 % TCAD

61.0 %

53.0 %

AF = atrial fibrillation; AR = allograft rejection; HR = hazard ratio of AF when AR is present; POAF = post-operative atrial fibrillation; TCAD = transplant coronary artery disease; ∑AF = overall AF during follow-up.

Table 3: Atrial Flutter Frequency and Significance in Transplanted Patients Author Chang9

Year 2013

Patients POAFL AR 217

Late AFL 18.4 %

AR/TCAD ∑AFL 27.3 % AR 40.0 % TCAD

Noheira7

2013

155

4.0 %

7.0 %

11.0 %

Dasari19

2010

228

3.0 %

4.0 %

7.0 %

Dizon6

2009 174

Cohn46

2008

498

1.6 %

Vaseghi5

2008

657

2.4 %

Ahmari16

2006

167

15.0 %

9.1 %

Total AR

28.3 % AR 3.3 % TCAD

HR 2.96

Khan1

2006

857

No association

2.8 %

No

Cui17

2001

892

2.0 %

50 %

78.0 % AR 51.0 % TCAD

11.7 %

83.0 %

Grant3

1995

66

3.0 %

50 %

4.6 %

Pavri2

1995

88

21.6 %

Jacquet47

1990

25

8.0 %

50 %

4,024

2.9 %

50 %

TOTAL

7.9 % 7.4 %

Contradictory results

29.5 % 8.6 %

62.8 %

AFL = atrial flutter; AR = allograft rejection; HR = hazard ratio of AFL when AR is present; POAFL = post-operative atrial flutter; TCAD = transplant coronary artery disease; ∑AFL = overall AFL during follow-up.

et al.5 and Chang et al.9 reported that 28 % of overall and late AFL, respectively, were associated with AR, but no comparison was done with sinus rhythm patients. Khan et al.1 did not find any association with rejection, but the Cui et al.17 study yielded a clear link when mild rejection (Grade 1–2 of the International Society for Heart and Lung Transplantation classification18) was also considered. In contrast to AF, no study has shown increased mortality in OHT patients experiencing AFL. In the Pavri et al.2 study a nonsignificant trend was weakened further by the fact that 78 % of those who died also had an episode of AF. Dasari et al.19 showed a significant increase in mortality associated with late arrhythmias only, but this analysis combined AF and AFL. Finally, Vaseghi et al.5 reported, in their stable (no AR) OHT cohort with SVT refractory to medical therapy, that 58 % were AFL. This was consistent with other studies20,21 where most stable OHT patients referred for ablation had cavotricuspid isthmus flutter and all were ablated successfully without any recurrence.

Other Supraventricular Tachycardias The following arrhythmias have been described only in stable OHT patients referred for electrophysiological testing and ablation,5,20,21 thus allowing for a precise diagnosis; however, the possibility that AR or TCAD may be triggers in some patients cannot be excluded.

After isthmus-dependent AFL, the most common reentrant arrhythmias are:

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• Atrial macro-reentrant tachycardia (see Figure 1) – mostly occurring in the upper right atrium, around the native and donor suture line.

The surgical scars at atrial suture lines can create areas of slower conduction, which were successfully targeted in all ablations.

Such arrhythmias are typically the second group described, due to surgery (see Table 1), and they have promoted in part the development of bicaval anastomosis.

• Recipient-to-donor atrial conduction tachycardia also usually involved the right atrial anastomosis. In these cases, ablations were successfully performed at the site of the earliest donor atrial activation on the suture line and the recipient atria was not targeted. Further, recipient tachycardia or atrial rhythm with exit block to the donor atrium can challenge physicians with complex electrocardiograms (ECGs) showing dual atrial tachycardia, 22 pseudo-atrioventricular (AV) block 23 or a pseudo-atrial tachycardia with atrial waves of two different morphologies (one from the donor and one from the recipient).

• AV and AV nodal reentrant tachycardia with successful ablation of the accessory or slow atrioventricular pathways. We classified these (see Table 1) as arrhythmias that come with the transplanted heart, even if the donor never experienced any tachycardias; changes in autonomic tone affecting the substrate are likely to be the mechanism of tachycardias in the recipient patient.

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Clinical Arrhythmias Figure 1: Left Macro-reentrant Scar-related Atrial Tachycardia Atriotomy Related Left Atrial Tachycardia – Iatrogenic Isthmus Atrio-atrial Conduction

A

1.37ms

B

LSPV

Donor left atrium

ABL ABL ABL ABL ABL ABL

LIPV

Transseptal Sheath

SCRSCR SCR SCR

Native left atrium

RA

SCR

MA

ABL

SCR

ABL MA MA

MA MA ABL

SCR

MA ABL

CS

Anastmosis

CS

1.30cr

In the Late Period (After the First Month)

C

A: Surface ECG showing atrial tachycardia at a rate of 150 beats/minute; B: Activation map demonstrates the tachycardia using an isthmus in the left atrium, involving the donor, but not native left atrium (grey). C: Fluoroscopic left anterior oblique view during mapping after transseptal catherisation. ABL = ablation catheter; CS = coronary sinus; LA and RA = left and right atrium. Reproduced with permission from Vaseghi, et al. 2008.5

Figure 2: Management of Atrial Arrhythmias after Orthotopic Heart Transplantation

Atrial fibrillation or atrial flutter

Rate control DC version ± Antiarrhythmics

EARLY

biopsy was negative. When anticoagulant therapy is needed, warfarin and dabigatran should be avoided because of the interaction with cyclosporin.

Rivaroxaban and apixaban are probably the best choices in this setting.

Use of antiarrhythmic drugs and calcium channel blockers is discouraged not only because of drug–drug interactions, but also because of the risk of severe bradycardia requiring pacing. Amiodarone should be avoided because of its prolonged effect, which may result in prolonged interaction needing monitoring of immunosuppressant levels, and prolonged sinus bradycardia requiring pacemaker implantation before patient discharge.

When truly essential, class I antiarrhythmic drugs are most commonly used as TCAD is not expected in the early stage. It is important to note that in the Vaseghi et al.5 study none of the patients with POAF or POAFL had recurrence after cardioversion and drug discontinuation during follow-up, unless associated with repeat AR episodes or severe TCAD. Thus, without evidence of an increased risk of developing paroxysmal or persistent AF, antiarrhythmic drugs should be discontinued as soon as possible and anticoagulation discontinued one month later.

LATE

All patients with atrial arrhythmias without significant contraindications should receive anticoagulation therapy, irrespective of their CHADS2/ CHA2DS2-VASc score. In the study by Chang et al., in which patients received anticoagulation based on CHADS2 score, the group with atrial arrhythmias suffered more nonfatal cerebrovascular events compared with those in sinus rhythm (13.7 versus 3.6 %).9 Both AF and AFL patients should first be screened for AR and TCAD, with appropriate treatment.

In the case of negative results, AF should be closely monitored with repeated biopsy and screened for sepsis. Antiarrhythmic drugs should be managed very carefully especially when patients have TCAD, and patients with stable paroxysmal or persistent AT should be considered for catheter ablation. In patients with persistent AT, anticoagulants should be discontinued one month after documented successful ablation, given the excellent follow-up results in these studies.5,20,21

Ventricular Tachycardia Wean inotropes Consider EMB ID evaluation

Consider EMB Angiography

Treat rejection or CAV

Treat rejection or infection

Discontinue antiarrhythmics at 3 months*

Consider RF ablation for stable flutter *Or as soon as possible. AF = atrial fibrillation; CAV = cardiac allograft vasculopathy; EMB = endomyocardial biopsy; ID = infectious disease; RF = radiofrequency ablation.

Although rejection may underlie some cases of early AF, late AF or flutter is associated with rejection, significant graft vasculopathy, or secondary causes. Reproduced with permission from Thajudeen, et al. 2012.48

Evaluation and Treatment In the Post-operative Period (First Month) Symptomatic treatment with rate control (beta-blockers) and cardioversion as needed is preferred during this period. In all cases, optimisation of electrolyte status and weaning inotropes will benefit the patient. It is important to diagnose and treat AR and, in the case of persistent AF or AFL, repeating endomyocardial multisite biopsy may be helpful if the previous

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Chang et al.9 analysed outcomes in patients experiencing ventricular tachycardia (VT; non-sustained and sustained) and have shown that among all arrhythmias this group had the poorest prognosis (89 % mortality at 83 months). The mean ejection fraction was normal and no patient died from a cardiovascular death; half of the deaths were associated with infection, one-third with AR and one-third with TCAD (there were some cases with both AR and TCAD). A case report24 described sustained bidirectional VT occurring during acute ischaemia in a patient with severe TCAD and ejection fraction (EF) of 40 %, requiring amiodarone, lidocaine and cardioversion. No VT was inducible with programmed stimulation and the patient underwent implantable cardioverter defibrillator (ICD) implantation but never had any appropriate therapy during follow-up. Thus, VT episodes should lead to careful evaluation of the underlying condition.

Bradyarrhythmias Bradyarrhythmias occur in 8–23 % of patients after OHT depending on the case series. In most cases sinus node dysfunction is the main complication but AV block may also occur. The aetiology of sinus node dysfunction is variable and the transplantation technique itself can have a major influence. In the 1995 study of Grant et al.,3 66 patients survived more than 30 days, of which 35 underwent the biatrial anastomotic technique and 31 the bicaval technique. Three patients from the biatrial surgery group (8.6 %) received a permanent pacemaker while none from the bicaval technique group did. In a

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large United Network for Organ Sharing (UNOS) registry of almost 36,000 transplant patients reported in 2010, Cantillon et al.25 found that the bicaval technique was strongly protective against a need for a pacemaker (odds ratio, 0.33), and overall 10.9 % of the population required a pacemaker implant.

Transplanted heart autonomic changes with sympathetic and parasympathetic decentralisation/denervation can also lead to decreased sinus node automaticity, resulting in increased baseline and decreased maximum heart rate during exercise.26 Prolonged donor heart ischaemia time can predispose to conduction system injury in the post-operative period,23 while rejection can involve the cardiac conduction system and lead to bradyarrhythmias.27 Abnormalities of sinoatrial (SA) nodal artery may also influence sinus node dysfunction in patients who undergo OHT. One study performed routine coronary angiography in the first six weeks after the OHT and found that 30 % of SA nodal artery anomalies were in patients with implanted pacemakers and 6 % in the control group (without permanent pacemaker). In the same study, no correlation was found between graft ischaemia time and bradycardia.23 Sinus node dysfunction was described as sinus bradycardia in 17 %, sinus arrest in 27 % and junctional rhythm in 47 % of patients, while 63 % of the patients were asymptomatic and 73 % presented in the early post-operative period.

AV node dysfunction has similar multiple possible aetiologies in patients after OHT. It is most common in the late period after OHT. One study analysed the incidence of AV block among 1,047 patients finding first-degree AV block in 8.3 %, Mobitz I in 0.6 %, Mobitz II in 0.1 % and complete AV block in 1.8 %.28 Pre-operative use of amiodarone in the recipient patient may also result in post-transplant bradycardia. MacDonald at al. reported that these patients required longer periods of atrial pacing immediately post-transplant (mean seven versus three days), but that there was no effect of prior amiodarone therapy on inotropic function or clinical outcome.29

Evaluation and Treatment In the perioperative period bradycardia may be managed with temporary pacing.28 However, in up to 50 % of cases, sympathomimetics such as terbutaline or isoproterenol may be used to maintain the heart rate over 90 beats per minute, while waiting for recovery of sinus node function.30 In the case of sinus node dysfunction after heart transplantation, the current European Society of Cardiology (ESC) guidelines (2013) state that “a period of clinical observation from five days up to some weeks is indicated in order to assess if the rhythm disturbance resolves” (Class I recommendation, level of evidence C).31 Prompt permanent pacemaker implantation is indicated for symptomatic bradycardia and persistent second- or third-degree AV block. As previously noted, overall 10.9 % of patients in the UNOS database required pacemaker implantation.25 In cases of sustained bradycardia, consider endomyocardial biopsy to exclude the possibility of rejection.

In patients with late onset symptomatic bradycardia, rejection and TCAD should be excluded. In one study six of 18 patients underwent pacemaker implantation (three with sinus node dysfunction and three with AV block) and only two of them became dependent during follow-up. This study also found that the mechanism for late onset bradyarrhythmias is unclear, but 30 % of cases occurred in patients with TCAD, while acute rejection was rarely seen (5 %).9 TCAD was shown as a main reason for SCD, presenting with asystole and bradycardia.32 The optimal time for pacemaker implantation and prophylactic pacemaker

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Figure 3: Management of Post-operative Bradycardia

Post-operative bradycardia HR <90

Persistent asymptomatic bradycardia

Temporary epicardial pacing

IV inotropes Isoproterenol Theophylline Terbutaline

Sustained symptomatic bradycardia

Evaluate for Rejection EMB*

Persistent asymptomatic bradycardia

Consider pacemaker implantation

Bradycardia resolved

Permanent pacemaker implantation

EMB = endomyocardial biopsy. Reproduced with permission from Thajudeen, et al. 2012.48

implantation for bradycardia during the rejection period is not well defined. Permanent pacing is indicated for OHT patients with persistent, inappropriate or symptomatic bradycardia not expected to resolve, with a class I recommendation, level of evidence C, according to the American Heart Association (AHA)/American College of Cardiology (ACC)/Heart Rhythm Society (HRS) guidelines.33

Sudden Cardiac Death Insights into SCD in OHT patients come from the Vaseghi et al. retrospective study34 of 628 patients, with 194 deaths, including 116 with a determined cause. In this cohort, one-third died of SCD, and interestingly, the terminal rhythm was asystole in 34 %, followed by pulseless electrical activity (PEA) in 20 % and ventricular fibrillation (VF) in only 10 % (unknown in 36 %). Almost two-thirds of SCDs were induced by acute ischaemia, and this subgroup yielded even more unexpected data since 50 % died from asystole, 44 % from PEA and only 6 % (one patient) from VF. In contrast, SCD in the general population is also associated with the same proportion of ischaemic heart disease (two-thirds), but VF is the most common mechanism occurring in up to two-thirds.35 Results in this OHT cohort could be prejudiced since it is difficult to rule out that VF degenerating to PEA or asystole occurred first, with PEA/asystole then recorded and counted as the initial rhythm. Nonetheless, among 11 patients implanted with ICDs for severe TCAD with depressed LVEF, out-of-hospital cardiac arrest, syncope or recurrent non-sustained ventricular tachycardia (NSVT), only one experienced an appropriate shock (which was possibly related to recurrent NSVT with an older defibrillator), while two patients received multiple inappropriate therapies (six shocks, five anti-tachycardia pacing).

Non-SCD patients in this cohort represented a very distinct profile as they died shortly after OHT (16 versus 38 months for SCD) and mostly from sepsis (43 versus 0 %), but almost never from ischaemia (4 %), and similarly from AR (13 versus 15 %). Again, the first documented rhythm was asystole (73 %).

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Clinical Arrhythmias As surgical techniques and immunosuppressive regimens have been refined, short-term mortality caused by sepsis has been replaced by increasing morbidity and mortality caused by TCAD. Prevention of SCD in this population has become a major concern in OHT care. The benefits of ICD implantation in OHT patients are limited and controversial. Indeed, patients who died from SCD had similar LVEF (48 %) to patients who died from non-SCD, which is not surprising considering that most patients died from asystole and not from VF. This is consistent with the cohort study of Leonelli et al.36 involving 89 patients, in which all five who died from SCD belonged to the group of patients with ECG evidence of progressive conduction system damage during follow-up (i.e. a new hemiblock or complete bundle branch block), of which two were directly related to bradycardia. All five patients had TCAD and the group experienced a mild deterioration of LVEF (62–55 %) during follow-up.

The authors proposed that TCAD (or AR), which is known to affect the myocardium could also directly injure the conduction system and increase risk of SCD from bradycardia. On the other hand, Ptaszek et al.37 reported, in a cohort of 10 patients implanted 15 years after OHT, including five with severe decrease in LV function, that three of them had appropriate ICD therapy during follow-up. It is possible that reinnervation long after the surgery may have induced a higher susceptibility to ventricular arrhythmias with beneficial effect from ICD implant.

Improvements in the prevention and treatment of TCAD should be the cornerstone for decreasing mortality, and prospective studies are needed to enhance screening and choice of device. OHT patients with sinus node dysfunction should be implanted with a dual chamber pacemaker because of additional risk of asystole associated with TCAD. Furthermore, even TCAD patients who have a borderline indication for pacing such as paroxysmal, asymptomatic bradycardia or progressive conduction disease may benefit from pacemaker implantation, as procedural and infection risks probably do not counterbalance the risk of asystole and SCD. At least TCAD patients should undergo a careful assessment of the conduction system integrity by repeat ECG, Holter monitoring or electrophysiological studies leading to a multidisciplinary improved estimation of SCD risk.

Finally, the use and benefit of beta-blocker therapy in TCAD patients should be carefully assessed in patients without pacemakers or ICDs because of asystole risk.

1. Khan M, Kalahasti V, Rajagopal V, et al. Incidence of atrial fibrillation in heart transplant patients: long-term follow-up.

J Cardiovasc Electrophysiol 2006;17(8):827–31.

2. Pavri BB, O’Nunain SS, Newell JB, et al. Prevalence and prognostic significance of atrial arrhythmias after orthotopic cardiac transplantation. J Am Coll Cardiol 1995;25(7):1673–80.

3. Grant SC, Khan MA, Faragher EB, et al. Atrial arrhythmias and pacing after orthotopic heart transplantation: bicaval versus standard atrial anastomosis. Br Heart J 1995;74(2):149–53.

4. Kendall SW, Ciulli F, Biocina B, et al. Atrioventricular orthotopic heart transplantation: a prospective randomised clinical trial in 60 consecutive patients. Transplant Proc 1993;25(1 Pt 2):1172–3.

5. Vaseghi M, Boyle NG, Kedia R, et al. Supraventricular tachycardia after orthotopic cardiac transplantation. J Am Coll Cardiol 2008;51(23):2241–9.

6. Dizon JM, Chen K, Bacchetta M, et al. A comparison of atrial arrhythmias after heart or double-lung transplantation at a single center: insights into the mechanism of post-operative atrial fibrillation. J Am Coll Cardiol 2009;54(22):2043–8.

7. Noheria A, Patel SM, Mirzoyev S, et al. Decreased postoperative atrial fibrillation following cardiac transplantation: the significance of autonomic denervation.

Pacing Clin Electrophysiol 2013;36(6):741–7.

8. Maisel WH, Rawn JD, Stevenson WG. Atrial fibrillation after cardiac surgery. Ann Intern Med 2001;135(12):1061–73.

9. Chang HY, Lo LW, Feng AN, et al. Long-term follow-up of arrhythmia characteristics and clinical outcomes in heart transplant patients. Transplant Proc 2013;45(1):369–75.

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Interesting Pathophysiological Findings Associated with Arrhythmias in Orthotopic Heart Transplantation OHT provides a unique model of the decentralised/denervated heart and reveals insights into the mechanism of arrhythmias. While one may assume that re-innervation occurs after OHT, Vaseghi et al.5 reported highly depressed heart rate variability parameters, even years after the graft surgery, which was consistent with previous studies.38,39 Specific findings are: • The lower rate of peri-operative AF after OHT compared with other thoracic surgeries, with predominantly absence of AF in stable OHT patients, strongly supports both the autonomic and the pulmonary vein trigger hypothesis for genesis of AF. Moreover, AF episodes occurring long after transplantation are only associated with rejection or ischaemia, which alter the normal atrial substrate.17 As expected, during the acute post-operative state, only denervation is likely to decrease AF in OHT patients, as suggested by the higher rates after maze7 or double-lung transplantation6 both of which require pulmonary vein isolation.

• In the stable OHT cohort of Vaseghi et al.,5 among patients presenting with SVT referred for ablation, only 13 % were asymptomatic while 58 % were able to feel palpitations. Beyond a possible referral bias, this interesting finding supports the idea that palpitations may reflect chest wall rather than cardiac sensitivity.40 • In the same study, one of the 14 patients with AFL was associated with a tachycardia induced cardiomyopathy, which fully reversed after ablation. Hence the autonomic nervous system does not appear to be critical in the generation of tachycardia-mediated cardiomyopathy.

• In a second study by Vaseghi et al.34 VF as the mechanism of SCD was rare, even during acute ischaemia. Such findings highlight the critical role of the autonomic nervous system in the genesis and maintenance of malignant ventricular arrhythmias, particularly during ischaemia, which has been demonstrated for decades to induce a sympathetic reflex.41 Sympathetic hyperinnervation, which follows the denervation of scarred myocardium leads to a heterogeneous response to sympathetic stimulation causing an increased incidence of VT/VF.42,43 Furthermore, cervicothoracic sympathectomy, particularly bilateral, can have a significant antiarrhythmic effect.44,45 The decreased sympathetic reflex in the setting of ischaemia involving conduction system could also be a factor in asystole by decreasing the likelihood of an escape rhythm emerging. n

10. Euler DE, Scanlon PJ. Acetylcholine release by a stimulus train lowers atrial fibrillation threshold. Am J Physiol 1987;253(4 Pt 2):H863–8.

11. Yusuf S, Theodoropoulos S, Mathias CJ, et al. Increased sensitivity of the denervated transplanted human heart to isoprenaline both before and after beta-adrenergic blockade.

Circulation 1987;75(4):696–704.

12. Ellenbogen KA, Thames MD, DiMarco JP, et al.

Electrophysiological effects of adenosine in the transplanted human heart. Evidence of supersensitivity. Circulation 1990;81(3):821–8.

13. Stengel S, Allemann Y, Zimmerli M, et al. Doppler tissue imaging for assessing left ventricular diastolic dysfunction in heart transplant rejection. Heart 2001;86(4):432–7.

14. Valantine HA, Appleton CP, Hatle LK, et al. A hemodynamic and Doppler echocardiographic study of ventricular function in long-term cardiac allograft recipients. Etiology and prognosis of restrictive-constrictive physiology. Circulation 1989;79(1):66–75.

15. Puleo JA, Aranda JM, Weston MW, et al. Noninvasive detection of allograft rejection in heart transplant recipients by use of Doppler tissue imaging. J Heart Lung Transplant 1998;17(2):176–84.

16. Ahmari SA, Bunch TJ, Chandra A, et al. Prevalence, pathophysiology, and clinical significance of post-heart transplant atrial fibrillation and atrial flutter. J Heart Lung Transplant 2006;25(1):53–60.

17. Cui G, Tung T, Kobashigawa J, et al. Increased incidence of atrial flutter associated with the rejection of heart transplantation. Am J Cardiol 2001;88(3):280–4.

18. Billingham ME, Cary NR, Hammond ME, et al. A working formulation for the standardization of nomenclature in the diagnosis of heart and lung rejection: Heart Rejection Study Group. The International Society for Heart Transplantation.

J Heart Transplant 1990;9(6):587–93.

19. Dasari TW, Pavlovic-Surjancev B, Patel N, et al. Incidence, risk factors, and clinical outcomes of atrial fibrillation and atrial flutter after heart transplantation. Am J Cardiol 2010;106(5):737–41.

20. Nof E, Stevenson WG, Epstein LM, et al. Catheter ablation of atrial arrhythmias after cardiac transplantation: findings at EP study utility of 3-D mapping and outcomes. J Cardiovasc Electrophysiol 2013;24(5):498–502.

21. Elsik M, Teh A, Ling LH, et al. Supraventricular arrhythmias late after orthotopic cardiac transplantation: electrocardiographic and electrophysiological characterization and radiofrequency ablation. Europace 2012;14(10):1498–505.

22. Nevzorov R, Ben-Gal T, Strasberg B, Haim M. Atrial flutter in a post-transplant recipient. Isr Med Assoc J 2012;14(7):448–9.

23. DiBiase A, Tse TM, Schnittger I, et al. Frequency and mechanism of bradycardia in cardiac transplant recipients and need for pacemakers. Am J Cardiol 1991;67(16):1385–9.

24. Bhavnani SP, Clyne CA. Bidirectional ventricular tachycardia due to coronary allograft vasculopathy a unique presentation. Ann Noninvasive Electrocardiol 2012;17(4):405–8.

25. Cantillon DJ, Tarakji KG, Hu T, et al. Long-term outcomes and clinical predictors for pacemaker-requiring bradyarrhythmias after cardiac transplantation: analysis of

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the UNOS/OPTN cardiac transplant database. Heart Rhythm 2010;7(11):1567–71.

26. Banner NR, Patel N, Cox AP, et al. Altered sympathoadrenal response to dynamic exercise in cardiac transplant recipients. Cardiovasc Res 1989;23(11):965–72.

27. Cooper MM, Smith CR, Rose EA, et al. Permanent pacing following cardiac transplantation. J Thorac Cardiovasc Surg 1992;104(3):812–6.

28. Cui G, Kobashigawa J, Margarian A, Sen L. Cause of atrioventricular block in patients after heart transplantation.

Transplantation 2003;76(1):137–42.

29. Macdonald P, Hackworthy R, Keogh A, et al. The effect of chronic amiodarone therapy before transplantation on early cardiac allograft function. J Heart Lung Transplant 1991;10(5 Pt 1):743–8; discussion 748–9.

30. Redmond JM, Zehr KJ, Gillinov MA, et al. Use of theophylline for treatment of prolonged sinus node dysfunction in human orthotopic heart transplantation. J Heart Lung Transplant 1993;12(1 Pt 1):133–8; discussion 138–9.

31. 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). Europace 2013;15(8):1070–118.

32. Grinstead WC, Smart FW, Pratt CM, et al. Sudden death caused by bradycardia and asystole in a heart transplant patient with coronary arteriopathy. J Heart Lung Transplant 1991;10(6):931–6.

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33. Epstein AE, DiMarco JP, Ellenbogen KA, et al. ACC/AHA/ HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to revise the ACC/ AHA/NASPE 2002 guideline update for implantation of cardiac pacemakers and antiarrhythmia devices): developed in collaboration with the American Association for Thoracic Surgery and Society of Thoracic Surgeons. Circulation 2008;117(21):e350–408.

34. Vaseghi M, Lellouche N, Ritter H, et al. Mode and mechanisms of death after orthotopic heart transplantation.

Heart Rhythm 2009;6(4):503–9.

35. Podrid PJ, Myerburg RJ. Epidemiology and stratification of risk for sudden cardiac death. Clin Cardiol 2005;28(11 Suppl 1):I3–11.

36. Leonelli FM, Dunn JK, Young JB, Pacifico A. Natural history, determinants, and clinical relevance of conduction abnormalities following orthotopic heart transplantation.

Am J Cardiol 1996;77(1):47–51.

37. Ptaszek LM, Wang PJ, Hunt SA, et al. Use of the implantable cardioverter-defibrillator in long-term survivors of orthotopic heart transplantation. Heart Rhythm 2005;2(9):931–3.

38. Stevenson LW, Sietsema K, Tillisch JH, et al. Exercise capacity for survivors of cardiac transplantation or sustained medical therapy for stable heart failure. Circulation 1990;81(1):78–85.

39. Quigg RJ, Rocco MB, Gauthier DF, et al. Mechanism of the attenuated peak heart rate response to exercise after orthotopic cardiac transplantation. J Am Coll Cardiol

1989;14(2):338–44.

40. Khalsa SS, Rudrauf D, Feinstein JS, Tranel D. The pathways of interoceptive awareness. Nat Neurosci 2009;12(12):1494–6.

41. Brown AM, Malliani A. Spinal sympathetic reflexes initiated by coronary receptors. J Physiol 1971;212(3):685–705.

42. Cao JM, Fishbein MC, Han JB, et al. Relationship between regional cardiac hyperinnervation and ventricular arrhythmia. Circulation 2000;101(16):1960–9.

43. Chen PS, Chen LS, Cao JM, et al. Sympathetic nerve sprouting, electrical remodeling and the mechanisms of sudden cardiac death. Cardiovasc Res 2001;50(2):409–16.

44. Vaseghi M, Gima J, Kanaan C, et al. Cardiac sympathetic denervation in patients with refractory ventricular arrhythmias or electrical storm: intermediate and long-term follow-up. Heart Rhythm 2014;11(3):360–6.

45. Bourke T, Vaseghi M, Michowitz Y, et al. Neuraxial modulation for refractory ventricular arrhythmias: value of thoracic epidural anesthesia and surgical left cardiac sympathetic denervation. Circulation 2010;121(21):2255–62.

46. Cohn WE, Gregoric ID, Radovancevic B, et al. Atrial fibrillation after cardiac transplantation: experience in 498 consecutive cases. Ann Thorac Surg 2008;85(1):56–8.

47. Jacquet L, Ziady G, Stein K, et al. Cardiac rhythm disturbances early after orthotopic heart transplantation: prevalence and clinical importance of the observed abnormalities. J Am Coll Cardiol 1990;16(4):832–7.

48. Thajudeen A, Stecker EC, Shehata M, et al. Arrhythmias after heart transplantation: mechanisms and management. J Am Heart Assoc 2012;1:e001461.

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Sudden Unexplained Death – Treating the Family Greg Mellor1 and Elijah R Behr2 1. Clinical Research Fellow & Specialist Registrar Cardiology; 2. Reader in Cardiovascular Medicine & Honorary Consultant Cardiologist & Electrophysiologist Cardiac Research Centre, Institute of Cardiovascular and Cell Sciences, St. George’s University of London, London

Abstract Sudden unexplained death in the context of a normal heart at post-mortem and negative toxicological analysis is termed sudden arrhythmic death syndrome (SADS). SADS is often due to cardiac genetic disease, particularly channelopathies. Assessment of family members of SADS victims will reveal at least one affected individual in up to half of families. Specialist evaluation begins with an expert cardiac autopsy that improves diagnostic accuracy and minimises erroneous interpretation of minor pathological findings. Retention of appropriate material for post-mortem genetic testing, ‘the molecular autopsy’, is recommended as this may provide a genetic diagnosis in up to a third of cases.

Clinical assessment of families initially comprises 12-lead ECG with high right ventricular leads, echocardiogram and exercise testing.

Additional investigations include sodium channel blocker and epinephrine provocation tests. Families with a diagnosis should be managed as per guidelines. Those with negative investigations can generally be discharged unless they are young and/or symptomatic.

Keywords Sudden death, sudden arrhythmic death syndrome, family assessment, post-mortem, molecular autopsy, exercise test Disclosure: The authors have no conflicts of interest to declare.

Received: 29 September 2014 Accepted: 3 November 2014 Citation: Arrhythmia & Electrophysiology Review, 2014;3(3):156–60 Access at: www.AERjournal.com Correspondence: Dr. Elijah R Behr, Cardiac Research Centre, Institute of Cardiovascular and Cell Sciences, St. George’s University of London, London SW17 0RE E: ebehr@sgul.ac.uk

Sudden unexplained death syndrome (SUDS)1 is rare in the young but when it occurs it is devastating for family and friends, and affects whole communities. That it can affect fit, athletic individuals and may be related to competitive sports only adds to the sense of incomprehension and injustice felt by wider society. In comparison with the older population, where sudden death is more common and mostly a consequence of ischaemic heart disease,2 in the young it is more commonly related to heritable cardiac disease such as cardiomyopathies, channelopathies and aortopathy.

Therefore, systematic evaluation of family members of sudden death victims can reveal other affected individuals and potentially prevent further deaths.

The reported incidence of SUDS is variable.3–5 This is due mainly to methodological differences between studies and differing population characteristics. Winkel et al. 3 analysed the death certificates of all deaths occurring in persons aged less than 35 years in Denmark over a seven-year period. They identified 625 cases of SUD and calculated an incidence of 2.8 per 100,000 person-years. A similar study by Papadakis et al.4 conducted in England and Wales found a rate of 1.8 per 100,000 person-years. The rate of sudden death in persons aged 14–35 in the Republic of Ireland was reported as 2.9 per 100,000 person-years. 5 Studies of post-mortem findings in cases of SUDS in the young have shown a high prevalence of a structurally normal heart.3,5–9 In the context of a normal post-mortem examination and negative toxicology, SUDS is referred to as the sudden arrhythmic death syndrome (SADS).1 SADS has been shown to represent 17–43 % of all sudden cardiac deaths in the young (see Figure 1).

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The European Heart Rhythm Association (EHRA), Heart Rhythm Society (HRS) and Asia Pacific Heart Rhythm Society (APHRS) recently published an expert consensus statement on the management of inherited arrhythmia syndromes.1 This outlines the need for investigation of family members of SUDS victims (see Figure 2). Systematic investigation of first-degree relatives is recommended, with subsequent focused investigation of further relatives in families with positive findings. The recommendation is based upon previous studies that have shown that familial assessment reveals affected individuals in 18–53 % of families.10–15 SADS deaths are often due to undiagnosed ion channelopathies, most commonly long QT syndrome (LQTS), Brugada syndrome (BrS) and catecholaminergic polymorphic ventricular tachycardia (CPVT). Family members of SADS victims may also be diagnosed with cardiomyopathy, including hypertrophic cardiomyopathy (HCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC) where phenotypic expression in the sudden death case has been undetectable even at expert autopsy.12 If a post-mortem examination has not been carried out, the differential diagnosis of SUDS is wider, including a higher proportion of cardiomyopathy and additional familial diagnoses such as aortopathy and premature coronary artery disease due to familial hypercholesterolaemia. It must also be considered that some cases of SUDS may not be due to cardiac disease.

Specialist Cardiac Post-mortem Familial evaluation begins with a comprehensive and expert post-mortem examination of the SUDS proband. It is recommended that all SUDS victims with an apparently normal post-mortem are evaluated by a specialist cardiac pathologist16 in order to detect subtle macroscopic and histological markers of cardiomyopathy

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that may not be diagnosed by a general pathologist, and to avoid over-interpretation of minor pathological findings that may lead to erroneous diagnoses of cardiomyopathy.

The need for expert input, working to internationally agreed guidelines and diagnostic criteria,16 is illustrated by the significant disagreement between diagnoses made by general and specialist cardiac pathologists. De Noronha et al.17 examined 200 consecutive cases of sudden cardiac death referred to a specialist pathology centre. The referring pathologist had made a provisional diagnosis in 158 cases and there was disagreement with the specialist cardiac pathologist in 41 % of these cases (kappa 0.48), with the general pathologist over-diagnosing cardiomyopathy, in particular ARVC, and under-diagnosing the structurally normal heart. In addition, Papadakis et al.18 demonstrated that familial evaluation in cases of SUDS with minor pathological findings at autopsy reveals a similar prevalence of channelopathy in first-degree relatives as in a contemporaneous SADS cohort. These findings include idiopathic left ventricular hypertrophy without myocardial disarray; fat within the free wall of the right ventricle without associated fibrosis to support ARVC;19 minor coronary artery disease without evidence of acute occlusion, ischaemia or prior infarction; and isolated lymphocytic inflammatory foci and minor ventricular dilatation. These features may be considered as common and should not automatically be considered as diagnostic of the cause of death. Therefore, such cases should be considered as SADS. It is also recommended that there is retention of fresh spleen or other suitable material for DNA extraction and post-mortem genetic analysis or ‘molecular autopsy’ in all SADS cases.1 Post-mortem non-invasive imaging has been shown to be useful in cases of non-cardiac death.20 When sudden cardiac death is due to ischaemic heart disease, computerised tomography (CT) coronary angiography can reliably identify coronary artery stenoses or occlusions,21 but is less useful in identifying ischaemic myocardium, the presumed trigger for sudden death. While cardiac magnetic resonance imaging (MRI) has a well-established role in the diagnosis of several cardiomyopathies during life, there are very few reports concerning post-mortem radiological imaging in non-ischaemic sudden cardiac death. At present, these methods have not been sufficiently validated to be considered routine, but may complement the traditional post-mortem in the future.

Molecular Autopsy Since SADS is due primarily to undiagnosed channelopathies, post-mortem genetic analysis, ‘the molecular autopsy’, may identify a causative mutation in a responsible gene. This can then facilitate cascade screening in surviving family members, complement clinical evaluation and reassure those who are shown not to be carriers.1,22 The molecular autopsy has progressed since early reports.23,24 Studies analysing the main genes responsible for CPVT and LQTS have demonstrated diagnostic yields of up to 32 %.24–28 In the largest series to date, Tester et al. report the findings from molecular autopsy of 173 consecutive sudden cardiac deaths over a 12-year period.28 They used comprehensive sequencing of LQTS genes (KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2) and focused sequencing of the CPVT1 gene (RYR2) and found causative mutations in 45 (26 %) cases. Positive findings were more common in those cases with exercise-related sudden deaths and in females.

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Figure 1: Proportion of Morphologically Normal Hearts Found at Post-mortem in Published Series of Sudden Unexplained Death Syndrome Corrado et al. 20016

Doolan et al. 20047

17 %

Puranik et al. 20058

31 %

de Noronha et al. 20099

29 %

Winkel et al. 20113

Margey et al. 20115

23 %

26 %

43 %

Figure 2: Algorithm to Describe the Investigative Strategy for the Identification of Inherited Heart Disease in Families that have Suffered a Sudden Unexplained Death Syndrome Event SUDS Identifiable cause If disease is likely to be inherited (e.g. HCM, ARVC) then instigate appropriate evaluation in inherited cardiac disease clinic

Molecular autopsy/ post-morterm genetic testing (Class IIa)†

Pathology (Class I) • Coroner’s or medical examiner’s autopsy undertaken • Retention of tissue suitable for DNA extraction • Expert cardiac pathology

No autopsy undertaken Suspicion of genetic disease (premature sudden death, family history of sudden death)

SADS (Class I) • Normal autopsy • Negative toxicology • Normal expert pathologist’s assessment‡ Retrospective work-up of personal/family history and circumstances of the sudden death (Class I)

Inherited Cardiac Disease Clinic Assessment of (Class I): • First-degree relatives • Obligate carriers • Symptomatic relatives Initial evaluation (Class I): • Historical assessment and pedigree* • Physical examination • Resting ECG* • Exercise ECG* • Echocardiogram

Other investigations (Class IIa and IIb): • Sodium channel blocker test* • CMR Imaging* • 24 hour ECG* • Signal-averaged ECG* • Epinephrine test • Fasting cholesterol (in no autopsy)

Diagnosis made?†

Manage according to diagnosis • Refer to other chapters • Offer family cascade clinical and/or genetic testing†

Yes

No

Follow-up (Class I) • If asymptomatic and fully grown adult discharge from care • If symptoms develop or new information becomes available in family then review • If child, then follow-up in case of age-related expression of disease

‡ Treat equivocal findings as normal; † Refer to HRS/EHRA Genetic Testing recommendations; * Investigations with greatest yield. ARVC = arrhythmogenic right ventricular cardiomyopathy; CMR = cardiovascular magnetic resonance; ECG = electrocardiogram; EHRA = European Heart Rhythm Association; HCM = hypertrophic cardiomyopathy; HRS = Heart Rhythm Society; SADS = sudden arrhythmic death syndrome; SUDS = sudden unexplained death syndrome.

Reproduced with permission from Priori et al. 2013.1

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Clinical Arrhythmias Next generation sequencing may be of further benefit allowing a greater number of potentially causative genes to be tested. Bagnall et al. have reported whole exome sequencing-based molecular autopsy in 28 SUDS cases. In addition to three putative pathogenic rare variants in the more commonly analysed LQTS genes, six rare variants were found after including 25 further genes commonly associated with cardiomyopathies and ion channel disease (calcium channel subunits, CACNA1C and CACNA2D1; desmoplakin, DSP; sarcomere associated genes, MYBPC3 and TTN).29 There was, however, uncertainty over the pathogenicity of these variants, which were labelled as ‘variants of unknown significance’ (VUS). In addition, next generation sequencing coverage can be uneven and genetic yields will never reach 100 %.30 Therefore, a negative result does not exclude the presence of genetic disease or the need for familial evaluation where otherwise indicated.

Thus the increased diagnostic yield and benefit of the next generation molecular autopsy will only be realised once there is improved interpretation of the VUS, and the clinical and genetic context of the family has been addressed.

Familial Assessment Several studies have shown that family screening of SUDS and SADS relatives reveals evidence of inherited cardiac conditions in a significant proportion of family members screened10–15 with yields of 18–53 % reported. Tan et al. found that positive findings were more likely when a larger number of family members were investigated, and where there had been two or more sudden unexplained deaths below the age of 40 in a single family. There was a trend toward positive diagnoses seen more commonly when the proband died during exercise or with emotional stress, although this did not reach statistical significance.11 The guidelines advise the systematic evaluation of first-degree blood relatives with a focus on symptomatic relatives and obligate carriers.

Assessment should ideally be carried out by, or discussed with, an appropriately experienced specialist. Initially the prior history, circumstances surrounding the sudden death and the family’s history should be evaluated31 as well as any ante-mortem electrocardiograms (ECGs). Each relative’s personal medical history should be assessed and a physical examination performed. A resting 12-lead ECG is recommended in all cases given its simplicity, wide availability and high diagnostic yield.11 Transthoracic echocardiography should be performed. This is principally to confirm a structurally normal heart, although a small minority of SADS relatives may be diagnosed with cardiomyopathy.12

Exercise Electrocardiogram The exercise ECG is recommended as a first-line investigation.1 Increasing ventricular ectopy and/or tachyarrhythmia with exercise can be seen in various channelopathies or cardiomyopathies and is a diagnostic criterion in both ARVC19 and CPVT.1 However, two-thirds of patients with ectopy during exercise do not go on to have any other supporting evidence of cardiac disease.32 Findings of ST segment depression may support coronary artery disease, although the limitations of exercise testing for ischaemic heart disease are well-known and correlation with the overall clinical picture is required. The use of the exercise ECG to diagnose LQTS has been limited by difficulties in precise measurement of the T wave at rapid heart rates and by the significant artifact caused by exercise. More recently, Sy et al. found that QTc prolongation in the recovery phase

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after exercise can be used to accurately diagnose LQTS in suspected cases with a normal or borderline QT interval at rest.33,34 The results of this study were subsequently integrated into a modified Schwartz score, with a cut-off QTc ≥480 ms at the fourth minute of recovery.35 It has also been proposed that the exercise ECG may have a role in risk stratification in early repolarisation syndrome (ERS). The early repolarisation (ER) pattern is common in the general population and benign in the vast majority – although it has been associated with idiopathic ventricular fibrillation36 and an increased risk of sudden death.37 Bastiaenen et al. showed that in the majority of individuals with ER, J-point elevation was suppressed during exercise. ER with a horizontal ST segment where the J-point elevation persisted into exercise was associated with prior unexplained syncope.38 However, further investigation and validation is required before exercise testing is considered a risk stratification tool in ERS. Investigation beyond the initial combination of resting ECG, echocardiography and exercise testing are class IIa and IIb recommendations.1 These include sodium channel blocker provocation testing, ambulatory ECG monitoring, signal-averaged ECG, epinephrine test and a fasting serum cholesterol level if no post-mortem has been carried out and premature coronary artery disease is suspected.

Brugada Syndrome and Ajmaline Provocation The recent consensus document states that a diagnosis of BrS can now be made in “patients with ST-segment elevation with type 1 morphology ≥2mm in ≥1 lead among the right precordial leads V1, V2 positioned in the 2nd, 3rd or 4th intercostal space occurring either spontaneously or after provocative drug test with intravenous administration of class I anti-arrhythmic drugs.” The ECG changes seen in BrS correlate to abnormalities of the right ventricular outflow tract.39–41 Anatomically, this structure is commonly positioned superior to the standard V1 and V2 ECG electrode positions42 (right and left parasternal edges in the fourth intercostal spaces). The use of high right ventricular leads with electrodes in corresponding positions in the second and/or third intercostal space have been shown to increase sensitivity of observing a type 1 Brugada ECG pattern both in those with a spontaneous pattern and in the context of ajmaline provocation.43–45 Although, according to the previous BrS consensus statement, a type 1 ECG pattern was required in ≥2 leads,46 it has since been shown that the clinical profile and arrhythmic risk is similar in those with the type 1 Brugada pattern seen in a single lead.47 Savastano et al. have suggested that the new diagnostic criteria improve sensitivity while maintaining specificity.48 ECG changes in patients with BrS can be dynamic and therefore in those family members where initial investigations have been unremarkable, provocative testing with sodium channel blocking drugs is recommended (IIa). Ajmaline, flecainide, procainamide or pilsicanide can be used. Ajmaline has the benefit of a very short half-life minimising the length of the test and need for prolonged monitoring afterwards. It has a good safety profile, although rare cases of cholestatic hepatitis have been reported.49 The recommended dose is 1 mg/kg given intravenously over five minutes.46 Precipitation of a type 1 Brugada ECG pattern in one or more lead, in the standard or high intercostal space positions, constitutes a positive result.1 Due to the lack of a gold standard investigation to compare with and the lack of data regarding the effect of ajmaline in healthy controls, the specificity of ajmaline provocation in SADS family members is unknown and false positives cannot be excluded.

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Epinephrine Infusion Ackerman et al. first showed that epinephrine infusion (0.1 μg/kg/ minute) could be used as a diagnostic tool in LQTS with genotypepositive LQT1 patients demonstrating paradoxical QT prolongation.50 Shimizu et al. then showed that paradoxical QT prolongation differentiated genotype positive LQT1 patients with normal resting QTc intervals from normal controls.51 These early studies concluded that epinephrine infusion was both sensitive and specific for the diagnosis of LQT1, but caution must be exercised when extrapolating results from such well-defined patient groups. Krahn et al. reported results of epinephrine infusion given at 0.1 μg/kg/minutes in 170 consecutive cases comprising cardiac arrest survivors and relatives of sudden death victims, all with normal resting QTc measurements. An abnormal result, defined as a QT prolongation of ≥30 ms, was reported in 18 % of cases. Prolongation of 1–25 ms reported as a borderline result was seen in 14 % of cases. However, there was only modest correlation between an abnormal response to epinephrine and exercise, and only 20 % of individuals with an abnormal epinephrine response who subsequently underwent genotyping had a mutation identified. The authors therefore concluded that epinephrine testing is likely to be sensitive for LQTS but the specificity is questionable.

Epinephrine infusion can also be used for the diagnosis of CPVT. The presence of multifocal ventricular premature beats (VPBs) or bidirectional or polymorphic ventricular tachycardia (VT) is considered a positive result. Studies similar to those for LQTS have demonstrated variable sensitivity52–54 but abnormal results in controls are rare.51,55 However, the lack of a gold standard test or large systematic studies mean that, as for LQTS, the true specificity remains unclear.

such as HCM or ARVC was not specified. These would have been excluded in the SADS cases by definition. ERS was also diagnosed in 6 % of families. While the latest recommendations state that ERS can be diagnosed in a SCD victim where an ante-mortem ECG has shown the ER pattern,1 many SADS probands never have an ECG since the majority are asymptomatic until their fatal episode.31 The high prevalence of ER in the general population,37 especially in young adults,56 and the lack of available risk stratification tools also contribute to making the diagnosis of ERS challenging and controversial in asymptomatic SADS relatives.

Management The majority of individuals assessed will have reassuring findings.

If fully grown adults, patients can be discharged without further follow-up. Children and adolescents may need periodic re-evaluation due to age-related penetrance of many of the conditions in question.57 Those with borderline or inconclusive initial investigations may also benefit from repeat assessment, although it is important to be clear that no formal diagnosis has been made.

The management of individuals with positive diagnoses should follow recognised guidelines for the specific conditions,1 which will frequently involve lifestyle modification and serial monitoring. Initial reports suggested a high rate of intervention with beta-blockers in 51 % and implantable cardioverter defibrillator (ICD) in 11 % of affected individuals.12 More recently, Caldwell et al. reported that betablockers were initiated in 40 % of affected relatives and 9 % received a primary prevention ICD.58

Psychological Support Unexplained Cardiac Arrest It is recommended that survivors of unexplained cardiac arrest (UCA) with documented ventricular fibrillation (VF) and their relatives are assessed in a similar manner to relatives of SUDS victims. Van der Werf et al. reported on the results of such assessment in 69 consecutive survivors of cardiac arrest.13 A definite or probable diagnosis was made in 42 survivors (61 %). The diagnosis was of an inherited cardiac condition in 31 survivors (45 %). This rate was understandably higher than in SUDS relatives in the same study – first-degree relatives have only a 50 % chance of carrying the same mutation; many of the conditions being sought show incomplete penetrance; and not all first-degree relatives come forward for assessment.

More recently, Kumar et al. found a discrepancy between the yield of investigations in SADS relatives (18 %) compared with UCA relatives (62 %) despite similar protocol of evaluation.15 Some methodological factors contributed. For example, sodium channel provocation was only undertaken in a small proportion of relatives and high ECG leads were not used. Cardiac arrest survivors were excluded if coronary disease, valvular disease or impaired LV function were identified, yet the proportion of probands with other structural heart diseases

1. 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. Europace 2013;15:1389–406.

2. Zheng ZJ, Croft JB, Giles WH, Mensah GA. Sudden cardiac death in the United States, 1989 to 1998. Circulation 2001;104:2158–63.

3. Winkel BG, Holst AG, Theilade J, et al. Nationwide study of sudden cardiac death in persons aged 1-35 years. Eur Heart J 2011;32:983–90.

4. Papadakis M, Sharma S, Cox S, et al. The magnitude of sudden cardiac death in the young: a death certificate-based

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The sudden death of a young family member can have multiple psychological effects on a family and it should be noted that familial assessment is often carried out at a time when grieving may still be prominent. In addition, diagnosis of a heritable condition can engender feelings of guilt, anxiety and depression, particularly in the parents of a sudden death victim. Access to psychological support should be available for families and good relationships with patient support groups and charities working in the field of young sudden death can be beneficial.

Summary and Conclusion Familial assessment of SADS family members is an important tool in reducing the burden of sudden death in the young. A significant proportion of family members will be diagnosed with cardiac genetic disease, the majority of whom can be offered effective treatment and lifestyle modifications without the need for ICD implantation. Negative findings offer reassurance to unaffected family members. Simple non-invasive tests remain the cornerstone of investigation with questions over specificity in SADS family members existing over many of the more recently described protocols. The molecular autopsy may offer a complementary role in the evaluation of families. n

review in England and Wales. Europace 2009;11:1353–8.

5. Margey R, Roy A, Tobin S, et al. Sudden cardiac death in 14to 35-year olds in Ireland from 2005 to 2007: a retrospective registry. Europace 2011;13:1411–8.

6. Corrado D, Basso C, Thiene G. Sudden cardiac death in young people with apparently normal heart. Cardiovasc Res 2001;50:399–408.

7. Doolan A, Langlois N, Semsarian C. Causes of sudden cardiac death in young Australians. Med J Aust 2004;180:110–2.

8. Puranik R, Chow CK, Duflou JA, et al. Sudden death in the young. Heart Rhythm 2005;2:1277–82.

9. de Noronha SV, Sharma S, Papadakis M, et al. Aetiology of

sudden cardiac death in athletes in the United Kingdom: a pathological study. Heart 2009;95:1409–14.

10. Behr E, Wood DA, Wright M, et al. Cardiological assessment of first-degree relatives in sudden arrhythmic death syndrome. Lancet 2003;362:1457–9.

11. Tan HL, Hofman N, van Langen IM, et al. Sudden unexplained death: heritability and diagnostic yield of cardiological and genetic examination in surviving relatives. Circulation 2005;112:207–13.

12. Behr ER, Dalageorgou C, Christiansen M, et al. Sudden arrhythmic death syndrome: familial evaluation identifies inheritable heart disease in the majority of families.

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13. van der Werf C, Hofman N, Tan HL, et al. Diagnostic yield in sudden unexplained death and aborted cardiac arrest in the young: the experience of a tertiary referral center in The Netherlands. Heart Rhythm 2010;7:1383–9.

14. McGorrian C, Constant O, Harper N, et al. Family-based cardiac screening in relatives of victims of sudden arrhythmic death syndrome. Europace 2013;15:1050–8.

15. Kumar S, Peters S, Thompson T, et al. Familial cardiological and targeted genetic evaluation: Low yield in sudden unexplained death and high yield in unexplained cardiac arrest syndromes. Heart Rhythm 2013;10:1653–60.

16. Basso C, Burke M, Fornes P, et al. Guidelines for autopsy investigation of sudden cardiac death. Virchows Arch 2008;452:11–8.

17. de Noronha SV, Behr ER, Papadakis M, et al. The importance of specialist cardiac histopathological examination in the investigation of young sudden cardiac deaths. Europace 2014;6:899–907.

18. Papadakis M, Raju H, Behr ER, et al. Sudden cardiac death with autopsy findings of uncertain significance: potential for erroneous interpretation. Circ Arrhythm Electrophysiol 2013;6:588–96.

19. Marcus FI, McKenna WJ, Sherrill D, et al. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the task force criteria. Circulation 2010;121:1533–41.

20. Roberts IS, Benamore RE, Benbow EW, et al. Post-mortem imaging as an alternative to autopsy in the diagnosis of adult deaths: a validation study. Lancet 2012;379:136–42.

21. Roberts IS, Benamore RE, Peebles C, et al. Technical report: diagnosis of coronary artery disease using minimally invasive autopsy: evaluation of a novel method of postmortem coronary CT angiography. Clin Radiol 2011;66:645–50.

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

23. Ackerman MJ, Tester DJ, Driscoll DJ. Molecular autopsy of sudden unexplained death in the young. Am J Forensic Med Pathol 2001;22:105–11.

24. Tester DJ, Ackerman MJ. Postmortem long QT syndrome genetic testing for sudden unexplained death in the young.

J Am Coll Cardiol 2007;49:240–6.

25. Gladding PA, Evans CA, Crawford J, et al. Posthumous diagnosis of long QT syndrome from neonatal screening cards. Heart Rhythm 2010;7:481–6.

26. Skinner JR, Crawford J, Smith W, et al. Prospective, population-based long QT molecular autopsy study of postmortem negative sudden death in 1 to 40 year olds.

Heart Rhythm 2011;8:412–9.

27. Winkel BG, Larsen MK, Berge KE, et al. The prevalence of mutations in KCNQ1, KCNH2, and SCN5A in an unselected national cohort of young sudden unexplained death cases.

J Cardiovasc Electrophysiol 2012;23:1092–8.

28. Tester DJ, Medeiros-domingo A, Will ML, et al. Cardiac channel molecular autopsy: insights from 173 consecutive cases of autopsy-negative sudden unexplained death

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referred for postmortem genetic testing. Mayo Clin Proc 2012;87:524–39.

29. Bagnall RD, Das KJ, Duflou J, Semsarian C. Exome analysisbased molecular autopsy in cases of sudden unexplained death in the young. Heart Rhythm 2014;11:655–62.

30. Wilde AA, Behr ER. Genetic testing for inherited cardiac disease. Nat Rev Cardiol 2013;10:571–83.

31. Mellor G, Raju H, de Noronha SV, et al. Clinical characteristics and circumstances of death in the sudden arrhythmic death syndrome. Circ Arrhythmia Electrophysiol 2014; CIRCEP.114.001854 [Epub ahead of print].

32. Raju H, Papadakis M, Bastiaenen R, et al. BCS Abstracts 2011, 50 Diagnostic role of exercise tolerance testing in familial premature sudden cardiac death. Heart 2011;97:A33–4.

33. Sy RW, van der Werf C, Chattha IS, et al. Derivation and validation of a simple exercise-based algorithm for prediction of genetic testing in relatives of LQTS probands.

Circulation 2011;124:2187–94.

34. Horner JM, Horner MM, Ackerman MJ. The diagnostic utility of recovery phase QTc during treadmill exercise stress testing in the evaluation of long QT syndrome. Heart Rhythm 2011;8:1698–704.

35. Schwartz PJ, Crotti L. QTc behavior during exercise and genetic testing for the long-QT syndrome. Circulation 2011;124:2181–4.

36. Haïssaguerre M, Derval N, Sacher F, et al. Sudden cardiac arrest associated with early repolarization. N Engl J Med 2008;358:2016–23.

37. Tikkanen JT, Anttonen O, Junttila MJ, et al. Long-term outcome associated with early repolarization on electrocardiography. N Engl J Med 2009;361:2529–37.

38. Bastiaenen R, Raju H, Sharma S, et al. Characterization of early repolarization during ajmaline provocation and exercise tolerance testing. Heart Rhythm 2013;10:247–54.

39. Postema PG, van Dessel PF, Kors JA, et al. Local depolarization abnormalities are the dominant pathophysiologic mechanism for type 1 electrocardiogram in brugada syndrome a study of electrocardiograms, vectorcardiograms, and body surface potential maps during ajmaline provocation. J Am Coll Cardiol 2010;55:789–97.

40. Lambiase PD, Ahmed AK, Ciaccio EJ, et al. High-density substrate mapping in Brugada syndrome: combined role of conduction and repolarization heterogeneities in arrhythmogenesis. Circulation 2009;120:106–17, 1–4.

41. Nademanee K, Veerakul G, Chandanamattha P, et al.

Prevention of ventricular fibrillation episodes in Brugada syndrome by catheter ablation over the anterior right ventricular outflow tract epicardium. Circulation 2011;123:1270–9.

42. Veltmann C, Papavassiliu T, Konrad T, et al. Insights into the location of type I ECG in patients with Brugada syndrome: correlation of ECG and cardiovascular magnetic resonance imaging. Heart Rhythm 2012;9:414–21.

43. Shimizu W, Matsuo K, Takagi M, et al. Body surface distribution and response to drugs of ST segment elevation in Brugada syndrome: clinical implication of eighty-sevenlead body surface potential mapping and its application to twelve-lead electrocardiograms. J Cardiovasc Electrophysiol 2000;11:396–404.

44. Sangwatanaroj S, Prechawat S, Sunsaneewitayakul B, et al.

New electrocardiographic leads and the procainamide test for the detection of the Brugada sign in sudden unexplained death syndrome survivors and their relatives. Eur Heart J 2001;22:2290–6.

45. Govindan M, Batchvarov VN, Raju H, et al. Utility of high and standard right precordial leads during ajmaline testing for the diagnosis of Brugada syndrome. Heart 2010;96:1904–8.

46. Antzelevitch C, Brugada P, Borggrefe M, et al. Brugada syndrome: report of the second consensus conference: endorsed by the Heart Rhythm Society and the European Heart Rhythm Association. Circulation 2005;111:659–70.

47. Richter S, Sarkozy A, Paparella G, et al. Number of electrocardiogram leads displaying the diagnostic coved-type pattern in Brugada syndrome: a diagnostic consensus criterion to be revised. Eur Heart J 2010;31:1357–64.

48. Savastano S, Rordorf R, Vicentini A, et al. A comprehensive electrocardiographic, molecular, and echocardiographic study of Brugada syndrome: validation of the 2013 diagnostic criteria. Heart Rhythm 2014;11:1176–83.

49. Mellor G, Fellows I, Williams I. Intrahepatic cholestatic hepatitis following diagnostic ajmaline challenge. Europace 2013;15:314.

50. Ackerman MJ, Khositseth A, Tester DJ, et al. Epinephrineinduced QT interval prolongation: a gene-specific paradoxical response in congenital long QT syndrome. Mayo Clin Proc 2002;77:413–21.

51. Shimizu W, Noda T, Takaki H, et al. Epinephrine unmasks latent mutation carriers with LQT1 form of congenital longQT syndrome. J Am Coll Cardiol 2003;41:633–42.

52. Krahn AD, Gollob M, Yee R, et al. Diagnosis of unexplained cardiac arrest: role of adrenaline and procainamide infusion.

Circulation 2005;112:2228–34.

53. Krahn AD, Healey JS, Chauhan VS, et al. Epinephrine infusion in the evaluation of unexplained cardiac arrest and familial sudden death: from the cardiac arrest survivors with preserved ejection fraction registry. Circ Arrhythm Electrophysiol 2012;5:933–40.

54. Marjamaa A, Hiippala A, Arrhenius B, et al. Intravenous epinephrine infusion test in diagnosis of catecholaminergic polymorphic ventricular tachycardia. J Cardiovasc Electrophysiol 2012;23:194–9.

55. Vyas H, Hejlik J, Ackerman MJ. Epinephrine QT stress testing in the evaluation of congenital long-QT syndrome: diagnostic accuracy of the paradoxical QT response. Circulation 2006;113:1385–92.

56. Walsh JA 3rd, Ilkhanoff L, Soliman EZ, et al. Natural history of the early repolarization pattern in a biracial cohort: CARDIA (Coronary Artery Risk Development in Young Adults) Study.

J Am Coll Cardiol 2013;61:863–9.

57. Wong LC, Roses-Noguer F, Till JA, Behr ER. Cardiac evaluation of pediatric relatives in sudden arrhythmic death syndrome: a 2-center experience. Circ Arrhythm Electrophysiol 2014;7:800–6.

58. Caldwell J, Moreton N, Khan N, et al. The clinical management of relatives of young sudden unexplained death victims; implantable defibrillators are rarely indicated.

Heart 2012;98:631–6.

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Diagnostic Electrophysiology & Ablation

Ventricular Tachycardia Ablation – The Right Approach for the Right Patient Mouha nna d M Sa dek , R obert D S c h a l l e r, G r e g o r y E S u p p l e, D a v i d S Fra n k e l , M i c h a e l P Rile y, Ma t hew D Hutc h i n s o n , Fe r m i n C G a r c i a , D a v i d L i n , S a n j a y D i x i t , Eric a S Z ad o, D a v i d J Ca l l a n s, Fra n c i s E M a r c h l i n s k i Section of Cardiac Electrophysiology, Cardiovascular Division, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, US

Abstract Scar-related reentry is the most common mechanism of monomorphic ventricular tachycardia (VT) in patients with structural heart disease. Catheter ablation has assumed an increasingly important role in the management of VT in this setting, and has been shown to reduce VT recurrence and implantable cardioverter defibrillator (ICD) shocks. The approach to mapping and ablation will depend on the underlying heart disease etiology, VT inducibility and haemodynamic stability. This review explores pre-procedural planning, approach to ablation of both mappable and unmappable VT, and post-procedural testing. Future developments in techniques and technology that may improve outcomes are discussed.

Keywords Ventricular tachycardia, catheter ablation, entrainment mapping, pace mapping, substrate modification, core isolation, epicardial ablation, septal ablation, surgical ablation Disclosure: Drs Marchlinski, Callans, Garcia and Hutchinson received research grant support and honoraria from Biosense Webster on topics unrelated to the content of this report. The other authors have no conflicts of interest to declare.

Acknowledgements: This manuscript was supported in part by the F Harlan Batrus Research Fund.

Received: 8 September 2014 Accepted: 15 October 2014 Citation: Arrhythmia & Electrophysiology Review, 2014;3(3):161–7 Access at: www.AERjournal.com Correspondence: Francis E. Marchlinski, Hospital of the University of Pennsylvania 9 Founders Pavilion – Cardiology, 3400 Spruce Street Philadelphia, Pennsylvania 19104. E: Francis.Marchlinski@uphs.upenn.edu

Scar-related reentrant ventricular tachycardia (VT) may be present in a variety of structural heart disease (SHD) phenotypes. In this setting, VT circuits are comprised of viable myocytes separated by fibrosis, allowing for the slow conduction needed to facilitate reentry.1,2 Aetiologies of fibrosis include ischaemic heart disease (IHD), inflammatory conditions, infiltrative cardiomyopathy, dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy and arrhythmogenic right ventricular (RV) dysplasia.

and more AAD use in long-term follow-up.14–16 For the most part, VT ablation remains underutilised and some patients may benefit from earlier intervention.17

Implantable cardioverter defibrillators (ICDs) are the mainstay of therapy for the prevention of sudden cardiac death in patients with SHD.3 However, ICD shocks are associated with diminished quality of life and increased mortality.4–6 Anti-arrhythmic drugs (AADs) have an important role in shock reduction; however these agents often have limited efficacy and significant side-effects.7,8

Pre-procedural Planning

Catheter ablation has assumed an increasingly important role in the management of VT. In patients with IHD and drug-refractory VT, ablation has been shown to reduce arrhythmia recurrence and ICD therapies.9–11 Patients who have VT rendered non-inducible by an ablation procedure have a lower VT recurrence rate and mortality compared with those who still have inducible arrhythmias after the ablation.12 Catheter ablation has also been shown to be effective in the treatment of VT storm in patients with SHD receiving chronic AAD therapy.13 In the setting of non-ischaemic SHD, catheter ablation outcome varies according to the nature of the underlying heart disease, with a greater need for epicardial mapping and ablation, higher recurrence rate

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Although ablation also has an important role in the management of patients with idiopathic VT, this review will focus on ablation of scarrelated reentrant VT, the most common mechanism of monomorphic VT in patients with SHD.

Heart failure optimisation is important for decreasing the risk of haemodynamic deterioration during the procedure. This occasionally requires pre-operative assessment of ventricular filling pressures and intravenous (IV) diuresis. When feasible, AADs should be held prior to ablation for a minimum of five half-lives to allow for induction and targeting of all potential VTs. For patients at high risk for VT during the interim or patients requiring amiodarone, bridging with IV lidocaine in a monitored setting has been our standard practice. If severe peripheral vascular disease is suspected, imaging should be performed to guide decisions regarding retrograde aortic versus transseptal left ventricular access, as well as to whether percutaneous left ventricular assist devices (LVADs) can be safely introduced via the femoral artery.

Electrocardiographic Characterisation Twelve-lead electrocardiograms (ECGs) of all clinical VTs are important in localising VT exit sites, identifying potential ablation targets and directing the best ablation strategy including possible epicardial access.

In the setting of non-ischaemic IHD, morphological criteria suggesting

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Diagnostic Electrophysiology & Ablation Figure 1: Important Mapping Concepts

A

B

C

D

A) Sinus rhythm electrograms (EGMs) demonstrating late potentials and multicomponent EGMs (arrows). B) Right ventricular pacing utilised to expose late potentials (arrows) hidden within the QRS during sinus rhythm (left panel) and biventricular pacing (right panel).

C) Entrainment mapping with capture of the far field EGM (left panel). A reduction in pacing output (right panel) results in successful capture of the local EGM (arrow) and evidence of concealed entrainment. D) EGMs recorded from abnormal substrate are poorly coupled to the rest of the myocardium. RV pacing results in separation of the late potential (hidden within the sinus QRS beat), and extrastimulus results in further delay.

an epicardial exit include the presence of Q waves in leads where they do not belong; lead I for basal anterolateral scar (coupled with the absence of inferior Q waves) and leads II and aVF for basal inferior scar.

Other criteria based on the identification and quantification of slow conduction in the initial portion of the QRS includes a longer pseudodelta wave, larger maximum deflection index and longer QRS duration.

These criteria are not as sensitive or specific as morphological criteria for the identification of epicardial origin.18 Of note, in the setting of IHD, neither morphological nor quantitative criteria have been shown to reliably predict an epicardial VT exit site.19 In the absence of ECG data, ICD electrograms (EGMs) of the clinical event can be used to confirm that VT occurring spontaneously is consistent with induced VTs in the lab.

Procedural Setup Our preferred practice is to perform VT ablation with conscious sedation due to several potential advantages including avoidance of arrhythmia suppression by anaesthetic agents, maintenance of higher blood pressure during mapping and faster recovery times. Potential disadvantages include patient discomfort and inadvertent patient movement that can alter the electroanatomical map. If the need for epicardial access arises, general anaesthesia is preferred in order to maximise safety and minimise patient discomfort.

Access to the LV can be obtained via retrograde aortic, transseptal or, rarely, transapical approaches. It has been our routine practice to utilise retrograde access except in patients with aortic valve pathology, significant atheroma / calcification in the ascending aorta or severe peripheral arterial disease. In those patients in whom epicardial access is planned, full sternal preparation and setup for coronary angiography are also performed.

In the setting of baseline haemodynamic compromise, or if mapping during haemodynamically unstable VT is anticipated, consideration may be given to the use of mechanical assist devices. Intra-aortic balloon pumps (IABPs) have a limited role in maintaining haemodynamic stability in the setting of VT and low cardiac output,25 and have not been shown to improve procedural outcomes. Percutaneous LVADs allow for end-organ perfusion during long periods of tachycardia. They have been shown to be safe and effective in supporting haemodynamic status during the procedure, potentially reducing ablation time and hospital length of stay.26,27 There are associated costs and potential morbidities with the use of such devices, and these must be weighed against the benefits. To date no improvement in arrhythmia outcome with these devices has been documented.

Substrate Characterisation Prior to ablation, detailed endocardial and/or epicardial electroanatomical voltage mapping are routinely performed during normal sinus or paced rhythm. Conventionally, normal endocardial bipolar voltage is defined as >1.5 millivolts (mV); normal epicardial bipolar voltage is defined as >1 mV. Bipolar signal amplitude <0.5 mV correlates with dense fibrosis on surgical pathology. Intermediate values are indicative of border zones.28,29

Pre-procedural Imaging Pre-procedural echocardiography is routinely performed to assess biventricular function, elucidate aortic valve pathology prior to retrograde LV access and exclude intramural LV thrombus. Consideration may also be given to the assessment of coronary anatomy, especially when mapping during VT in patients with IHD is desired and exercise testing is equivocal or not easily performed. Of note, patients with coronary artery disease may still exhibit a non-ischaemic substrate / aetiology for VT, as suggested by the presence of multiple VTs of basal origin.20 Further assessment of the location and extent of scar can be performed with magnetic resonance imaging (MRI), and may help in procedural planning and characterising the appropriate target for ablation especially in patients with non-ischaemic SHD. In experienced centres, cardiac MRI can be safely performed in patients with implanted devices,21 although interpretation may be limited by image distortion due to device artifact.22 Patients with non-ischaemic SHD typically exhibit one of two scar patterns on MRI, namely basal anteroseptal and inferolateral.23 This has important implications for the ablation procedure, with a higher need for epicardial access in the antero- or inferolateral subtype and the higher recurrence rate in the anteroseptal (mid-myocardial) subtype.24

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Unipolar endocardial voltage (recorded between the tip of the ablation catheter and Wilson’s central terminal) can also be assessed for characterisation of mid-myocardial or epicardial scar.30 Confirmation of adequate contact with the ventricular myocardium is important when assessing signal amplitude, and tools such as intracardiac echocardiography (ICE) or contact-force sensing can be helpful.

Markers of abnormal or slow conduction, usually present in and around the area of scar, are identified and tagged during mapping.

These include late potentials (LPs), which are low-amplitude EGMs occurring after the end of the surface QRS, and multicomponent or fractionated EGMs.31,32 Of note, mapping of abnormal EGMs during RV pacing may be more sensitive than during normal sinus rhythm (NSR) or biventricular pacing due to a change in the direction of the activation wave front (see Figure 1).33 Following substrate characterisation, VT induction is attempted (Figure 2). This involves programmed stimulation and burst pacing, with the possible use of isoproterenol. When VT is induced, a recording of the device EGM at 25 mm/second sweep speed is compared

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Ventricular Tachycardia Ablation – The Right Approach for the Right Patient

with the EGM recorded during the clinical VT episode. The degree of haemodynamic stability during VT will determine the type of mapping that will be pursued prior to ablation. Factors associated with haemodynamically tolerated VT include preserved cardiac output, shorter duration of VT episode, longer VT cycle length and VT induction in a consciously sedated patient.

Ablation of Mappable VT During haemodynamically tolerated scar-related VT, the onset of the surface QRS corresponds temporally to the emergence of the diastolic VT circuit from the scar. Hence, activation mapping can be performed as a rapid method of tracing back the activation wave front within normal myocardium to the vicinity of the VT exit site. Within the area of scar, progressively earlier diastolic activation may be recorded.

Mid-diastolic signals are of specific importance as they may represent potential regions of slow-conduction vital to maintaining the VT circuit, where ablation can result in tachycardia termination. However the mere presence of diastolic activation during VT does not guarantee an appropriate ablation target.

Figure 2: Approach to Ventricular Tachycardia Ablation Substrate Characterisation (Voltage map, identify abnormal EGMs)

VT Induction Protocol (ECG assessment of all VTs) Mappable VT (Inducible, haemodynamically stable)

Unmappable VT (Non-inducible, haemodynamically unstable)

Entrainment Mapping + Ablation

Limited Entrainment +/- Ablation

Limited Substrate Ablation to Complement Entrainment Mapping

Pace Mapping/Channel Mapping with Late Potentials Ablation

More Extensive but Targeted Substrate Ablation

Entrainment mapping (see Figure 3), or continuous resetting of the reentrant VT circuit, is designed to identify sites that are vital to maintaining the VT circuit. During haemodynamically tolerated VT, sites with diastolic activation are chosen for entrainment pacing. To

Core Isolation of Sites with Good Entrainment Criteria and Substrate Surrogates Suggesting VT Isthmus

minimise temporal changes in the excitable gap of the reentrant circuit, entrainment is performed only 10–20 milliseconds faster than the tachycardia cycle length (TCL). Ensuring local capture by reducing the pacing output may be necessary to avoid capturing far field EGMs (see Figure 1) and ensure a more accurate response to pacing that can be used to identify a VT isthmus site amenable to more limited ablation.

The approach to VT ablation depends on VT inducibility and haemodynamic stability.

Although considerable overlap, patients with mappable VT undergo targeted substrate modification following entrainment-guided ablation. Patients with unmappable VT undergoing limited entrainment (if possible) prior to more extensive substrate ablation. Substrate ablation may be guided by pacemapping, channel assessment and location of late potentials.

When possible the core of the VT substrate which houses the machinery for the VT circuit based on entrainment and substrate assessment will be isolated to achieve endpoint beyond non-inducibility.

Pacing within the protected VT circuit results in a paced QRS morphology that is identical to the spontaneous VT. This is termed concealed fusion, and occurs when the pacing wave front collides antidromically with the propagating VT wave front, while the orthodromic wave front activates the ventricle in an identical manner to the spontaneous VT. The mere presence of concealed fusion is not synonymous with a critical VT circuit element, since “blind end” channels or “bystanders” are often present; these channels are adjacent to, but not part of, the VT circuit.

To prove that a specific site is an integral part of the reentrant circuit (i.e. entrance, isthmus or exit site), the post-pacing interval (PPI) should approximate the tachycardia cycle length (TCL). Also in these locations, the stimulus-to-QRS interval (S-QRS) will approximate the EGM-to-QRS.34 Once a protected part of the circuit is identified, the S-QRS timing indicates the conduction time between the pacing site and the exit of the circuit. A shorter S-QRS would suggest a site closer to the exit, whereas a long S-QRS indicates a site closer to the entrance.

to induce clinical VT may make this approach challenging, particularly in the setting of general anaesthesia. The presence of multiple VT morphologies also makes entrainment mapping challenging. In patients with well-tolerated clinical VT, 74 % will have at least one unmappable VT induced at electrophysiology (EP) study.36 In the irrigated VT ablation trial, 54 % of induced VT morphologies were unmappable, most commonly due to haemodynamic instability.9 Alternative ablation methods utilise mapping and ablation in sinus or paced rhythm (see Figure 4), and have shown comparable efficacy to entrainment mapping.37

Ablation lesions delivered at critical components of the VT circuit are most predictive of VT termination and rendering it noninducible.35 Other phenomena such as termination of VT by a non-captured pacing stimulus or by mechanical catheter pressure may indicate mapping at a site integral for VT propagation. Reasons why ablation at these areas may not be successful include a broad isthmus or the involvement of mid-myocardial/epicardial substrate that extends beyond the lesion size created by currently available catheters.

Ablation of Unmappable VT Although entrainment mapping is the preferred method for characterising the VT circuit, haemodynamic instability during tachycardia and the need

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Channel Identification and Empiric Lines Attempts have been made to identify conducting channels within scar. In sinus rhythm, such channels may serve as a zone of slow conduction for reentrant VT. They can be identified by reducing the usual voltage cutoff to identify regions of relatively preserved voltage within the dense scar.38–40 Ablation transecting these channels has been proposed as a substrate modification strategy. We have shown that only 30 % of these channels actually predicted a VT isthmus site, although the predictability increased to 85 % for channels that contain isolated LPs.39 However, only 44 % of mappable VTs were associated with any identified channel. Thus, the use of channel identification alone to characterise VT circuits has a low sensitivity and specificity.

Other reports regarding ablation of VT during sinus rhythm investigated the utility of empiric ablation lines. Such lines can be either single or multiple, and transect from the middle of the scar to the border zones.28 Other investigators studied the utility of shorter lines projecting from an area identified as an isthmus or a good pace map.41 Although such ablation lesions may appear on the electroanatomical maps as a

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Diagnostic Electrophysiology & Ablation Figure 3: Entrainment Mapping and Ablation During Ventricular Tachycardia

Bystander: Entrain with CF, PPI>TCL

Entrance site: Entrain with CF, PPI=TCL, S-QRS/TCL >50%

Outer loop: Entrain with fusion, PPI=TCL

Critical isthmus: Entrain with CF, PPI=TCL, S-‐QRS/TCL 30–50%

Exit site: Entrain with CF, PPI=TCL, S‐QRS/TCL <30%

CF = constant fusion, PPI = post-pacing interval, TCL = tachycardia cycle length, S-QRS = stimulus-to-QRS interval. Dense scar is depicted in black with a conducting channel of viable myocardium. Active VT circuit is depicted with red arrows and bystander areas with purple arrows. Pacing is performed faster than the TCL (pale blue arrows), and the response indicates the relationship of the pacing location to the VT circuit. Ablation delivered at the isthmus (red dot) results in VT termination.

line that transects myocardial tissue, assessment of block is rarely performed. More recent studies have utilised more extensive substrate modification strategies in an effort to further reduce VT recurrence.

Substrate Modification During substrate modification, abnormal EGMs including LPs and fractionated EGMs in and around the scar are targeted in an attempt to ablate all potential channels that can support VT reentry. This approach has been studied extensively in patients with scar-related VT and has shown improved long-term prognosis.42–44 Due to the probabilistic nature of substrate modification, it is accepted that a large amount of ablation will be required. In fact, some centres have suggested a more extensive endocardial and epicardial scar ablation strategy in patients with IHD, termed scar homogenisation.45 Whether this is necessary or superior to the standard endocardial approach requires further investigation.

There are caveats to substrate-guided ablation. The presence of abnormal EGMs does not necessarily predict involvement in the VT circuit. Thus, because elimination of all such EGMs is preferred with this approach, it does require extensive ablation and longer procedural times. It can be difficult to eliminate abnormal potentials, even with long ablation lesions. In addition, standard mapping may fail to detect all abnormal EGMs.42 Detailed “remapping” at the end of the procedure is also frequently performed in order to confirm complete

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elimination of the specifically targeted arrhythmogenic substrate.

Pace Mapping Pace mapping involves pacing from areas of abnormal EGMs in and around the scar in an attempt to match the clinical VT morphology, and can help approximate the anatomic VT location. Pacing from within the scar can also identify slow-conduction channels, marked by a prolonged S-QRS.46 VT exit site pacing will yield a “matched” QRS with a short S-QRS. Isthmus site pacing close to the exit will yield a “matched” QRS with a long S-QRS. Entrance site pacing, however, will frequently yield a “nonmatched” QRS as the stimulus wave front may also exit antidromically in a different manner from the VT.47 Recently, it has been recognised that an abrupt transition between a paced-QRS that matches the clinical VT (exit site) and a non-matched paced-QRS (entrance site) can identify an isthmus.48 Typical isthmus sites are located in areas with low EGM voltages (< 1.5 mV EGM), with dimensions ranging from 21-59 mm length by 15-47 mm width. Once characterised, isthmus transection with ablation frequently eliminates the targeted VT. There are important caveats to pace mapping. Although pace mapping may approximate the location of the exit site of the circuit, it does not distinguish isthmus sites from bystander sites, which can only be

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Figure 4: Mapping and Ablation During Normal Sinus Rhythm

Entrance site: Non-match Bystander site: Possible match

Exit site: Match

LP Ablation

Pace Mapping

Entrance site: Non-match

Exit site: Match Scar Homogenisation

Core Isolation

Isthmus Transection

LP= late potentials. Dense scar is depicted in black with a conducting channel of viable myocardium. Inactive VT circuit is depicted with orange arrows and bystander areas with light purple arrows. Different approaches to mapping and ablation include LP ablation, pace mapping with isthmus identification and transection, scar homogenisation and core isolation. Ablation (red dots) is targeted at interrupting the VT circuit.

done with entrainment mapping. In addition, pacing at an entrance site, although potentially a successful ablation site, may yield a “nonmatched” QRS. This is in contrast to entrainment, where concealed fusion can be observed all along the isthmus including the entrance location, but with differing S-QRS. In addition, varying the pacing rate may alter the paced-QRS morphology.49 To minimise this, pacing at VT TCL is suggested. We also recommend using the lowest possible pacing output to reduce the possibility of far field capture.

Scar or VT Core Isolation In addition to pace mapping and substrate modification, recent techniques involving electrical isolation of the scar have been developed. In patients with IHD, electrical isolation of the entire lowvoltage area with a circumferential line along the border zone was associated with a reduction in VT recurrence.50 There is concern about the haemodynamic consequence of extensively ablating in proximity to normal myocardium at the edge of scar.

In our institution, we have focused on electrical isolation of the core portion of the scar that is involved in the VT circuit, rather than the entire scar. In addition to the endpoint of clinical VT non-inducibility, the ability to demonstrate entrance and exit block from the isolated

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area of scar may improve ablation outcome. Further studies are needed to validate this approach and compare it with other commonly used techniques.

Post-procedural Testing Following ablation, programmed stimulation is performed with a goal of clinical VT non-inducibility.51 If non-clinical VTs are induced, the decision to perform further ablation is weighed against the risk of a longer procedure time with potential haemodynamic consequences from fluid overload. It is our practice to try to eliminate all inducible VTs if patients remain haemodynamically stable and are tolerating the procedure well.

At our institution, non-invasive programmed stimulation (NIPS) is performed for all patients with SHD via the implanted ICD approximately 48 hours post-VT ablation while withholding AADs. Despite VT non-inducibility at the end of the procedure some patients may still have VT inducible at NIPS, and those have a higher risk of long-term recurrence, including with VT storm.52 In patients with inducible clinical VT at NIPS, consideration is given to repeat the ablation prior to discharge. In those patients with inducible non-clinical VTs, the 12-lead morphology and device EGMs of these VTs are stored for use and review in case of recurrence. Results of the NIPS can also guide device programming and management of AADs.

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Diagnostic Electrophysiology & Ablation Figure 5: Electroanatomic Mapping in a Patient with Ventricular Tachycardia and Underlying Dilated Cardiomyopathy A

B

D LAO

C

nerve (via high-output pacing from the ablation catheter). With few exceptions, ablation at sites within 5 mm of a major coronary artery is generally avoided. Different strategies for phrenic nerve protection during ablation have been described, including epicardial balloon inflation and instillation of air/saline into the pericardial space (see Figure 5).56 Surgical backup is recommended for all epicardial cases in the event of uncontrolled bleeding due to ventricular laceration or vascular damage. In the event of an operative repair, surgical epicardial cryoablation targeting regions of visible epicardial scar or guided by prior mapping data is feasible.57

E RAO

Septal Ablation

Endocardial mapping reveals normal bipolar (panel A) but abnormal unipolar voltage (panel B), suggestive of mid-myocardial or epicardial scar. Epicardial bipolar mapping (panel C) reveals extensive scar substrate. Due to phrenic nerve capture in this area, inflation of a contrastfilled balloon (blue arrow) in the epicardium was utilised to separate the phrenic nerve from the epicardial surface, with the ablation catheter (red arrow) in contact with the epicardium below the balloon (panels D and F). A left ventricular assist device was used to facilitate mapping and ablation (purple arrow).

Septal VT substrate poses a particular challenge in patients with DCM.58 Due to septal thickness, endocardial ablation may have difficulty penetrating deep into the septal scar. In addition, potential damage to the conduction system should be considered with the possible need for permanent pacing. In cases of intraseptal VT morphologies refractory to conventional ablation parameters, our approach has been the application of long (2–3 minutes) ablation lesions on both sides of the septum targeting areas of unipolar abnormality. Alternative approaches such as trans-coronary ethanol infusion, bipolar ablation on both sides of the septum and needle ablation catheters have been described.59,60

Surgical VT Ablation

Special Situations Patients with non-ischaemic SHD such as DCM may exhibit epicardial or mid-myocardial substrate. Pre-procedural MRI imaging, 12-lead ECG morphology of the clinical VT and or unipolar voltage mapping may identify such substrate.18,53 An endocardial unipolar signal amplitude of <8.3 mV suggests mid-myocardial or epicardial scar.30 Typically, scar in these patients is found along the basal lateral epicardium or the septal mid-myocardium.24 Epicardial VT ablation is rarely required in post-infarct patients.54

In rare cases where patients have failed multiple percutaneous VT ablation attempts and are also not candidates for cardiac transplant, surgical VT ablation can also be offered.57 In these cases, detailed characterisation of the underlying substrate and identification of the critical components of the VT circuit is performed in the EP lab.

Following this, radiofrequency (RF) ablation lesions that were partially successful are targeted in the operating room by cryoablation, accomplishing much larger lesions.57

Future Directions Epicardial Ablation Our standard practice is to reverse anticoagulation prior to epicardial access. Consideration may be given to upfront epicardial access if there is a clear indication (such as previously failed endocardial ablation). Once epicardial access is obtained, as described by Sosa and colleagues,55 the ablation approach is similar to endocardial ablation. Due to the presence of epicardial fat and coronary vessels, abnormal EGMs are defined not just by low voltage, but also by the presence of fractionation and LPs.29 Prior to applying ablation lesions, a safe distance must be confirmed from the coronary arteries (via coronary angiography) and the phrenic

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Advances in mapping tools such as multipolar catheters may decrease procedural times and improve the ability to detect and target abnormal EGMs. The utilisation of contact-force sensing may also improve myocardial contact to enable better ablation penetration and reduce the risk of VT recurrence. Improvement of percutaneous LVADs may allow their safe use in a larger subset of patients in order to reduce filling pressures and facilitate entrainment mapping. Randomised clinical trials and large volume centre registries comparing novel ablation endpoints (e.g. scar homogenisation or core isolation) will hopefully provide improved procedural outcome and guide clinicians to the best ablation strategy, particularly in patients with non-ischaemic substrate. n

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14. Piers SRD, Leong DP, van Huls van Taxis CFB, et al. Outcome of ventricular tachycardia ablation in patients with nonischemic cardiomyopathy: the impact of noninducibility.

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15. Tokuda M, Tedrow UB, Kojodjojo P, et al. Catheter ablation of ventricular tachycardia in nonischemic heart disease. Circ Arrhythm Electrophysiol 2012;5:992–1000.

16. Dinov B, Fiedler L, Schönbauer R, et al. Outcomes in catheter ablation of ventricular tachycardia in dilated nonischemic cardiomyopathy compared with ischemic cardiomyopathy: results from the Prospective Heart Centre of Leipzig VT (HELP-VT) Study. Circulation 2014;129:728–36.

17. Frankel DS, Mountantonakis SE, Robinson MR, et al.

Ventricular tachycardia ablation remains treatment of last resort in structural heart disease: argument for earlier intervention. J Cardiovasc Electrophysiol 2011;22:1123–8.

18. Vallès E, Bazan V, Marchlinski FE. ECG criteria to identify epicardial ventricular tachycardia in nonischemic cardiomyopathy. Circ Arrhythm Electrophysiol 2010;3:63–71.

19. Martinek M, Stevenson WG, Inada K, et al. QRS characteristics fail to reliably identify ventricular tachycardias that require epicardial ablation in ischemic heart disease. J Cardiovasc Electrophysiol 2012;23:188–93.

20. Aldhoon B, Tzou WS, Riley MP, et al. Nonischemic cardiomyopathy substrate and ventricular tachycardia in the setting of coronary artery disease. Heart Rhythm 2013;10:1622–7.

21. Nazarian S, Hansford R, Roguin A, et al. A prospective evaluation of a protocol for magnetic resonance imaging of patients with implanted cardiac devices Ann Intern Med 2011;155:415–24.

22. Mesubi O, Ahmad G, Jeudy J, et al. Impact of ICD artifact burden on late gadolinium enhancement cardiac MR imaging in patients undergoing ventricular tachycardia ablation. Pacing Clin Electrophysiol 2014;37:1274–83.

23. Piers SRD, Tao Q, van Huls van Taxis CFB, et al. Contrastenhanced MRI-derived scar patterns and associated ventricular tachycardias in nonischemic cardiomyopathy: implications for the ablation strategy. Circ Arrhythm Electrophysiol 2013;6:875–83.

24. Oloriz T, Silberbauer J, Maccabelli G, et al. Catheter ablation of ventricular arrhythmia in nonischemic cardiomyopathy: anteroseptal versus inferolateral scar sub-types. Circ Arrhythm Electrophysiol 2014;7:414–23.

25. Papaioannou TG, Stefanadis C. Basic principles of the intraaortic balloon pump and mechanisms affecting its performance. ASAIO J 2005;51:296–300.

26. Miller MA, Dukkipati SR, Mittnacht AJ, et al. Activation and entrainment mapping of hemodynamically unstable ventricular tachycardia using a percutaneous left ventricular assist device. J Am Coll Cardiol 2011;58:1363–71.

27. Aryana A, Gearoid O’Neill P, Gregory D, et al. Procedural and clinical outcomes after catheter ablation of unstable ventricular tachycardia supported by a percutaneous left ventricular assist device. Heart Rhythm 2014;11:1122–30.

28. Marchlinski FE, Callans DJ, Gottlieb CD, Zado E. Linear ablation lesions for control of unmappable ventricular tachycardia in patients with ischemic and nonischemic cardiomyopathy. Circulation 2000;101:1288–96.

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29. Cano O, Hutchinson M, Lin D, et al. Electroanatomic substrate and ablation outcome for suspected epicardial ventricular tachycardia in left ventricular nonischemic cardiomyopathy. J Am Coll Cardiol 2009;54:799–808.

30. Hutchinson MD, Gerstenfeld EP, Desjardins B, et al.

Endocardial unipolar voltage mapping to detect epicardial ventricular tachycardia substrate in patients with nonischemic left ventricular cardiomyopathy. Circ Arrhythm Electrophysiol 2011;4:49–55.

31. Bogun F, Good E, Reich S, et al. Isolated potentials during sinus rhythm and pace-mapping within scars as guides for ablation of post-infarction ventricular tachycardia. J Am Coll Cardiol 2006;47:2013–9.

32. Kühne M, Abrams G, Sarrazin J-F, et al. Isolated potentials and pace-mapping as guides for ablation of ventricular tachycardia in various types of nonischemic cardiomyopathy. J Cardiovasc Electrophysiol 2010;21:1017–23.

33. Arenal A, Glez-Torrecilla E, Ortiz M, et al. Ablation of electrograms with an isolated, delayed component as treatment of unmappable monomorphic ventricular tachycardias in patients with structural heart disease.

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34. Waldo AL, Henthorn RW. Use of transient entrainment during ventricular tachycardia to localize a critical area in the reentry circuit for ablation. Pacing Clin Electrophysiol 1989;12:231–44.

35. Stevenson WG, Friedman PL, Sager PT, et al. Exploring postinfarction reentrant ventricular tachycardia with entrainment mapping. J Am Coll Cardiol 1997;29:1180–9.

36. Callans DJ, Zado E, Sarter BH, et al. Efficacy of radiofrequency catheter ablation for ventricular tachycardia in healed myocardial infarction. Am J Cardiol 1998;82:429–32.

37. Volkmer M, Ouyang F, Deger F, et al. Substrate mapping vs. tachycardia mapping using CARTO in patients with coronary artery disease and ventricular tachycardia: impact on outcome of catheter ablation. Europace 2006;8:968–76.

38. Arenal A, del Castillo S, Gonzalez-Torrecilla E, et al.

Tachycardia-related channel in the scar tissue in patients with sustained monomorphic ventricular tachycardias: influence of the voltage scar definition. Circulation 2004;110:2568–74.

39. Mountantonakis SE, Park RE, Frankel DS, et al. Relationship between voltage map “channels” and the location of critical isthmus sites in patients with post-infarction cardiomyopathy and ventricular tachycardia. J Am Coll Cardiol 2013;61:2088–95.

40. Hsia HH, Lin D, Sauer WH, et al. Anatomic characterization of endocardial substrate for hemodynamically stable reentrant ventricular tachycardia: identification of endocardial conducting channels. Heart Rhythm 2006;3:503–12.

41. Soejima K, Suzuki M, Maisel WH, et al. Catheter ablation in patients with multiple and unstable ventricular tachycardias after myocardial infarction: short ablation lines guided by reentry circuit isthmuses and sinus rhythm mapping.

Circulation 2001;104:664–9.

42. Vergara P, Trevisi N, Ricco A, et al. Late potentials abolition as an additional technique for reduction of arrhythmia recurrence in scar related ventricular tachycardia ablation.

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43. Jaïs 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.

44. Arenal Á, Hernández J, Calvo D, et al. Safety, long-term results, and predictors of recurrence after complete endocardial ventricular tachycardia substrate ablation in patients with previous myocardial infarction. Am J Cardiol 2013;111:499–505.

45. Di Biase L, Santangeli P, Burkhardt DJ, et al. Endo-epicardial homogenization of the scar versus limited substrate ablation for the treatment of electrical storms in patients with ischemic cardiomyopathy. J Am Coll Cardiol 2012;60:132–41.

46. Stevenson WG, Sager PT, Natterson PD, et al. Relation of pace mapping QRS configuration and conduction delay to ventricular tachycardia reentry circuits in human infarct scars. J Am Coll Cardiol 1995;26:481–8.

47. Nayyar S, Wilson L, Ganesan AN, et al. High-density mapping of ventricular scar: a comparison of ventricular tachycardia (VT) supporting channels with channels that do not support VT. Circ Arrhythm Electrophysiol 2014;7:90–8.

48. de Chillou C, Groben L, Magnin-Poull I, et al. Localizing the critical isthmus of postinfarct ventricular tachycardia: the value of pace-mapping during sinus rhythm. Heart Rhythm 2014;11:175–81.

49. Goyal R, Harvey M, Daoud EG, et al. Effect of coupling interval and pacing cycle length on morphology of paced ventricular complexes. Implications for pace mapping.

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50. Tilz RR, Makimoto H, Lin T, et al. Electrical isolation of a substrate after myocardial infarction: a novel ablation strategy for unmappable ventricular tachycardias—feasibility and clinical outcome. Europace 2014;16:1040–52.

51. Aliot EM, Stevenson WG, Almendral-Garrote JM, et al. EHRA/ HRS expert consensus on catheter ablation of ventricular arrhythmias: developed in a partnership with the European Heart Rhythm Association (EHRA), a registered branch of the European Society of Cardiology (ESC), and the Heart Rhythm Society (HRS); in collaboration with the American College of Cardiology (ACC) and the American Heart Association (AHA). Heart Rhythm 2009;6:886–933.

52. Frankel DS, Mountantonakis SE, Zado ES, et al. Noninvasive programmed ventricular stimulation early after ventricular tachycardia ablation to predict risk of late recurrence. J Am Coll Cardiol 2012; 59:1529–35.

53. Bazan V, Gerstenfeld EP, Garcia FC, et al. Site-specific twelve-lead ECG features to identify an epicardial origin for left ventricular tachycardia in the absence of myocardial infarction. Heart Rhythm 2007;4:1403–10.

54. Sarkozy A, Tokuda M, Tedrow UB, et al. Epicardial ablation of ventricular tachycardia in ischemic heart disease. Circ Arrhythm Electrophysiol 2013;6:1115–22.

55. Sosa E, Scanavacca M, d’ Avila A, Pilleggi F. A new technique to perform epicardial mapping in the electrophysiology laboratory. J Cardiovasc Electrophysiol 1996;7:531–6.

56. Di Biase L, Burkhardt JD, Pelargonio G, et al. Prevention of phrenic nerve injury during epicardial ablation: comparison of methods for separating the phrenic nerve from the epicardial surface. Heart Rhythm 2009;6:957–61.

57. Anter E, Hutchinson MD, Deo R, et al. Surgical ablation of refractory ventricular tachycardia in patients with nonischemic cardiomyopathy. Circ Arrhythm Electrophysiol 2011;4:494–500.

58. Haqqani HM, Tschabrunn CM, Tzou WS, et al. Isolated septal substrate for ventricular tachycardia in nonischemic dilated cardiomyopathy: incidence, characterization, and implications. Heart Rhythm 2011;8:1169–76.

59. Tokuda M, Sobieszczyk P, Eisenhauer AC, et al. Transcoronary ethanol ablation for recurrent ventricular tachycardia after failed catheter ablation: an update. Circ Arrhythm Electrophysiol 2011;4:889–96.

60. Sapp JL, Beeckler C, Pike R, et al. Initial human feasibility of infusion needle catheter ablation for refractory ventricular tachycardia. Circulation 2013;128:2289–95.

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Clinical Arrhythmias

Pathophysiology and Management of Arrhythmias Associated with Atrial Septal Defect and Patent Foramen Ovale Henry C hubb, 1 , 2 John W hit a k e r , 1 S t e v e n E Wi l l i a m s , 1, 3 Ca t h e r i n e E H e a d , 3 N a t a l i A Y Ch u n g, 3 Mat t h e w J Wr i g h t 1 a n d M a r k O ’ N e i l l 1, 3 1. Division of Imaging Sciences and Biomedical Engineering, King’s College London; 2. Department of Paediatric Cardiology, Evelina London Children’s Hospital; 3. Adult Congenital Heart Disease Group, Department of Cardiology, Guy’s and St Thomas’ NHS Foundation Trust and Evelina London Children’s Hospital, London, UK

Abstract Atrial septal defects (ASDs) are among the most common of congenital heart defects and are frequently associated with atrial arrhythmias. Atrial and ventricular geometrical remodelling secondary to the intracardiac shunt promotes evolution of the electrical substrate, predisposing the patient to atrial fibrillation and other arrhythmias. Closure of an ASD reduces the immediate and long-term prevalence of atrial arrhythmias, but the evidence suggests that patients remain at an increased long-term risk in comparison with the normal population. The closure technique itself and its timing impacts future arrhythmia risk profile while subsequent transseptal access following surgical or device closure is complicated. Newer techniques combined with increased experience will help to alleviate some of the difficulties associated with optimal management of arrhythmias in these patients.

Keywords Atrial septal defect, patent foramen ovale, device closure, atrial arrhythmias, atrial fibrillation, atrial flutter, transseptal puncture, remodelling Disclosure: The authors have no conflicts of interest to declare.

Received: 17 September 2014 Accepted: 11 November 2014 Citation: Arrhythmia & Electrophysiology Review, 2014;3(3):168–72 Access at: www.AERjournal.com Correspondence: Mark O’Neill, Division of Imaging Sciences and Biomedical Engineering and Cardiovascular Medicine, 4th Floor, North Wing, St Thomas’ Hospital, Westminster Bridge Road, London, SE1 7EH, UK. E: mark.oneill@kcl.ac.uk

Atrial Septal Defects and Patent Foramen Ovale Nomenclature The atrial septum is a complex structure, with the true septum comprised of two layers containing a potential flap valve. The septum primum extends from caudal to cranial within the atria, on the left side of the septum secundum. The septum secundum is a crescent-shaped infolding of the atrial roof, extending from the anterosuperior aspects of the atria, and the hole left within the crescent is the fossa ovalis.1 The fossa ovalis is usually sealed shut by the (intact) septum primum (see Figure 1).

A fenestration-type secundum atrial septal defect (ASD) is formed by a defect, or fenestration, within the septum primum. However, a flaptype secundum ASD is also described, and is present when there is a deficiency in the septum primum, which fails to reach to the septum secundum. A patent foramen ovale (PFO) is characterised by the failure of the septum primum to fuse with the septum secundum after birth, and a probe-patent PFO occurs in approximately 25 % of the population.2 The distinction between a PFO and flap-type secundum ASD is not dichotomous but is on a spectrum, dependent upon the size of the gap remaining between the septum primum and secundum, which may change in size with cardiac loading conditions. However, it is generally accepted that an ASD, rather than a PFO, is present when the defect is present throughout the cardiac cycle.

Defects within the atrial septum may also occur in a variety of other positions. This review will focus primarily on those within the ‘true’

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atrial septum (secundum ASD). Sinus venosus defects, coronary sinus defects and primum ASDs (partial atrioventricular septal defect [AVSD]) are beyond the scope of this article, but many of the pathophysiological and management principles still apply.

Current Management of Atrial Septal Defects and Patent Foramen Ovales The consequences of left-to-right shunt across an ASD are right atrial (RA), right ventricular (RV) and to a lesser extent left atrial (LA) volume overload. This is associated with an increased pulmonary blood flow (raised Qp:Qs) and long-term repercussions that include right-sided heart failure and arrhythmias. The recommendations for medical or interventional treatments are summarised in the American College of Cardiology (ACC)/American Heart Association (AHA) guidelines 3 – closure is generally recommended unless the ASD is small (<5 mm) and asymptomatic with no evidence of cardiac compromise. However, even then progression of pathology should be closely monitored and age alone is not a contraindication to repair.4,5 The choice of surgical versus interventional device closure is based on ASD anatomical features and centre preference, but generally surgery is reserved for those defects with unsuitable anatomy.6 The management of PFOs is more controversial, and indications for closure are generally cryptogenic stroke or systemic arterial embolisation, with further considerations including decompression illness and possibly migraine with aura.2

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Arrhythmias Associated with Atrial Septal Defect and Patent Foramen Ovale

Arrhythmias in Patients with Unrepaired Atrial Septal Defect and Patent Foramen Ovale

Figure 1: Diagrammatic Representations of the Interatrial Septum and its Anatomical Relations

Prevalence of Arrhythmias Atrial arrhythmias (AAs) – atrial fibrillation (AF) and/or flutter (AFL) – are significantly increased in patients with ASDs; the prevalences are summarised in Table 1. In unoperated adults, the estimated incidence of AAs is approximately 10 % under the age of 40 years,7 rising to at least 20 % with increased age, pulmonary arterial pressure and systemic hypertension. 8,9 Additional studies have suggested that the incidence is increased in male patients, those with chronic obstructive pulmonary disease, reduced ejection fraction and hypertension.7 For patients with a PFO, the incidence of AA prior to defect closure does not appear to be significantly raised.2 However, the evidence is limited and is confounded by the fact that many PFOs are only detected following thromboembolic events, which may represent undetected episodes of AA in some cases.

To our knowledge there is no conclusive evidence of an increased risk of ventricular arrhythmias in patients with ASDs, despite the evidence of geometric and electrical remodelling of the RV myocardium.10 There are reports of sudden cardiac death in patients with both repaired and unrepaired ASD, but much of the risk could represent coronary artery disease in an older population.11

Pathophysiology of Arrhythmias The left-to-right shunt enabled by the presence of an ASD results in cardiac remodelling secondary to long-standing haemodynamic overload. It is this geometrical remodelling that plays an important role in the pathogenesis of AAs. Changes in atrial tissue properties, including interstitial fibrosis, increased myocyte size and alterations in ultracellular structure have been described12,13 and predispose to AF in particular.14 Electrical remodelling has also been widely described, even in the absence of AA. The P-wave duration and dispersion is increased,15,16 with lengthened sinus node recovery time and conduction delay across the crista terminalis,15 which is likely to play a key role in the arrhythmogenesis of AFL. Interestingly, in contrast to studies of conventional patients with AF, the atrial effective refractory period (AERP) is usually lengthened in the ASD patients.15

Right atrial view SVC

Left atrial view SVC Aorta Septum secundum

Aorta Septum secundum

Septum primum f

Fossa Ovalis

CS

R

f

Fossa Ovalis

EV IVC

Tricuspid valve

Flap-valve (f-v) and fenestration (fen) ASD

Aorta

f

SS

PFO. Free edge of PFO flap (arrows) can be retracted into the fossa (----) SVC

ASD f-v

IVC

Mitral valve

Aorta

SVC

SS PFO

f

f

f

ASD fen Mitral valve

IVC

Mitral valve

IVC

CS = coronary sinus; EVR = eustachian valve ridge; f = fused septal layers; IVC = inferior vena cava; MV = mitral valve; PFO = patent foramen ovale; SVC = superior vena cava; SS = septum secundum. Adapted with permission from Lee et al. 2012.48

Management of Pre-procedural Atrial Arrhythmias Standard pharmacological management strategies for arrhythmias should be employed in patients with ASDs and arrhythmias, with an aim to restore sinus rhythm where possible. AF should be treated with both antiarrhythmic therapy and anticoagulation,3 and direct-current (DC) cardioversion has a similar safety and efficacy profile to that performed in patients without structural heart disease.19 However, the presence of AAs should be considered an indication for closure of an ASD, unless there is a compelling reason not to do so.

Although the rhythm may not revert to sinus post-procedure, there are likely to be benefits in terms of symptoms.4

Arrhythmias After Atrial Septal Defect Closure The majority of geometrical remodelling is reported on the right side of the heart, which is subject to the most dramatic flow and pressure changes. However, there are also left-sided geometrical changes in those with an ASD, with moderately increased LA dimensions found on cardiac magnetic resonance (CMR)17,18 and electroanatomical mapping (EAM).13 Importantly, these changes are also associated with electrical remodelling. Roberts-Thomson et al. compared a group of patients undergoing ASD closure with those with left-sided accessory pathways, and again found prolonged AERP and slower conduction in those with ASDs, alongside reduced bipolar voltage and enhanced inducibility of AF.13 Finally, the possibility of abnormalities of the native interatrial conduction pathways, secondary to the anatomical defect, should also be considered.

In summary, remodelling of both the right and left atrium contributes to arrhythmogenesis and the heterogeneity of that remodelling process between atria may contribute to the propensity for native arrhythmias in this patient group.

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Reverse Remodelling Post-closure Following ASD closure, there is a rapid decrease in RV and RA volumes, but this improvement is not universal.17,18,20 Cardiac geometric reverse remodelling is reduced in older patients and those who have developed markers of decompensation, such as higher pulmonary arterial pressure (PAP) and larger right-sided chambers.20 In particular, those with AF pre-procedure are less likely to improve, and there is even evidence that the LA volumes actually increase post-procedure in those with AF.18 The evidence of electrical reverse remodelling post-closure is much more limited than that for geometrical reverse remodelling.

In a small follow-up study, Morton et al. found that there were no significant changes in AERP, sinus node recovery time or transcristal conduction, but some trends towards improvement. 15 There are also more generalised changes found on the surface electrocardiogram (ECG), with reduction of P-wave duration, P-wave dispersion and QT dispersion.10,21

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Clinical Arrhythmias Table 1: Prevalence of Atrial Arrhythmias in Patients with Atrial Septal Defect or Patent Foramen Ovale

Pre-procedure Post-procedure

Arrhythmia Prevalence (age) No Pre-procedural Arrhythmia

Had Pre-procedural Arrhythmia

20 years 40 years

60 years

10 year

30 days

1 year

PFO

<0.5 %*

<0.5 %*

1.0 %*

All ages 4–7 %24–27

0.3–1.0 %26,27

2.5 %25,27

Minimal data

ASD

<2 %46

10–15 %46 20–40 %7,9,46

Closed 2–4 %26,47 0–0.5 % 8,22

6–8 %9,34,46

70–90 %8,22

60 %8 70 %33

30 days 1 year

aged <25 years

Closed aged 12 %27

>40 years

8 % 8

40–60 %33,46

Minimal data

10 year

93 %27 Minimal data

90–100 %23,27 Minimal data

Studies differ in terms of stringency of assessment for arrhythmia, definition of arrhythmias, co-morbidities and exact length of follow-up. ‘Pre-procedural arrhythmia’ does not differentiate between paroxysmal and persistent rhythms, and prevalence in patients with pre-procedural arrhythmia assumes no concomitant intervention for arrhythmia around the time of ASD closure. *No documented data, but publications generally agree that prevalence does not differ significantly from the normal population. ASD = atrial septal defect; PFO = patent foramen ovale.

The comparison between device and surgical closure is skewed by the inherent difference in substrate, with surgical closure now generally reserved for larger ASDs. Once patient selection is controlled for, a significant difference in arrhythmia prevalence post-closure has not been demonstrated, despite the presence of an atriotomy and sutured patch7 in the surgical group.

Patients with Pre-procedural Arrhythmias There is strongly supportive evidence that the prevalence of AAs is decreased following closure of an ASD. On meta-analysis of the available literature, the odds ratio for AA prevalence immediately post-procedure (<30 days) is 0.80 (95 % confidence interval [CI] 0.66–0.97), improving to 0.47 (95 % CI 0.36–0.62)) over mid-term follow-up (30 days to five years).7,22 Up to 40 % of patients with pre-procedural arrhythmias revert to sinus rhythm8,21 (see Table 1).

However, many AAs may recur in the longer term (>5 years), their progression stalled rather than terminated. Younger patients and patients with paroxysmal (rather than permanent) AF or AFL prior to ASD closure are more likely to remain in sinus rhythm.8,22 In contrast, although other studies have demonstrated no change in rhythm for the elderly and those with permanent AF at the time of device closure,4,23 there is clear symptomatic improvement in terms of ventricular function and markers of cardiac failure.

The longest term outcome (>10 years) is less clear-cut. Attie et al. randomised patients over 40 years old to surgical or medical treatment of ASD, and they were followed up for a mean of seven years. At enrolment, 21 % had AF or AFL, with a further 5 % noted to have another supraventricular tachycardia. Over the course of follow-up, a further 8 % developed AAs, with no significant difference between the interventional and non-interventional groups.9

Patients without Pre-procedural Arrhythmias Pathophysiology of New-onset Arrhythmias The majority of long-term post-procedural arrhythmias are likely to be related to progression of pre-existing atrial substrate abnormalities, with an increased incidence with age and severity of markers of remodelling secondary to the ASD. However, there are subsets of arrhythmias that do not conform to this paradigm.

The first comprises patients with very early onset arrhythmias, in the days and weeks following closure. For those undergoing device closure, it has been hypothesised that the early, transient arrhythmias are likely to be triggered by local irritation. This applies particularly to the PFO closure patients who are unlikely to have suffered from the same extent of atrial remodelling pre-closure,

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with minimal intracardiac shunt. Incidences range from 1 to 6 %, but arrhythmias will cease in up to two-thirds of these patients by one-year post-procedure.22,24–28 Whilst there is no evidence of a device-specific effect in the ASD closure group, there is suggestion that some PFO closure devices may entail a slightly higher risk.25 The second group are those with new right-sided arrhythmias following surgical closure. Right-sided arrhythmia circuits may involve the atriotomy scar, the cavotricuspid isthmus (CTI), the patch site or combinations of these in multi-loop circuits. A dual-loop reentry circuit involving reentry around both the tricuspid annulus (CTI-dependent) and the atriotomy scar is not uncommon.29 In addition, areas of abnormal conduction related to scar may serve not only as a crucial pathway of slow conduction in the formation of reentrant circuits, but also as the site of origin of a focal atrial tachycardia.29–31 Surgical technique for closure of ASDs has also evolved with increased employment of the anterolateral minithoracotomy, subxiphoid and limited median sternotomy approaches, and their implications for the atriotomy should be considered in the electrophysiological approach to these patients.

The third group comprises those patients who have undergone device closure and develop persistent arrhythmias related to the closure device itself. It is worth noting that a potential central barrier of non-conduction (the defect) for formation of a reentrant circuit pre-exists any closure device, but a native reentrant atrial tachycardia around an ASD is a rare event. However, there remains the possibility of device-related inflammation and scarring, with subsequent anisotropic conduction.

Such a mechanism is rare, but there are reports of macroreentrant circuits occurring de novo post-procedurally around the device itself,32 although device type or size does not affect incidence.27 Finally, it has been hypothesised that the interatrial conduction, largely via Bachmann’s bundle lying in the roof of the atrium at the superior margin of the fossa ovalis, may be compromised by surgical or device closure.

This is reflected in the finding of increased P-wave duration index postclosure,26 and may provide further substrate for arrhythmogenesis.

Long-term Risk of Arrhythmias Post-closure Over the longer term, it appears that the risk of new AAs is increased in proportion to the extent of pre-closure exposure to haemodynamic remodelling forces. In the longest follow-up studies of the surgical population, freedom from arrhythmia is good for those whose ASD was repaired at a young age and prior to development of raised PAPs (up to 97 % arrhythmia free at 27 years).33 On the other hand, the risk of AAs is much higher for older patients, especially those undergoing closure over the age of 40 years. In the two years following ASD or PFO closure, de novo AF has been

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Arrhythmias Associated with Atrial Septal Defect and Patent Foramen Ovale

reported in 12 % and 7 %, respectively, well above the baseline population risk.8,27 Late after closure (>20 years), an AA prevalence of up to 59 % has been found in the oldest patients.33

Figure 2: Transseptal Puncture Adjacent to ASD Closure Device A

B

C

D

There are also findings of long-term sinus node dysfunction, with a prevalence of up to 40 % in long-term surgical follow-up studies.34 This is consistent with the findings of pre- and post-procedural sinus node dysfunction on electrophysiological (EP) study.15

Management of Post-procedural Arrhythmias Interventional Techniques It is clear that the incidence of AF is raised in the ASD population post-closure, and left atrial access can pose considerable problems.

In the surgical population, conventional needle puncture positioning techniques are hampered by the loss of the second ‘jump’ of the puncture needle into the fossa ovalis. In addition, the patch or native septum may be tougher (especially Gore-Tex® patches), thickened or fibrotic and balloon dilation of the puncture site may be needed prior to passage of the transseptal sheath.35 Radiofrequency-assisted transseptal puncture may offer advantages over conventional transseptal techniques.36 The presence of a closure device provides an obstacle to transseptal access. There are multiple methods for circumventing this issue – it is often possible to find a portion of atrial septum not covered by device, and transoesophageal echocardiography or intracardiac echocardiography (ICE) are invaluable in this regard.35,37–39 Pre-procedural computed tomography (CT) may also assist in puncture site selection.39 A suitable puncture site, once identified, is most often infero-posterior (see Figure 2). Radiofrequency (RF) energy-assisted septal perforation can be considered,37 but there are ex vivo reports that suggest that caution is necessary when RF energy is used in close proximity to a device. Pedersen et al. tested a RF transseptal needle (Bayliss Medical Company Inc, Montreal, Canada) with an Amplatzer device in a saline bath, and arcing and damage to the device was noted with direct contact of the needle.39 For those patients where the whole of the true septum is covered, typically with devices >26 mm in diameter, there are further options.

The ASD device may be clearly visualised on fluoroscopy or ICE, and a Brockenbrough transseptal needle may be used to enter the LA through the device itself. However, most devices may be resistant to the advancement of the sheath, and high pressure balloons (generally angioplasty balloons) or multiple sequential dilations may be used to enable access.37,38,40 Alternatively, a retrograde approach via the aorta using a magnetic navigation system has also been described.41 Once access has been established, conventional LA mapping and ablation techniques are used similar to those employed in the normal adult population, with no evidence of any device impact on EAM function (see Figure 3, EAM generated anatomy of the right atrium, with no significant impact of device presence). The atrial arrhythmia substrate remains incompletely understood and many of the recent developments in mechanistic mapping of AF42 have not yet been translated to the adult congenital heart disease (ACHD) population, largely because of the relatively smaller numbers of eligible patients. There is an increased incidence of atrial fibrosis in ASD patients manifesting as regions of low voltage amplitude and spontaneous electrical scarring. This is accompanied by regional atrial conduction delay, double potentials, fractionated potentials and increased inducibility of sustained AF.13

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Panels A and B: two transseptal punctures of the atrial septum infero-posterior to the atrial septal defect (ASD) closure device (26 mm Amplatzer Septal Occluder). Panel C: transoesophageal 3D view of the ASD closure device viewed from the right atrium. Panel D: Carto® 3 (Biosense Webster/Johnson and Johnson, US) electroanatomical map of pulmonary vein isolation procedure, viewed from the septal side, with red dots demarcating ablation lesions.

Figure 3: Electroanatomical Mapping of ASD Closure Device A

B

C

Panel A: Carto® 3 electroanatomical map (EAM) of the right atrium, viewed from the septal side, with tricuspid valve annulus to the left of the image. The artefactual electrograms noted on mapping of the atrial septal defect (ASD) closure device (Panel B) are symbolised by yellow dots, outlined by a dashed white circle. Note the correspondence of device location with low unipolar voltage (red colour) and the minimal distortion of EAM acquisition. Panel C: typical right atrial flutter in the same patient, successfully treated by cavotricuspid isthmus ablation (red dots marking ablation visible underneath tricuspid valve in A).

Overall, reported success rates following pulmonary vein isolation (PVI) are close to those achieved in patients without ASD.35,37 Concerns of post-procedural residual shunt and displacement of the device have so far proved to be unfounded, but most operators have

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Clinical Arrhythmias advocated waiting at least six months after device placement prior to electrophysiological intervention in the event that a pre-closure procedure has not been performed.37,40 Right-sided arrhythmias are also more common in the ASD population than controls, and standard techniques can be employed for their management. It should be noted that non-CTI dependent macroreentry circuits are often present, particularly in the surgical population. For these patients, consideration should be given to ablating from the atriotomy to the inferior vena cava (IVC), in addition to a CTI line, even when the only identified circuit is CTI dependent (see Figure 3).29 Focal atrial tachycardias and arrhythmias common in all patient groups, such as atrioventricular (AV) nodal reentry tachycardias, may also occur.

The idea of combining ASD closure with an arrhythmia intervention is not a new one, and surgical closure has previously been combined with a maze-type procedure4,43 or irrigated RF ablation44 with good results. There are also very limited reports of RF catheter ablation prior to device closure of ASD at a separate procedure.45

Conclusions

Pre-emptive Treatment

ASDs are associated with an increased prevalence of atrial arrhythmias. Timely closure of a significant ASD results in a reduced incidence of future arrhythmias, and may also reduce arrhythmia burden in patients who have already developed an arrhythmia prior to closure. However, patients remain at an increased risk of AAs in the long term compared with the normal population, with the greatest increase in risk in older patients or those with evidence of haemodynamic complications related to the ASD.

One approach that has been initially successful has been to combine an interventional closure of the ASD with DC cardioversion, which may be effective in restoring and maintaining sinus rhythm in at least the medium term.22 However, intermittent episodes of paroxysmal atrial fibrillation (PAF) were noted prior to reversion to long-standing sinus rhythm, and it has been suggested that cardioversion might be best postponed for 3–6 months, once atrial reverse remodelling has occurred.

Given the future propensity for AAs, and the challenges of intervention post-device closure, there may be a subgroup of patients that would benefit from risk stratification and prophylactic interventional electrophysiological procedures, a dilemma that as yet remains unanswered. Alternatively, increased adoption of biodegradable devices and new interventional EP techniques may help alleviate some of the issues related to interventional EP procedures in this group. n

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4. Hanninen M, Kmet A, Taylor DA, et al. Atrial septal defect closure in the elderly is associated with excellent quality of life, functional improvement, and ventricular remodelling.

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5. Webb G, Gatzoulis MA. Atrial septal defects in the adult: recent progress and overview. Circulation 2006;114:1645–53.

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8. Gatzoulis MA, Freeman MA, Siu SC, et al. Atrial arrhythmia after surgical closure of atrial septal defects in adults.

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10. Santoro G, Pascotto M, Sarubbi B, et al. Early electrical and geometric changes after percutaneous closure of large atrial septal defect. Am J Cardiol 2004;93:876–80.

11. Koyak Z, Harris L, de Groot JR, et al. Sudden cardiac death in adult congenital heart disease. Circulation 2012;126:1944–54.

12. Ueda A, Adachi I, McCarthy KP, et al. Substrates of atrial arrhythmias: histological insights from patients with congenital heart disease. Int J Cardiol 2013;168:2481–6.

13. Roberts-Thomson KC, John B, Worthley SG, et al. Left atrial remodeling in patients with atrial septal defects. Heart Rhythm 2009;6:1000–6.

14. Andrade J, Khairy P, Dobrev D, Nattel S. The clinical profile and pathophysiology of atrial fibrillation: relationships among clinical features, epidemiology, and mechanisms. Circ Res 2014;114:1453–68.

15. Morton JB, Sanders P, Vohra JK, et al. Effect of chronic right atrial stretch on atrial electrical remodeling in patients with an atrial septal defect. Circulation 2003;107:1775–82.

16. Fang F, Luo XX, Lin QS, et al. Characterization of mid-term atrial geometrical and electrical remodeling following device closure of atrial septal defects in adults. Int J Cardiol 2013;168:467–71.

17. Teo KSL, Dundon BK, Molaee P, et al. Percutaneous closure of atrial septal defects leads to normalisation of atrial and

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ventricular volumes. J Cardiovasc Magn Reson 2008;10:55.

18. Thilén U, Persson S. Closure of atrial septal defect in the adult. Cardiac remodeling is an early event. Int J Cardiol 2006;108:370–5.

19. Ammash NM, Phillips SD, Hodge DO, et al. Outcome of direct current cardioversion for atrial arrhythmias in adults with congenital heart disease. Int J Cardiol 2012;154:270–4.

20. Fang F, Yu CM, Sanderson JE, et al. Prevalence and determinants of incomplete right atrial reverse remodeling after device closure of atrial septal defects. Am J Cardiol 2011;108:114–9.

21. Kaya MG, Baykan A, Dogan A, et al. Intermediate-term effects of transcatheter secundum atrial septal defect closure on cardiac remodeling in children and adults. Pediatr Cardiol 2010;31:474–82.

22. Giardini A, Donti A, Sciarra F, et al. Long-term incidence of atrial fibrillation and flutter after transcatheter atrial septal defect closure in adults. Int J Cardiol 2009;134:47–51.

23. Taniguchi M, Akagi T, Ohtsuki S, et al. Transcatheter closure of atrial septal defect in elderly patients with permanent atrial fibrillation. Catheter Cardiovasc Interv 2009;73:682–6.

24. Alaeddini J, Feghali G, Jenkins S, et al. Frequency of atrial tachyarrhythmias following transcatheter closure of patent foramen ovale. J Invasive Cardiol 2006;18:365–8.

25. Staubach S, Steinberg DH, Zimmermann W, et al. New onset atrial fibrillation after patent foramen ovale closure. Catheter Cardiovasc Interv 2009;74:889–95.

26. Johnson JN, Marquardt ML, Ackerman MJ, et al.

Electrocardiographic changes and arrhythmias following percutaneous atrial septal defect and patent foramen ovale device closure. Catheter Cardiovasc Interv 2011;78:254–61.

27. Spies C, Khandelwal A, Timmermanns I, Schräder R. Incidence of atrial fibrillation following transcatheter closure of atrial septal defects in adults. Am J Cardiol 2008;102:902–6.

28. Burow A, Schwerzmann M, Wallmann D, et al. Atrial fibrillation following device closure of patent foramen ovale.

Cardiology 2008;111:47–50.

29. Teh AW, Medi C, Lee G, et al. Long-term outcome following ablation of atrial flutter occurring late after atrial septal defect repair. Pacing Clin Electrophysiol 2011;34:431–5.

30. Chubb H, Williams SE, Wright M, et al. Tachyarrhythmias and catheter ablation in adult congenital heart disease. Expert Rev Cardiovasc Ther 2014;12:751–70.

31. de Groot NM, Zeppenfeld K, Wijffels MC, et al. Ablation of focal atrial arrhythmia in patients with congenital heart defects after surgery: Role of circumscribed areas with heterogeneous conduction. Heart Rhythm 2006;3:526–35.

32. Marai I, Suleiman M, Lorber A, Boulos M. Iatrogenic intraatrial macro-reenterant tachycardia following transcatheter closure of atrial septal defect treated by radiofrequency ablation. Ann Pediatr Cardiol 2011;4:192–4.

33. Murphy JG, Gersh BJ, McGoon MD, et al. Long-term outcome after surgical repair of isolated atrial septal defect. Follow-up at 27 to 32 years. N Engl J Med 1990;323:1645–50.

34. Roos-Hesselink JW, Meijboom FJ, Spitaels SE, et al. Excellent survival and low incidence of arrhythmias, stroke and heart

failure long-term after surgical ASD closure at young age A prospective follow-up study of 21-33 years. Eur Heart J 2003;24:190–7.

35. Lakkireddy D, Rangisetty U, Prasad S, et al. Intracardiac echoguided radiofrequency catheter ablation of atrial fibrillation in patients with atrial septal defect or patent foramen ovale repair: a feasibility, safety, and efficacy study. J Cardiovasc Electrophysiol 2008;19:1137–42.

36. Esch JJ, Triedman JK, Cecchin F, et al. Radiofrequencyassisted transseptal perforation for electrophysiology procedures in children and adults with repaired congenital heart disease. Pacing Clin Electrophysiol 2013;36:607–11.

37. Santangeli P, Di Biase L, Burkhardt JD, et al. Transseptal access and atrial fibrillation ablation guided by intracardiac echocardiography in patients with atrial septal closure devices. Heart Rhythm 2011;8:1669–75.

38. Li X, Wissner E, Kamioka M, et al. Safety and feasibility of transseptal puncture for atrial fibrillation ablation in patients with atrial septal defect closure devices. Heart Rhythm 2014;11:330–5.

39. Pedersen ME, Gill JS, Qureshi SA, Rinaldi CA. Successful transseptal puncture for radiofrequency ablation of left atrial tachycardia after closure of secundum atrial septal defect with Amplatzer septal occluder. Cardiol Young 2010;20:226–8.

40. Chen K, Sang C, Dong J, Ma C. Transseptal puncture through Amplatzer septal occluder device for catheter ablation of atrial fibrillation: use of balloon dilatation technique. J Cardiovasc Electrophysiol 2012;23:1139–41.

41. Miyazaki S, Nault I, Haïssaguerre M, Hocini M. Atrial fibrillation ablation by aortic retrograde approach using a magnetic navigation system. J Cardiovasc Electrophysiol 2010;21:455–7.

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45. Crandall MA, Daoud EG, Daniels CJ, Kalbfleisch SJ. Percutaneous radiofrequency catheter ablation for atrial fibrillation prior to atrial septal defect closure. J Cardiovasc Electrophysiol 2012;23:102–4.

46. Oliver JM, Gallego P, González A, et al. Predisposing conditions for atrial fibrillation in atrial septal defect with and without operative closure. Am J Cardiol 2002;89:39–43.

47. Butera G, Carminati M, Chessa M, et al. Percutaneous versus surgical closure of secundum atrial septal defect: comparison of early results and complications. Am Heart J 2006;151:228–34.

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Diagnostic Electrophysiology & Ablation

Three-dimensional Rotational Angiography as a Periprocedural Imaging Tool in Atrial Fibrillation Ablation T om JR De P ot ter, Ga zmend B a r d h a j , A n i e l l o V i g g i a n o , K e i t h M o r r i c e a n d Pe t e r G e e l e n Arrhythmia Unit, Cardiovascular Center, OLV Hospital, Aalst, Belgium

Abstract Atrial fibrillation (AF) ablation relies increasingly on three-dimensional (3D) visualisation tools to help guide an operator in performing a procedure safely and successfully. Current generation non-fluoroscopic navigation systems can be used as stand-alone tools, but also offer the capability to integrate information from additional imaging studies in order to enhance 3D model accuracy. Between available imaging modalities, 3D rotational angiography offers a set of interesting features such as near realtime availability, applicability in high-volume workflows, integration with other imaging systems (fluoroscopic or non-fluoroscopic) and very low incremental cost per procedure. Applicability of this imaging approach in AF ablation, as a complement or substitute to other imaging/navigation tools, is reviewed.

Keywords Atrial fibrillation ablation, periprocedural imaging, rotational angiography Disclosure: The authors have no conflicts of interest to declare.

Received: 11 September 2014 Accepted: 6 November 2014 Citation: Arrhythmia & Electrophysiology Review, 2014;3(3):173–6 Access at: www.AERjournal.com Correspondence: Tom De Potter, Cardiovascular Center, OLV Hospital, Moorselbaan 164, B9300 Aalst, Belgium. E: tom.de.potter@olvz-aalst.be

Percutaneous catheter treatment for atrial fibrillation (AF) has seen an exponential uptake since the first cases were published exactly two decades ago.1 Evolving over different approaches and treatment strategies, current standard of care consists of pulmonary vein isolation (PVI) through radiofrequency (RF) or other energy sources. While this treatment has been shown to be superior to pharmacological treatment in the setting of paroxysmal AF, considerable variation in reported outcomes exists.2,3 Part of this variation is attributed to the aforementioned change in strategies over time – a clear evolution exists from electrophysiology (EP)-guided (and anatomically rather straightforward) approaches such as trigger elimination inside the pulmonary veins (PVs) to more empirical creation of circular lesions around the PVs.3 This latter approach eliminates challenges such as trigger identification and reduces safety concerns such as PV stenosis, but introduces new complexities that are mostly related to catheter positioning in the complex three-dimensional (3D) space of the left atrium (LA).

One of the peculiarities of catheter manipulation in the LA is the usefulness, or rather lack of usefulness, of basic two-dimensional (2D) fluoroscopy. Unlike conventional procedures (e.g. right atrial or ventricular manipulation), fluoroscopy landmarks for AF ablation are few and far between. On top of that, safe and successful PVI requires precise energy delivery at crucial complex 3D structures, such as the left superior PV left atrial appendage transition. In order to achieve this goal, several tools have been developed that either help the operator understand anatomy, facilitate 3D catheter navigation or decrease radiation exposure; and ideally combine several of these useful features.4–7

Rotational Angiography Three-dimensional rotational angiography (3DRA) is an innovative method that allows reconstruction of tomographic slices of a volume

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of interest in a manner similar to computed tomography (CT), using single-plane radiographic equipment.8,9 The reconstructed 3D models can be used instead of conventional CT or magnetic resonance imaging (MRI) to complement non-fluoroscopic navigation systems, or can be overlaid on 2D fluoroscopic images. In contrast to CT/MRI this technology allows near realtime 3D imaging that is acquired during an ongoing ablation procedure, thereby avoiding volume mismatch due to changes in volume status, rhythm or even table geometry (influencing chest geometry). Not only does 3DRA offer advantages in terms of accuracy over pre-procedural imaging, it also has important benefits from a logistics and cost-effectiveness perspective. Table 1 lists the impact of 3DRA in different clinical scenarios, explained below. Table 2 lists the impact of different workflow options for 3DRA.

Three-dimensional Rotational Angiography as Computed Tomography Substitute At its core, 3DRA is a technology that produces CT-like tomography slices.

These slices can be used to perform measurements or – more commonly for EP procedures – to make a 3D reconstruction of a structure of interest.

Image integration is routinely performed for complex ablation procedures and has been shown to be useful in understanding potentially variant anatomy and enhancing procedural efficacy.4–6 Reconstructed 3DRA volumes correlate well with CT-derived volumes and can therefore be used as a substitute in this setting. Compared with CT, patient radiation exposure is reduced and can be brought to levels well below accepted values for interventional procedures.10 A workflow based on imaging in the EP lab allows logistic independence from other departments, making ‘on the spot’ decision trees possible. In addition, cost benefits are reasonable to expect as the incremental cost of performing a single 3DRA amounts to contrast agent and a pigtail catheter. Table 1 and 2 summarise the impact of using 3DRA in different scenarios.

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Diagnostic Electrophysiology & Ablation Table 1: Impact of Three-dimensional Rotational Angiography in Different Settings on Procedural Aspects

Anatomy/ Radiation Time Accuracy Reduction Gain

Cost Reduction

3DRA as CT substitute

=

+

-

++

3DRA as EAM substitute

++

--

++

+++

3DRA/EAM integration

+++

+++

+

- (vs EAM)

+ (vs CT/EAM)

See text for details. CT = computed tomography; EAM = electroanatomical mapping; 3DRA = three-dimensional rotational angiography.

Table 2: Advantages and Disadvantages of Several Three-dimensional Rotational Angiography Workflow Choices Advantage(s) Use of GA

Disadvantage(s)

Control of apnoea, motion Increases complexity Allows easy asystole

Conscious

Less complexity

sedation

Challenging to get consistent results with direct LA injection workflow

Adenosine for

de facto standard for guiding RF ablation.7 EAM allows an operator to reconstruct any geometry by navigating a catheter within the space of that geometry. The obvious drawback is that any geometry is ‘unknown’ at the beginning of the mapping phase – an operator needs to discover geometry in the course of the procedure. This means significant operator expertise is required and the potential for ‘missing’ certain parts of the anatomy is present – especially in cases of variant anatomy such as presence of a roof vein or other congenital anomalies. On top of that, some alternative approaches for PVI such as single-shot devices (balloon cryotherapy, multipolar RF) are not compatible with EAM systems. In these settings 3D LA visualisation is completely absent – positioning of these devices depends on assumptions of PV antrum shape for which purpose-built catheters are used, generally requiring 2D contrast injections to verify adequate placement.

Near-perfect standstill

low output

Impractical without GA Quality degradation in case of PVCs

Rapid RV pacing

Robust workflow,

May induce VT/VF

for low output

predictable quality

Difficult without GA

Direct LA

Optimal image quality

Needs low output

injection

No need for timing bolus

Indirect RA/AP

No need for GA/

Needs timing of bolus

injection

asystole

Image quality degradation Difficult long apnoea

AP = arteria pulmonalis; GA = general anaesthesia; LA = left atrium; PVCs = premature ventricular contractions; RA = right atrium; RV = right ventricle; VF = ventricular fibrillation; VT = ventricular tachycardia.

Figure 1: Three-dimensional Rotational Angiography Model of the Right Atrium, Overlaid on Two-dimensional Rotational Angiography Fluoroscopy (Postero-anterior View)

As an alternative to an EAM workflow or as a complement to a single-shot device workflow, 3DRA models can be overlaid on live fluoroscopy. As typically the same manufacturer provides the fluoroscopy equipment and the 3DRA segmentation workstation, these systems are linked and able to communicate with each other.

This allows the fluoroscopy system to show an appropriately sized and rotated 3D model for any live 2D fluoroscopy angle an operator chooses. Modern systems allow tagging of points of interest (such as ablation sites for tracking), and most recent developments allow activation and substrate maps to be integrated in the 2D/3D model by linking an EP recording system to the setup (see Figure 1).

A purely 3DRA-based workflow has limitations compared with EAM, mainly due to the inherent 2D nature of the live fluoroscopy image and the physical constraints within which a fluoroscopy gantry needs to operate. Also, importantly, catheter visualisation is only possible using ongoing fluoroscopy exposure. However, from a cost perspective important gains are achievable because no high disposable cost is incurred – a 3DRA model as an EAM substitute may therefore make very good sense in well-selected clinical scenarios.

Three-dimensional Rotational Angiography and Electroanatomical Mapping Integration Further integration of imaging modalities has led to the linking of existing fluoroscopy systems to EAM systems. This allows an EAM system to display 2D X-ray backgrounds corresponding to a particular orientation and fuse them with the 3D display. The intuitive application of such a feature is catheter positioning (e.g. coronary sinus placement) with minimal use of fluoroscopy. More importantly though, this integration means the fluoroscopy and EAM system now share a single coordinate system – any point in ‘true’ 3D space is defined precisely and identically in both systems.

As a result of this, a linked fluoro-EAM system is able to display a 3DRA-derived volume in its correct position without having to collect even a single anatomy point from the catheter, eliminating any experience barrier and eliminating the potential for ‘missed’ regions of anatomy.

A roving catheter is tracked by software (yellow circle) and an activation map is projected on the three-dimensional shell, based on timing of local bipolar electrograms (EGMs) at the catheter tip.

Three-dimensional Rotational Angiography as Electroanatomical Mapping Substitute Due to the aforementioned challenges in 3D navigation of the LA, electroanatomical mapping (EAM) has quickly evolved to become the

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Combining the benefits of 3DRA (complete and detailed, CT-like anatomy) with the benefits of EAM (non-fluoroscopic catheter navigation) allows for a highly reproducible workflow for PVI that is potentially able to reduce procedural time (elimination of mapping time) and radiation exposure (near elimination of fluoroscopy for catheter manipulation) while maintaining a high standard of safety

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Three-dimensional Rotational Angiography for Atrial Fibrillation Ablation

and efficacy (accurate 3D representation of the target structures of interest). The authors have developed such a workflow, which has been used in several hundred consecutive PVI procedures over the past 18 months.

Figure 2: Three-dimensional Rotational Angiography Reconstruction (Semi-transparent Green) Positioned in the Three-dimensional Space of a CARTO® system Without the Use of Additional Mapping

Independent verification of the accuracy of the 3DRA/EAM integrated model, such as contact force sensing indicating contact at the visualised tissue wall, may allow an operator to develop enough confidence in the 3D model to use it exclusively – that is without requiring additional fluoroscopy once the 3DRA has been acquired. In such a workflow, given a high enough degree of spatial accuracy of the 3D map, fluoroscopy is only needed for initial setup, LA access and catheter placement. Routine exposure measurements in our lab using high sensitivity realtime digital dosimeters consistently confirm patient effective doses around 1 mSv (mainly from the 3DRA acquisition) and operator doses, measured outside the lead apron, around 1 µSv – well below daily natural background radiation and therefore in the range of completely insignificant exposure.

Figure 2 shows an example of such a resulting workflow, with EAM mapping and intracardiac echocardiography (ICE) mapping used for backup verification purposes. Of note are the 3DRA volume (semi-transparent green), the EAM volume (semi-transparent grey) and the ICE structures (solid green and purple, marking the left common ostium, the right inferior PV and the oesophagus). The 3DRA volume is positioned in the EAM system without any merging to the EAM shell – its position is determined by 3DRA/EAM integration.

Contact is indicated by the EAM contact force measurement and confirmed on ICE. The EAM shell is significantly smaller than the 3DRA shell, in particular near the mitral valve where mapping is difficult and potentially dangerous (due to mapping catheter entrapment in the subvalvular apparatus). The ICE structures are accurate yet rudimentary due to incomplete visualisation from different angles. The 3DRA shell aligns exactly with the EAM ablation tags, which are generated automatically by the system based on contact and position stability – providing another independent verification of 3D model accuracy.

Alternative Realtime Imaging Modalities Intracardiac Echocardiography Currently, ICE is widely used as a realtime imaging modality in AF, in particular in the US – Medicare data suggests application in 67 % of PVI cases.11 The clear benefit of ICE over 3DRA is that it allows continuous realtime visualisation of geometry and catheter position without radiation exposure. Additional benefits may include transseptal puncture guidance, LA appendage thrombus assessment, monitoring for complications and visualisation of the oesophagus position. Transoesophageal echography can provide these additional benefits equally well but does not allow the first, clear benefit of realtime monitoring during ablation because of concerns regarding leaving a bulky echo probe in proximity to the LA posterior wall during RF application. However, a purely ICE-based workflow (without EAM integration) suffers from incomplete visualisation of anatomy and is again heavily dependent on operator skill and training. As a result, in most cases ICE is used in AF ablation cases for accessing the LA safely but discarded or only used as a complementary tool to EAM for the remainder of the procedure. Furthermore, disposable catheter costs are significant – resource allocation considerations in no-reuse environments have therefore led to much lower adoption rates outside the US.

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Accuracy of positioning is confirmed by intracardiac echocardiography (ICE), by contact force at the three-dimensional wall and by matching electroanatomical mapping (EAM).

See text for details.

Direct Visualisation Laser balloon ablation is a recently described technique sharing features of single-shot approaches as well as point-by-point techniques.12 A unique feature of this approach is that the system contains an integrated endoscope allowing direct visualisation of the target structures for ablation. Although experience is limited, some centres have published long-term follow-up (four years) with encouraging results.13

Magnetic Resonance Imaging MRI is already widely used in EP labs, mostly as a pre-procedural imaging technique offering either information about size/shape of cardiac chambers of interest or additional information such as identification of arrhythmia substrates (e.g. post-infarction scarring of the ventricle) to guide ablation. Furthermore, MRI has been shown to be very useful for lesion visualisation induced by RF with high spatial and temporal resolution, and for the identification of oedema (T2-weighted imaging) and necrosis using delayed enhancement (DE) imaging. MRI thus offers the potential benefit of delineating areas with permanent tissue damage, thereby guiding ablation and improving the procedural endpoints.14,15 For these reasons, realtime MRI (RTMRI) has been proposed as a new tool for guiding and monitoring EP procedures and ablations.16,17 While it is still in an early research phase, currently limited by extensive logistic and infrastructure requirements, technological advancements may well bring RTMRI into the clinical research setting in the near future, at which point additional benefits of MRI such as substrate visualisation may become significant.18

Conclusion Technological advances have evolved the field of AF ablation – an anatomically challenging procedure is increasingly supported by advanced imaging solutions. These solutions are increasingly used synergistically by integrating different systems. Several established and novel approaches aim to provide an intuitive and maximally

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Diagnostic Electrophysiology & Ablation accurate representation of the LA and its specific anatomic regions in order to enhance procedural safety and efficacy during ablation.

Of these, 3DRA is an imaging modality that is currently applicable

1. Haïssaguerre M, Marcus FI, Fischer B, Clementy J. Radiofrequency catheter ablation in unusual mechanisms of atrial fibrillation: Report of three cases. J Cardiovasc Electrophysiol 1994;5:743–51.

2. Piccini JP, Lopes RD, Kong MH, et al. Pulmonary vein isolation for the maintenance of sinus rhythm in patients with atrial fibrillation: a meta-analysis of randomized, controlled trials.

Circ Arrhythm Electrophysiol 2009;2:626–33.

3. Calkins H, Kuck KH, Cappato R, et al. HRS/EHRA/ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints and research trial design. Europace 2012;14:528–606.

4. Dong J, Dickfeld T, Dalal D, et al. Initial experience in the use of integrated electroanatomic mapping with threedimensional MR/CT images to guide catheter ablation of atrial fibrillation. J Cardiovasc Electrophysiol 2006;17:459–66.

5. Martinek M, Nesser HJ, Aichinger J, et al. Impact of integration of multislice computed tomography imaging into three-dimensional electroanatomic mapping on clinical outcomes, safety, and efficacy using radiofrequency ablation for atrial fibrillation. Pacing Clin Electrophysiol 2007;30:1215–23.

6. Malchano ZJ, Neuzil P, Cury RC, et al. Integration of cardiac CT/MR imaging with three-dimensional electroanatomical

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in high-volume clinical settings, potentially as a stand-alone tool or integrated in 3D navigation systems – the latter allowing near-zero radiation workflows for PVI. n

mapping to guide catheter manipulation in the left atrium: Implications for catheter ablation of atrial fibrillation.

J Cardiovasc Electrophysiol 2006;17:1221–9.

7. Bertaglia E, Bella PD, Tondo C, et al. Image integration increases efficacy of paroxysmal atrial fibrillation catheter ablation: results from the CartoMerge Italian Registry.

Europace 2009;11:1004–10.

8. Orlov MV, Hoffmeister P, Chaudhry GM, et al. Threedimensional rotational angiography of the left atrium and esophagus–A virtual computed tomography scan in the electrophysiology lab? Heart Rhythm 2007;4:37–43.

9. Ector J, De Buck S, Nuyens D, et al. Adenosine-induced ventricular asystole or rapid ventricular pacing to enhance three-dimensional rotational imaging during cardiac ablation procedures. Europace 2009;11:751–62.

10. Viggiano A, De Potter T, Peytchev P, Geelen P. Exposure reduction by optimization of the imaging toolchain in pulmonary vein isolation. Acta Cardiol 2013;5:541.

11. Steinberg BA, Hammill BG, Daubert JP, et al. Periprocedural imaging and outcomes after catheter ablation of atrial fibrillation. Heart 2014;100:1871–7.

12. Gerstenfeld EP, Michele J. Pulmonary vein isolation using a compliant endoscopic laser balloon ablation

system in a swine model. J Interv Card Electrophysiol 2010;29:1–9.

13. Sedivá L, Petru J, Skoda J, et al. Visually guided laser ablation: a single-centre long-term experience. Europace 2014; doi:10.1093/europace/euu168 [Epub ahead of print].

14. Reddy VY, Schmidt EJ, Holmvang G, Fung M. Arrhythmia recurrence after atrial fibrillation ablation: can magnetic resonance imaging identify gaps in atrial ablation lines?

J Cardiovasc Electrophysiol 2008;19:434–7.

15. Sohns C, Karim R, Harrison J, et al. Quantitative magnetic resonance imaging analysis of the relationship between contact force and left atrial scar formation after catheter ablation of atrial fibrillation. J Cardiovasc Electrophysiol 2013; doi: 10.1111/jce.12298 [Epub ahead of print].

16. Bock M, Müller S, Zuehlsdorff S, et al. Active catheter tracking using parallel MRI and real-time image reconstruction. Magn Reson Med 2006;55:1454–9.

17. Susil RC, Yeung CJ, Halperin HR, et al. Multifunctional interventional devices for MRI: a combined electrophysiology/ MRI catheter. Magn Reson Med 2002;47:594–600.

18. Dukkipati SR, Mallozzi R, Schmidt EJ, et al. Electroanatomic mapping of the left ventricle in a porcine model of chronic myocardial infarction with magnetic resonance-based catheter tracking. Circulation 2008;118:853–62.

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Diagnostic Electrophysiology & Ablation

Evaluating the Cost-effectiveness of Catheter Ablation of Atrial Fibrillation Andrew Y C ha ng , 1 D a n i e l K a i s e r , 1 A d i t y a U l l a l , 2 A l e x a n d e r C P e r i n o 1 ,2 P a ul A H e i d e n r e i c h 1 ,2 a n d M i n t u P Tu r a k h i a 1 ,2 1. Department of Medicine, Stanford University School of Medicine, Stanford, California; 2. Veterans Affairs Palo Alto Health Care System, California, US

Abstract Atrial fibrillation (AF) is one of the most common cardiac conditions treated in primary care and specialty cardiology settings, and is associated with considerable morbidity, mortality and cost. Catheter ablation, typically by electrically isolating the pulmonary veins and surrounding tissue, is more effective at maintaining sinus rhythm than conventional antiarrhythmic drug therapy and is now recommended as first-line therapy. From a value standpoint, the cost-effectiveness of ablation must incorporate the upfront procedural costs and risks with the benefits of longer term improvements in quality of life (QOL) and healthcare utilisation. Here, we present a primer on cost-effectiveness analysis (CEA), review the data on cost-effectiveness of AF ablation and outline key areas for further investigation.

Keywords Atrial fibrillation, catheter ablation, cost-effectiveness, health policy, review Disclosure: Dr Turakhia is a consultant to Medtronic Inc., St Jude Medical Inc. and Precision Health Economics. He has received speaking honorarium from St Jude Medical, Medtronic and Biotronik. The other authors have no conflicts of interest to declare.

Received: 17 September 2014 Accepted: 22 November 2014 Citation: Arrhythmia & Electrophysiology Review, 2014;3(3):177–83 Access at: www.AERjournal.com Correspondence: Mintu Turakhia, MD MAS, Palo Alto VA Health Care System, Stanford University, 3801 Miranda Ave - 111C, Palo Alto CA 94304. E: mintu@stanford.edu

Support: Dr. Turakhia is supported by a Veterans Health Services Research & Development Career Development Award (CDA09027-1) and a VA Health Services and Development MERIT Award (IIR 09-092). The content and opinions expressed are solely the responsibility of the authors and do not necessarily represent the views or policies of the Department of Veterans Affairs.

Atrial fibrillation (AF) is the most frequently encountered arrhythmia in clinical practice.1,2 The prevalence of AF in the United States ranges from 2.7 to 6.1 million, with 5.6 to 12 million additional cases projected by 2050.1 Medicare spending for new AF diagnoses has reached $15.7 billion per year as extrapolated from a 2004–2006 dataset, primarily driven by its complications (e.g. stroke, heart failure, tachycardia and myocardial infarction).3,4 Management of AF generally consists of preventing stroke and managing the rhythm, either by controlling the ventricular rate independent of rhythm (rate control) or by restoring and maintaining sinus rhythm (rhythm control). Maintenance of sinus rhythm is usually reserved for patients with symptoms attributable to AF, but may also be beneficial in heart failure or structural heart disease.5 Over the last 15 years, pulmonary vein or antral isolation by catheter ablation has matured as a therapeutic option for rhythm control and has been shown to have greater efficacy than antiarrhythmic drug (AAD) therapy alone.6–8 Investigation into its cost-effectiveness, however, has been limited.

Multiple studies have demonstrated that anticoagulation with warfarin or with target-specific anticoagulants is cost-effective in moderateto high-risk patients with AF.9,10 The data are more variable for catheter ablation, in part due to the heterogeneity of treatment, patient selection, and the challenge of comparing a procedure with upfront risks and costs to a daily pharmaceutical therapy with a

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more consistent risk and cost profile. In this review, we present key considerations in estimating the costs and effectiveness of ablation, highlighting limitations of the current literature and areas requiring additional research.

A Primer on Cost-Effectiveness Analysis Cost-effectiveness analysis (CEA) attempts to determine the value of an intervention by comparing the costs and outcomes (clinical effectiveness) of two or more therapies.11 Value in healthcare is conceptually defined as Value = Effectiveness/Cost.

Effectiveness can be measured in the years of life gained from a therapy. However, since not all health states are equally desirable, quality-adjusted life years (QALYs) are incorporated by multiplying a “utility” value to the life-years of survival gained (where a utility of 1.0 represents ideal health). Note that this framework does not give preference to longevity or utility: 10 years of perfect health is considered equivalent to five years of health at 50 % utility.

Considerations in the effectiveness of a study intervention include magnitude of effect (number of life-years or improvement in quality of life [QOL] added by procedure), efficacy (the success rate of the procedure), and complications.

Healthcare costs are usually generated from published fee schedules of reimbursements from payers, or from empirical assessments of

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Diagnostic Electrophysiology & Ablation actual reimbursements of claims (e.g. Medicare data in the US). The costs of procedures, medications and services often vary across hospitals and regions even for the same payer. Costs not only reflect out-of-pocket expenditures of the procedure or medication, but also incorporate long-term healthcare expenses, which may include complications, repeat procedures and other spending (e.g. hospitalisation fees). Costs must also be adjusted for inflation to reflect current prices.

Value is quantified with the incremental cost-effectiveness ratio (ICER) and represents a cost per QALY gained expressed as ICER = [Cost (A) – Cost (B)] / [Benefit (A) – Benefit (B)]. Larger ICERs indicate poorer cost-effectiveness. In the US, ICERs are not officially used for policy determination, but are considered by European governments such as the UK and the Netherlands. In practice, the willingness-topay threshold based on acceptability of value is $50,000USD/QALY in the US and £20,000/QALY in the UK.12 ICERs below this range are generally regarded as cost-effective. ICERs above $100,000USD/ QALY or £40,000/QALY are considered too expensive. In the case that a treatment is both less expensive and more effective than its comparator, we say that it “dominates” the alternative.

The balance between cost and effectiveness also depends on the time horizon, or duration over which the treatment’s costs and benefits are considered. Short time horizons (e.g. two to five years) can fail to capture long-term value of a therapy, particularly when there is high early cost or risk such as with a procedure. On the other hand, econometric models utilising significant assumptions over long time horizons (e.g. a lifetime) can have magnified distortion from inaccurate inputs. Investigators may also overestimate the long-term benefits of certain interventions.11,13 CEA incorporates cost and effectiveness data in several approaches.

One is trial-based, where costs and benefits are calculated alongside an ongoing randomised clinical trial (RCT). The advantage of this method is that “real numbers” are gathered during the course of the comparison of interventions. Furthermore, because incremental differences in cost and QALY are of interest, randomisation helps to balance all other confounders in both groups. The disadvantage of a trial-based approach is that characteristics of randomised trial populations are often not generalisable to patients considered for the treatment in a healthcare system.14,15 Trial patients may have higher compliance, greater symptom burden, and may receive more regular or protocolled follow-up. Also, since clinical trials are costly, their time horizons are often short.

An alternative approach is a model-based study, which instead uses a set of inputs of cost, QOL and estimates of risks and benefits of treatment. Models are desirable as they can extrapolate findings over long time horizons. An example is the Markov decision analysis model, in which hypothetical patients enter various health states over the length of a set time horizon, simulating a disease course.

The multiple branch points allow for the input of various clinical parameters, enabling researchers to approximate society-level populations. Unfortunately, this approach is limited by the strength of model design or inputs, which may not reflect the full heterogeneity of clinical practice and often must assume values where data do not exist. Models can be tested for their sensitivity to these input assumptions through one-way sensitivity analysis, where an assumed variable is changed over a range of values to determine its impact on the model’s outcome.

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Hybrid approaches, combining trial-based utilities and cost for shortterm inputs and model-derived values for longer term inputs, have been increasingly used.16 All AF CEAs have been model-based, as existing RCTs have not reported long-term cost or QOL data.

Cost of Catheter Ablation Costs of AF ablation range considerably between countries and even within the same healthcare system. For example, two studies in 2003 reported average procedural costs of €4,715 in France and $17,173 in the US, based on hospital billing records.17,18 A Japanese report estimated a cost range of ¥1,063,200–¥4,059,280 (2010).19 Data from government fee schedules were used to generate expenses of $21,294CAD in Canada (2007) and $26,584USD in the US (2008).20,21 Unfortunately, many of these published cost estimates incorporated into CEA analyses are over 10 years old and simply adjusting for inflation may fail to reflect present-day costs. Recently, we analysed 26,000 patients with commercial healthcare insurance in the US who underwent AF ablation between 2006 and 2011. The median cost was substantial and with considerable variation ($21,300USD; Interquartile Range 25–75 %: $12,000–$38,500USD). We also found that cost increased by 22 % from 2006 to 2011, which far exceeds the rate of healthcare inflation in the US (data unpublished).

Effectiveness and Safety of Catheter Ablation A meta-analysis comparing AF ablation with AAD therapy included 63 studies with nine RCTs.6 The authors concluded that the single and multiple procedure success rates for maintaining normal sinus rhythm (NSR) were 57 % and 77 %, respectively (compared with 52 % on AAD alone). Of note, the mean follow-up period of their component studies was 14 months, with significant variation between studies (two to 30 months). Other trials and reviews have reported efficacy values as optimistic as 88 %.7,22–25 More recently, our group updated the Calkins review by extending its cohort through January 2012. We found the pooled success rates for single and multiple procedures to be 61±18 % and 73±14 %, respectively.8 A major limitation of these results is the considerable variation in the definition of treatment failure and method of ascertainment.

Moreover, no studies evaluated QOL as a primary outcome, making assessment of utility difficult. However, other observational studies have shown that AF is associated with reductions in QOL, which improves after restoration of NSR from ablation.7,18,21,26 A utility value calculated for a 2009 CEA was 0.725 for patients having AF, with a 0.065 post-procedure improvement if patients remained in NSR.21 AF ablation also carries procedural risk, such as haemorrhage and stroke.6,27 Data from the California State Inpatient Database indicated an in-hospital complication rate of 5.1 % after ablation.27 52.1 % of the reported adverse events were vascular (44.1 % haemorrhagic).

Cardiac perforation or tamponade accounted for 44 % of the complications. Less common complications included stroke (4.7 %), pneumothorax or haemothorax (1.9 %), and transient ischaemic attack (1.4 %). Only one inpatient death was reported for the cohort of 4,156. The 30-day readmission rate was 9.4 %, mostly attributable to AF recurrence. These adverse event rates are comparable to those reported in clinical trials and international site surveys.6,7,28,29 Two of these studies demonstrated higher 30-day and longer term rates of major complication with AAD treatment.6,7 In the international survey of AF ablation, the complication rate (up to 19 months out) among

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181 centres who responded to the survey was 5.9 %.28 A follow-up survey published five years later found a similar major complication rate of 4.5 %.29

model was the rate of NSR maintenance over a lifetime in the ablation group. As such, ICERs were calculated for annual probability of reversion to AF following ablation at 5 %, 10 %, and 15 %, yielding $8,280USD/ QALY, $26,460USD/QALY and $48,310USD/QALY, respectively.

Cost-Effectiveness of Catheter Ablation We identified eight major studies evaluating the cost-effectiveness of catheter-directed ablation of AF by performing a literature search of MEDLINE, PubMed and Web of Science for articles published between January 2006 and October 2014.21,30–38 Seven of the studies examined RF ablation, while one examined cryoballoon ablation. All the studies utilised a Markov model and reported their findings as ICERs. A compilation of the model parameters is provided in Table 1 and QALYs, costs and ICERs are summarised in Table 2. The analyses differed in type of AF considered (paroxysmal, persistent or both), the role of ablation as a first-line or second-line treatment, control group (AAD or rate control), anticoagulation regimen and time horizon.

Further details of each study will be reviewed case by case below.

Chan (2006) The first published CEA compared AF ablation to rate and rhythm control (with amiodarone) using a US societal perspective.30 Costeffectiveness over a lifetime time horizon was assessed in several patient scenarios. AF ablation vs. rate control had ICERs of $51,800USD/ QALY and $28,700USD/QALY in hypothetical patients aged 65 and 55 years, respectively, at moderate stroke risk. If the 65-year-old’s stroke risk profile was changed to low-risk, then the ICER increased to $98,900USD/QALY. Noteworthy assumptions of this model driving ICER included the cost of AF ablation, efficacy of rate control, success rate of AF ablation, utility of warfarin therapy, rate of haemorrhage on warfarin, and stroke rate of AF. The model assumed utility benefit to be near zero between NSR and AF.

Rodgers/McKenna (2008) Subsequent CEAs analysed real-world data from the UK.31,32,39 Unlike the previous analysis, the comparator to catheter ablation was AAD, and ablation was treated as second-line therapy for patients failing AAD. For a predominantly male (80 %), younger (mean age 52 years) patient population with CHADS2 score of 1, the study yielded an ICER of £25,510/QALY over a five-year time horizon and an ICER of £7,780/ QALY over a lifetime horizon. Important assumptions of this analysis with impact on ICER included the success rate of ablation, stroke risk of NSR, and improvement in QOL in NSR compared with AF.

Reynolds (2009) The next published study revisited the US viewpoint, evaluating ablation as second-line treatment in a 60-year-old male cohort with paroxysmal AF.21 Over a five-year time horizon, an ICER of $51,431USD/ QALY for ablation vs. AAD was obtained. The model assumed a first procedure ablation success rate of 60 % and that AAD medications would not be continued once NSR was achieved in the ablation group, as well as no difference in stroke or mortality risk between NSR and AF. Improved utility values in the NSR population compared with AF were calculated using the SF-12 and SF-36 questionnaires.40,41 Key assumptions with greatest effect on sensitivity analysis were NSR and AF utility and ablation cost.

Eckard (2010) A CEA of the Swedish population analysing ablation versus AAD as second-line therapy over a lifetime horizon found that AAD was dominated by ablation.33 The assumption with the greatest impact on the

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Assasi/Blackhouse (2010/2013) An analysis of the Canadian population determined an ICER of $59,194CAD/QALY for RF ablation compared with AAD (amiodarone) over a five-year time horizon for a base case cohort of 65-year-old male patients with paroxysmal AF and CHADS2 score of 2.34,35 Though a lifetime time horizon was not explored, the model extrapolated results over a 20-year horizon, finding ablation to be dominant over AAD. The authors noted that, contrary to the Reynolds study, their model produced a higher ICER ($86,129CAD/QALY) when assuming that restoring NSR had no impact on stroke risk. Their model was highly sensitive to AF and NSR utility, with ICERs ranging from $38,390CAD/QALY to $221,839CAD/QALY for AF disutility values of 0.08 and 0.0, respectively. Interestingly, the probability of AF recurrence following ablation was not an assumption that impacted their ICER estimate significantly.

Ollendorf (2010) A White Paper by the Institute for Clinical and Economic Review investigated the cost-effectiveness of AF rhythm control strategies in multiple contexts.36 The project considered a variety of therapies including rhythm and rate control, catheter ablation and surgery.

The group’s model utilised three hypothetical patient cohorts: a 60-year-old male group with paroxysmal AF and CHADS2 score of 0, a 65-year-old male group with persistent AF and CHADS2 of 1, and a 75-year-old male group with persistent AF and CHADS2 of 3.

AF ablation was examined as both first- and second-line treatment compared with rate control as second-line treatment following failure of AAD (amiodarone). For first-line ablation compared with secondline rate control, the 60-year-old low risk group yielded an ICER of $26,869USD/QALY, the 65-year-old moderate risk group: $60,804USD/ QALY, and the 75-year-old high-risk group: $80,615USD/QALY. For second-line ablation compared to second-line rate control, the 60-year-old low risk group yielded an ICER of $37,808USD/QALY, the 65-year-old moderate risk group: $73,947USD/QALY, and the 75-year old high-risk group: $96,846USD/QALY. The authors also compared second-line catheter ablation with thorascopic off-pump surgical ablation and determined that in all three groups, catheter ablation dominated surgical ablation. Assumptions with greatest impact on one-way sensitivity were AF and NSR utility and stroke risk following AF conversion to NSR. The decreased use of warfarin following conversion to NSR, as well as the impact of warfarin on QOL, did not significantly alter the Ollendorf model.

Aronsson (2014) A recent CEA based on the European MANTRA-PAF (Medical Antiarrhythmic Treatment or Radiofrequency Ablation in Paroxysmal Atrial Fibrillation) multicentre clinical trial determined an ICER of €50,570/QALY when comparing RF ablation with AADs as first-line therapy for a lifetime time horizon in Denmark, Finland, Germany and Sweden.37 Subgroup analysis suggested that ablation was more cost-effective in younger patients, as an ICER of €3,434/QALY was calculated for patients ≤50 years, whereas it rose to €108,937/QALY for patients >50 years. The study was unique in that it incorporated the rate of crossovers in the AAD group to ablation, and the model was found to be most sensitive to the cost of ablation and readiness of offering crossovers.

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Turakhia_Final.indd 180

UK

USA

All Types

Country

AF Type

Paroxysmal

USA Paroxysmal

Canada (Ontario)

AAD (amiodarone)

65 y.o. mod risk

55 y.o. mod risk

AF ablation success

rate, RC success rate,

AF stroke rate,

Warfarin utility,

Warfarin bleed risk

Assumptions with

greatest impact on

sensitivity analysis

rate over lifetime

AF ablation success

Ablation cost

NSR and AF utility,

CHADS2 of 2

Male

65 years old

utility

NSR and AF

Time horizon,

Age >80 years

Age 70–79 years

Age >69 years

3 groups:

stroke risk

NSR and AF

NSR and AF utility,

75 y.o. high risk

65 y.o. mod risk

60 y.o. low risk

3 groups (Male):

Ablation costs

for recurrent AF,

Follow-up care costs

Time horizon,

population

STOP-AF trial

Based on

AF = atrial fibrillation, AAD = anti-arrhythmic drug, RC = rate control, ASA = aspirin, NSR = normal sinus rhythm, y.o. = year old, mod = moderate, CAD = Canadian dollar, ICER = incremental cost-effectiveness ratio, QALY = quality-adjusted life year.

NSR stroke risk

NSR and AF utility,

AF Ablation success rate, Time horizon,

CHADS2 of 1

Male

60 years old

Ablation costs

crossovers,

of offering

Readiness

trial population

MANTRA-PAF

Based on

80% male

Mean age: 52 years

if bleeding

Warfarin, then ASA

65 y.o. low risk

based on risk

Warfarin or ASA

3 model groups:

Warfarin

Warfarin

between groups

Assumed same

Model Patient Assumptions

Warfarin, ASA or none

Warfarin

1.5–1.6 based

24 months

based on risk

N/A

1.3

on patient age

1.4

Warfarin or ASA

1.3

85 % at

Lifetime

trial data

MANTRA-PAF

Markov Model

sotalol)

propafenone,

flecainaide,

AAD (amiodarone

First-line

Radiofrequency

Anticoagulation

1.3

12 months

71 % at

5 years

STOP-AF trial data

Published literature,

Markov Model

then RC

amiodarone third),

first sotalol second,

AAD (propafenone,

Second-line

Paroxysmal

Europe

Aronsson et al.37 2014

1.3

N/A

82 % (paroxysmal),

5 years / lifetime

Number of Ablation Attempts

76 %

79 % (persistent)

78 %

Medicare data

Published literature,

90 %

Lifetime

5 years

74–84 %

5 years

80 %

5 years / lifetime

AF Ablation Success Rate

Canadian mortality,

FRACTAL registry, stroke, cost data

national data

Swedish clinical and

Lifetime

FRACTAL registry

Medicare data,

Published literature,

Time Horizon

practicing MD

costs from

Published literature,

Medicare data

Published literature,

Published literature,

Markov Model

Published literature,

Markov Model

Model Inputs

Markov Model

Markov Model

Markov Model

Model Type

Markov Model

then RC

then RC

AAD (amiodarone),

First- and second-line

flecainaide)

AAD (amiodarone,

Second-line

amiodarone second),

flecainide first,

AAD (sotalol/

Second-line

(amiodarone)

AAD (amiodarone)

Rate Control, AAD

Therapeutic Comparator

Line Therapy

Second-line

First-line

Second-line

Radiofrequency Radiofrequency Radiofrequency Radiofrequency Radiofrequency Radiofrequency Cryoballoon

First- or Second-

Paroxysmal

UK

Reynolds et al.38 2014

Ablation Type

Persistent

Proxysmal and

USA

Assasi/Blackhouse Ollendorf et al.34 et al.36 2010/ 2013 2010

persistent

Paroxysmal and

Sweden

Reynolds Eckard et al.33 et al.21 2009 2010

Mostly paroxysmal

Rodgers/McKenna et al.31 2008/ 2009

Chan et al.30

Year of Study 2006

Table 1: Summary of Model Parameters

Diagnostic Electrophysiology & Ablation

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Cost-effectiveness of Catheter Ablation

20-year

low risk

60 y.o.

mod risk

65 y.o.

high risk

75 y.o.

Cryoballoon

≤50 y.o.

>50 y.o.

Aronsson et al.37

horizon

--

Reynolds

5-year

--

et al.(2014)38

horizon

3.57

Ollendorf et al.36

Lifetime

6.00

(First-line)

horizon

8.96

--

Assasi/ Blackhouse

5-year

11.63

--

et al.34

Eckard

horizon

--

3.40

Reynolds

65 y.o.

3.42

5.80

et al.(2009)21 et al.33

low risk

9.46

8.67

Rodgers/McKenna31

65 y.o.

3.51

11.12

0.035

Table 2: Summary of Study Results Chan et al.30

mod risk

12.14

--

0.142

55 y.o.

11.18

3.27

0.17

mod risk

11.40 8.68

0.21

11.06 3.38

0.30

14.26

QALYs

10.77

0.51

AF Ablation 10.76

0.51

11.21

0.14

10.81 0.78

13.95 0.13

--

Comparison 1.37

--

0.42

£21,162

0.19

$34,410

0.25

$38,245

0.31

$34,044

Incremental

--

£26,027

$21,150 CAD

£26,016

$9,860

$43,036

$26,584

$52,369

--

$59,380

Cost

--

AF Ablation

£17,627

(5-year)

$1,660

(annual)

$17,759

$19,898

$20,332

£15,367

$20,265

£15,352

--

$24,540

$12,611 CAD

$39,391

$1,640

$50,509

€3,685

Comparison

€488

$6,686

£3,535

£10,660

$16,651

£10,664

$17,913

$18,496

ICER Dominant

CAD/QALY

$13,779

$12,978

$51,431/

$71 CAD

$8,871

QALY

$8,539 CAD

Incremental

£7,780

€108,937 /QALY

/QALY

£25,510

€3,434

/QALY

/QALY

$98,900

<€50,000/QALY:

£21,957/QALY

/QALY

~90 % for ≤50 y.o.

$80,615

$51,800

£20,000/QALY:

/QALY

/QALY

Multiple

$60,804

$28,700

N/A

$50,000 CAD /QALY: 30 %

/QALY

/QALY

N/A

group.

$26,869

Ablation vs.

£20,000/QALY: 16.5 %

unlikely

86 % £40,000/

$100,000 CAD/QALY: 89 %

QALY: 97.2 %

£30,000/QALY:

/QALY

Comparator $50,000/QALY: 40 %

£30,000/QALY: 68.6 %

Dominant

Probability of Cost$100,000/QALY: 78 %

$59,194

Effectiveness of Willingness-to-pay

AF Ablation at Threshhold

AF = atrial fibrillation, AAD = anti-arrhythmic drug, RC = rate control, ASA = aspirin, NSR = normal sinus rhythm, y.o. = year old, mod = modera te, CAD = Canadian dollar, ICER = incremental cost-effectiveness ratio, QALY = quality-adjusted life year

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ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

Diagnostic Electrophysiology & Ablation Reynolds (2014) The aforementioned studies examined cost-effectiveness of AF ablation by radiofrequency ablation. A recent paper was the first to analyse that of cryoballoon ablation, which utilises freezing rather than burning to isolate arrhythmogenic foci.38,42 Cryoballoon ablation was modelled from the UK perspective over a five-year time horizon as a second-line therapy compared with AADs in paroxysmal AF. They calculated an ICER of £21,957/QALY. The model was most sensitive to cost of follow-up care for recurrent AF and cost of ablation. Notably, the base-case ICER was comparable with that reported by the Rodgers/McKenna groups of radiofrequency ablation (£25,510/QALY).

Limitations, Future Directions One-way sensitivity analyses of the above CEA studies show that the ICERs derived from their models are most sensitive to several input assumptions, which indicate areas requiring additional investigation.

The three most commonly reported assumptions and input values were time horizon, the success rate of ablation and the QOL utility of restoring NSR. As such, for more accurate modeling, we must better determine the long-term effects that catheter ablation has on outcomes and costs, including maintenance of NSR, hospitalisations associated with recurrent AF to its relationship with heart failure, stroke and mortality. Ablation studies should also monitor patient QOL, instead of simply quantifying AF suppression rates and duration.

Lastly, trends seen in AF ablation clinical trials such as high crossover rates should be accounted for when considering true definitions of first-line and second-line therapy.

As for future trends, our findings of ongoing cost escalation of AF ablation could cause the incremental cost of the procedure to rise to the point that ICERs may far exceed willingness-to-pay thresholds. Nevertheless, the field of electrophysiology is constantly evolving, and new research may improve cost effectiveness. For example, improved patient selection (of those with high likelihood of QOL improvement, not just those less likely to have AF recurrence), cost containment, and emerging approaches of ablation with

1. Go A, Mozaffarian D, Roger V, et al. Heart disease and stroke statistics-2014 update: a report from the American Heart Association. Circulation 2014;129:e28–e292.

2. Miyasaka Y, Barnes M, Gersh B, et al. Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence. Circulation 2006;114:119–25.

3. Lee W, Lamas G, Balu S, et al. Direct treatment cost of atrial fibrillation in the elderly American population: a Medicare perspective. J Med Econ 2008;11:281–98.

4. Sullivan E, Braithwaite S, Dietz K, et al. Health services utilization and medical costs among Medicare atrial fibrillation patients. Washington DC, US: Avalere Health; 2010.

5. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/ HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society.

J Am Coll Cardiol 2014; Epub ahead of print. doi: 10.1016/j. jacc.2014.03.021.

6. Calkins H, Reynolds M, Spector P, et al. Treatment of atrial fibrillation with antiarrhythmic drugs or radiofrequency ablation: two systematic literature reviews and metaanalyses. Circ Arrhythm Electrophysiol 2009;2:349–61.

7. Wilber D, Pappone C, Neuzil P, et al. Comparison of antiarrhythmic drug therapy and radiofrequency catheter ablation in patients with paroxysmal atrial fibrillation: a randomized controlled trial. JAMA 2010;303:333–40.

8. Perino A, Hoang D, Holmes T, et al. Association between success rate and citation count of studies of radiofrequency catheter ablation for atrial fibrillation: possible evidence of citation bias. Circ Cardiovasc Qual Outcomes 2014;7:687–92.

9. Freeman J, Zhu R, Owens D, et al. Cost-effectiveness of dabigatran compared with warfarin for stroke prevention in atrial fibrillation. Ann Intern Med 2011;154:1–11.

10. Solomon M, Ullal A, Hoang D, et al. Cost-effectiveness of pharmacologic and invasive therapies for stroke prophylaxis

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higher success rates and improved durability of the ablation result could all substantially bend the cost curve. Judicious selection of procedure equipment could also lower expenditures, as ablation costs vary by material manufacturers: Reported prices of individual ablation device components (e.g. catheter, ultrasound, needles) reveal an impressive range for the cost of a single procedure from $6,637–$12,603USD (2013) based on cheapest and most expensive components respectively.43 New technologies could further cut costs by simplifying the procedure.

Cryoballoon ablation was designed to obviate the need for a mapping system and creation of multiple ablative lesions, leading to shorter procedure times. On the other hand, standardisation of practice will be crucial, as many physicians perform radiofrequency with mapping at the same time as cryoablation, which would dramatically increase the cost.

Conclusions In summary, assessing the value of AF ablation from a healthcare or societal perspective is challenging. ICER estimates are high, close to willingness-to-pay thresholds, and may have considerable uncertainty around them. However, the data show that ablation may be costeffective in the right patient. For first-line therapy, the procedure may not be cost-effective because of a moderate likelihood of treatment response. In the CEA studies that examined AF ablation as first-line therapy, the threshold values calculated for efficacy were closely tied to the assumptions of stroke risk/QOL improvements. They yielded ICERs <$50,000USD/QALY for procedural efficacy of 80 %–88 % and annual stroke risk of NSR ≤0.76 % or QOL improvement of -0.02 QALYs.30,36,37 But in symptomatic patients who fail AAD therapy, the studies indicate that AF ablation is generally cost-effective, particularly in younger patients with high symptom burden, as they are more likely to be alive longer and experience toxic side effects of pharmaceutical approaches.30 Advances both in cost-saving policies and novel technologies with greater success rates will continue to expand the pool of patients for whom ablation is a cost-effective solution. n

in atrial fibrillation. J Cardiovasc Med 2012;13:86–96.

11. Drummond M, Sculpher M, Torrance G, et al. Methods for the Economic Evaluation of Health Care Programmes. New York, US: Oxford University Press; 2005.

12. Grosse S. Assessing cost-effectiveness in healthcare: history of the $50,000 per QALY threshold. Expert Rev Pharmacoecon Outcomes Res 2008;8:165–78.

13. Drummond M, Sculpher M. Common methodological flaws in economic evaluations. Med Care 2005;43(7 Suppl):5–14.

14. Weiss N, Koepsell T, Psaty B. Generalizability of the results of randomized trials. Arch Intern Med 2008;168:133–5.

15. Dhruva S, Redberg R. Variations between clinical trial participants and Medicare beneficiaries in evidence used for Medicare national coverage decisions. Arch Intern Med 2008;168:136–40.

16. Cohen D, Osnabrugge R, Magnuson E, et al. Costeffectiveness of percutaneous coronary intervention with drug-eluting stents vs. bypass surgery for patients with 3-Vessel or left main coronary artery disease: final results from the SYNTAX trial. Circulation 2014;130:1146-57.

17. Weerasooriya R, Jais P, Heuzey J, et al. Cost analysis of catheter ablation for paroxysmal atrial fibrillation. Pacing Clin Electrophysiol 2003;26:292–4.

18. Goldberg A, Menen M, Mickelsen S, et al. Atrial fibrillation ablation leads to long-term improvement of quality of life and reduced utilization of healthcare resources. J Interv Card Electrophysiol 2003;8:59–64.

19. Noro M, Kujime S, Ito N, et al. Cost effectiveness of radiofrequency catheter ablation vs. medical treatment for atrial fibrillation in Japan – cost performance for atrial fibrillation. Circ J Off J Jpn Circ Soc 2011;75:1860–6.

20. Khaykin Y, Morillo C, Skanes A, et al. Cost comparison of catheter ablation and medical therapy in atrial fibrillation. J Cardiovasc Electrophysiol 2007;18:907–13.

21. Reynolds M, Zimetbaum P, Josephson M, et al. Costeffectiveness of radiofrequency catheter ablation compared with antiarrhythmic drug therapy for paroxysmal atrial

fibrillation. Circ Arrhythm Electrophysiol 2009;2:362–9.

22. Oral H, Scharf C, Chugh A, et al. Catheter ablation for paroxysmal atrial fibrillation: segmental pulmonary vein ostial ablation versus left atrial ablation. Circulation 2003;108:2355–60.

23. Noheria A, Kumar A, Wylie J, et al. Catheter ablation vs antiarrhythmic drug therapy for atrial fibrillation: a systematic review. Arch Intern Med 2008;168:581–6.

24. Terasawa T, Balk E, Chung M, et al. Systematic review: comparative effectiveness of radiofrequency catheter ablation for atrial fibrillation. Ann Intern Med 2009;151:191–202.

25. Nair G, Nery P, Diwakaramenon S, et al. A systematic review of randomized trials comparing radiofrequency ablation with antiarrhythmic medications in patients with atrial fibrillation. J Cardiovasc Electrophysiol 2009;20:138–44.

26. Wazni O, Marrouche N, Martin D, et al. Radiofrequency ablation vs antiarrhythmic drugs as first-line treatment of symptomatic atrial fibrillation: a randomized trial. JAMA 2005;293:2634–40.

27. Shah R, Freeman J, Shilane D, et al. Procedural complications, rehospitalizations, and repeat procedures after catheter ablation for atrial fibrillation. J Am Coll Cardiol 2012;59:143–9.

28. Cappato R, Calkins H, Chen S, et al. Worldwide survey on the methods, efficacy, and safety of catheter ablation for human atrial fibrillation. Circulation 2005;111:1100–5.

29. Cappato R, Calkins H, Chen S, et al. Updated worldwide survey on the methods, efficacy, and safety of catheter ablation for human atrial fibrillation. Circ Arrhythm Electrophysiol 2010;3:32–8.

30. Chan P, Vijan S, Morady F, et al. Cost-effectiveness of radiofrequency catheter ablation for atrial fibrillation. J Am Coll Cardiol 2006;47:2513–2520.

31. Rodgers M, McKenna C, Palmer S, et al. Curative catheter ablation in atrial fibrillation and typical atrial flutter: systematic review and economic evaluation. Health Technol Assess 2008;12:iii–iv, xi–xiii, 1–198.

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32. McKenna C, Palmer S, Rodgers M, et al. Cost-effectiveness of radiofrequency catheter ablation for the treatment of atrial fibrillation in the United Kingdom. Heart 2008;95:542–9.

33. Eckard N, Davidson T, Walfridsson H, et al. Cost-effectiveness of catheter ablation treatment for patients with symptomatic atrial fibrillation. J Atr Fibrillation 2009;1:15–25.

34. Assasi N, Blackhouse G, Xie F, et al. Ablation procedures for rhythm control in patients with atrial fibrillation: clinical and cost-effectiveness analysis. Technology Report no.

128. Ottawa, Canada: Canadian Agency for Drugs and Technologies in Health; 2010.

35. Blackhouse G, Assasi N, Xie F, et al. Cost-effectiveness of catheter ablation for rhythm control of atrial fibrillation. Int J Vasc Med 2013;2013: Epub ahead of print.

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doi:10.1155/2013/262809.

36. Ollendorf DA, Silverstein MD, Bobo T, et al. Management options for atrial fibrillation. US Institute for Clinical and Economic Review; 2010.

37. Aronsson M, Walfridsson H, Janzon M, et al. The costeffectiveness of radiofrequency catheter ablation as first-line treatment for paroxysmal atrial fibrillation: results from a MANTRA-PAF substudy. Eur. Europace 2014; Epub ahead of print. doi: 10.1093/europace/euu188.

38. Reynolds MR, Lamotte M, Todd D, et al. Cost-effectiveness of cryoballoon ablation for the management of paroxysmal atrial fibrillation. Europace 2014;16:652–9.

39. Bourke J, Dunuwille A, O’Donnell D, et al. Pulmonary vein ablation for idiopathic atrial fibrillation: six month outcome

of first procedure in 100 consecutive patients.

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J Health Econ 2002;21:271–92.

41. Brazier J, Roberts J. The estimation of a preferencebased measure of health from the SF-12. Med Care 2004;42:851–9.

42. Packer D, Kowal R, Wheelan K, et al. Cryoballoon ablation of pulmonary veins for paroxysmal atrial fibrillation.

J Am Coll Cardiol 2013;61:1713–23.

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Device Therapy

Management of Cardiac Implantable Electronic Device Infection Cristian Podoleanu1 and Jean-Claude Deharo2 1. Cardiology Department, University of Medicine and Pharmacy Tîrgu Mures, Tîrgu Mures, Romania; 2. Cardiology Department, CHU La Timone, Marseille, France

Abstract Despite improved preventive measures, infection associated with the use of cardiac implantable electronic devices (CIEDs) to treat often life-threatening conditions is rising at an average annual rate of almost 5 %. This rise is being driven by the increasing complexity of CIED technology and by the advancing age and co-morbidities of the patients. Although CIED infection is usually suspected based on local signs at the generator pocket site, diagnosis can be challenging in patients presenting no local manifestations or symptoms. Diagnostic methods include microbiological testing and echocardiography, and may be completed by positron emission tomography (PET)/computed tomography (CT) scan in selected cases. CIED infection requires a multidisciplinary approach in view of hardware extraction, targeted antibiotic therapy and reimplantation on an as-needed basis. Antibiotic prophylaxis targeting staphylococcal flora is recommended but the relation of these infections to medical care exposes patients to multi-resistant bacteria. New preventive measures utilising an antibacterial sleeve look promising. Treatment can be started on an empirical basis using an antistaphylococcal agent but must be continued using targeted antibiotic therapy. Crucial questions remain as to the best prevention strategy, optimal duration and timing of antibiotic therapy, and the most effective reimplantation technique.

Keywords Infection, pacemaker, defibrillator Disclosure: C Podoleanu has nothing to declare; JC Deharo has received honoraria for lectures from Spectranetics Received: 11 July 2014 Accepted: 22 September 2014 Citation: Arrhythmia & Electrophysiology Review, 2014;3(3):184–9 Access at: www.AERjournal.com Correspondence: Jean-Claude Deharo, Cardiology Department, CHU La Timone, 264 Rue Saint Pierre, 13385 Marseille Cx 5, France. E: jean-claude.deharo@ap-hm.fr

The increasing use of cardiac implantable electronic devices (CIEDs) for management of cardiac conditions has over the last few years been associated with higher infection rates.1 Expanded CIED use alone cannot account for this rise,2–4 which involves both patient- and device-related factors. Indeed patients are tending to be older and presenting with co-morbidities, while devices are becoming more sophisticated and requiring more leads and revision.5

study showed sharp increases in the proportion of CIED recipients with organ system failure (from 5.0 % to 8.0 % [p<0.001]) and with a diagnosis of diabetes mellitus (from 14.5 % to 16.5 % [p=0.005]). The mean age of patients presenting with CIED infection was 67 ± 16 years with a predominance of white patients (56 %) and males (66 %). The rise in CIED infection-related hospital admissions was not proportional to the increase in number of procedures.

Epidemiology

A Danish population-based cohort study including more than 46,000 consecutive patients showed that the incidence rate of surgical site infection after pacemaker (PM) implantation was 4.82 per 1,000 PM-years (192 cases) after initial implantation and 12.12 per 1,000 PM-years (133 cases) after replacement. Independent factors associated with an increased infection risk were: number of operations including replacements, male sex, younger age, implantation during early study period and absence of antibiotics (p<0.001).7

Analysis of hospital discharge records including 4.2 million CIED implantations performed over the 16-year period from 1993 to 2008 showed that 69,000 patients required treatment for CIED infection. The average annual increase in CIED implantation was 4.7 %. Implantation of cardiac defibrillators accounted for half of the 96 % overall increase in CIED implantation. The incidence of infection increased by 210 % from 2,660 cases in 1993 to 8,230 cases in 2008.

The annual rate of infection rose at a steady pace until 2004 when it jumped from 1.53 % during that year to 2.41 % in 2008 (p<0.001).6 In terms of patient demographics, the occurrence of CIED infection was greatest in white males over 65 years of age, and the most significant associated co-morbidities were renal failure, respiratory failure, heart failure and diabetes. The greatest risk factors for mortality were respiratory failure (odds ratio [OR] 13.58; 95 % confidence interval [CI] 12.88–14.3), renal failure (OR 4.28; 95 % CI 4.04–4.53) and heart failure (OR 2.71; 95 % CI 2.54–2.88).6 These findings are in line with data from a national US survey2 including over 22,000 patients treated between 1996 and 2006. The

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Deharo_FINAL.indd 184

Analysis of the prospective REPLACE Registry (Complication Rates Associated With Pacemaker or Implantable Cardioverter-Defibrillator Generator Replacements and Upgrade Procedures) evaluating complications in patients who underwent CIED replacement at 72 US sites over six months revealed several interesting findings.8 The low infection rate of 1.3 %, was consistent with current practice including widespread use of antibiotic prophylaxis and other preventive measures.

Post-operative haematoma was more frequent in patients who developed infection. Sites reporting higher infection rates had sicker patients and lower overall procedure volumes.

© RADCLIFFE CARDIOLOGY 2014

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Management of Cardiac Implantable Electronic Device Infection

Recently a risk evaluation score based on seven factors – early pocket reopening, male sex, diabetes, upgrade procedure, heart failure, hypertension and glomerular filtration rate <60 mL/min – was proposed.9 A retrospective analysis of 1,651 patients showed that scores ranged from 0 to 25 and identified three risk groups: • Low: score 0–7 with 1.0 % infection, • Medium: score 8–14 with 3.4 % infection, • High: score ≥15 with 11.1 % infection.

It has recently been shown that ventricular assist device placement is also frequently complicated by infections.10 However, this specific problem is beyond the scope of this review.

Figure 1: Various Presentations of Pocket Infection.

A

B

C

D

Diagnosis The clinical manifestations of CIED infection are highly variable. They can be divided into two somewhat overlapping categories, i.e. pocket infection and systemic infection.11,12 Pocket infection is usually due to surgical site contamination. Most cases occur within weeks or months following implantation but intervals of more than one year have been noted with micro-organisms such as Corynebacterium, Propionibacterium and certain species of coagulase-negative Staphylococci. Except in cases involving Staphylococcus aureus septicaemia, haematogenous contamination of the pocket from a distant focus is rare.13 Diagnostic suspicion of pocket infection is usually based on clinical symptoms such as local pain and discomfort due to inflammation of the generator pocket. In rare cases, patients with CIED infection may present with fever of unknown origin.

Local signs may range from local redness to frank cutaneous erosion with exposure of the generator and/or leads (see Figure 1).4 In a study including 105 consecutive cases of infection, frank exposure occurred in 31 patients and infection with fistula, abscess or purulent collection occurred in 50 patients. The remaining patients presented inflammation or impending exteriorisation.14 A recent survey of European centres showed that the most common diagnostic features of pocket infection were pain, swelling and erythema at the device pocket site. At most centres (68.1 %), these findings led to immediate hospitalisation for laboratory tests, echocardiographic examination and adequate treatment.1 Appearance of skin pre-erosion over the can or lead is a common sign for suspicion of infection.

One long-term 33-case study of outcomes after reimplantation of pulse generators showed that documented infection occurred in more than 50 % of patients with local inflammatory manifestations or granulomatous-like changes involving the skin overlying the implantation site. The recommended treatment for these patients is to remove the pacing system before infection spreads to leads and cardiac tissue. The only cases in which infection did not occur after pocket revision involved patients in whom pre-erosion was due to mechanical causes.15 Systemic infections are usually due to haematogenous contamination in patients with multiple co-morbidities. The main sources of systemic infection are skin or soft tissue infections, pneumonia and bacteraemia associated with either intra-vascular catheters or invasive procedures. In most patients with systemic infection, blood cultures are positive, but prior antibiotic therapy can render cultures negative. Infective endocarditis is a common complication in patients with systemic infections, and lead or valve vegetations develop in nearly 25 % of cases.11,12,16–18 Device-related endocarditis is often more insidious. Fever and chills are frequent when infection involves the intracardiac part of the PM or implantable cardioverter defibrillator

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(A) Voluminous Collection Inside the Generator Pocket in a Patient Presenting Fever and Chills. (B) Pus and Erythematous Skin Overlying the Subcutaneous Route of a Lead.

(C) Dehiscence of Infected Skin with Exposure of Lead Sleeve. (D) Redness and Thinning of Skin at Bottom of Pacemaker Pocket

(ICD) leads. In this situation, ultrasound examination may depict vegetations in the tricuspid valve.19 A few patients may present with positive blood cultures with no evidence of pocket or lead infection.

In these cases, the likelihood of CIED infection is greater if persistent unexplained bacteraemia is associated with Staphylococcus aureus than with gram-negative cocci. Another situation is the one of patients with CIED and infective endocarditis. Interestingly, a study in a population of PM recipients presenting infective endocarditis demonstrated three almost equally frequent infection scenarios characterised by: infection exclusively on PM leads, combination PM-lead and valvular infection (right or left valves), and isolated valvular infection apparently independent of PM leads.20 Several virulence factors contribute to the ability of micro-organisms to cause CIED infections. They include adherence factors, biofilm formation and microbial persistence.21 Staphylococci are the micro-organisms most frequently responsible for CIED infections. Other pathogens include other gram-positive cocci, Propionibacterium acnes and gram-negative bacilli. Figure 2 shows the distribution of pathogens encountered in patients managed for CIED infections at a tertiary European centre. Although there are no recent data specifically on the antibiotic sensitivity of micro-organisms causing CEID infections,18 the relation of these infections to medical care exposes patients to multi-resistant bacteria. Findings showing that contamination in some locations is associated with methicillin-resistant staphylococci in nearly 50 % of cases11,12 justify empirical use of vancomycin pending positive identification of the organism. Gram-negative bacteria or polymicrobial infection are rare but probabilistic antibiotherapy covering gram-negative bacteria may be justified in patients with severe systemic infection. Fungal infections occur mainly in immunosuppressed patients.

Since identification of the pathogen responsible for the CIED infection is crucial for defining targeted antibiotherapy, at least two blood culture sets should be collected before starting antibiotics, and tissue from the explanted generator pocket and lead-tip should be cultured.

Results should be interpreted in the light of the overall context since mistaken interpretation of positive cultures can unnecessarily prolong

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Device Therapy Figure 2: Pie Graph Showing Distribution of Infective Agents Identified at our Tertiary Centre in 197 Patients with Infected Cardiac Implantable Electronic Device

27.9 % 30.1 % 7.6 % 5.7 % 14.8 %

7.1 % 6.7 %

Coagulase-negative staphylococci

Propionibacterium acnes

Oxacillin sensitive S. aureus

Gram-negative bacilli

Oxacillin resistant S. aureus

No identified pathogen

Other gram-positive cocci Note that no micro-organism was found in 27.9 % of the patents, reflecting the high number of patients who had received antibiotics before referral. Source: Personal data published in Deharo et al., 2012.46

Figure 3: Ultrasound Image Showing ‘Ghost’ After Lead Extraction in a Patient with Cardiac Implantable Electronic Device Related Endocarditis – A Residual Tube-shaped Formation (arrow) Appears Along the Pathway of the Removed Lead

effusion, ventricular dysfunction, and dyssynchrony and pulmonary vascular pressure.4 Interestingly, a recent study carried out in a 212-patient cohort to determine the incidence, diagnostic value and outcome of intracardiac masses detected by echocardiography after device removal indicated that floating masses called ‘ghosts’ were observed in 8 % of patients who underwent percutaneous device extraction following infection as compared with 0 % of uninfected patients (see Figure 3). Based on these findings, it was concluded that presence of a ghost was indicative of device infection.24 In a multicentre feasibility study, intracardiac echocardiography (ICE) was compared with TOE for diagnosis of CIED-related endocarditis in 152 patients with endocarditis and 10 controls. Results showed that ICE was associated with better diagnostic yield.25 The main limitations of TOE are poor detection of small intracardiac vegetations, occurrence of reverberation artifacts, and technical issues involving the distance between the probe and tricuspid valve. Another study indicated that ICE could be helpful in predicting the risks and complications of lead extraction procedures.26 Further study will be needed to confirm these preliminary results and to determine the situations in which the benefits of ICE might offset its invasiveness and higher cost.

A promising technique to enhance imaging of infected leads is 18 F-fluorodeoxyglucose positron emission tomography/computerised tomography (FDG-PET/CT). In a pilot study of patients with suspected pacing system infections, PET scanning revealed lead infection in six out of 10 patients.27 Another study aimed at assessing the diagnostic yield of FDG-PET/CT in patients with cardiac CIED infection showed that the sensitivity and specificity of PET were 86.7 % (59.5–98.3, 95 % CI) and 100.0 % (42.1–100, 95 % CI), respectively, in patients with pocket site infection and 30.8 % (9.1–61.4, 95 % CI) and 62.5 % (24.5–91.5, 95 % CI), respectively, in patients with cardiac device-related infective endocarditis.28 FDG-PET/CT has also been useful for distinguishing CIED infection from recent post-implant changes and for guiding therapy.29

Treatment and Prevention

LA = left atrium; RA = right atrium; SVC = superior vena cava.

antibiotic therapy and increase related toxicities.3,22 In a large study of CIED infection, cultures of leads from 854 out of 1,204 (70.9 %) patients tested positive with isolation of a single micro-organism in 663 cases (77.6 %), two micro-organisms in 175 cases (20.5 %) and more than two micro-organisms in 14 cases (1.8 %). In 116 cases, material from the pocket was also cultured yielding results consistent with those from the leads in 69 cases (59 %). Blood cultures performed in 359 cases were consistent with lead cultures in only 124 cases (35 %).

Based on these findings, it was concluded that blood cultures are more likely to be contaminated and that monomicrobial CIED infection due to Staphylococcus species is common.23 The preferred technique for diagnostic imaging is transoesophageal echocardiography (TOE) because its sensitivity for detection of lead-related vegetations is greater than transthoracic echocardiography (TTE). Studies involving patients with endocarditis show that vegetations on the tricuspid valve or device lead were successfully detected in 90–96 % of cases with TOE as compared with only 22–43 % of cases with TTE.20,23 Conversely, TOE is less effective than TTE for assessment of prognostic factors such as pericardial

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The general principles of CIED infection treatment involve effective antibiotic treatment, complete removal of the generator and leads, and implantation of a new system on an as-needed basis.4,30 A multidisciplinary approach with a team including, but not limited to, electrophysiologists, infectious disease specialists and cardiac surgeons is the key to successful management. Figure 4 shows the diagnostic and therapeutic approach currently used at a tertiary European centre.

The antibiotic of choice for initial empirical therapy is vancomycin because of its broad antistaphylococcal spectrum and of growing oxacillin-resistance. Alternatives include cefazolin or nafcillin in patients with oxacillin-susceptible staphylococcal strains.4 One report described the use of high-dose daptomycin therapy in 25 mostly elderly, male patients with large lead vegetations and severe co-morbidities. Administration of daptomycin at a median daily dosage of 8.3 mg/kg for a median duration of 20 days achieved an 80 % clinical success rate and complete microbiological success in 92 % of patients.31 After identification of the micro-organism, empirical antibiotherapy should be replaced by targeted treatment using the appropriate antibiotic defined on the basis of at least two independent blood cultures. In patients presenting infection confined to the pocket and subcutaneous tissue as documented by sterile blood cultures and negative result at TOE,4,11 targeted treatment must be continued for 10–14 days after hardware removal. In patients

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Figure 4: Flow Chart for Cardiac Implantable Electronic Device Infection Management

High clinical probability of CIED infection

Pacemaker dependency assessment Blood counts / Inflammation tests Blood cultures Transthoracic and transoesophageal echocardiogram Search for peripheral septic foci

No

Yes

Temporary pacing (preferred) using screw-in lead and re-use pacemaker

Alternative option: Epicardial PM when surgery is indicated or endocardial route is contraindicated

Complete hardware removal (transcutaneous unless failed or contraindicated) Culture of pocket tissue and material

Presence of vegetations and/or peripheral foci and/or ≥2 positive blood cultures and/or positive cultures of pocket tissue or material No

10 days oral antibiotics

CIED endocardial reimplantation Day 3 to Day 14 Yes

4–6 weeks intravenous antibiotherapy of adapted antibiotics or empirical vancomycin when no pathogen

Reimplantation of appropriate CIED using appropriate route, including SC-ICD CIED = cardiac implantable electronic device; PM = pacemaker; SC-ICD = subcutaneous implantable cardioverter defibrillator

presenting documented CEID-related endocarditis or positive bacteraemia, targeted intravenous antibiotherapy must be continued for 4–6 weeks.4 Total CIED removal is mandatory for patients presenting documented valvular and/or lead endocarditis or sepsis, pocket infection with abscess formation, device erosion or valvular endocarditis without definite involvement of the CIED.32 Early hardware removal has been associated with improved outcomes but complications cannot be ruled out. In a retrospective study including 416 patients with CIED infection, 44 (12.0 %) developed complications related to device removal and three (0.8 %) died. Although device removal complications have been linked with higher mortality at 30 days and at one year, comparison of patients undergoing immediate removal with patients undergoing delayed or no removal has demonstrated a three-fold decrease in one-year mortality.33 In a cohort study including 177 patients with CIED endocarditis, the one-year mortality rate was 19.9 % for patients who underwent device removal during hospitalisation versus 38.2 % for patients who did not undergo device removal.34 Conservative management of the infected CIED has been reported in small case series. This approach should only be used if the risk of extraction outweighs the potential benefit, i.e. for patients whose condition contraindicates the removal procedure or whose life expectancy is short due to co-morbidity or advanced age.35 In rare cases where infection is superficial or confined to the incisional scar, it may be possible to leave the device in situ and administer oral antibiotics for 7–14 days.4 At the clinical level, however, these patients are difficult to differentiate from patients presenting early deep infection and require close follow-up after treatment.

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Prophylaxis with systemic antibiotics targeting staphylococcal flora is strongly recommended before implantation of a CIED because of the risk of contamination by micro-organisms on normal skin.18,30,36 A metaanalysis comprising 2,023 patients showed that administration of antibiotic prophylaxis, mainly using antistaphylococcal penicillins and first-generation cephalosporins, immediately before permanent PM implantation consistently achieved a protective effect (OR 0.256; 95 % CI 0.10–0.656).30 Most experts advocate use of first-generation cephalosporins such as cefazolin for systemic prophylaxis. A study including 852 patients described use of an intravenous course of 2 g cefazolin 20 minutes before new permanent PM implantation or pulse generator replacement. Analysis of early phase outcomes showed minor complications in nine patients (1.0 %). During long-term follow-up, major infectious complications were observed in six patients (0.7 %).37 A randomised controlled prospective study comparing CIED implantation with or without cefazolin prophylaxis was undertaken but prematurely discontinued after reaching 65 % of the planned enrolment, due to appearance of a significant difference in favour of the antibiotic arm (0.63 versus 3.28 infected patients, p=0.016).38 Although vancomycin is not generally recommended, it may be considered as an alternative at centres where oxacillin resistance is high.4 With no evidence documenting its efficacy, administration of post-operative antibiotic therapy is not recommended due to its potential association with adverse side-effects and selection of drug resistant organisms.4,8 Recently a new technique to reduce surgical site infections was proposed. The CIED is implanted within an antibacterial polypropylene mesh sleeve that releases minocycline and rifampicin in the generator

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Device Therapy Figure 5: Photo and X-ray Illustrating Temporary Pacing in a Pacemaker-dependent Patient Using a Right Ventricular Screw-in Lead Introduced via the Left Internal Jugular Vein and Connected to a Re-use Pacemaker Taped on the Thorax

indicated that outcomes were worse in patients deemed cured after removal but not reimplanted than in patients with successful cardiac resynchronisation therapy (CRT) reimplantation.44 When needed, replacement device implantation should be carried out in an alternative location such as the contralateral side, iliac vein or epicardial implantation. With regard to timing, it seems reasonable to postpone reimplantation until infection has resolved, but there are no clear guidelines.4,12,45 Relevant decisionmaking factors include presence of bacteraemia or sterile blood cultures before and after removal, and type of the identified pathogen strain.4,11,12 In the literature, intervals for reimplantation have ranged from 24 hours to 14 days.4 For PM-dependent patients, temporary pacing is an option4 but it is not recommended45 and has the risk of malfunction and short-term capability. Tarakji et al.12 recently reported that the recurrent infection rate was higher in patients in whom device extraction and reimplantation were performed during the same hospital stay. This finding suggests that a waiting period is required for safe reimplantation. Epicardial pacing is an option but has been associated with higher mortality rates.46 An interesting alternative is temporary pacing using a screw-in pacing lead connected to a re-use can strapped on the skin of the patients,47,48 the so called ‘semi-permanent’ pacing (see Figure 5). This approach allows patients to safely await implantation of a new device for the recommended 72 hours to 14 days depending on clinical status.

Outcomes CIED infection is a severe medical condition causing significant morbidity and mortality. Despite adequate treatment, reported death rates range from 8.0 % to 26.9 %.4,5,17,49–52 Several predictors of long-term mortality have been identified including older age, heart failure, infective endocarditis, renal failure and long-term corticosteroid therapy.46,53 However, these high mortality rates must be seen in the context of populations with multiple co-morbidities.

Indeed, device patients have shown high mortality rates.54–56

pocket. Preclinical and small-scale clinical studies suggest that this technique can reduce CIED infection in high-risk patients.9,39–41 Prospective registries are ongoing and randomised studies are warranted to validate routine use of this promising prophylactic tool.

Reimplantation of a Device After Infection Reimplantation is a major concern in patients treated for CIED infection. Before undertaking reimplantation, a careful individual assessment should be carried out to confirm if there is a continued need for a new CIED.4,32,42 A retrospective review indicated that reimplantation was unnecessary in one-third of cases.11 Another report described a study carried out in 188 patients to test the safety of deferring PM after CIED removal for infection. Selection of patients eligible for deferring reimplantation was based on electrocardiographic and monitoring data. Assessment of outcomes after a 12-month follow-up period indicated that these data were useful in distinguishing patients for whom reimplantation could be safely deferred from patients requiring a new implant.43 In contrast with these findings, a study on 151 patients who underwent extraction of biventricular pacing devices for infection-related complications

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While the overall benefits of device removal are unquestionable,4 performing the procedure using a multidisciplinary approach employing device extraction and directed antibiotic therapy is probably crucial to decreasing mortality.46 In a prospective cohort study designed to evaluate a systematic approach to managing CIED infections, a total of 194 patients admitted for CIED infection between 2004 and 2008 were enrolled and matched by age, sex and type of device to a cohort of uninfected CIED patients.46 Results at one-year showed that all-cause long-term mortality in the study cohort was not significantly different from controls (14.3 % versus 11.0 %, respectively) despite an initial in-hospital mortality rate of 4.1 % in the study cohort. Similarly the one-year mortality rate was not significantly different in patients with pocket infection versus infective endocarditis (12.5 % versus 15.5 %, respectively). The only factors associated with long-term mortality in patients with infected CIED were older age, CRT device infection, thrombocytopaenia (platelet count <100 giga/litre at admission) and renal dysfunction (serum creatinine >150 mmol/litre). Coagulase-negative staphylococci were associated with a lower risk of death. Fourteen (11.2 %) of the 125 patients who underwent device reimplantation died. After adjusting for the previously identified predictors (i.e. age, CRT device infection, thrombocytopaenia and coagulase-negative staphylococci) reimplantation with an epicardial right ventricular pacing system was

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significantly associated with mortality (hazard ratio [HR] 2.85, 95 % CI 1.08–7.50, p=0.034). Twelve of 14 (85.7 %) patients who died had been reimplanted with epicardial systems as compared with 54 of 111 (48.6 %) survivors.

In another study that enrolled 189 patients with CIED infection, treatment consisted of immediate removal in 183 (96 %), removal after failure of medical therapy in three (2 %) and parenteral antimicrobial therapy in all patients.11 In-hospital mortality after a mean follow-up of 175 days was 3.7 %. During follow-up after discharge, relapse or

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3. Baddour LM. Cardiac device infection-or not. Circulation 2010;121:1686–7.

4. Baddour LM, Epstein AE, Erickson CC, et al. Update on cardiovascular implantable electronic device infections and their management: A scientific statement from the American Heart Association. Circulation 2010;121:458–77.

5. Baman TS, Gupta SK, Valle JA, Yamada E. Risk factors for mortality in patients with cardiac device-related infection.

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persistent pocket infection was noted in 5 % of patients while the remaining 95 % were infection-free at the end of the study period.

Conclusion Infection of CIED is a growing problem. In any form, CIED infection is a severe complication requiring hardware extraction and targeted antibiotic therapy in most cases. Further study is necessary to determine the best prevention strategy, optimal duration and timing of antibiotic therapy, and most effective guidelines for reimplantation. n

20. Duval X, Selton-Suty C, Alla F, et al. Endocarditis in patients with a permanent pacemaker: a 1-year epidemiological survey on infective endocarditis due to valvular and/or pacemaker infection. Clin Infect Dis 2004;39:68–74.

21. Nagpal A, Baddour LM, Sohail MR. Microbiology and pathogenesis of cardiovascular implantable electronic device infections. Circ Arrhythm Electrophysiol 2012;5:433–41.

22. Pichlmaier M, Marwitz V, Kühn C, et al. High prevalence of asymptomatic bacterial colonization of rhythm management devices. Europace 2008;10:1067–72.

23. Bongiorni MG, Tascini C, Tagliaferri E, et al. Microbiology of cardiac implantable electronic device infections. Europace 2012;14:1334–9.

24. Le Dolley Y, Thuny F, Mancini J, et al. Diagnosis of cardiac device-related infective endocarditis after device removal.

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25. Narducci ML, Pelargonio G, Russo E, et al. Usefulness of intracardiac echocardiography for the diagnosis of cardiovascular implantable electronic device-related endocarditis. J Am Coll Cardiol 2013;61:1398–405.

26. Bongiorni MG, Di Cori A, Soldati E, et al. Intracardiac echocardiography in patients with pacing and defibrillating leads: A feasibility study. Echocardiography 2008;25:632–8.

27. Ploux S, Riviere A, Amraoui S, et al. Positron emission tomography in patients with suspected pacing system infections may play a critical role in difficult cases. Heart Rhythm 2011;8:1478–81.

28. Cautela J, Alessandrini S, Cammilleri S, et al. Diagnostic yield of FDG positron-emission tomography/computed tomography in patients with CEID infection: a pilot study. Europace 2013;15:252–7.

29. Sarrazin JF, Philippon F, Tessier M, et al. Usefulness of fluorine-18 positron emission tomography/computed tomography for identification of cardiovascular implantable electronic device infections. J Am Coll Cardiol 2012;59:1616–25.

30. Baddour LM, Cha YM, Wilson WR. Clinical practice. Infections of cardiovascular implantable electronic devices. N Engl J Med 2012;367:842–9.

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33. Le KY, Sohail MR, Friedman PA, et al. Impact of timing of device removal on mortality in patients with cardiovascular implantable electronic device infections. Heart Rhythm 2011;8:1678–85.

34. Athan E, Chu VH, Tattevin P, et al. Clinical characteristics and outcome of infective endocarditis involving implantable cardiac devices. JAMA 2012;307:1727–35.

35. Lopez JA. Conservative management of infected pacemaker and implantable defibrillator sites with a closed antimicrobial irrigation system. Europace 2013;15:541–5.

36. Da Costa A, Lelièvre H, Kirkorian G, et al. Role of the preaxillary flora in pacemaker infections: a prospective study.

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37. Bertaglia E, Zerbo F, Zardo S, et al. Antibiotic prophylaxis with a single dose of cefazolin during pacemaker implantation: Incidence of long-term infective complications. Pacing Clin Electrophysiol 2006;29:29–33.

38. de Oliveira JC, Martinelli M, Nishioka SA, et al. Efficacy of antibiotic prophylaxis before the implantation of pacemakers and cardioverter-defibrillators: results of a large, prospective, randomized, double-blinded, placebo-controlled trial. Circ Arrhythm Electrophysiol 2009;2:29–34.

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human pathogen infection and demonstration of efficacy by an antimicrobial pouch for pacing devices. Pacing Clin Electrophysiol 2009;32:898–907.

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42. Deharo JC, Bongiorni MG, Rozkovec A, et al. Pathways for training and accreditation for transvenous lead extraction: a European Heart Rhythm Association position paper. Europace 2012;14:124–34.

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44. Rickard J, Tarakji K, Cheng A, et al. Survival of patients with biventricular devices after device infection, extraction, and reimplantation. JACC Heart Fail 2013;1:508–13.

45. Habib G, Hoen B, Tornos P, et al. Guidelines on the prevention, diagnosis, and treatment of infective endocarditis (new version 2009): the Task Force on the Prevention, Diagnosis, and Treatment of Infective Endocarditis of the European Society of Cardiology (ESC). Endorsed by the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and the International Society of Chemotherapy (ISC) for Infection and Cancer. Eur Heart J 2009;30:2369–413.

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49. Uslan DZ, Sohail MR, St Sauver JL, et al. Permanent pacemaker and implantable cardioverter defibrillator infection: a population-based study. Arch Intern Med 2007;167:669–75.

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54. Brunner M, Olschewski M, Geibel A, et al. Long-term survival after pacemaker implantation. Prognostic importance of gender and baseline patient characteristics. Eur Heart J 2004;25:88–95.

55. Cleland JG, Daubert JC, Erdmann E, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005;352:1539–49.

56. Goldenberg I, Gillespie J, Moss AJ, et al. Long-term benefit of primary prevention with an implantable cardioverterdefibrillator: an extended 8-year follow-up study of the Multicenter Automatic Defibrillator Implantation Trial II. Circulation 2010;122:1265–71.

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C a rd i a c Res y n ch r o n i s a ti o n T h e r a p y o r M i tr a C l i p ® I m p l a n t ati o n f o r Pa t i en t s w i th S e v e r e M i tr a l R e g u r g i ta ti o n a n d L ef t B u n d l e B r a n c h B l o c k ?

Jens K ienem u n d , K a r l - H e i n z - Ku c k a n d Ch r i s t i a n F r e r k e r Department of Cardiology, Asklepios Clinic St. Georg, Hamburg, Germany

Abstract Secondary or functional mitral regurgitation (FMR) is a common problem in patients with chronic heart failure (HF). About one-third of patients with chronic HF also have left bundle branch block (LBBB). Approximately one-third of patients with an indication for cardiac resynchronisation therapy (CRT) have moderate-to-severe FMR. This FMR may either be a consequence of systolic dysfunction or it may occur due to dyssynchrony. Both directly reducing FMR and correcting cardiac dyssynchrony are viable therapeutic approaches in selected patients, according to the 2012 European Society of Cardiology (ESC) Guidelines for valvular heart disease. Initial presence of FMR is an independent predictor of lack of clinical response to CRT. Patients undergoing CRT without signs of significant clinical improvement may be considered candidates for the percutaneous MitraClip® procedure. As yet, there are not enough data to select patients that would benefit from being treated primarily with MitraClip. A clinical trial in HF patients to be randomised to either MitraClip procedure or CRT is needed to confirm actual ESC Guideline therapy.

Keywords

Heart failure, mitral regurgitation, systolic dysfunction, dyssynchrony, MitraClip®, cardiac resynchronisation therapy Disclosure: The authors have no conflicts of interest to declare.

Received: 4 September 2014 Accepted: 18 November 2014 Citation: Arrhythmia & Electrophysiology Review, 2014;3(3):190–3 Access at: www.AERjournal.com Correspondence: Dr Christian Frerker, Department of Cardiology, Asklepios Clinic St. Georg, Lohmühlenstrasse 5, 20099 Hamburg. E: c.frerker@asklepios.com

Prevalence of Functional Mitral Regurgitation in Patients with Chronic Heart Failure Secondary or functional mitral regurgitation (FMR) is a common problem in patients with chronic heart failure (HF) due to dilated cardiomyopathy, regardless of aetiology.1 FMR results from an imbalance between the closing and the tethering forces that act on the mitral valve leaflets.2,3 A chart review of Koelling et al. found that almost half of their 1,436 patients with left ventricular (LV) systolic dysfunction and an ejection fraction ≤35 % also had mitral regurgitation (MR), with 29.7 % having moderate and 18.9 % having severe MR.4 Overall, the prevalence of severe MR in patients with HF and ventricular dysfunction is estimated at nearly 30 %.2 MR confers a worsening of prognosis of patients with ventricular dysfunction.4

Prevalence of Left Bundle Branch Block in Patients with Chronic Heart Failure Disturbance of (systolic) cardiac synchrony is another problem frequently found in patients with HF. Caused by the cardiomyopathy itself; it further aggravates systolic dysfunction, resulting in an even lower left ventricular ejection fraction (LVEF) and development or worsening of clinical symptoms. The dyssynchrony can either be seen on echocardiography or in a 12-lead electrocardiogram as an intraventricular conduction delay (IVCD) or a bundle branch block.

However, the prevalence of left bundle branch block (LBBB) is low in the general population – about one-third of patients with chronic HF

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show LBBB with a QRS duration ≥120 ms.5–8 In the EuroHeart Failure Survey, 41 % of all patients with LV dysfunction (LVEF ≤35 %) had a documented QRS duration ≥120 ms. These prolonged QRS durations were due to LBBB or other forms of IVCD in 34 % and due to right bundle branch block (RBBB) in 7 % of all cases.9 Correspondingly, of the 1,391 patients enlisted in the Italian Network of Congestive Heart Failure registry, 6 % had complete RBBB and 31 % had complete LBBB or unspecific IVCD. The annual incidence of LBBB is estimated at 10 % in ambulatory patients with chronic HF and LV systolic dysfunction.10

Concomitant Presence of Functional Mitral Regurgitation and Cardiac Resynchronisation Therapy Indication Approximately one-third of patients with an indication for cardiac resynchronisation therapy (CRT) also have moderate-to-severe FMR.11,12 This concomitant presence creates a certain predicament since the FMR may either be a consequence of systolic dysfunction, changed ventricular geometry and size of the left ventricle or it may occur due to this very dyssynchrony.12 In addition, MR itself is known to cause HF progression, as permanent volume overload (produced by MR) has been shown to perpetuate and worsen mechanisms leading to its genesis13 – or as Carabello wrote, “MR begets MR”.14 Physicians are then confronted with two possible therapeutic options – treat the severe MR or resynchronise the ventricles? The European Society of Cardiology (ESC) Guidelines clearly suggest CRT, as it is included in the definition of ‘optimal medical therapy’, which is fundamental for every invasive procedure (see Figure 1).

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Cardiac Resynchronisation Therapy as a Valuable Option – Its Indications

Figure 1: 2012 ESC Guidelines on the Management of Valvular Heart Disease

CRT resynchronises the contractions of right and left ventricles, and reduces the degree of (systolic and diastolic) FMR both acutely15–18 and in the long term,19–23 at rest and during exercise.24,25 Therefore, CRT is an accepted Class I indication for selected patients.26,27 Although various ways of selecting patients for biventricular pacing have been suggested, the major selection criterion for entry into clinical trials has been the QRS duration. It remains the cornerstone of dyssynchrony assessment, as reflected in the 2013 ESC Guidelines on cardiac pacing and CRT.28,29 These guidelines state that CRT can be considered in patients with chronic HF and left ventricular systolic dysfunction (LVEF ≤35 %) and a documented QRS duration ≥120 ms who remain in New York Heart Association (NYHA) functional class II or worse, despite appropriate medical treatment. CRT is recommended in the aforementioned patient population and LBBB with QRS duration ≥150 ms (Class IA) and LBBB with QRS duration ≥120 ms (Class IB).29

The 2013 European Society of Cardiology Guidelines CRT aims to normalise intraventricular, interventricular and atrioventricular asynchrony, which may then entail a reduction in left ventricular end-systolic diameter (LVESD) and volume, an increase in LVEF, improvement of the myocardial performance index and a reduction in the diastolic and systolic indices of sphericity.30 CRT further increases longitudinal systolic function by particularly reducing left intraventricular dyssynchrony,31 contributing to the reduction in annular dilation.32 Thus, both directly reducing FMR (surgically or percutaneously) and correcting cardiac dyssynchrony are viable therapeutic approaches in selected patients with symptomatic HF. According to the 2012 ESC Guidelines for valvular heart disease, the percutaneous MitraClip® procedure “may be considered in patients with symptomatic severe secondary MR despite optimal medical therapy (including CRT if indicated), who fulfill the echo criteria of eligibility, are judged inoperable or at high surgical risk by a team of cardiologists and cardiac surgeons, and who have a life expectancy greater than 1 year (recommendation class IIb, level of evidence C)”.33

Responders and Non-responders to Cardiac Resynchronisation Therapy As is often the case in medicine, some patients do respond to therapy and some do not, despite best efforts. With respect to CRT, Reuter et al.34 defined as non-responders: patients without improvement in NYHA functional class or quality of life score after CRT. The presence of MR grade 0–I was an independent predictor of lack of response. Diaz-Infante et al.35 semi-quantitatively assessed two groups (MR grade 0–II and MR grade III–IV). Patients who died, underwent heart transplantation or did not improve >10 % in their six-minute walk distance, were considered non-responders. MR grade III–IV was a predictor of non-response.13,30,35,36 In patients with FMR, CRT is able to reduce moderate or severe baseline MR to a non-significant grade in one-third of patients. In a study from 2010, CRT reduced MR from significant to non-significant in 34 % of patients but worsened it to severe MR in another 11 %.13 FMR has been reported to persist in about 20–25 % of CRT patients and, in an additional 10–15 %, it may actually worsen after CRT.37 CabreraBueno et al. observed that six months after initiating CRT one-third of patients with severe FMR had improved to non-significant MR, whereas reverse ventricular remodeling, defined as a reduction of at

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least 10 % in LV end-systolic volume, was achieved in two-thirds of patients (mean relative reduction ± 35 %).30 However, persistence of severe MR is associated with less or no reverse remodeling, worse clinical course and a significantly higher rate of clinical and major arrhythmic events.13,38,39 A change in LV end-diastolic volume after CRT proved to be the most powerful independent predictor of long-term survival. Reduction of end-diastolic volume strongly predicts lower mortality and fewer hospital admissions for HF in the long term.40 The initial presence of FMR is an independent predictor of lack of clinical response to CRT35 and of less reverse remodeling than in patients without FMR at baseline.30 CRT does have the potential to reduce the severity of MR,13,20 but data about the ‘point of no return’ of MR in systolic dysfunction are lacking. Di Biase et al. identified the degree of post-CRT reduction in MR severity at three-month followup (in 794 patients) as an independent predictor of response, strongly correlated with MR reduction at 12 months.11

Clip After Cardiac Resynchronisation Therapy?

As previously discussed, compared with patients in whom CRT reduces MR, the persistence of severe MR after CRT is associated with less reverse remodeling, poor clinical outcome and a significantly higher rate of clinical and major arrhythmic events.13,38,39 Patients undergoing CRT in accordance with the guidelines of the ESC/American Heart Association (AHA) 26,27 without signs of significant clinical improvement may be considered candidates for the percutaneous MitraClip procedure.29 The MitraClip (Abbott Vascular, Menlo Park, California, US) has been developed to reduce MR in the beating heart.41 It aims to adapt both mitral valve leaflets (edge-to-edge) by way of a clip, thus dividing one gaping regurgitant orifice into two smaller ones, effectively creating a double-orifice valve. It was the first percutaneous device for MR to be compared with conventional mitral valve surgery in a randomised trial in patients with structural MR (compared with Endovascular Valve Edge-to-Edge Repair [EVEREST II] trial) and fills a therapeutic gap for patients with severe MR who are considered inoperable or at high peri-operative risk.42,43 Among smaller studies, the EVEREST II

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Device Therapy trial (189 percutaneously treated patients) and the ACCESS-Europe Phase I trial (117 patients) have already proved this catheter-based treatment to be both safe and efficient with respect to total MR reduction, sustained reverse remodeling of the LV with reduction of LVESD, reduced sphericity and increase of LVEF, and finally clinical benefits such as improvement in NYHA functional class, six-minute walk distance and quality of life data.44–46 However, percutaneous repair is associated with a higher necessity of repeat procedures and less improvement in LV dimensions. These divergences were insignificant though in the subset of patients with FMR.47 MitraClip implantation has become an established therapeutic option in patients with significant MR, particularly elderly patients with substantial co-morbidities and ineligibility for surgical repair; it has found its place as a therapeutic option in ESC Guideline recommendations.33,43,44,48,49 The Percutaneous Mitral Valve Repair in Cardiac Resynchronisation Therapy (PERMIT-CARE) feasibility study50 enrolled 51 symptomatic CRT non-responders with predominantly ischaemic cardiomyopathy and moderate-to-severe FMR in 46 % and severe FMR in 54 %; the authors observed that MitraClip therapy achieved a reduction by at least one degree of MR severity almost instantly in most patients. In addition, there were significant reductions in both end-diastolic and end-systolic LV volumes observed at six and 12 months. The considerable improvement in NYHA functional class achieved within the ensuing 3–12 months is proof of significant FMR being one of the major reasons for a lack of response to CRT.50 Despite certain pre- and post-procedural risks, the procedure was judged feasible and safe, taking into account the high morbidity (logistic European System for Cardiac Operative Risk Evaluation [EuroSCORE] 29.7 ± 19.4 %) of a cohort mostly considered ineligible for mitral valve surgery.50 In-line with recent MitraClip studies,44,49 three out of four patients were in NYHA functional class II or better at discharge and 12-month follow-up.50 This clinical improvement strongly correlated with a significant reduction in FMR severity.

Less than 20 % of the PERMIT-CARE patients had FMR of grade ≥2 at discharge and in only 10 % did significant FMR persist at one-year follow-up.50 Long-term observations of FMR changes in CRT patients are still lacking.

1. Trichon BH, O’Connor CM. Secondary mitral and tricuspid regurgitation accompanying left ventricular systolic dysfunction: Is it important, and how is it treated? Am Heart J 2002;144:373–6.

2. Trichon BH, Felker GM, Shaw LK, et al. Relation of frequency and severity of mitral regurgitation to survival among patients with left ventricular systolic dysfunction and heart failure. Am J Cardiol 2003;91:538–43.

3. Aikawa K, Sheehan FH, Otto CM, et al. The severity of functional mitral regurgitation depends on the shape of the mitral apparatus: a three-dimensional echo analysis. J Heart Valve Dis 2002;11:627–36.

4. Koelling TM, Aaronson KD, Cody RJ, et al. Prognostic significance of mitral regurgitation and tricuspid regurgitation in patients with left ventricular systolic dysfunction. Am Heart J 2002;144:524–9.

5. Clark AL, Goode K, Cleland JG. The prevalence and incidence of left bundle branch block in ambulant patients with chronic heart failure. Eur J Heart Fail 2008;10:696–702.

6. Shenkman HJ, Pampati V, Khandelwal AK, et al. Congestive heart failure and QRS duration: establishing prognosis study.

Chest 2002;122:528–34.

7. Baldasseroni S, Opasich C, Gorini M, et al. Left bundle-branch block is associated with increased 1-year sudden and total mortality rate in 5517 outpatients with congestive heart failure: a report from the Italian network on congestive heart failure. Am Heart J 2002;143:398–405.

8. Iuliano S, Fisher SG, Karasik PE, et al. QRS duration and mortality in patients with congestive heart failure. Am Heart J 2002;143:1085–91.

9. Rao RK, Kumar UN, Schafer J, et al. Reduced ventricular volumes and improved systolic function with cardiac

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Clip Before Cardiac Resynchronisation Therapy?

At present, no articles have been published on MitraClip therapy performed before initiating CRT. This may be due to the recommendations of the 2013 ESC Guidelines on the management of valvular heart disease.33

Conclusions Symptomatic patients with chronic HF due to dilated cardiomyopathy need to be assessed both before and 3–6 months after receiving CRT, in particular with respect to the progression of pre-existing FMR or the development of new FMR. Response to CRT may be assessed by improvement in NYHA functional class and reverse LV remodeling, characterised by reduction in LV volumes and improved systolic and/ or diastolic function within 3–6 months. On the other hand, reliable predictors of failure to respond to CRT are still lacking. The extent of reverse remodeling is still the most important predictor of long-term prognosis.40,50–53 Considering that overall reverse remodeling was observed in the PERMIT-CARE cohort despite FMR grade ≥2 persisting at six months in up to 70 % of patients, this suggests that even a limited reduction in ventricular loading may induce reverse remodeling in CRT non-responders.50 However, evidence is still lacking.

Peri-procedural and overall mortality out to two years appear to be high in the PERMIT-CARE study, with 5.8 % and 20.0 %, respectively;50 but taking into account the patients’ poor pre-operative conditions and the dismal prognosis of non-responders,37 the possible benefits outweigh the risks.

Unfortunately, there are no data allowing a profound answer to the question: which patients with HF and FMR could benefit most from being treated primarily with MitraClip instead of or before CRT? This might be attributable to the 2012 ESC Guidelines on the management of valvular heart disease, which clearly suggest that a percutaneous MitraClip procedure should be considered in non-responders to CRT only. Proper randomised studies to either confirm or weaken the above-mentioned treatment sequence are clearly lacking. Referring to the guidelines, we therefore strongly suggest a clinical trial in HF-patients with both FMR and LBBB to be randomised to either MitraClip procedure or CRT. n

resynchronization therapy: a randomized trial comparing simultaneous biventricular pacing, sequential biventricular pacing, and left ventricular pacing. Circulation 2007;115:2136–44.

10. Gasparini M, Bocchiardo M, Lunati M, et al. Comparison of 1-year effects of left ventricular and biventricular pacing in patients with heart failure who have ventricular arrhythmias and left bundle-branch block: the Bi vs Left Ventricular Pacing: an International Pilot Evaluation on Heart Failure Patients with Ventricular Arrhythmias (BELIEVE) multicenter prospective randomized pilot study. Am Heart J 2006;152:155 e1–7.

11. Di Biase L, Auricchio A, Mohanty P, et al. Impact of cardiac resynchronization therapy on the severity of mitral regurgitation. Europace 2011;13:829–38.

12. Dickstein K, Vardas PE, Auricchio A, et al. 2010 focused update of ESC Guidelines on device therapy in heart failure: an update of the 2008 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure and the 2007 ESC Guidelines for cardiac and resynchronization therapy.

Developed with the special contribution of the Heart Failure Association and the European Heart Rhythm Association.

Eur J Heart Fail 2010;12:1143–53.

13. Cabrera-Bueno F, Molina-Mora MJ, Alzueta J, et al.

Persistence of secondary mitral regurgitation and response to cardiac resynchronization therapy. Eur J Echocardiogr 2010;11:131–7.

14. Carabello BA. Ischemic mitral regurgitation and ventricular remodeling. J Am Coll Cardiol 2004;43:384–5.

15. Breithardt OA, Sinha AM, Schwammenthal E, et al. Acute effects of cardiac resynchronization therapy on functional mitral regurgitation in advanced systolic heart failure. J Am Coll Cardiol 2003;41:765–70.

16. Kanzaki H, Bazaz R, Schwartzman D, et al. A mechanism

for immediate reduction in mitral regurgitation after cardiac resynchronization therapy: insights from mechanical activation strain mapping. J Am Coll Cardiol 2004;44:1619–25.

17. Ypenburg C, Lancellotti P, Tops LF, et al. Acute effects of initiation and withdrawal of cardiac resynchronization therapy on papillary muscle dyssynchrony and mitral regurgitation. J Am Coll Cardiol 2007;50:2071–7.

18. Briongos-Figuero S, Santos-Gallego CG, Moya Mur JL. Free mitral regurgitation due to asynchrony and improvement with cardiac resynchronization. J Am Coll Cardiol 2012;60:232.

19. Brandt RR, Reiner C, Arnold R, et al. Contractile response and mitral regurgitation after temporary interruption of long-term cardiac resynchronization therapy. Eur Heart J 2006;27:187–92.

20. Cleland JG, Daubert JC, Erdmann E, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005;352:1539–49.

21. St John Sutton MG, Plappert T, Abraham WT, et al. Effect of cardiac resynchronization therapy on left ventricular size and function in chronic heart failure. Circulation 2003;107:1985–90.

22. Ypenburg C, Lancellotti P, Tops LF, et al. Mechanism of improvement in mitral regurgitation after cardiac resynchronization therapy. Eur Heart J 2008;29:757–65.

23. Abraham WT, Fisher WG, Smith AL, et al. Cardiac resynchronization in chronic heart failure. N Engl J Med 2002;346:1845–53.

24. Lancellotti P, Mélon P, Sakalihasan N, et al. Effect of cardiac resynchronization therapy on functional mitral regurgitation in heart failure. Am J Cardiol 2004;94:1462–5.

25. Madaric J, Vanderheyden M, Van Laethem C, et al. Early and late effects of cardiac resynchronization therapy on exercise-induced mitral regurgitation: relationship with left ventricular dyssynchrony, remodelling and cardiopulmonary

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performance. Eur Heart J 2007;28:2134–41.

26. Swedberg K, Cleland J, Dargie H, et al. Guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 2005): The Task Force for the Diagnosis and Treatment of Chronic Heart Failure of the European Society of Cardiology. Eur Heart J 2005;26:1115–40.

27. Hunt SA, Abraham WT, Chin MH, et al. ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation 2005;112:e154–235.

28. Hawkins NM, Petrie MC, MacDonald MR, et al. Selecting patients for cardiac resynchronization therapy: electrical or mechanical dyssynchrony? Eur Heart J 2006;27:1270–81.

29. European Society of Cardiology (ESC)1; European Heart Rhythm Association (EHRA), 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). Europace 2013;15:1070–118.

30. Cabrera-Bueno F, García-Pinilla JM, Peña-Hernández J, et al.

Repercussion of functional mitral regurgitation on reverse remodelling in cardiac resynchronization therapy. Europace 2007;9:757–61.

31. Porciani MC, Macioce R, Demarchi G, et al. Effects of cardiac resynchronization therapy on the mechanisms underlying functional mitral regurgitation in congestive heart failure.

Eur J Echocardiogr 2006;7:31–9.

32. Vinereanu D. Mitral regurgitation and cardiac resynchronization therapy. Echocardiography 2008;25:1155–66.

33. Joint Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology (ESC)1; European Association for Cardio-Thoracic Surgery (EACTS), Vahanian A, Alfieri O, Andreotti F, et al. Guidelines on the management of valvular heart disease (version 2012). Eur

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Heart J 2012;33:2451–96.

34. Reuter S, Garrigue S, Barold SS, et al. Comparison of characteristics in responders versus nonresponders with biventricular pacing for drug-resistant congestive heart failure. Am J Cardiol 2002;89:346–50.

35. Diaz-Infante E, Mont L, Leal J, et al. Predictors of lack of response to resynchronization therapy. Am J Cardiol 2005;95:1436–40.

36. Richardson M, Freemantle N, Calvert MJ, et al. Predictors and treatment response with cardiac resynchronization therapy in patients with heart failure characterized by dyssynchrony: a pre-defined analysis from the CARE-HF trial. Eur Heart J 2007;28:1827–34.

37. Ypenburg C, van Bommel RJ, Borleffs CJ, et al. Long-term prognosis after cardiac resynchronization therapy is related to the extent of left ventricular reverse remodeling at midterm follow-up. J Am Coll Cardiol 2009;53:483–90.

38. Anand IS, Carson P, Galle E, et al. Cardiac resynchronization therapy reduces the risk of hospitalizations in patients with advanced heart failure: results from the Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure (COMPANION) trial. Circulation 2009;119:969–77.

39. Saxon LA, Bristow MR, Boehmer J, et al. Predictors of sudden cardiac death and appropriate shock in the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) Trial. Circulation 2006;114:2766–72.

40. Yu CM, Bleeker GB, Fung JW, et al. Left ventricular reverse remodeling but not clinical improvement predicts long-term survival after cardiac resynchronization therapy. Circulation 2005;112:1580–6.

41. Feldman T, Foster E, Glower DD, et al. Percutaneous repair or surgery for mitral regurgitation. N Engl J Med 2011;364:1395–406.

42. Mauri L, Garg P, Massaro JM, et al. The EVEREST II Trial: design and rationale for a randomized study of the evalve mitraclip system compared with mitral valve surgery for mitral regurgitation. Am Heart J 2010;160:23–9.

43. Feldman T, Wasserman HS, Herrmann HC, et al.

Percutaneous mitral valve repair using the edge-to-edge technique: six-month results of the EVEREST Phase I Clinical Trial. J Am Coll Cardiol 2005;46:2134–40.

44. Feldman T, Kar S, Rinaldi M, et al. Percutaneous mitral repair with the MitraClip system: safety and midterm durability in the initial EVEREST (Endovascular Valve Edge-to-Edge REpair Study) cohort. J Am Coll Cardiol 2009;54:686–94.

45. Foster E, Kwan D, Feldman T, et al. Percutaneous mitral valve repair in the initial EVEREST cohort: evidence of reverse left ventricular remodeling. Circ Cardiovasc Imaging 2013;6:522–30.

46. Maisano F, Franzen O, Baldus S, et al. Percutaneous mitral valve interventions in the real world: early and 1-year results from the ACCESS-EU, a prospective, multicenter, nonrandomized post-approval study of the MitraClip therapy in Europe. J Am Coll Cardiol 2013;62:1052–61.

47. Mauri L, Foster E, Glower DD, et al. 4-year results of a randomized controlled trial of percutaneous repair versus surgery for mitral regurgitation. J Am Coll Cardiol 2013;62:317–28.

48. Tamburino C, Ussia GP, Maisano F, et al. Percutaneous mitral valve repair with the MitraClip system: acute results from a real world setting. Eur Heart J 2010;31:1382–9.

49. Franzen O, Baldus S, Rudolph V, et al. Acute outcomes of MitraClip therapy for mitral regurgitation in high-surgical-risk patients: emphasis on adverse valve morphology and severe left ventricular dysfunction. Eur Heart J 2010;31:1373–81.

50. Auricchio A, Schillinger W, Meyer S, et al. Correction of mitral regurgitation in nonresponders to cardiac resynchronization therapy by MitraClip improves symptoms and promotes reverse remodeling. J Am Coll Cardiol 2011;58:2183–9.

51. Solomon SD, Foster E, Bourgoun M, et al. Effect of cardiac resynchronization therapy on reverse remodeling and relation to outcome: multicenter automatic defibrillator implantation trial: cardiac resynchronization therapy.

Circulation 2010;122:985–92.

52. Kramer DG, Trikalinos TA, Kent DM, et al. Quantitative evaluation of drug or device effects on ventricular remodeling as predictors of therapeutic effects on mortality in patients with heart failure and reduced ejection fraction: a meta-analytic approach. J Am Coll Cardiol 2010;56:392–406.

53. Verhaert D, Grimm RA, Puntawangkoon C, et al. Long-term reverse remodeling with cardiac resynchronization therapy: results of extended echocardiographic follow-up. J Am Coll Cardiol 2010;55:1788–95.

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Supported Contribution – Opinion

Stroke Prevention in Atrial Fibrillation – Outcomes and Future Directions Katrina Mountfort Me d i c a l Wr i t e r, R a d c l i f f e Ca r d i o l o g y Rev iewed for a c c ura c y by : J ohn Ca m m 1 , G r e g o r y L i p 2 , A n d r e a s G o e t t e 3 a n d J e a n - Y v e s L e H e u z e y 4 1. St. George’s University Hospital, London, UK; 2. University of Birmingham, Birmingham, UK; 3. St Vincenz-Hospital, Paderborn, Germany; 4. Georges Pompidou European Hospital and Paris Descartes University, Paris, France

Abstract Stroke prevention is central to the management of patients with atrial fibrillation (AF). Vitamin K antagonists (VKAs) are the established and long-standing option for stroke prevention therapy in patients with AF. However, non-VKA oral anticoagulants (NOACs) have recently been developed and demonstrated non-inferior efficacy vs VKA treatment, with fewer limitations in clinical practice and with reduced risks of major bleeding. In order to discuss the usage, efficacy and safety of NOACs, a satellite symposium was held at the Cardiostim/ EHRA Europace Congress in Nice in June 2014. At present, three NOACs, a direct thrombin inhibitor (dabigatran) and two direct factor Xa inhibitors (rivaroxaban and apixaban) have been approved in Europe for stroke prevention in patients with AF. In addition, the once-daily factor Xa inhibitor edoxaban has recently been evaluated in this setting in the phase III Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation – Thrombolysis In Myocardial Infarction Study 48 (ENGAGE AF-TIMI 48) that compared edoxaban 30 mg once daily (low-dose regimen) with dose-adjusted warfarin (international normalised ratio 2.0–3.0). ENGAGE AF-TIMI 48 was the largest trial with a NOAC to date, and demonstrated that both dosing regimens of once-daily edoxaban were non-inferior to well-managed warfarin treatment for the prevention of stroke or systemic embolism and also provided significant reductions in the risk of haemorrhagic stroke, cardiovascular mortality, major bleeding and intracranial bleeding. In summary, the recent availability of NOACs has enabled physicians to avoid the limitations of VKA therapy in clinical practice and tailor anticoagulant treatment to the individual patient. However, worldwide usage of oral anticoagulant therapy remains suboptimal compared with guideline recommendations, and further dissemination of its benefits may prove helpful.

Keywords Non-VKA oral anticoagulant, NOAC, vitamin K antagonist, atrial fibrillation, stroke prevention in atrial fibrillation Disclosure: John Camm served as an advisor or speaker for: AstraZeneca, ChanRX, Gilead, Merck, Menarini, Otsuka, Sanofi, Servier, Xention, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Pfizer, Boston Scientific, Biotronik, Medtronic, St. Jude Medical, Actelion, GlaxoSmithKline, InfoBionic, Incarda, Johnson & Johnson, Mitsubishi, Novartis, Takeda. Prof Gregory Lip has served as a consultant or speaker for Bayer, Astellas, Merck, Sanofi, BMS/Pfizer, Biotronik, Medtronic, Portola, Boehringer Ingelheim, Microlife Medtronic and Daiichi-Sankyo. Prof Andreas Goette has received honoraria from Daiichi Sankyo Inc. Jean-Yves LeHeuzey served as an advisor or consultant or received research grants from: Bristol-Myers Squibb, Meda, Boehringer Ingelheim, Servier, Bayer, Daiichi Sankyo.

Received: 23 July 2014 Accepted: 10 November 2014 Citation: Arrhythmia & Electrophysiology Review, 2014;3(3):194–200 Access at: www.AERjournal.com

Support: The publication of this article was supported by Daiichi Sankyo.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is characterised by rapid and irregular heart rates. It is a lifethreatening condition present in up to 1.5 % of the population and accounts for approximately 15 % of all stroke events.1 While relatively unusual in those under 55 years, its incidence increases substantially with age, particularly between the ages of 65 and 80 years,2 and its incidence and prevalence are rising at rates that are not completely explained by an aging population.3 Patients with AF have an approximately five-fold increased risk of stroke compared with those without AF.4 Consequently, AF and AF-related stroke are a major burden on healthcare systems in Europe and the US.5,6 Stroke risk can vary up to 20-fold between patients with AF, depending upon the presence or absence of clinical risk factors.

These risk factors were collated in the CHADS2 scoring scheme for stroke risk and subsequently revised in the CHA2DS2-VASc scheme.7 In recent years a large number of interesting studies have investigated the use of new oral anticoagulants for stroke prevention in patients with AF.

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This article aims to outline the usage, efficacy and safety of nonvitamin K antagonist oral anticoagulants (NOACs), to describe the recent Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation – Thrombolysis In Myocardial Infarction Study 48 (ENGAGE AF-TIMI 48) and its implications for stroke prevention in AF, and to consider future directions in oral anticoagulation in AF, based on a satellite symposium held at the Cardiostim/EHRA Europace Congress in Nice in June 2014.

The Evolving Treatment Landscape for Atrial Fibrillation in Europe – What Choice for Stroke Prevention?

For a number of years, vitamin K antagonist (VKA) therapy has been used for stroke prevention in patients with AF. In terms of stroke prevention, it is superior to aspirin and its benefit is not offset by the occurrence of major bleeding.8 In the 1990s, the use of warfarin increased

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substantially, following a number of clinical trials that demonstrated a significant reduction in stroke risk compared with placebo.9 However, VKA therapy has several limitations that make it difficult to use in clinical practice. These include an unpredictable pharmacokinetic response, narrow therapeutic index, slow onset and offset of action, the need for routine coagulation monitoring and frequent dose adjustment, and numerous food–drug and drug–drug interactions.10–12 In recent years, NOACs that directly inhibit thrombin or factor Xa have been developed for stroke prevention in patients with AF (see Figure 1). Investigations have been performed with one direct thrombin inhibitor (dabigatran) and three factor Xa inhibitors (rivaroxaban, apixaban and edoxaban). The first study to be completed was the Randomised Evaluation of Long Term Anticoagulant Therapy With Dabigatran Etexilate (RE-LY) trial in 2009, which showed that dabigatran was non-inferior to warfarin for prevention of stroke and systemic embolism, and also associated with lower rates of major bleeding.13 Following this pivotal clinical trial, three factor Xa inhibitors have demonstrated non-inferiority to warfarin in terms of prevention of stroke and systemic embolism: rivaroxaban in the Rivaroxaban-Once Daily, Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) trial,14 apixaban in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial15 and edoxaban in the ENGAGE AF-TIMI 48 trial.16 A summary of the major findings of clinical trials to date is given in Table 1.17 At present, three NOACs (dabigatran, rivaroxaban and apixaban) have been approved for stroke prevention in patients with AF in Europe.

A recent meta-analysis of the clinical trials with NOACs in patients with AF found they had a favourable risk-benefit profile overall compared with warfarin, with significant reductions in stroke and systemic embolism, intracranial haemorrhage, mortality, and a reduction in the risk of major bleeding, although there was as an increased risk of gastrointestinal bleeding.18 Although all four NOACs significantly reduced the risk of haemorrhagic stroke, reduction in ischaemic stroke was only seen with dabigatran 150 mg twice daily.13 There was also a degree of variation between the NOACs vs warfarin in gastrointestinal bleeding, with an increase with dabigatran 110 mg and 150 mg twice daily, rivaroxaban and high-dose edoxaban 60 mg once daily treatment, whereas no increase with apixaban and lowdose edoxaban 30 mg once daily. In addition, dabigatran 110 mg and 150 mg twice daily and low-dose edoxaban 30 mg once daily were associated with a decrease in all-cause mortality.13,16 As the majority of patients with AF are aged over 75 years, a recent meta-analysis analysed data from participants in clinical trials aged 75 years and over, and concluded that NOACs were associated with equal or greater efficacy than conventional therapy and did not cause excess bleeding in this population.19 However, when comparing efficacy and safety observations with the different NOACs it is important to consider that no head-to-head comparison of the NOACs has been performed, and also that the four pivotal trials had different designs and patients with varying risk of stroke, making comparisons between the studies highly confounded.

Edoxaban has not yet received approval for use in Europe, however dabigatran, rivaroxaban and apixaban are in clinical use in many countries. A recent US study combined clinical trial data and a real world sample, taken from Medco patients during 2007–2010 (see Table 2).20 The

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Figure 1: Action of Anticoagulants in the Coagulation Cascade XIIa Extrinsic pathway

XIa IXa

Intrinsic pathway

Rivaroxaban Apixaban Edoxaban

VIIa Xa

TF

VIIIa

Inhibition of thrombolysis IIa (Thrombin)

Platelet activation Reactivation of coagulation cascade

Heparins via antithrombin Xa, IIa

Va

Warfarin II, VII, IX, X Fondaparinux Idraparinux Xabans Xa Hirudin Bivalirudin Argatroban Dabigatran...

IIa (thrombin)

FIBRIN

Note that edoxaban is not registered for use in the EU and the USA at the time of publication.

Table 1: Clinical Trials Evaluating NOACs vs Warfarin in AF Trial Dose of NOAC

NOAC Warfarin P-value (%/y) (%/y)

Stroke/Systemic Embolism

RE-LY

Dabigatran 110 mg bd

1.53

1.69

Dabigatran 150 mg bd

1.11

1.69

<0.001

ROCKET-AF

Rivaroxaban 15–20 mg oda 2.1

2.4

0.12

ARISTOTLE

Apixaban 2.5–5 mg bdb

0.34

1.27c 1.60c 0.01

ENGAGE AF-TIMI 48 Edoxaban 60 mg odd

1.57 1.8

0.08

2.04 1.8

0.1

Edoxaban 30 mg odd

according

the data publicatio

Intracranial Haemorrhage

RE-LY

Dabigatran 110 mg bd

0.23

0.74

<0.001

Dabigatran 150 mg bd

0.30

0.74

<0.001

The data the prima

ROCKET-AF

Rivaroxaban 15–20 mg oda 0.5

0.7

0.02

For intrac

ARISTOTLE

Apixaban 2.5–5 mg bdb

0.33 0.80 <0.001

Dabig 11

ENGAGE AF-TIMI 48 Edoxaban 60 mg odd

0.39 0.85 <0.001

0.26 0.85 <0.001

Apix, 0.33

Major Bleeding

Edox 60,

RE-LY

Dabigatran 110 md bd

2.71

3.36

0.003

For haem

Dabigatran 150 mg bd

3.11

3.36

0.31

Rivarox, 0

ROCKET-AF

Rivaroxaban 15–20 mg oda 3.6

3.4

0.58

ARISTOTLE

Apixaban 2.5–5 mg bdb

Edoxaban 30 mg odd

2.13 3.09 <0.001

ENGAGE-AF-TIMI 48 Edoxaban 60 mg odd

2.75 3.43 <0.001

1.61 3.43 <0.001

Edoxaban 30 mg odd

Total Mortality

RE-LY

Dabigatran 110 mg bd

3.75

4.13

Dabigatran 150 mg bd

3.64

4.13

0.051

ROCKET-AF

Rivaroxaban 15–20 mg oda 4.5

4.9

0.15

ARISTOTLE

Apixaban 2.5–5 mg bdb

0.13

3.52 3.94 0.047

ENGAGE AF-TIMI 48 Edoxaban 60 mg odd

3.99 4.35 0.08

3.80 4.35 0.006

Edoxaban 30 mg odd

a. 15 mg od if CrCl 30–49 ml/min. b. 2.5 mg bd if ≥2 of the following: age ≥80 years, BW <60 kg, creatine ≥1.5 mg/dl. c. This number includes both embolic and haemorrhagic strokes. d. dose reduced by 50 % (60 mg to 30 mg od and 30 mg to 15 mg od) if if CrCl 30–50 ml/ min, BW <60 kg, concomitant verapamil or quinidine. BW = body weight; CrCl = creatinine clearance; NOAC = non-vitamin K antagonist oral anticoagulants; bd = twice daily; od = once daily. Source: Katritsis et al, 201317

study concluded that if relative risk reductions from randomised clinical trials persist in the real world, apixaban gives the greatest clinical benefit

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Supported Contribution – Opinion

Specific patient characteristics

Figure 2: Factors That May Be Considered in Determining Choice of NOAC Previous stroke (secondary prevention)

Consider best investigated agent or greatest reduction of 2nd stroke

Rivaroxaban Apixaban

Previous GI bleeding or high risk

Consider agent with the lowest reported incidence of GI bleed

Apixaban [Edoxaban]

High risk of ischaemic stroke, low bleeding risk

Consider agent/dose with the best reduction of ischaemic stroke

Dabigatran 150

High risk of bleeding e.g. HAS-BLED ≥3

Consider agent/dose with the lowest incidence of bleeding

Dabigatran 110 Apixaban [Edoxaban]

CAD, previous MI or high-risk for ACS/MI

Consider agent with a positive effect in ACS

Rivaroxaban

Renal impairment

Consider agent least dependent on renal function

Apixaban Rivaroxaban

GI upset/disorders

Consider agent/dose with no reported GI effects

Apixaban Rivaroxaban [Edoxaban]

Patient preference

Consider once-daily formulation

Rivaroxaban [Edoxaban]

GI = gastrointestinal; CAD = coronary artery disease; ACS = acute coronary syndrome; MI = myocardial infarction. Adapted from Savelieva and Camm, 2014.21 Note that edoxaban is not registered for use in the EU and the USA at the time of publication.

Table 2: Combined Real World and Clinical Trial Data for Apixaban, Dabigatran and Rivaroxaban

ARISTOTLE Apixaban vs Warfarin

RE-LY Dabigatran vs Warfarin

ROCKET-AF Rivaroxaban vs Warfarin

Stroke MBEIH Stroke MBEIH Stroke MBEIH

Warfarin treated 5.3 10.0 5.3 10.0 5.3 10.0 event rate per

Medco Medco

Medco Medco

Medco Medco

0.79

0.64

0.85

PY in real-world Medco patients Relative risk for

0.79

10.7

1.14

NOAC from clinical trial Estimated real-world 4.18 7.9 3.4 10.7 4.5 11.4 event rate for NOAC per 100 PYs Absolute risk

-1.1

-2.1

-1.9

+0.7

-0.8

+1.4

reduction (NOACwarfarin) in realworld per 100 PYs Net clinical outcome

-3.2

-1.2

+0.6

32

84

–

–

–

166

(stroke+MBEIH) difference in realworld for NOAC vs warfarin per 100 PYs NNT in real-world to avoid one net clinical outcome vs warfarin per year NNH in real-world to cause one net clinical outcome vs warfarin per year MBEIH = major bleeding excluding intracranial haemorrhage. NNH = number needed to harm. Source: Amin, 201420

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vs warfarin of the three NOACs in terms of stroke and major bleeding excluding intracranial haemorrhage events avoided.

Alongside these clinical trial data, an important issue in choosing between the NOACs is the potential for patient reluctance in switching from a once-daily VKA to a twice-daily NOAC, rather than a once-daily NOAC. Treatment discontinuation is also of relevance and apixaban and edoxaban treatment were both associated with a lower rate of discontinuation compared with warfarin.15,16 Therefore, considering these aspects of NOAC treatment, it has been suggested that the choice of NOAC be guided by specific patient characteristics (see Figure 2).21 An additional treatment option for patients with non-valvular AF is percutaneous closure of the left atrial appendage (LAA). A multicentre, non-inferiority trial randomised 707 patients to percutaneous closure of the LAA and subsequent discontinuation of warfarin or warfarin treatment. Efficacy was assessed by a primary composite endpoint of stroke, cardiovascular death and systemic embolism. The efficacy of percutaneous closure of the LAA with this device was noninferior to that of warfarin therapy. Although there was a higher rate of adverse safety events in the intervention group than in the control group, events in the intervention group were mainly a result of peri-procedural complications.22 Longer term (mean 2.3 years) data from this study confirmed that LAA closure was noninferior to systemic anticoagulation with warfarin. There were more primary safety events in the LAA closure group (5.5 % per year; 95 % confidence interval [CI], 4.2 %–7.1 % per year) than in the control group (3.6 % per year; 95 % CI, 2.2 %–5.3 % per year; relative risk, 1.53; 95 % CI, 0.95–2.70).23 This is therefore a recommended treatment option for patients at high risk of stroke and in whom longterm treatment with oral anticoagulation is contraindicated.

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ENGAGE AF-TIMI 48 – Implications for Stroke Prevention in Atrial Fibrillation An extensive phase II dose-ranging program was undertaken with edoxaban to inform the design of phase III studies. A phase II study in 1,146 patients with non-valvular AF compared a number of edoxaban dosing strategies (30 mg once daily, 60 mg once daily, 30 mg twice daily and 60 mg twice daily) with open-label, dose-adjusted warfarin.

Edoxaban 30 mg and 60 mg once daily both had a similar safety profile to warfarin and were both associated with less bleeding than edoxaban 30 mg twice daily.24 Therefore in the phase III ENGAGE AF-TIMI 48 study, only once-daily edoxaban treatment was compared with warfarin.

ENGAGE AF-TIMI 48 was a double-blind, double-dummy, randomised, international study in patients with confirmed non-valvular AF.16 The study compared two once-daily edoxaban regimens with doseadjusted warfarin (international normalised ratio [INR] 2.0–3.0).25 The edoxaban dose was halved in patients at risk of edoxaban overexposure or bleeding at randomisation or at any time during the study (dose reduction criteria: body weight ≤60 kg, creatinine clearance 30–50 ml/min, or concomitant treatment with a strong P-glycoprotein inhibitor). In addition to dose reduction, comprehensive assessment of patient INR values and a transition period at study end were undertaken.25 Patients (n=21,105) who had AF documented by electrocardiogram in the previous 12 months and a CHADS2 score ≥2, were randomised 1:1:1 to low-dose edoxaban 30 mg once daily (or reduced to 15 mg once daily), high-dose edoxaban 60 mg once daily (or reduced to 30 mg once daily) or dose-adjusted warfarin (INR 2.03.0). Randomisation was stratified by CHADS2 score and anticipated drug exposure. The primary efficacy endpoint was a composite of stroke (ischaemic or haemorrhagic) and systemic embolic events, and the non-inferiority boundary for the upper limit of the 97.5 % CI was 1.38. The primary safety endpoint was major bleeding.

Of patients enrolled, 99.6 % received the drug. Completeness of follow-up was 99.5 %, and 99.1 % of those enrolled were present at final visit. Only 8.8 % of patients per year came off study drug, 0.9 % withdrew consent and only one patient was lost to follow-up.

Compared with other NOAC trials in AF, ENGAGE AF-TIMI 48 was the longest trial with a median follow up of 2.8 years, and had the highest median time in therapeutic range (TTR) of 68.4 %.16 The primary efficacy analysis in the modified intention to treat (mITT) on-treatment population found stroke or systemic embolism at a rate of 1.50 % per year in the well-controlled warfarin group, 1.18 % per year in the high-dose edoxaban 60 mg once-daily group (hazard ratio [HR] 0.79; p<0.001 for non-inferiority; p=0.02 for superiority) and 1.61% per year in the low-dose edoxaban 30 mg once-daily group (HR 1.07; p=0.005 for non-inferiority; p-value not significant for superiority). The Kaplan-Meier curve for the primary efficacy outcome in the intention to treat (ITT) population showed a lower rate of stroke or systemic embolism in the high-dose edoxaban group from early in the study (see Figure 3). Key secondary outcomes included a lower

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Figure 3: ENGAGE AF-TIMI 48: Kaplan-Meier of Primary Efficacy Outcome in the ITT Population 8 Stroke or systemic embolic event (%)

In conclusion, the landscape of atrial fibrillation and antithrombotic treatment has dramatically evolved in recent years, as a result of the availability of NOACs. As no head-to-head comparison of NOACs has been performed, it has been suggested, when choosing a NOAC therapy, to take into account individual patient factors and medical history.

6 4 2 0

0

0.5

1.0

1.5

Years

2.0

2.5

3.0

3.5

Warfarin Edoxaban 60 mg (HR=0.87, 0.73–1.04) Edoxaban 30 mg (HR=1.13, 0.96–1.34) ITT = intention to treat. Source: Giugliano et al, 2013.16

rate of haemorrhagic stroke with both doses of edoxaban (HR 0.33 and 0.54 for low-dose and high-dose edoxaban, respectively, vs warfarin).

In terms of ischaemic stroke, no difference was seen between highdose edoxaban and warfarin, but a statistically significant increase was seen with the low dose (HR 1.41; p<0.001). All-cause mortality was significantly reduced with low-dose edoxaban vs warfarin (HR 0.87, p=0.006) and a non-significant reduction was seen with the high-dose edoxaban group. However, cardiovascular mortality was significantly reduced with both low-dose and high-dose edoxaban regimens vs warfarin (HR 0.85; p=0.008 and HR 0.86; p=0.013, respectively). There was also no statistically significant difference in the rate of myocardial infarction between the low-dose and highdose edoxaban groups and warfarin.16 In terms of safety outcomes, compared with warfarin, the annualised rate of major bleeding was significantly lower with both high-dose edoxaban (2.75 % vs. 3.43 %; HR 0.80; p<0.001) and also low-dose edoxaban (1.61 % vs. 3.43 %; HR 0.47; p<0.001). Significant reductions in fatal bleeding and intracranial haemorrhage were also observed with both edoxaban regimens vs warfarin (p≤0.006 for all comparisons).

A significantly lower rate of gastrointestinal bleeding was seen in the low-dose edoxaban group vs warfarin (HR 0.67; p<0.001), but a significantly higher rate occurred in the high-dose edoxaban group (HR 1.23; p=0.03). Analysis of three net clinical outcomes (stroke/ disabling stroke, systemic embolism, major/life-threatening bleeding and all-cause mortality) showed that all were significantly reduced with both dosage regimens of edoxaban compared with warfarin (p<0.01 for all comparisons).16 At the end of the study, patients were extensively monitored during transition to open-label oral anticoagulant therapy. Patients were either transitioned to open-label VKA, overlapping active low-dose edoxaban and VKA for 2 weeks or until the INR reached 2.2, whichever came first; or transitioned to an open-label NOAC. In the case of an INR <2.0, NOAC treatment was initiated. If the INR was ≥2.0, INR measurements were repeated until the INR dropped below 2.0, then the NOAC was initiated. This approach resulted in a similar incidence of stroke or systemic embolism in all three treatment groups (0.16 %, 0.15 % and 0.15 % with warfarin, high-dose and low-dose edoxaban, respectively), and also with the incidence of major bleeding through 14 days (0.13 %, 0.09 % and 0.11 % with warfarin, high-dose and lowdose edoxaban, respectively).16

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Supported Contribution – Opinion Figure 4: ESC Guidelines – Choice of Anticoagulant Atrial filbrillation

Valvular AF

YES

NO (i.e. non-valvular AF) <65 years and lone AF (including females)

YES

NO

Future Directions for Oral Anticoagulants in Atrial Fibrillation – Where Do We Go From Here?

Assess risk of stroke (CHA2DS2-VASc score)

0

1

≥2

Oral anticoagulant therapy

Assess bleeding risk (HAS-BLED score) Consider patient values and preferences

NOAC

No antithrombotic therapy

VKA

AF = atrial fibrillation; HAS-BLED = Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile international normalised ratio, Elderly (> 65 years), Drugs/alcohol concomitantly; CHA2DS2-VASc = Congestive heart failure, Hypertension, Age 75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65–74 years, Sex category; NOAC = non-VKA oral anticoagulants; VKA = vitamin K antagonist. Source: Camm et al, 2012.30

Figure 5: Preadmission Medications in Patients with Known Atrial Fibrillation Who Were Admitted with Acute Ischaemic Stroke (High-Risk Cohort, n=597)

29%

29% No antithrombotic therapy Subtherapeutic warfarin (INR <2.0)

2%

10% 29%

Therapeutic warfarin (INR ≥2) Single antiplatelet drug Dual antiplatelet therapy

Source: Gladstone et al, 2009.31

In a recent subanalysis of the ENGAGE AF-TIMI 48 study, the efficacy of edoxaban was assessed relative to warfarin according to AF subtype.26 The guidelines state that no difference in stroke risk exists between different AF subtypes. The likelihood of stroke and systemic embolus was lower in paroxysmal AF subtypes compared with other forms of AF. In addition, the efficacy and safety of edoxaban compared to warfarin was preserved across the subtypes of AF. In terms of bleeding, no differences were seen according to AF subtype.26

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In summary, compared with well-managed warfarin, both once-daily highdose and low-dose edoxaban were non-inferior for prevention of stroke and systemic embolism, with a trend to decreased stroke and systemic embolism in the high-dose edoxaban ITT analysis. Both edoxaban regimens also reduced major bleeding, intracranial haemorrhage, haemorrhagic stroke and cardiovascular death compared with warfarin.

There was also no excess in stroke or bleeding during the transition to oral anticoagulant at the end of the trial. A recent review suggested that, given the limitations with long-term warfarin therapy, once-daily edoxaban may provide a convenient long-term alternative for patients.27

The availability of NOACs has enabled clinicians to tailor therapy to the patient, and it has been suggested that the availability of four NOACs has left the physician spoilt for choice.28 In order to facilitate future use of NOACs, there is a need for a consensus on the terminology used to describe them. The acronym NOAC is no longer appropriate, since these agents are now neither new nor novel, and new terminology is increasingly used in different countries. However, an acronym change may result in confusion when encountered in older publications or guidelines. It has therefore been recommended that the NOAC acronym should refer to non-VKA oral anticoagulants.29 In the past, European guidelines focused on identifying ‘high risk patients’ as VKA therapy was considered troublesome and inconvenient. However, the ESC guidelines have evolved to reflect the efficacy and safety of the NOACs and a recent 2012 update recommended a practice shift towards greater focus on identification of ‘truly low risk’ patients with AF (aged <65 years and CHADS2 score of 0 for men or 1 for women), for whom antithrombotic therapy is not needed (see Figure 4).30 Effective stroke prevention can then be given to those patients at higher risk.

Given the advances in AF management and the updated ESC guidelines, there is a need for the systematic collection of information on the current management and treatment of AF. Data from a Canadian 2009 prospective stroke registry of 597 patients with AF at high risk of stroke showed that the majority of stroke events occurred in patients who were not within the therapeutic INR range, and only 10 % of patients with acute stroke and known AF had INR values ≥2.0 at admission (see Figure 5).31 Aspirin, which is now known to be of limited efficacy in preventing stroke in AF,32 is still in widespread use.33 There is a need to identify and treat the untreated and switch sub-optimally managed patients to NOACs. The use of NOACs requires new approaches in many aspects of daily use and in specific clinical situations, including renal impairment and urgent surgical interventions. The European Heart Rhythm Association (EHRA) has also published a comprehensive guide detailing practical aspects of use of NOACs.34 In Europe, large registry studies investigating the use of NOACs in real-world settings are ongoing: the Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIAAF),35 the Global Anticoagulant Registry in the Field (GARFIELD),36 the Eurobservational Research Programme Atrial Fibrillation (EORP)37 and Prevention of Thromboembolic Events – European Registry in Atrial Fibrillation (PREFER in AF).38 Preliminary data from the GARFIELD study indicate that the proportion of patients receiving anticoagulant therapy varies widely between countries, from less than 30 % in China to more than 90 % in Italy. The registry also found that only 57 % of patients take

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anticoagulant therapy, and that a minority (43 %) achieved adequate INR control over the first 12 months.39 Recently, data have been published from the smaller PREFER in AF registry that examined differences among western European countries.38 The proportion of patients taking VKAs varied between 86.0 % (France) and 71.4 % (Italy). Warfarin was used predominantly in the UK and Italy (74.9 % and 62.0 %, respectively), phenprocoumon in Germany (74.1 %), acenocoumarol in Spain (67.3 %), and fluindione in France (61.8 %). The major sites for INR measurements were biology laboratories in France, anticoagulation clinics in Italy, Spain and the UK, and the physicians’ offices or self-measurement in Germany.40

The individual patient’s values and preferences regarding stroke prevention and bleeding in AF are also important in the decision of which therapy to use. A recent study found considerable inter-patient variability in opinions. Overall, patients required at least a 0.8 % annual absolute risk reduction and 15 % relative risk reduction in the risk of stroke in order to agree to initiate antithrombotic therapy, and patients were willing to endure 4.4 major bleeds in order to prevent one stroke. In addition, 12 % of patients were medication averse and were not willing to consider antithrombotic therapy; even if it was 100 % effective in preventing strokes.42

The EORP-AF registry found that oral anticoagulants were used in 80 % of patients, an increase over the last decade, but were predominantly VKAs (71.6 %), with NOACs being used in only 8.4 %.

Other antithrombotics (mostly antiplatelet therapy, especially aspirin) were still used in one-third of patients, and no antithrombotic treatment in 4.8 %. Oral anticoagulants were used in 56.4 % of patients with CHA2DS2-VASc score of 0, with 26.3 % having no antithrombotic therapy. The study concluded that compliance with the treatment guidelines for patients with the lowest and higher stroke risk scores remains suboptimal.37 At present, there are no laboratory tests to assess the adherence of patients treated with NOACs.

A growing body of data is becoming available regarding the long-term efficacy and safety of NOACs. A recent US Food and Drug Administration (FDA) study in Medicare patients comparing dabigatran with warfarin, found there was no risk of increased MI with dabigatran. The latter was associated with a lower risk of clot-related strokes, bleeding in the brain, and death, but an increased risk of major gastrointestinal bleeding compared with warfarin.43 An ongoing clinical trial (Edoxaban vs Warfarin in Subjects Undergoing Cardioversion of Atrial Fibrillation [ENSURE-AF]) is currently comparing edoxaban to warfarin in subjects with AF who are undergoing cardioversion.44

Concluding Remarks The global position is more worrying. The RE-LY AF registry enrolled

Stroke prevention is central in the management of AF. This is

15,400 patients at presentation to an emergency department at 164 sites and found a large global variation in AF management. The use of oral anticoagulation among patients with a CHADS2 score of ≥2 was greatest in North America (65.7 %) but was only 11.2 % in China.

If VKAs are used, good quality anticoagulation control is essential.

It is widely recognised that TTR is the best measure of assessing anticoagulant quality control. The mean TTR was 62.4 % in Western Europe and 50.9 % in North America, but only between 32 % and 40 % in India, China, Southeast Asia, and Africa.41 It is evident, therefore, that wider education regarding stroke prevention in AF is needed.

irrespective of rate or rhythm control and it is recommended that management is patient centred and symptom directed. The latest clinical trial of the NOAC edoxaban (ENGAGE AF-TIMI 48) demonstrated its non-inferior efficacy and improved safety vs well-managed warfarin.

In addition to these clinical data with edoxaban and with the other NOACs, an increasing body of registry data is emerging that indicates VKA therapy is under-utilised and suboptimal in clinical practice, suggesting a switch to a NOAC may be of benefit for patients. There is therefore a need for increased education regarding the importance of anticoagulant use in AF. n

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