AER 8.1 by Radcliffe Cardiology

Arrhythmia & Electrophysiology Review Volume 8 • Issue 1 • Spring 2019

Volume 8 • Issue 1 • Spring 2019

www.AERjournal.com

Papillary Muscle Ventricular Tachycardia or Ectopy: Diagnostics, Catheter Ablation and the Role of Intracardiac Echocardiography Josef Kautzner and Petr Peichl

Atrial Fibrosis: Translational Considerations for the Management of AF Patients Stylianos Tzeis, Dimitrios Asvestas and Panos Vardas

The Atrial Phenotype of the Inherited Primary Arrhythmia Syndromes Giulio Conte, Ulrich Schotten and Angelo Auricchio

Baseline I

VT Isthmus Characteristics: Insights from High-density Mapping II III Ruairidh Martin, Mélèze Hocini, Michel Haïsaguerre, Pierre Jaïs and Frédéric Sacher aVR aVL aVF

V1 II V2 II V1 III V2 III V1 IV V2 IV Ajmaline challenge I II III

III aVR

aVR aVL aVF

aVL aVF V1

V1 II V2 II V1 III V2 III V1 IV V2 IV

Electroanatomical Mapping During Catheter Ablation in a Woman with Thalassaemia and AF

V2 V3 V4 V5 V6

Post Morphology ofablation the I Anterior Right Ventricular II Papillary Muscle III

I II

ECG and Epicardial Potential Duration Map After Ajmaline

aVR aVL aVF

ISSN – 2050-3369

V1 II V2 II V1 III V2 III V1 IV V2 IV

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ESC Congress Paris 2019 Together with

World Congress of Cardiology 31 August - 4 September

Spotlight Global Cardiovascular Health

Abstract submission: December - 14 February Clinical Case submission: Mid January - 1 March Late-Breaking Science submission: Mid March - 21 May Early registration deadline: 31 May Late registration deadline: 31 July

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Volume 8 • Issue 1 • Spring 2019

www.AERjournal.com Official journal of

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

Section Editor – Arrhythmia Mechanisms / Basic Science

Section Editor – Clinical Electrophysiology and Ablation

Section Editor – Implantable Devices

Andrew Grace

Hugh Calkins

Angelo Auricchio

University of Cambridge, Cambridge

Johns Hopkins Medicine, Baltimore

Fondazione Cardiocentro Ticino, Lugano

Editorial Board Charles Antzelevitch

Warren Jackman

Carina Blomström-Lundqvist

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

Uppsala University, Uppsala

Johannes Brachmann Klinikum Coburg, II Med Klinik

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

Pedro Brugada

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

Pierre Jaïs University of Bordeaux, CHU Bordeaux

Prapa Kanagaratnam Imperial College Healthcare NHS Trust, London

Josef Kautzner Karl-Heinz Kuck

Alfred Buxton

Pier Lambiase

University of Pennsylvania, Philadelphia

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

Riccardo Cappato IRCCS Humanitas Research Hospital, Rozzano, Milan

Ken Ellenbogen Virginia Commonwealth University, Richmond

Sabine Ernst Royal Brompton & Harefield NHS Foundation Trust, London

Hein Heidbuchel Antwerp University and University Hospital, Antwerp

Gerhard Hindricks University of Leipzig. Frankfurt

Carsten W Israel JW Goethe University, Frankfurt

IRCCS Policlinico San Donato, Milan

Sunny Po Heart Rhythm Institute, University of Oklahoma Health Sciences Center, Oklahoma City

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

Asklepios Klinik St Georg, Hamburg

David J Callans

Carlo Pappone

ALFA – Alliance to Fight Atrial Fibrillation, Venice-Mestre

Institute for Clinical and Experimental Medicine, Prague

University of Brussels, UZ-Brussel-VUB Beth Israel Deaconess Medical Center, Boston

Cover image © AdobeStock

Mark O’Neill

Lankenau Institute for Medical Research, Pennsylvania

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

Samuel Lévy

Frédéric Sacher Bordeaux University Hospital, Electrophysiology and Heart Modelling Institute, Bordeaux

Richard Schilling Barts Health NHS Trust, London

Aix-Marseille University, Marseille

Cecilia Linde

William Stevenson Vanderbilt School of Medicine, Nashville

Karolinska University, Stockholm

Richard Sutton

Gregory YH Lip University of Liverpool, Liverpool

National Heart and Lung Institute, Imperial College London, London

Francis Marchlinski

Panos Vardas

University of Pennsylvania Health System, Philadelphia

Heraklion University Hospital, Heraklion

John Miller

Marc A Vos

Indiana University School of Medicine, Indiana

University Medical Center Utrecht, Utrecht

Fred Morady

Hein Wellens

Cardiovascular Center, University of Michigan

University of Maastricht, Maastricht

Sanjiv M Narayan

Katja Zeppenfeld

Stanford University Medical Center

Leiden University Medical Center, Leiden

Andrea Natale

Douglas P Zipes

Texas Cardiac Arrhythmia Institute, St David’s Medical Center, Austin, Texas

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

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Published by Radcliffe Cardiology. All information obtained by Radcliffe Cardiology and each of the contributors from various sources is as current and accurate as possible. However, due to human or mechanical errors, Radcliffe Cardiology and the contributors cannot guarantee the accuracy, adequacy or completeness of any information, and cannot be held responsible for any errors or omissions, or for the results obtained from the use thereof. Published content is for information purposes only and is not a substitute for professional medical advice. Where views and opinions are expressed, they are those of the author(s) and do not necessarily reflect or represent the views and opinions of Radcliffe Cardiology. Radcliffe Cardiology, Unit F, First Floor, Bourne End Business Park, Cores End Road, Bourne End, Buckinghamshire SL8 5AS, UK © 2019 All rights reserved ISSN: 2050-3369 • eISSN: 2050–3377

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Established: October 2012 | Frequency: Quarterly | Current issue: Spring 2019

Aims and Scope

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• Arrhythmia & Electrophysiology Review aims to assist time-pressured physicians to stay abreast of key advances and opinion in heart failure. • Arrhythmia & Electrophysiology Review comprises balanced and comprehensive articles written by leading authorities, addressing the most pertinent developments in the field. • Arrhythmia & Electrophysiology Review provides comprehensive updates on a range of salient issues to support physicians in continuously developing their knowledge and effectiveness in day-to-day clinical practice.

• Contributors are identified by the Editor-in-Chief with the support of the Editorial Board and Managing Editor. • 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. • The ‘Instructions to Authors’ document and additional submission details are available at www.AERjournal.com • Leading authorities wishing to discuss potential submissions should contact the Managing Editor, Jonathan Mckenna jonathan.mckenna@radcliffe-group.com

Structure and Format • Arrhythmia & Electrophysiology Review is a quarterly journal comprising review articles, expert opinion articles and guest 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 Editorial Board. • Articles are fully referenced, providing a comprehensive review of existing knowledge and opinion. • Each edition of Arrhythmia & Electrophysiology Review is available in full online at www.AERjournal.com

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

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Contents

Foreword 6

Genetic Approaches for the Treatment of Bradycardias Demosthenes G Katritsis DOI: https://doi.org/10.15420/aer.2019.8.1.FO1

Clinical Arrhythmias Atrial Fibrillation and Dementia: Exploring the Association, Defining Risks and Improving Outcomes

T Jared Bunch, Oxana Galenko, Kevin G Graves, Victoria Jacobs and Heidi T May DOI: https://doi.org/10.15420/aer.2018.75.2

Brugada Syndrome: Progress in Diagnosis and Management Carlo Pappone and Vincenzo Santinelli DOI: https://doi.org/10.15420/aer.2018.73.2

Brugada Syndrome: Progress in Genetics, Risk Stratification and Management Jorge Romero, Dan L Li, Ricardo Avendano, Juan Carlos Diaz, Roderick Tung and Luigi Di Biase DOI: https://doi.org/10.15420/aer.2018.66.2

Obesity and Atrial Fibrillation: Epidemiology, Pathophysiology and Novel Therapeutic Opportunities

Vishal Vyas and Pier Lambiase DOI: https://doi.org/10.15420/aer.2018.76.2

Atrial Fibrosis: Translational Considerations for the Management of AF Patients

Stylianos Tzeis, Dimitrios Asvestas and Panos Vardas DOI: https://doi.org/10.15420/aer.2018.79.3

The Atrial Phenotype of the Inherited Primary Arrhythmia Syndromes

Giulio Conte, Ulrich Schotten and Angelo Auricchio DOI: https://doi.org/10.15420/aer.2019.4.2

Electrophysiology and Ablation The Evolving Role of Catheter Ablation in Patients With Heart Failure and AF

Sandeep Prabhu, Wei H Lim and Richard J Schilling DOI: https://doi.org/10.15420/aer.2019.9.2

Ventricular Tachycardia Isthmus Characteristics: Insights from High-density Mapping

Ruairidh Martin, Mélèze Hocini, Michel Haïsaguerre, Pierre Jaïs and Frédéric Sacher DOI: https://doi.org/10.15420/aer.2018.78.2

Complications of Cryoballoon Pulmonary Vein Isolation

Shinsuke Miyazaki and Hiroshi Tada DOI: https://doi.org.10.15420/aer.2018.72.2

Papillary Muscle Ventricular Tachycardia or Ectopy: Diagnostics, Catheter Ablation and the Role of Intracardiac Echocardiography

Josef Kautzner and Petr Peichl DOI: https://doi.org/10.15420/aer.2018.80.2

Drugs and Devices Introducing Vernakalant into Clinical Practice

Angela JM Hall and Andrew RJ Mitchell DOI: https://doi.org/10.15420/aer.2018.71.2

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INTERNATIONAL MEDICAL CONFERENCE

UPDATES IN SPORTS CARDIOLOGY 18TH OCTOBER 2019 LONDON, ENGLAND

ONLY £75 TO ATTEND

INTERNATIONAL SPEAKERS

The annual CRY Conference attracts speakers and delegates from around the globe. Many of the world’s leading experts on sports cardiology, young sudden cardiac death and inherited cardiac conditions present contemporary topics and developments in their respective elds.

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Professor Domenico Corrado FOR MORE INFORMATION VISIT: WWW.C-R-Y.ORG.UK/CRY-INTERNATIONAL-CONFERENCE Untitled-8 1

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Foreword

Genetic Approaches for the Treatment of Bradycardias

ince the identification of the hyperpolarisation-activated cyclic nucleotide channel 4 (HNC4), a major constituent of the pacemaker current (If) in the sinoatrial node, as a modulator of heart rate,1 several genetic causes of sinus bradycardia by means of mutations in ion channel encoding genes have been described. They may result in isolated sick sinus sydrome or other arrhythmia and cardiomyopathy syndromes.2,3

Gene ‘therapy’ strategies using gene transfer vectors have, therefore, been attractive as an alternative method for treating bradycardia syndromes, and non-viral methods, including the revolution of CRISPR gene editing technology, are also becoming available. Genetics may be of service in treating bradycardias in other ways too. Very recently, one heterozygous mutation, KCNJ3 c.247A>C, p.N83H, was identified as a novel cause of hereditary bradyarrhythmias.4 KCNJ3 encodes the inwardly rectifying potassium channel Kir3.1, which combines with Kir3.4 (encoded by KCNJ5) to form the acetylcholine-activated potassium channel (IKAChchannel) with specific expression in the atrium. Studies on patients with sporadic AF also identified another five rare mutations in KCNJ3 and KCNJ5, suggesting the relevance of both genes to these arrhythmias.4 More importantly, in this study, NIP-151, a benzopyran derivative and selective IKACh channel blocker, effectively inhibited the mutant IKACh channel and up-regulated heart rate in a zebrafish model. Thus, pharmacological blockade of IKACh channels appears as a promising, safe therapy for increasing heart rate or preventing AF in patients with sick sinus syndrome and gain-of-function mutations in the IKACh channel. I believe that a new era is beginning for the treatment of conduction disorders in humans. Perhaps the possibility of treating sick sinus syndrome and AV block without any invasive pacing procedure is not very far away. The cardiology community is eagerly awaiting clinical implementation of this possibility. Demosthenes G Katritsis Editor-in-Chief, Arrhythmia and Electrophysiology Review Hygeia Hospital, Athens, Greece

Milanesi R, Baruscotti M, Gnecchi-Ruscone T, et al. Familial sinus bradycardia associated with a mutation in the cardiac pacemaker channel. N Engl J Med 2006;354:151–7. https://doi.org/10.1056/ NEJMoa052475; PMID: 16407510. Milano A, Vermeer AM, Lodder EM, et al. HCN4 mutations in multiple families with bradycardia and

left ventricular noncompaction cardiomyopathy. J Am Coll Cardiol 2014;64:745–56. https://doi.org/10.1016/j. jacc.2014.05.045; PMID: 25145517. Schweizer PA, Schröter J, Greiner S, et al. The symptom complex of familial sinus node dysfunction and myocardial noncompaction is associated with mutations in the HCN4 channel. J Am Coll

Cardiol 2014;64:757–67. https://doi.org/10.1016/j. jacc.2014.06.1155; PMID: 25145518. Yamada N, Asano Y, Fujita M, et al. Mutant KCNJ3 and KCNJ5 potassium channels as novel molecular targets in bradyarrhythmias and atrial fibrillation. Circulation 2019. https://doi.org/10.1161/CIRCULATIONAHA. 118.036761; PMID: 30764634; epub ahead of press.

DOI: https://doi.org/10.15420/aer.2019.8.1.FO1

Access at: www.AERjournal.com

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Supporting lifelong learning for arrhythmologists Arrhythmia & Electrophysiology Review, led by Editor-in-Chief Demosthenes Katritsis and underpinned by an editorial board of world-renowned physicians, comprises peer-reviewed articles that aim to provide timely update on the most pertinent issues in the field. Available in print and online, Arrhythmia & Electrophysiology Reviewâ&#x20AC;&#x2122;s articles are free-to-access, and aim to support continuous learning for physicians within the field.

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

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

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Clinical Arrhythmias

Atrial Fibrillation and Dementia: Exploring the Association, Defining Risks and Improving Outcomes T Jared Bunch, 1,3 Oxana Galenko, 1 Kevin G Graves, 2 Victoria Jacobs 1 and Heidi T May 1 1. Intermountain Medical Center Heart Institute, Murray, UT, US; 2. University of Utah, Salt Lake City, UT, US; 3. Department of Internal Medicine, Stanford University, Palo Alto, CA, US

Abstract AF is strongly associated with a spectrum of cranial injuries including stroke and dementia. Dementia risk is seen in patients with and without a prior stroke and includes idiopathic forms of dementia, such as Alzheimer’s disease. The initiation, use and efficacy of anticoagulation have been shown in multiple observational trials to have an impact on dementia risk. Cerebral hypoperfusion during AF can result in cognitive decline and patients with cranial atherosclerosis may have unique susceptibility. Therapies to carefully control the ventricular rate and catheter ablation have been shown in observational trials to lower dementia risk. There is a need for further research in multiple areas and the observational trials will require prospective trials confirmation. Recent guidelines for AF have advocated the initiation of effective anticoagulation, the treatment of associated disease conditions that may influence the progression of AF and catheter ablation, with long-term management of risk factors to lower risk of dementia.

Keywords AF, stroke, dementia, ageing, cognition, anticoagulants Disclosure: TJB is the recipient of research grants from Boston Scientific and Boehringer Ingelheim, but receives no personal compensation. All other authors have no conflicts of interest to declare. Received: 10 December 2018 Accepted: 5 February 2019 Citation: Arrhythmia & Electrophysiology Review 2019;8(1):8–12. DOI: https://doi.org/10.15420/aer.2018.75.2 Correspondence: T Jared Bunch, Intermountain Heart Rhythm Specialists, Intermountain Medical Center, Eccles Outpatient Care Center, 5169 Cottonwood St, Suite 510 Murray, UT 84107, US. E: Thomas.bunch@imail.org Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

AF is the most common sustained arrhythmia in clinical practice and is increasing worldwide.1,2 AF has been associated with an increased risk of mortality, although data suggest that longevity is increasing after diagnosis. This is attributed to medical therapies to reduce stroke and heart failure, and the management of other comorbidites.3,4 As a consequence, patients are living longer with AF and the detrimental impact of the arrhythmia and its management can been seen with long-term end organ dysfunction.

AF and Dementia Risk With and Without Overt Cerebral Ischaemic Injury AF is strongly associated with risk of stroke, and patients who experience a stroke have higher rates of progressive cognitive impairment and dementia. Two meta-analyses have shown a composite elevated risk of dementia in patients with AF who have a stroke (RR 2.43–2.70).5,6 AF patients are also two times more likely to experience silent or subclinical strokes than those without AF.7 Silent clinical infarcts are common in AF patients, with MRI revealing these injuries in 40% of patients imaged.7 The premise of a silent infarct is evolving and is likely a misnomer. In AF patients who have subclinical strokes, long-term rates of cognitive dysfunction and dementia are increased compared with those who do not have a stroke.8,9 In an analysis of 37,025 patients, we found that patients with AF had higher rates of multiple forms of dementia, including idiopathic or

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Alzheimer’s disease, than patients who did not have AF.10 The combined disease state of AF and dementia was significantly associated with mortality (HR 1.38–1.45). Two meta-analyses have evaluated the relationship between AF and incident dementia in patients without clinical stroke or cognitive dysfunction. In this analysis of eight studies, AF was independently associated with increased risk of dementia (HR 1.42; p<0.001).11 Although both dementia and AF are diseases of ageing, two large observational studies found a unique and elevated risk in AF patients who were relatively young (<67–70 years of age).10,12 The association between AF and idiopathic dementia independent of subsequent small or repetitive subclinical strokes is not known. In a subanalysis of the Atherosclerosis Risk In Communities (ARIC) study, cognitive decline was only present in those AF patients who had a subsequent silent cerebral infarct.13 In a study of Alzheimer’s disease patients, MRI imaging of AF patients showed much higher rates of cerebral infarcts and total gray matter volume loss, compared with those who did not have AF.14 The presence of AF in the absence of stroke has also been associated with progressive cognitive dysfunction, without overt dementia. In an analysis from the Cardiovascular Health Study, patients with AF experienced a more rapid decline of cognitive scores – assessed by the Modified Mini Mental State Exam – than those in sinus rhythm (−10.3 versus −6.4 over 5 years for patients with AF and those in sinus

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AF and Dementia rhythm, respectively).15 The risk of cognitive impairment was higher in AF patients with other comorbid diseases such as heart failure, diabetes, kidney disease, etc.16 Worldwide dementia trends show an increased risk in women, particularly in those >80 years of age. Current estimates are that one in two women and one in three men will develop a stroke, dementia or Parkinson’s disease, with the first two diseases comprising the greatest risk.17 We studied 35,608 patients without a history of AF or dementia. In this population 14,377 (40.4%) were women. The 5-year rates of AF were higher in men than women (14.0% in men versus 11.9% in women; p<0.0001), although dementia (1.1% in women versus 0.9% in men; p=0.09) and stroke rates (3.4% in women versus 2.6% in men; p<0.0001) were higher in women. Among the patients who developed AF, the 5-year rate of dementia in women was 2.9% versus 2.3% in men (p=0.180), and the long-term rate was 3.7% in women and 3.0% in men (p=0.110).18 With these emerging data regarding brain injury, it is critical that we start to expand our view of potential brain injuries in patients with AF (Figure 1).

AF and Dementia Risk with Anticoagulation If macro- and micro-cerebral ischaemic events are significant mechanisms underlying the association of AF with both vascular and idiopathic forms of dementia, then the initiation, use and efficacy of anticoagulation is critical. We studied this concept in an analysis of 2,605 AF patients with no history of dementia or cognitive impairment. These patients were enrolled at warfarin therapy start. This analysis showed that as time in therapeutic range (TTR) is decreased among the categories, the associated dementia risk is increased (versus >75%) (<25% HR 5.34; p<0.0001; 26–50% HR 4.10; p<0.0001; and 51–75% HR 2.57; p=0.001).19 There was a risk of cognitive decline with both over- and under-anticoagulation, suggesting that not only are cerebral ischaemic events a significant risk factor for dementia, but micro- and macro-bleeds also are. In a more recent national study, 444,106 patients were studied over 1.5 million years of risk. Patients treated with anticoagulation at baseline had a 29% lower risk of dementia than patients without anticoagulant treatment (1.14 versus 1.78 per 100 patient years at risk; p<0.001).20 In this analysis, delays in initiation of anticoagulation had a negative impact on the benefit observed with anticoagulation use (0–1 years HR 0.66; 1–3 years HR 0.80; 3–5 years HR 1.12; >5 years HR 0.80; p<0.001). Unfortunately, underuse and delayed use remain significant issues within our system (Table 1) and worldwide – particularly in women – even in AF patients considered at moderate to high risk.21,22 Direct oral anticoagulants (DOACs) have reduced rates of stroke and intracranial haemorrhage, compared with warfarin.23 In a propensitybased analysis of 5,254 patients (2,627 in the warfarin and DOAC groups), the use of DOACs was associated with a reduced risk of stroke or transient ischaemic attack (p<0.0001), major bleed (p<0.0001), and bleed (p=0.140). In regard to total cerebral events, patients treated with a DOAC were 43% less likely to develop stroke, transient ischaemic attack or dementia than those taking warfarin.24 In a nationwide analysis – limited by the small number of patients who actually received DOAC therapy – use of the newer anticoagulants was associated with a greater relative reduction in dementia risk

ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW

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Figure 1: Spectrum of Brain Injury in Patients with AF

Clinical and subclinical strokes

Clinical and subclinical bleeds

Atrophy and volume loss Gray matter changes Amyloid plaques

Repetitive microbleeds and/or clots

Cerebral hypotension/ hypoperfusion

(HR 0.40) when compared with warfarin.20 A potential benefit of DOAC therapy versus warfarin for brain health and preservation of cognition in AF patients requires prospective evaluation. The Impact of Anticoagulation Therapy on the Cognitive Decline and Dementia in Patients with Non-Valvular Atrial Fibrillation (CAF) trial will evaluate warfarin versus dabigatran over 2 years with serial cognitive testing every 6 months (NCT03061006). As of December 2018, the study was approximately 70% enrolled. The data regarding anticoagulation use and efficacy are compelling and prompted us to ask if AF contributes to dementia independently in patients treated long term with anticoagulation. In a study of 10,537 patients anticoagulated with warfarin for both AF (n=4,460) and nonAF reasons (thromboembolism n=5,868; valvular heart disease n=209) with no history of dementia, we evaluated the risk of dementia and the potential augmented risk of AF.25 In both groups there was a higher risk of dementia in patients with a low TTR compared with a high TTR, highlighting the critical role of anticoagulation on outcomes. Additionally, in a propensity-based analysis the presence of AF conveyed additional risk for general dementia (HR 2.42; p<0.0001) and Alzheimer’s disease (HR 2.04; p<0.0001).

AF and Dementia Risk Related to Arrhythmia, Haemodynamic Changes and Cranial Perfusion Many patients with AF experience symptoms of fogginess, mental slowing, or feeling off during transitions from sinus rhythm to AF. The correlation of dynamic cognitive changes with arrhythmia transition cannot be explained by a mechanism of repetitive cerebral injury events from macro- or micro-clots or bleeds. A compelling mechanism to explain abrupt cognitive decline with AF is that the arrhythmia unmasks cerebral microvascular dysfunction. In an autopsy study of Alzheimer’s disease patients, cerebral atherosclerosis was common.26 The most common area of disease was found in the circle of Willis, which is critical to allow adaptive compensation to all brain regions in the setting of altered blood flow or hypotension. As general vascular risk factors increase, the risk of dementia and the negative relative impact of AF increases.27 A modelling analysis was performed to examine the haemodynamic impact of AF on brain perfusion. In this analysis, variance in R-R intervals coupled with loss of atrioventricular synchrony result in reduced cranial blood flow that causes repetitive hypoperfusions at

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Clinical Arrhythmias Table 1: Delays in Initiation of Antithrombotic Therapies in Patients with Newly Diagnosed AF Time to Initiation

Acetylsalicylic acid/

Warfarin (n=4,408)

clopidogrel (n=21,781) General population ≤30 days

48.0%

5.2%

31 days to 1 year

10.5%

12.4%

>1 year to 3 years

13.1%

17.1%

>3 years

28.4%

65.3%

CHA2DS2-VASc 2–4 ≤30 days

50.7%

4.8%

31 days to 1 year

10.2%

12.5%

1 year to 3 years

13.6%

17.9%

>3 years

25.5%

64.8%

67.1%

7.9%

CHA2DS2-VASc >5 ≤30 days 31 days to 1 year

8.8%

18.4%

1 year to 3 years

10.9%

25.4%

>3 years

13.2%

48.3%

Figure 2: Mechanisms of Risk of Cognitive Decline and Dementia in Patients with AF

Risk of Dementia Related to Inflammation, Oxidative Stress and Genetic Components in AF From a histologic evaluation, Alzheimer’s disease is associated with the accumulation of abnormally folded beta-amyloid and tau proteins that form cerebral plaques. These plaques are associated with cerebral atrophy and cellular death. Amyloid deposits and misfolded proteins are also seen in degenerative atrial myopathy in AF patients.31 Whether the same predisposition of atrial changes associated with amyloid deposits is seen in the brain of patients with AF-related cognitive decline is unknown. From a genetic standpoint the apolipoprotein E epsilon4 allele is associated with risk of dementia and amyloid deposits. However, this allele did not act as a second hit or contributor of accelerated cognitive decline in patients with AF.32 Oxidative stress, inflammation and endothelial dysfunction have been shown to increase the risk of Alzheimer’s disease.33–35 In patients with AF, biomarkers of oxidative stress, inflammation and endothelial dysfunction are elevated.36–38 These markers associated with both disease states suggest both organs that manifest end organ disease – brain (dementia) and heart (AF) – reflect symptoms of a systemic and inflammatory vascular disease that has early roots in hypertension, obesity, low physical activity and metabolic syndrome.27 Figure 2 highlights pathways of cranial injury with common mediators that are likely to drive incidence and progression.

Improving Risk Prediction of Cognitive Decline in Patients with AF Micro- and macroemboli/bleeds Disruptions of blood–brain barrier/cytotoxicity Gray matter lesions Volume loss

Cerebral hypoperfusion Inflammation, oxidative stress, vascular disease and ? genetic risks

Arteriolar hypotension Capillary hypertension Gray matter lesions Volume loss

the arteriolar level and hypertensive events at the capillary level.28 The quantitative impact of repetitive microvascular haemodynamic compromise can be significant in AF patients as another cause of chronic ischaemic injuries and, as such, is considered one of the causes of leukoaraiosis or white matter changes.15 Management of rate and rhythm can improve outcomes. In a small study of patients with persistent AF who were compared with sinus rhythm controls, atrioventricular node ablation resulted in a steady and predictable heart rate (R-R interval), improved frontal and temporal blood flow leading to improved memory and learning and a flow pattern similar to those in sinus rhythm.29 We have also found, in an observational analysis, that patients with AF treated with catheter ablation have lower rates of stroke and dementia than patients who have AF not treated with ablation. Although this finding reflects procedural and referral biases, what was interesting is that patients treated with catheter ablation had stroke and dementia rates similar to patients without a history of AF. For example, Alzheimer’s dementia occurred in 0.2% of the AF ablation patients, compared with 0.9% of the AF no ablation patients and 0.5% of the no AF patients (p<0.0001).30

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Preservation of cognition must be a critical goal in the long-term management of patients with AF. If we consider the concept that chronic cognitive changes reflect repetitive cranial injuries from macro- or micro-clots and bleeds, then traditional risk scores should predict dementia. As discussed previously, the timing, use and efficacy of anticoagulation does influence dementia risk in AF patients. The CHADS2 and CHA2DS2-VASc scores are risk scores used to minimise risk of macro events or clinical events.39 These scores are largely comprised of static baseline risk factors and only augment with time. These scores also do not have the ability to discriminate between the severities of individual diseases, such as a patient with poorly controlled hypertension versus well controlled hypertension. As a consequence, the predictive values of each score are relatively poor, with C-statistics ranging from 0.50–0.70 across multiple cohorts of the study.40 Although these scores also predict dementia risk, there remains broad variability in risk across all CHADS2 and CHA2DS2-VASc strata.27 Risk scores that can be used dynamically and judge severity of disease will likely perform better, so can potentially have an impact on clinical care. For example, a dynamic score can assist in understanding current brain health and risk when transitioning from warfarin with a low TTR to a DOAC therapy, or after lifestyle modifications including increasing activity, lowering weight and improving blood pressure and glycemic control. Risk factor management is complex and multiple factors related to lifestyle drive both AF incidence, progression and adverse outcomes.41 When lifestyle modification is advocated in patients – with the assistance of a multidisciplinary team – arrhythmia-related outcomes can be improved, and some diseases can be reversed. This concept has many potential positive inroads towards cognitive health and

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AF and Dementia the role of adherence to healthy lifestyle choices directed by a multidisciplinary team needs further study. The sex-specific Intermountain Mortality Risk Scores (IMRS) are a dynamic measurement of systemic health comprised of commonly performed blood tests (complete blood count and basic metabolic profile). These blood tests are used routinely in clinical practice and the individual components used to measure organ and systemic health. The composite IMRS, when separated into three risk categories (low, moderate, high), individually predict risk of incident dementia in both men and women.42 These scores also segregate risk across all CHA2DS2-VASc scores highlighting the value of understanding physiology in the setting of baseline risk.43 The same value of IMRS can be seen in better discerning risk of stroke, as the IMRS improves the C-statistic when combined with CHADS2 and CHA2DS2-VASc scores in both men and women.43 In conclusion, recent guidelines were provided to raise awareness of the critical association between cognitive decline, dementia and cardiovascular disease, to identify key areas of additional research needed and to provide recommendations on how to lower risk. 44 In regard to risk in patients with AF, a recommendation for appropriate anticoagulation was made to prevent stroke and cognitive dysfunction. Other areas that may be useful for recommendations

10.

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o AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed G atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA 2001;285:2370–5. https://doi.org/10.1001/jama.285.18.2370; PMID: 11343485. Chugh SS, Havmoeller R, Narayanan K, et al. Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study. Circulation 2014;129:837–47. https://doi.org/10.1161/CIRCULATIONAHA.113.005119; PMID: 24345399. Asbach S, Olschewski M, Faber TS, et al. Mortality in patients with atrial fibrillation has significantly decreased during the last three decades: 35 years of follow-up in 1627 pacemaker patients. Europace 2008;10:391–4. https://doi.org/10.1093/ europace/eun014; PMID: 18326852. Schnabel RB, Yin X, Gona P, et al. 50 year trends in atrial fibrillation prevalence, incidence, risk factors, and mortality in the Framingham Heart Study: a cohort study. Lancet 2015;386:154–62. https://doi.org/10.1016/S01406736(14)61774-8; PMID: 25960110. Kwok CS, Loke YK, Hale R, et al. Atrial fibrillation and incidence of dementia: a systematic review and metaanalysis. Neurology 2011;76:914–22. https://doi.org/10.1212/ WNL.0b013e31820f2e38; PMID: 21383328. Kalantarian S, Stern TA, Mansour M and Ruskin JN. Cognitive impairment associated with atrial fibrillation: a meta-analysis. Ann Intern Med 2013;158:338–46. https://doi.org/10.7326/00034819-158-5-201303050-00007; PMID: 23460057. Kalantarian S, Ay H, Gollub RL, et al. Association between atrial fibrillation and silent cerebral infarctions: a systematic review and meta-analysis. Ann Intern Med 2014;161:650–8. https://doi.org/10.7326/M14-0538; PMID: 25364886. Gaita F, Corsinovi L, Anselmino M, et al. Prevalence of silent cerebral ischemia in paroxysmal and persistent atrial fibrillation and correlation with cognitive function. J Am Coll Cardiol 2013;62:1990–7. https://doi.org/10.1016/j. jacc.2013.05.074; PMID: 23850917. Vermeer SE, Prins ND, den Heijer T, et al. Silent brain infarcts and the risk of dementia and cognitive decline. N Engl J Med 2003;348:1215–22. https://doi.org/10.1056/NEJMoa022066; PMID: 12660385. Bunch TJ, Weiss JP, Crandall BG, et al. Atrial fibrillation is independently associated with senile, vascular, and Alzheimer’s dementia. Heart Rhythm 2010;7:433–7. https://doi. org/10.1016/j.hrthm.2009.12.004; PMID: 20122875. Santangeli P, Di Biase L, Bai R, et al. Atrial fibrillation and the risk of incident dementia: a meta-analysis. Heart Rhythm 2012;9:1761–8. https://doi.org/10.1016/j.hrthm.2012.07.026; PMID: 22863685. de Bruijn RF, Heeringa J, Wolters FJ, et al. Association Between Atrial Fibrillation and Dementia in the General Population. JAMA Neurol 2015;72:1288–94. https://doi.org/10.1001/ jamaneurol.2015.2161; PMID: 26389654. Chen LY, Lopez FL, Gottesman RF, et al. Atrial fibrillation and cognitive decline-the role of subclinical cerebral infarcts: the atherosclerosis risk in communities

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include when to consider a DOAC rather than warfarin, optimising TTR to >70%, managing lifestyle changes such as prevention of smoking, hypertension, obesity, diabetes, sleep apnoea, etc., to lower risk of both disorders, and rhythm control – particularly in younger patients (<65 years of age) – which may include ablation in highly-trained centres with long-term follow-up to optimise post-ablation care.

Clinical Perspective • AF is associated with long-term risk of cognitive decline and dementia. • Dementia rates are higher in women and those who have AF. • Chronic cerebral ischaemic injuries from macro- and microclots and bleeds is a mechanism supported by trials of anticoagulation use and cranial imaging. • Unmasked cerebral vascular dysfunction, through haemodynamic, oxidative and inflammatory mechanisms, is also a probable mechanism that can explain abrupt cognitive changes with onset of AF. • Several mechanisms of risk can be targeted with current pharmacological and nonpharmacological therapies that may lower dementia risk and, as such, require prospective study.

study. Stroke 2014;45:2568–74. https://doi.org/10.1161/ STROKEAHA.114.005243; PMID: 25052319. Graff-Radford J, Madhavan M, Vemuri P, et al. Atrial fibrillation, cognitive impairment, and neuroimaging. Alzheimers Dement 2016;12:391–8. https://doi.org/10.1016/j.jalz.2015.08.164; PMID: 26607820. Thacker EL, McKnight B, Psaty BM, et al. Atrial fibrillation and cognitive decline: a longitudinal cohort study. Neurology 2013;81:119–25. https://doi.org/10.1212/ WNL.0b013e31829a33d1; PMID: 23739229. Coma M, Gonzalez-Moneo MJ, Enjuanes C, et al. Effect of Permanent Atrial Fibrillation on Cognitive Function in Patients With Chronic Heart Failure. Am J Cardiol 2016;117:233–9. https://doi.org/10.1016/j.amjcard.2015.10.038; PMID: 26686573. Licher S, Darweesh SKL, Wolters FJ, et al. Lifetime risk of common neurological diseases in the elderly population. J Neurol Neurosurg Psychiatry 2019;90:148–56. https://doi. org/10.1136/jnnp-2018-318650; PMID: 30279211. Golive A, May HT, Bair TL, et al. The Impact of Gender on Atrial Fibrillation Incidence and Progression to Dementia. Am J Cardiol 2018;122:1489–95. https://doi.org/10.1016/j. amjcard.2018.07.031; PMID: 30195396. Jacobs V, Woller SC, Stevens S, et al. Time outside of therapeutic range in atrial fibrillation patients is associated with long-term risk of dementia. Heart Rhythm 2014; 11:2206–13. https://doi.org/10.1016/j.hrthm.2014.08.013; PMID: 25111326. Friberg L and Rosenqvist M. Less dementia with oral anticoagulation in atrial fibrillation. Eur Heart J. 2018;39:453–60. https://doi.org/10.1093/eurheartj/ehx579; PMID: 29077849. Steinberg BA, Gao H, Shrader P, et al. International trends in clinical characteristics and oral anticoagulation treatment for patients with atrial fibrillation: Results from the GARFIELD-AF, ORBIT-AF I, and ORBIT-AF II registries. Am Heart J 2017;194:132– 40. https://doi.org/10.1016/j.ahj.2017.08.011; PMID: 29223431. Go AS, Hylek EM, Chang Y, et al. Anticoagulation therapy for stroke prevention in atrial fibrillation: how well do randomized trials translate into clinical practice? JAMA 2003;290:2685–92. https://doi.org/10.1001/jama.290.20.2685; PMID: 14645310. Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2014;383:955–62. https://doi. org/10.1016/S0140-6736(13)62343-0; PMID: 24315724. Jacobs V, May HT, Bair TL, et al. Long-Term PopulationBased Cerebral Ischemic Event and Cognitive Outcomes of Direct Oral Anticoagulants Compared With Warfarin Among Long-term Anticoagulated Patients for Atrial Fibrillation. Am J Cardiol 2016;118:210–4. https://doi.org/10.1016/j. amjcard.2016.04.039; PMID: 27236255. Bunch TJ, May HT, Bair TL, et al. Atrial Fibrillation Patients Treated With Long-Term Warfarin Anticoagulation Have Higher Rates of All Dementia Types Compared With Patients Receiving Long-Term Warfarin for Other Indications. J Am Heart Assoc 2016;5:e003932. https://doi.org/10.1161/ JAHA.116.003932; PMID: 27402230.

26. B angen KJ, Nation DA, Delano-Wood L, et al. Aggregate effects of vascular risk factors on cerebrovascular changes in autopsy-confirmed Alzheimer’s disease. Alzheimers Dement 2014; 11:394–403. https://doi.org/10.1016/j.jalz.2013.12.025; PMID: 25022538. 27. Graves KG, May HT, Jacobs V, et al. Atrial fibrillation incrementally increases dementia risk across all CHADS2 and CHA2DS2VASc strata in patients receiving long-term warfarin. Am Heart J 2017;188:93–8. https://doi.org/10.1016/j. ahj.2017.02.026; PMID: 28577686. 28. Anselmino M, Scarsoglio S, Saglietto A, et al. Transient cerebral hypoperfusion and hypertensive events during atrial fibrillation: a plausible mechanism for cognitive impairment. Sci Rep 2016;6:28635. https://doi.org/10.1038/srep28635; PMID: 27334559. 29. Efimova I, Efimova N, Chernov V, et al. Ablation and pacing: improving brain perfusion and cognitive function in patients with atrial fibrillation and uncontrolled ventricular rates. Pacing Clin Electrophysiol 2012;35:320–6. https://doi.org/10.1111/j.15408159.2011.03277.x; PMID: 22126258. 30. Bunch TJ, Crandall BG, Weiss JP, et al. Patients treated with catheter ablation for atrial fibrillation have long-term rates of death, stroke, and dementia similar to patients without atrial fibrillation. J Cardiovasc Electrophysiol 2011; 22:839–45. https://doi.org/10.1111/j.1540-8167.2011.02035.x; PMID: 21410581. 31. Rocken C, Peters B, Juenemann G, et al. Atrial amyloidosis: an arrhythmogenic substrate for persistent atrial fibrillation. Circulation 2002;106:2091–7. https://doi.org/10.1161/01. CIR.0000034511.06350.DF; PMID: 12379579. 32. Rollo J, Knight S, May HT, et al. Incidence of dementia in relation to genetic variants at PITX2, ZFHX3, and ApoE epsilon4 in atrial fibrillation patients. Pacing Clin Electrophysiol 2015;38:171–7. https://doi.org/10.1111/pace.12537; PMID: 25494715. 33. Wardlaw JM, Smith C and Dichgans M. Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging. Lancet Neurol 2013;12:483–97. https://doi. org/10.1016/S1474-4422(13)70060-7; PMID: 23602162. 34. Poggesi A, Inzitari D and Pantoni L. Atrial Fibrillation and Cognition: Epidemiological Data and Possible Mechanisms. Stroke 2015;46:3316–21. https://doi.org/10.1161/ STROKEAHA.115.008225; PMID: 26396028. 35. Poggesi A, Pasi M, Pescini F, et al. Circulating biologic markers of endothelial dysfunction in cerebral small vessel disease: A review. J Cereb Blood Flow Metab 2016;36:72–94. https://doi. org/10.1038/jcbfm.2015.116; PMID: 26058695. 36. Goette A, Kalman JM, Aguinaga L, et al. EHRA/HRS/APHRS/ SOLAECE expert consensus on atrial cardiomyopathies: definition, characterization, and clinical implication. Europace 2016;18:1455–90. https://doi.org/10.1093/europace/euw161; PMID: 27402624. 37. Goette A, Bukowska A, Lendeckel U, et al. Angiotensin II receptor blockade reduces tachycardia-induced atrial adhesion molecule expression. Circulation 2008;117:732–42. https://doi.org/10.1161/CIRCULATIONAHA.107.730101; PMID: 18227384.

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Clinical Arrhythmias 38. G oette A, Ittenson A, Hoffmanns P, et al. Increased expression of P-selectin in patients with chronic atrial fibrillation. Pacing Clin Electrophysiol 2000;23:1872–5. https://doi. org/10.1111/j.1540-8159.2000.tb07041.x; PMID: 11139946. 39. Lip GY, Nieuwlaat R, Pisters R, et al. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation. Chest 2010;137:263–72. https://doi.org/10.1378/chest.09-1584; PMID: 19762550. 40. Van Staa TP, Setakis E, Di Tanna GL, et al. A comparison of risk stratification schemes for stroke in 79,884 atrial fibrillation

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patients in general practice. J Thromb Haemost 2011;9:39–48. https://doi.org/10.1111/j.1538-7836.2010.04085.x; PMID: 21029359. 41. Brandes A, Smit MD, Nguyen BO, et al. Risk Factor Management in Atrial Fibrillation. Arrhythm Electrophysiol Rev 2018;7:118–27. https://doi.org/10.15420/aer.2018.18.2; PMID: 29967684. 42. Graves KG, May HT, Jacobs V, et al. CHA2DS2-VASc scores and Intermountain Mortality Risk Scores for the joint risk stratification of dementia among patients with atrial fibrillation. Heart Rhythm 2019;16:3–9. https://doi.org/10.1016/j. hrthm.2018.10.018; PMID: 30611392.

43. G raves KG, May HT, Knowlton KU, et al. Improving CHA2DS2VASc stratification of non-fatal stroke and mortality risk using the Intermountain Mortality Risk Score among patients with atrial fibrillation. Open Heart 2018;5:e000907. https://doi. org/10.1136/openhrt-2018-000907; PMID: 30564375. 44. Dagres N, Chao TF, Fenelon G, et al. European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) expert consensus on arrhythmias and cognitive function: what is the best practice? Heart Rhythm 2018;15:e37–60. https://doi.org/10.1016/j.hrthm.2018.03.005; PMID: 29563045.

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Clinical Arrhythmias

Brugada Syndrome: Progress in Diagnosis and Management Carlo Pappone and Vincenzo Santinelli Arrhythmology Department, IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy

Abstract Brugada syndrome (BrS) represents an inherited disorder associated with risk of sudden cardiac death due to VF in patients without structural heart disease. Currently, BrS is diagnosed by typical cove-shaped ST-segment elevation >2 mm in >1 RV precordial lead V1, V2 occurring spontaneously or after a sodium-channel blocker provocation test without any further evidence of malignant arrhythmias. An ICD should always be implanted in symptomatic BrS patients to prevent sudden death, despite high rates of complications with these devices. In asymptomatic people, an electrophysiological study should be performed to evaluate the need for an ICD. The recent discovery of a functional substrate has revolutionised our approach to the pathophysiology and management of BrS. Promising new therapeutic options have emerged in the last 3 years. Ajmaline is able to determine the extension of the substrate by prolonging the duration and fragmentation of abnormal epicardial electrograms. Substrate ablation results in the disappearance of both coved-type ECG and ventricular tachycardia/VF inducibility. These findings are clinically relevant, suggesting that epicardial ablation guided by ajmaline infusion may be an effective therapeutic option in BrS, potentially removing the need for ICD implantation.

Keywords Brugada syndrome, arrhythmic substrate, ventricular fibrillation, ventricular tachycardia, catheter ablation, ajmaline, ICD, right ventricular outflow tract Disclosure: The authors have no conflicts of interest to declare. Received: 4 December 2018 Accepted: 21 January 2019 Citation: Arrhythmia & Electrophysiology Review 2019;8(1):13–8. DOI: https://doi.org/10.15420/aer.2018.73.2 Correspondence: Carlo Pappone, IRCCS Policlinico San Donato, Department of Arrhythmology, Piazza E Malan, 20097-San Donato Milanese, Italy. E: carlo.pappone@af-ablation.org Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Historical Precedents

Brugada Syndrome Burden

Brugada syndrome (BrS) was first described more than 25 years ago as a clinical entity in people resuscitated from sudden cardiac death due to documented VF.1 The original 1992 case series described eight patients without apparent structural heart disease who all had VF associated with persistent coved ST-segment elevation in the right precordial leads.1 In 1996 this arrhythmic syndrome was named Brugada syndrome. The next year, BrS was recognised as the same clinical entity as sudden unexplained nocturnal death syndrome, first reported in 1917 in the Philippines.2 The syndrome was considered a familial disease because of syncope and/or sudden death in many relatives of a same family, and the first genetic alteration was identified in 1998.3

At present, it is challenging to establish the actual burden of the syndrome, mainly because we do not know the real number of asymptomatic people due to the high variability and fluctuations of the typical ECG pattern. The incidence appears to be low (<1%), but the condition is responsible for >10% of all sudden deaths and up to 20% of sudden deaths in structurally normal hearts. The prevalence is 8–10 times higher in men than women. More data are becoming available about unexpected deaths in different populations, so the real incidence of BrS needs to be updated.5

Typical presentation of the syndrome is syncope or resuscitated sudden death, and symptoms usually occur at night or at rest especially after a large meal. Fever is a common trigger, particularly in children. As subsequent registry data were published, it became apparent that the spectrum of risk is wide, with most patients classified as low risk. Despite intense research efforts, as documented by about 5,000 publications on BrS, controversies still exist over its pathophysiology, risk stratification and care. In the last 20 years, 12-lead surface ECG has represented the primary source of information for diagnosis and prognosis, but the speciﬁcity and accuracy of the abnormal ECG pattern are relatively low.4

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Clinical Presentation The most typical presentation of BrS is syncope or resuscitated cardiac arrest in the third or fourth decade of life due to polymorphic ventricular tachycardia (VT) or VF. Symptoms typically occur at night or at rest during the day, and also uncommonly during exercise. Monomorphic VT is rare and is more prevalent in children and infants, for whom fever is the most common trigger. Diagnosis may also be made on familial screening of patients with BrS or incidentally following a routine ECG. Symptoms typically first develop during adulthood, commonly at 40 years, but they may occur also in children or older people. More than 80% of adult patients are men, but there is an equal male:female ratio

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Clinical Arrhythmias Figure 1: Electrocardiographic Pattern of Brugada Syndrome Induced by Ajmaline in a Patient with Normal, Type 1 or Type 2 ECG Pattern at Baseline

Type 2

Spontaneous Type 1 Baseline

Ajmaline

Baseline

Normal ECG Ajmaline

Baseline

Ajmaline

I II III aVR aVL aVF V1 II V2 II V1 III V2 III V1 IV V2 IV Precordial leads V1 and V2 are placed in the second intercostal space, V3 and V4 are V1 and V2 placed in the third intercostal space, and V5 and V6 are V1 and V2 placed in the fourth intercostal space. Ajmaline increases coved-ST elevation in spontaneous type 1 ECG pattern, while in the type 2 ECG pattern it unmasks the typical Brugada syndrome ECG pattern.

in children. However, the clinical presentation of BrS has changed.6 In more recently diagnosed patients, there has been a decrease in resuscitated cardiac arrest as the first clinical presentation of the disease, thereby making inducibility and risk stratification crucial.6 Many people will remain asymptomatic throughout their life.

under continuous monitoring.11 The test is positive when a type 1 ECG pattern appears during infusion (Figure 1). In the presence of QRS widening (>130%) or the occurrence of frequent premature ventricular contractions (PVCs) or complex ventricular arrhythmias, pharmacological testing should be stopped.11

ECG Pattern

It should be emphasised that about a quarter of tests may deliver a false negative. This is important when evaluating a patient who has experienced a frank syncope or an aborted sudden death. Ajmaline is the ideal drug for this purpose because of its shorter duration of action (1 mg/kg over 10 minutes, maximum 100 mg; Figure 1); and higher sensitivity than flecainide, but it is not available in many countries. The IV formulation of flecainide (2 mg/kg over 10 minutes, maximum of 150 mg), is not always available in many countries in IV formulation although it is generally available as an oral formulation.

In 2012, an expert consensus panel clarified ECG characteristics and diagnostic criteria and established two ECG patterns for BrS.7 Type 1 (coved-type) represents the only diagnostic pattern for BrS, while type 2 (saddle-back type) is only suggestive of BrS. The type 2 pattern is characterised by an ST-segment elevation >0.5 mm (usually >2 mm in V2) in >1 right precordial lead (V1–V3) followed by a convex ST. To facilitate differentiation of type 2 ECG from other Brugada-like patterns, additional criteria have been suggested that utilise the triangle formed by the ascending and descending branch of the R-wave.8 Frequent day-by-day fluctuations in the ECG pattern may occur in the same patient, including a normal pattern (concealed BrS).9 Placement of the right precordial leads in more cranial positions can increase sensitivity due to variable anatomical correlation between the right ventricular outflow tract (RVOT) and V1–V2 in the standard position. Abnormal ECG intervals including P wave duration, PR or QRS duration may be commonly observed. In up to 20% of patients, AF or supraventricular tachycardia due to atrioventricular (AV) nodal re-entry or Wolff-Parkinson-White syndrome have been reported.10

A contraindication to pharmacological testing is PR prolongation in the baseline ECG because of the risk of inducing AV block. A drug challenge should be performed under strict monitoring of blood pressure and 12-lead ECG, and facilities for cardioversion and resuscitation should be available. Moving leads V1–V3 up to the second intercostal space improves diagnostic yield. The patient needs to be monitored for 3 hours or until the ECG is normalised as late positive tests have been reported. The plasma half-life of flecainide is 20 hours, while ajmaline is 5 minutes. Isoprenaline infusion may be employed to counteract these drugs if serious ventricular arrhythmias develop.

Pharmacological Testing

Genetic Basis

Further investigation is needed in cases where there is a suspicion of BrS (syncope, dizziness, agonal respiration, resuscitated cardiac arrest, family history of BrS or suggestive ECG pattern) but patients do not have a spontaneous type 1 ECG pattern. They should have a pharmacological test performed with a sodium-channel blocking drug

The first genetic alteration in BrS was identified in 1998 in the SCN5A gene by Chen et al.3 The current challenge in clinical genetics is the interpretation of genetic alterations and their translation into clinical practice.12 To date, nearly a quarter of BrS patients were found to be carriers of SCN5A variants. Over 300 SCN5A variants have been

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Diagnosis and Management of Brugada Syndrome

BrS is commonly accepted as an autosomal dominant channelopathy, however, recent data suggest that it follows a more complex polygenic inheritance model.12 BrS can result from the presence of several variants that confer susceptibility to the phenotype in a given person. At present, genetic analysis in BrS has little to contribute to diagnosis, prognosis and therapeutic management, in contrast to long QT syndrome type 3.12 It does not yet appear to play an important role in risk stratification. As a result, further large studies are required to clarify the exact role of novel genetic variants in BrS pathogenicity for potential therapeutic strategies.

Diagnostic Criteria Many patients with type 1 ECG pattern are asymptomatic. Therefore, the 2015 European Society of Cardiology (ESC) guidelines proposed a new diagnosis for BrS.13 This is essentially based on the typical ECG pattern, either spontaneous or after sodium-channel blocker, showing in at least one right precordial lead (V1 and V2) positioned in the second, third or fourth intercostal space, without requiring any evidence of malignant arrhythmia.

Ajmaline

After RF

Duration MAP

Baseline

Activation MAP

ECG findings predictive of SCN5A mutations include longer and progressive conduction delays (PQ, QRS and HV intervals). The degree of ST elevation and the occurrence of arrhythmias do not differ between subjects with and without an SCN5A mutation.12 Therefore, the presence or absence of an SCN5A mutation does not have any effect on the incidence of sudden cardiac death in BrS. It should be emphasised that BrS is not the only condition attributed to SCN5A mutations. It is well-known that long QT syndrome type 3, progressive cardiac conduction disease (Lenegre’s disease), idiopathic VF, sick sinus syndrome, dilated cardiomyopathy and familial AF are all linked to SCN5A mutations and overlapping syndromes have been reported.12

Figure 2: 3D Potential Duration Mapping, Activation Mapping and Voltage Mapping in Brugada Syndrome with Concealed ECG Pattern

Voltage MAP

found to be associated with BrS, the majority located in SCN5A, but the causal role of these mutations in BrS is not always clear. Even within families, the observed phenotypes carrying the same SCN5A variant are highly diverse. Environmental and epigenetic alterations also determine variable disease severity. However, the high number of variants may be an overestimate, according to recent guidelines from the American College of Medical Genetics.12

The potential duration map shows after ajmaline an abnormal area with prolonged fragmented epicardial potentials normalised after ablation (post-RF). Voltage and activation mapping are basically normal and similar before and after ablation.

• late potentials detected by signal-averaged ECG; • QRS widening; and • fragmented QRS. AF occurs in about 10–20% of BrS patients and is associated with increased risk of syncope and sudden cardiac death. Sick sinus syndrome, neurally mediated syncope and atrial standstill have also been described. Conduction delays in the RVOT have also been reported.

Misdiagnosis of Brugada Syndrome This definition was challenged in an expert consensus conference report endorsed by the Heart Rhythm Society, European Heart Rhythm Association, Asia Pacific Heart Rhythm Society and the Latin American Society of Cardiac Pacing and Electrophysiology.4 The task force was concerned that the ESC definition could result in over-diagnosis of BrS, particularly in patients who only display type 1 ECG after a drug challenge. Data suggest this latter group is at very low risk and that the presumed false-positive rate of pharmacological challenge is not trivial.14 ECG should thus be routinely performed when a diagnosis of BrS is suspected but is uncertain on a standard ECG, and in screening family members of BrS patients (Figure 1). Typical ECG changes of BrS can also be brought on following a meal and on standing. Rarely, ST changes of BrS may be detected in inferior or lateral leads.

Other ECG Findings in Brugada Syndrome In BrS, the PR interval may be increased (≥200 ms), particularly for genetic variants affecting the sodium-channel SCN5A, which frequently reflect the presence of an increased HV interval. Also described are: • P wave abnormalities (prolonged or biphasic P waves);

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Diagnosis of BrS requires exclusion of other causes of ST-segment elevation (Brugada phenocopies). It is well-known that spurious BrS type ECG changes can be observed following cardioversion, can last for a few hours and may lead to an incorrect diagnosis of BrS. Misdiagnosis of BrS can occur with: • • • • • • • • • • •

ECG changes of early repolarisation; athlete’s heart; right bundle branch block; acute pericarditis; MI; Prinzmetal angina; arrhythmogenic right ventricular cardiomyopathy (ARVC); myocarditis; Duchenne muscular dystrophy; electrolyte disturbances; and hypothermia.

As in all cases of Brugada phenocopies, a sodium-channel blocking agent will be usually negative.

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Clinical Arrhythmias Figure 3: Sustained Polymorphic Ventricular Tachycardia Degenerating to VF Induced with Ajmaline and Triple Extrastimulation in a Patient with Brugada Syndrome and No Inducible Ventricular Arrhythmia at Baseline I II III aVR aVL aVF V1 II ICS V2 II ICS V3 III ICS V4 III ICS V5 III ICS V6 IV ICS RVd VT/VF inducibility after ajmaline was associated with the appearance of a type 1 BrS-ECG pattern and a concomitant substrate increase from 3.4 cm2 at baseline to 7.2 cm2 after ajmaline infusion. The duration of prolonged fragmented potentials also increased from 145–226 ms.

Risk Stratification Asymptomatic people are the majority (about 63%) of newly diagnosed Brugada patients. Although the reported annual rate of asymptomatic BrS events has decreased over time, this is not negligible (0.5%–1.2% annual incidence), leading to a malignant arrhythmic events rate of 12% at 10-year follow-up in a population with a mean age of 40 years.4,5 Unfortunately, for most patients the first symptom is cardiac arrest or sudden cardiac death. Therefore, risk stratification of asymptomatic patients is of utmost importance. Identification and management of asymptomatic subjects at high risk of sudden death represent the major challenges in BrS.4,5,13–15 In cardiac arrest or patients with presumed arrhythmic syncope, these strategies are of little use, since these people are already recognised to be at high risk. Syncope in combination with a spontaneous type 1 ECG pattern is a universally accepted risk factor because up to 62% of symptomatic BrS patients will experience a new event 48–84 months after diagnosis, leading to sudden death. However, there are no clear-cut recommendations for the asymptomatic group. The recent guidelines neither encourage nor discourage electrophysiological study and VT/VF inducibility patterns for BrS stratification in patients with BrS.13 These recommendations are also supported by several large prospective registries and by a recent pooled individual patient data analysis including eight prospective studies.15 Several non-invasive risk stratification markers have been proposed, including signal-averaged ECGs, but the results derive from small observational studies and require validation in larger series.16

Management of Brugada Syndrome Management of patients with BrS continues to be challenging. There are limited therapeutic options, essentially ICD implantation and quinidine.13 An ICD is always indicated in symptomatic BrS, i.e. resuscitated cardiac arrest and/or non-vagal syncope, or nocturnal agonal respiration. An electrophysiological study may be performed in asymptomatic

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patients with spontaneous type 1 ECG to assess the need for an ICD.13–15 Although effective for preventing sudden cardiac death, ICD also carries a relevant risk of complications over the patient’s lifetime, particularly if the patient is younger at the time of device implantation.17 Beyond a high prevalence of inappropriate shocks, ICD implantation at a young age also exposes patients to recurrent risks of infection, secondary to device changes and lead complications, frequently requiring subsequent extraction procedures that carry a risk of death.17 ESC guidelines strongly recommend that all BrS patients should be educated about modulating or precipitating factors and taught to avoid these.13 Quinidine has a high rate of effectiveness in the electrophysiology laboratory and has been used to suppress VF in several clinical scenarios, including arrhythmic storms or multiple ICD shocks, or as an alternative to an ICD in children. Unfortunately, the use of quinidine is limited by its unavailability in many parts of the world and its relatively high incidence of side-effects.

Treatment of Arrhythmic Storms Isoprenaline infusion is effective in acute situations and quinidine is the only effective drug in long-term treatment. Cilostazol has also been shown to be effective and is recommended for long-term treatment.2

Epicardial Ablation in Brugada Syndrome: Moving from Promise to Reality Since its introduction in 1992, assessment of BrS has focused on parameters based on the ECG, 24-hour Holter recording, and/ or electrophysiological testing. However, in the last 30 years, the spectacular success of RF ablation in eliminating all supraventricular arrhythmias led electrophysiologists to search for arrhythmic substrate sites as a target for catheter ablation in patients with BrS and VF because antiarrhythmic drugs have been ineffective in preventing recurrent VF episodes. The recent discovery using 3D electroanatomical mapping of a well-defined potentially reversible arrhythmic substrate in patients with BrS is one of the new key research areas of the 21st century that will allow moving from promise to reality in the management and care of BrS.18–24

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Diagnosis and Management of Brugada Syndrome Figure 4: Sustained VF Induced with Double Extrastimulation After Ajmaline Infusion in a Brugada Syndrome Patient with a Baseline Spontaneous Normal ECG I II III aVR aVL aVF V1 II ICS V2 II ICS V3 III ICS V4 III ICS V5 IV ICS V6 IV ICS RVd The patient had a substrate size of 8.9 cm2 at baseline. After ajmaline, the substrate area increased to 14.8 cm2 and the duration of fragmented potentials increased from 180 ms to 259 ms.

Figure 5: Sustained Polymorphic Ventricular Tachycardia Degenerating to VF After Ajmaline Using Single Extrastimulation in a Patient with Brugada Syndrome

I II III aVR aVL aVF V1 II ICS V2 II ICS V3 III ICS V4 III ICS V5 IV ICS V6 IV ICS RVd The drug induced a type 1 ECG pattern and an impressive substrate increase from 9.8 cm2 at baseline to 19.4 cm2. The duration of abnormal fragmented potentials significantly increased after ajmaline from 132–291 ms.

Initial observations by Nademanee et al. in BrS patients with frequent electrical storms proved epicardial ablation to be effective in controlling ventricular arrhythmias during follow-up in eight of the nine patients.18 Subsequently, our group used 3D potential duration mapping by the CARTO system (Biosense Webster) to demonstrate for the first time that in BrS ajmaline was able to reveal highly variable arrhythmogenic substrates, characterised by abnormally prolonged and fragmented epicardial potentials (Figure 2). The substrate size ranged from a small area corresponding to the superior part of RVOT towards an extensive area from the medial to inferior aspect of the anterior RV free-wall without involving other regions of the RV or LV.19–21 Additionally, such abnormal electrograms were only recorded when coved-type ST-segment elevation was present, either spontaneously or after ajmaline provocation. These findings are clinically relevant and suggest that sodium-channel blockade, i.e. ajmaline and flecainide, or warm water instillation into the pericardium can unmask abnormal areas further and increase the size of the VF substrates to be targeted,

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thus leading to a more successful epicardial ablation that eliminates the Brugada pattern.19–22 Interestingly, many patients with concealed ECG pattern became inducible only after there was a consistent ajmaline-induced increase of the substrate size.21 Re-induction of coved-type ECG pattern by ajmaline after ablation was commonly caused by residual abnormal electrograms in the corresponding epicardial RVOT area.21 By contrast, disappearance of coved-type ECG pattern was due to elimination of the remaining epicardial substrate by catheter ablation.21 The presence of such abnormal potentials can be commonly transient and is correlated with ST-segment elevation and VT/VF inducibility.21 We also demonstrated that, independently from clinical presentation, inducibility by a single or double extrastimuli reflected larger substrates than inducibility by three extrastimuli (Figures 3–5). These original observations support the concept that BrS is a complex disease characterised by large but potentially reversible abnormal substrates representing the primary mechanism of malignant VT/VF. Unlike traditional stable substrates, which are characterised by scar or

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Clinical Arrhythmias fibrosis as in post-ischemic VT, the impressive variation in size and shape of the BrS substrate, as exposed by ajmaline, clearly suggests that a component is functional rather than a fixed structural replacement with fibrosis. We cannot exclude the fact that in the natural history of BrS over-exposure to specific triggers can facilitate substrate progression from functional to structural changes, as observed in patients with frequent electrical storms.23 Therefore, in BrS, epicardial ablation of all abnormal potentials areas should be guided by repeated infusion of ajmaline to unmask the entire substrate size in order to eliminate multiple re-entrant circuits leading to rapid unstable ventricular arrhythmias and VF. It is conceivable that a substrate-based, interventional approach can pave the way to a cure for BrS, potentially removing the need for ICD implantation or chronic quinidine therapy, as suggested by the preliminary results over short-term follow-up reports of >300 patients worldwide.25 However, epicardial ablation may be associated with potential risks and complications due to epicardial access and RF applications. Therefore, this procedure should be performed in highly experienced centres and ajmaline administration should

rugada P, Brugada J. Right bundle branch block, persistent B ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome. A multicenter report. J Am Coll Cardiol 1992;20:1391–6. https://doi. org/10.1016/0735-1097(92)90253-J; PMID: 1309182. Nademanee K, Veerakul G, Nimmannit S, et al. Arrhythmogenic marker for the sudden unexplained death syndrome in Thai men. Circulation 1997;96:2595–600. https://doi.org/10.1161/01.CIR.96.8.2595; PMID: 9355899. Chen Q, Kirsch GE, Zhang D, et al. Genetic basis and molecular mechanism for idiopathic ventricular fibrillation. Nature 1998;392:293–6. https://doi.org/10.1038/32675; PMID: 9521325. Antzelevitch C, Yan GX, Ackerman MJ, et al. J-Wave syndromes expert consensus conference report: Emerging concepts and gaps in knowledge. Heart Rhythm 2016; 13:e295–324. https://doi.org/10.1016/j.hrthm.2016.05.024; PMID: 27423412. Brugada J, Campuzano O, Arbelo E, et al. Present status of Brugada syndrome: JACC state-of-the-art review. J Am Coll Cardiol 2018;72:1046–59. https://doi.org/10.1016/j. jacc.2018.06.037; PMID: 30139433. Casado-Arroyo R, Berne P, Rao, JY, et al. Long-term trends in newly diagnosed Brugada syndrome. J Am Coll Cardiol 2016;68:614–23. https://doi.org/10.1016/j.jacc.2016.05.073; PMID: 27491905. Bayes de Luna A, Brugada J, Baranchuk A, et al. Current electrocardiographic criteria for diagnosis of Brugada pattern: a consensus report. J Electrocardiol 2012;45:433–42. https://doi. org/10.1016/j.jelectrocard.2012.06.004; PMID: 22920782. Chevallier S, Forclaz A, Tenkorang J, et al. New electrocardiographic criteria for discriminating between Brugada types 2 and 3 patterns and incomplete right bundle branch block. J Am Coll Cardiol 2011;58:2290–8. https://doi. org/10.1016/j.jacc.2011.08.039; PMID: 22093505. Richter S, Sarkozy A, Veltmann C, et al. Variability of the diagnostic ECG pattern in an ICD patient population with Brugada syndrome. J Cardiovasc Electrophysiol 2009;20:69–75. https://doi.

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be performed after patients are counselled appropriately for the potential arrhythmogenic implications of drug administration.

Clinical Perspective • The discovery of a dynamic frequently hidden arrhythmic substrate in Brugada syndrome (BrS) has provided new insights into pathophysiology and management of patients with BrS. • Ajmaline can prolong the duration and fragmentation of abnormal epicardial electrograms and reveal an arrhythmic substrate extending beyond the right ventricular outflow tract (RVOT). • Re-induction of coved-type ECG by ajmaline after epicardial ablation is caused by residual abnormal electrograms in the corresponding epicardial RVOT region, while disappearance of coved-type ECG is due to elimination of the remaining epicardial substrate. • These findings are clinically relevant suggesting that epicardial ablation, as guided by ajmaline infusion, may be considered as a new effective therapeutic option in BrS.

org/10.1111/j.1540-8167.2008.01282.x; PMID: 18775043. 10. H asdemir H, Alper AT, Güvenç TS, et al. Coexistent Brugada syndrome and Wolff-Parkinson-White syndrome: what is the first clinical presentation? Pacing Clin Electrophysiol 2011;34: 760–3. https://doi.org/10.1111/j.1540-8159.2010.02997.x; PMID: 21208236. 11. Poli S, Toniolo M, Maiani M, et al. Management of untreatable ventricular arrhythmias during pharmacological challenges with sodium-channel blockers for suspected Brugada syndrome. Europace 2018;20:234–42. https://doi.org/10.1093/ europace/eux092; PMID: 28521022. 12. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17:405–24. https://doi.org/10.1038/ gim.2015.30; PMID: 25741868. 13. Priori SG, Blomström-Lundqvist C, Mazzanti A, et al. 2015 ESC guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC). Eur Heart J 2015;36:2793–867. https://doi.org/10.1093/eurheartj/ehv316; PMID: 26320108. 14. Priori SG, Gasparini M, Napolitano C, et al. Risk stratification in Brugada syndrome: results of the PRELUDE (PRogrammed ELectrical stimUlation preDictive valuE) registry. J Am Coll Cardiol 2012;59:37–45. https://doi.org/10.1016/j.jacc.2011.08.064; PMID: 22192666. 15. Sroubek J, Probst V, Mazzanti A, et al. Programmed ventricular stimulation for risk stratification in the Brugada syndrome: a pooled analysis. Circulation 2016;133:622–30. https://doi. org/10.1161/CIRCULATIONAHA.115.017885; PMID: 26797467. 16. Haung Z, Patel C, Li W, et al. Role of signal-averaged electrocardiograms in arrhythmic risk stratification of patients with Brugada syndrome: a prospective study. Heart Rhythm 2009;6:1156–62. https://doi.org/10.1016/j.hrthm.2009.05.007;

PMID: 19632627. 17. H ernandez-Ojeda J, Arbelo E, Borras R, et al. Patients with Brugada syndrome and implanted cardioverter-defibrillators. long-term follow-up. J Am Coll Cardiol 2017;70:1991–2002. https://doi.org/10.1016/j.jacc.2017.08.029; PMID: 29025556. 18. 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– 79. https://doi.org/10.1161/CIRCULATIONAHA.110.972612; PMID: 21403098. 19. Brugada J, Pappone C, Berruezo A, et al. Brugada syndrome phenotype elimination by epicardial substrate ablation. Circ Arrhythm Electrophysiol 2015;8:1373–81. https://doi.org/10.1161/ CIRCEP.115.003220; PMID: 26291334. 20. Pappone C, Brugada J, Vicedomini G, et al. Electrical substrate elimination in 135 consecutive patients with Brugada syndrome. Circ Arrhythm Electrophysiol 2017;10:e005053. https://doi.org/10.1161/CIRCEP.117.005053; PMID: 28500178. 21. Pappone C, Ciconte G, Manguso F, et al. Assessing the malignant ventricular arrhythmic substrate in patients with Brugada syndrome. J Am Coll Cardiol 2018;71:1631–46. https://doi.org/10.1016/j.jacc.2018.02.022; PMID: 29650119. 22. Nademanee K, Haissaguerre M. Endocardial ablation approach for Brugada syndrome. An important first step or a quixotic quest. Circ Arrhythm Electrophysiol 2018;11:e006675. https://doi.org/10.1161/CIRCEP. 118.006675; PMID: 30354324. 23. Nademanee K, Raju H, de Noronha SV, et al. Fibrosis, connexin-43, and conduction abnormalities in the Brugada syndrome. J Am Coll Cardiol 2015;66:1976–86. https://doi. org/10.1016/j.jacc.2015.08.862; PMID: 26516000. 24. Nademanee K, Hocini M, Haïssaguerre M. Epicardial substrate ablation for Brugada syndrome. Heart Rhythm 2017;14:457–61. https://doi.org/10.1016/j.hrthm.2016.12.001; PMID: 27979714. 25. Fernandes GC, Fernandes A, Cardoso R, et al. Ablation strategies for the management of symptomatic Brugada syndrome: a systematic review. Heart Rhythm 2018;15:1140–7. https://doi.org/10.1016/j.hrthm.2018.03.019; PMID: 29572085.

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Clinical Arrhythmias

Brugada Syndrome: Progress in Genetics, Risk Stratification and Management Jorge Romero, 1 Dan L Li, 1,2 Ricardo Avendano, 1,3 Juan Carlos Diaz, 1 Roderick Tung 4 and Luigi Di Biase 1 1. Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, US; 2. Cardiovascular Division, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, US; 3. Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, US; 4. University of Chicago, School of Medicine, Chicago, IL, US

Abstract Brugada syndrome (BrS) is one of the most common causes of sudden cardiac death in normal structural heart individuals. First characterised in 1992, the global prevalence of BrS is unclear, with estimates placing it at around 0.05% and presenting most frequently in southeast Asian countries. This review aims to summarise the development in the understanding of BrS and, importantly, progress in its management, underpinned by knowledge regarding its genetics and molecular mechanisms. It also provides update on risk stratification and promising new therapies for BrS, including epicardial ablation. Future studies are required to increase understanding of the pathogenesis of this disease and to guide clinical practice.

Keywords Brugada syndrome, epicardial ablation, genetic testing, radiofrequency ablation, risk stratification Disclosure: The authors have no conflicts of interest to declare. Received: 14 November 2018 Accepted: 31 January 2019 Citation: Arrhythmia & Electrophysiology Review 2019;8(1):19–27. DOI: https://doi.org/10.15420/aer.2018.66.2 Correspondence: Luigi Di Biase, Department of Medicine (Cardiology), Montefiore-Einstein Center for Heart and Vascular Care, 111 East 210th Street, Bronx, NY 10467, US. E: ldibiase@montefiore.org Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Brugada syndrome (BrS), one of the most common causes of sudden cardiac death (SCD) in normal structural heart individuals, is a young entity in modern medicine. BrS was first characterised in 1992 by Brugada et al. as a distinct syndrome with “right bundle branch block, persistent ST elevation in precordial leads V1 to V2–3 and sudden cardiac death”.1 The true prevalence of BrS is not clearly known, with an estimation of 0.05%.2 The prevalence is lower in the Americas and Europe, and higher in Asia, particularly in southeast Asian countries such as Thailand and the Philippines.3

of BrS. Since the landmark discovery of SCN5A as the first gene linked to the aetiology of BrS, a wealth of knowledge has accumulated in various disciplines including genetics, pathophysiology, clinical manifestations, diagnosis and management, in particular epicardial catheter ablation.5 The complexity of this disease has also been increasingly recognised, with controversies and uncertainties awaiting future studies.

It is hypothesised that BrS accounts for 4–12% of all cases of SCD and 20% of SCD in individuals without structural heart disease.3 The numbers might be underestimated, as suggested by the largest prospective study to date on familial evaluation of sudden arrhythmic death syndrome (SADS).4 With routine application of ajmaline provocation testing and the inclusion of high right precordial leads (RPLs), BrS was shown to be the most prevalent diagnosis (n=85, 28% of families) among inherited cardiac diseases identified in SADS families (n=128, 42% of families).4 The use of high RPLs showed a 16% incremental diagnostic yield of ajmaline testing by diagnosing BrS in an additional 49 families. This study highlights the important role of routine ajmaline testing with high RPLs in improving the yield of diagnostic tests of BrS in SADS families.

Progress in Genetic Studies The first major susceptibility gene reported for BrS is SCN5A.5 Until 2010, almost 300 variations of this gene had been shown to be associated with BrS.6 Despite its role as the major susceptibility gene, SCN5A mutations only account for 11–28% of BrS proband genotypes.6 Other rare gene variations have been reported to be involved in BrS; however, the yield of testing for rare gene variants other than SCN5A has been extremely low.7 Furthermore, differentiation of rare pathogenic variants from rare yet benign variants has been challenging in rare diseases such as BrS. Large-population exome sequencing and in silico tools are likely to be of use in identifying the causative gene variations, although the presence of variants in the general population does not necessarily exclude the pathogenic possibility.8

The escalating number of publications on this subject in the past 26 years clearly underlines the progress in our understanding and management

In 2013, SCN10A was identified by a genome-wide association study as one of the genetic variants that could modulate the susceptibility

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This article provides an update on recent progress in the study of BrS over the past decade.

Access at: www.AERjournal.com

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Clinical Arrhythmias Figure 1A: Genome-wide Association Study Identified Two Susceptibility Loci for Brugada Syndrome

polymorphisms on BrS.9 Not only were three common genetic variants (SCN5A, SCN10A and HEY2) identified from the study as modulators for BrS susceptibility, but the risk of BrS also progressively increased in association with the escalating total number of alleles at the three associated loci.9

−log10 (p-value)

Models for Pathophysiology

16 12 8 4 0

17 19 21 X 18 20 22

Chromosome Plotted SNPs 24 r

100

0.8 0.6 80 0.4 0.2

20 16 15 12 10

60 40

8 5

EXOG SCN5A SCN10A 0 1 3 2 38.6 38.7 38.8

rs9388451

0.8 0.6 0.4 0.2

8 6

100 80 60

20 0

Recombination rate (cMMb)

20 25 −log1010(p-value) (p-value) −log

Plotted SNPs rs10428132

−log10 (p-value)

HY2 NCOA7 HINT3 TRMT11

SCN11A

5 7 9 11 13 15 17 19 21 X 4 38.9 6 8 10 12126.014 16 18 20 22 39.0 125.8 126.2 126.4 Chromosome Position on chromosome 6 (Mb) Position on chromosome 3 (Mb)

Plotted SNPs

0 EXOG SCN5A

SCN10A

−log10 (p-value)

−log10 (p-value) 2

Recombination rate (cMMb)

A study identified two susceptibility loci for Brugada syndrome. B genome-wide association 10 rs10428132 100 rs9388451 r r 100 Top: between two single-nucleotide 25Manhattan plot showing strong associations 0.8 0.8 0.6 0.6 80 8 80 polymorphisms (SNPs) and Brugada syndrome. Bottom: Association plots for 3q22 and 6q22, 0.4 0.4 20 0.2 respectively. SNPs are plotted with the0.2 chromosomal locations (x axis) and the associated 60 60 6 15 p-values (y-axis). SNPs are coloured according to their degrees of linkage disequilibrium 40 4 (r );10 the leading variants were marked as purple diamonds. The tall spikes represent the 40 recombination rate (right y axis) in the region of the chromosome. Source: Bezzina et al.20 20 2 5 2013.9 Reproduced with permission from Springer Nature. HY2 NCOA7 HINT3 TRMT11

SCN11A

38.9 39.0Components 125.8 126.0 126.4 Figure38.61B:38.7 The 38.8 Structural of the 126.2 Connexome Position on chromosome 3 (Mb)

BDesmosome

Position on chromosome 6 (Mb)

Gap junction

Nav1.5

Fascia adherence junction

Desmosome

Gap junction

Nav1.5

Fascia adherence junction The structural components of the connexome. The four structures – adherence junctions, desmosomes, gap junctions and voltage-gated sodium channels – at the intercalated disc might act as a single structural and functional entity, the connexome, reflecting the close interdependence and tight associations between these structures. Source: Moncayo-Arlandi and Brugada, 2017.22 Reproduced with permission from Springer Nature.

of BrS (Figure 1A).9 Subsequently, Hu et al. studied 150 unrelated BrS patients and used direct gene sequencing to identify 17 SCN10A mutations in 25 of these patients (16.7%). The identification of SCN10A as a susceptibility gene in this study improved the yield of genotype testing from <35% to >50% of BrS probands.10 However, the monogenic causative role of SCN10A in BrS was questioned by other groups.11,12 BrS was previously considered a rare disease of single-gene Mendelian inheritance until a genome-wide association study in 2013 demonstrated the strong effect of common genetic variations and

AER_Romero_FINAL.indd 20

There are three major mechanistic models explaining the electric abnormality in BrS, namely the repolarisation, depolarisation and neural crest models.13–15 Despite their differences, all three models agree that the major region of pathology is the right ventricular outflow tract (RVOT).13–15 Commonly considered as a channelopathy, evidence has revealed structural derangement of the right ventricle in BrS. Using cardiac MRI, BrS patients were found to have right ventricular (RV) motion abnormalities with mildly reduced systolic function and mildly increased RV end systolic volume, compared with normal individuals.16,17 Although late gadolinium enhancement was not detected in cardiac MRI, histological evidence of substantial fibrosis in the RVOT epicardium, corresponding to a low expression of Cx43, was found in the hearts (from autopsy or explanted hearts) of BrS individuals.18 Epicardial and interstitial fibrosis was identified in the slow-conducting RVOT region,18 the ablation of which abolished the BrS ECG pattern.19 A recent study has further shown that RVOT electroanatomical alterations (a low-voltage area) correlate with myocardial inflammation and arrhythmia vulnerability, supporting the hypothesis that BrS is a combination of electrical and structural disease.20 Furthermore, a phenotypic overlap between arrhythmogenic right ventricular cardiomyopathy and BrS has been reported in the literature. RV changes consistent with arrhythmogenic right ventricular cardiomyopathy were observed in patients with clinically diagnosed BrS.21 The concept of the connexome connects the two diseases.22 The connexome is comprised of structures including desmosomes, fascia adherence junctions, gap junctions and voltage-gated sodium channels at the cardiomyocyte intercalated disc (Figure 1B).22 Accumulating evidence has shown that these structures are closely interconnected and interdependent for anchorage and stabilisation. For instance, a mutation in PKP2 – the most important gene responsible for arrhythmogenic right ventricular cardiomyopathy – directly leads to a reduction in Nav1.5 trafficking and activity;23 Cx43 is required for Nav1.5 stability in the intercalated disk membrane.24 Therefore, sodium channel activity could be affected by the disruption of any connexome components.22

Update on Clinical Diagnosis A recent change in the BrS phenotype at presentation compared with earlier years (prior to 2003) has been noted.25 There is a decreased number of patients presenting with aborted SCD, spontaneous type 1 ECG pattern and arrhythmia inducibility during electrophysiology study (EPS), whereas the prevalence of syncope remains stable.25 This shift to a milder clinical profile is likely owing to better identification and thus improved diagnosis of BrS. The diagnostic criteria have been updated in the 2013 consensus statement by the Heart Rhythm Society (HRS), the European Heart Rhythm Association (EHRA) and the Asia Pacific Heart Rhythm Society (APHRS).26 Contrary to the prior 2005 HRS/EHRA criteria, the 2013 HRS/ EHRA/APHRS consensus statement has listed several differences.

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Brugada Syndrome Firstly, the ECG pattern criteria for diagnosing BrS are different. The 2005 criteria required ST elevation in ≥2 RPLs (V1–V3) in a standard position (the 4th intercostal space) for the diagnosis of type 1 BrS.2 In the 2013 consensus statement, a type 1 Brugada ECG pattern in ≥1 RPL (V1–V2), whether in a standard or a higher position (the second and third intercostal space),26 was promoted, which increases the sensitivity of diagnosis. Secondly, the 2005 criteria required at least one of the clinical presentations (documented ventricular tachycardia [VT] or VF, syncope, nocturnal agonal respiration family history of SCD or type 1 ECG, or ventricular arrhythmia inducibility in EPS) for diagnosis.2 However, clinical presentations are no longer essential for diagnosis in the new consensus statement.26 BrS could be definitively diagnosed based on ECG pattern and after the exclusion of other differential diagnoses (e.g. atypical right bundle branch block, early repolarisation, MI, arrhythmogenic right ventricular cardiomyopathy).26 Thirdly, the 2013 consensus statement has weakened the importance of differentiating between spontaneous type 2 and type 3 BrS ECG patterns, and highlights the importance of the type 1 ECG pattern, whether it is spontaneous or drug induced.26 The 2013 consensus statement recommendation for diagnosing BrS was subsequently adopted by the 2015 European Society of Cardiology guidelines for managing ventricular arrhythmias and preventing SCD.27

Advances in Management Risk Stratification for ICD Symptoms (including syncope and aborted SCD) and a spontaneous type 1 BrS ECG pattern are known to carry a significantly higher risk of ventricular arrhythmia and SCD in BrS patients.28–30 Aside from a spontaneous type 1 ECG pattern, other ECG features such as QRS fractionation (HR 4.94), a wide S-wave in lead I (HR 39.1) and inferolateral early repolarisation (HR 4.87) have also been shown to portend a high risk of future ventricular arrhythmia in BrS patients (Figure 2).30–33 To date, ICD placement is the most accepted therapy for preventing SCD in high-risk BrS patients. On the other hand, long-term complications of ICD, including inappropriate shocks, infection, injury and device malfunction, can significantly increase patient health burden and decrease quality of life.34 Current guidelines recommend ICD placement in individuals with aborted SCD (class Ia), syncope (judged likely to be secondary to ventricular arrhythmia) and a spontaneous type 1 ECG pattern (class IIa), and ventricular arrhythmia inducibility during programmed stimulation study (class IIb).26 The role of EPS in the risk stratification of BrS patients has been debated for years, yet it still remains controversial owing to inconsistent results among different studies29,30,35–38 and meta-analyses.39,40 The reason for different observations in various studies is likely multifactorial, including patient populations (e.g. the percentage of patients with symptoms at presentation, spontaneous versus drug-induced type 1 ECG pattern), different protocols for programmed stimulations (e.g. stimulation sites and numbers of extrastimuli) in different centres, as well as follow-up durations (Table 1). Sroubek et al. performed a pooled analysis using individual-level data from eight studies (1,312 BrS patients) and found that arrhythmia inducibility was associated with an increased risk of cardiac events (HR 2.66, multivariate analysis).36 Notably, although several early studies applied two stimulation sites (RV apex and RVOT), a less aggressive strategy involving only RV apex is currently recommended to increase the specificity of the test.41

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Figure 2: ECG Features that Predict a Higher Risk of Cardiac Events A

hV1

hV2

III

aVR

aVL

ECG of BrS patients without a significant S-wave in lead I aVF

aVF hV3 hV4

aVR

aVL

hV5

aVF

hV6

hV1

hV2

B ECG of BrS patients with a significant S-wave in lead I I

A: QRS fragmentation is associated with a higher risk of arrhythmia. Arrowheads point to the fragmentation of QRS in inferior leads, V1 and high V1–2 leads. B: A wide S-wave in lead I is associated with a higher risk of arrhythmia. A wide S-wave in lead I in five Brugada syndrome patients are shown in contrast to four Brugada syndrome patients without significant S in lead I. C: An inferolateral early repolarisation pattern is associated with a higher risk of arrhythmia. Arrows point to J-point elevations. Source: Morita et al. 2017, Calò et al. 2016 and Georgopoulos et al. 2018.31–33 Reproduced with permission from Wolters Kluwer Health, Elsevier and Oxford University Press.

Furthermore, the study by Sroubek et al. showed that up to two extrastimuli was associated with increased risk of future arrhythmic events, while up to three extrastimuli reduced the test’s specificity.36 With a milder current clinical profile of BrS patients compared with earlier years, ventricular arrhythmia inducibility during EPS might lose its predicting power owing to significantly lower pre-test probability and the need for a longer follow-up duration.25 On the other hand, a negative EPS study does not eliminate the future risk of ventricular arrhythmia,except potentially in asymptomatic patients with druginduced type 1 ECG.35,36 A recent study from the Survey on Arrhythmic Events in Brugada Syndrome (SABRUS) – a multicentre international survey that included BrS patients with arrhythmia events – showed that among the BrS patients who exhibited arrhythmic events after prophylactic ICD, 25% did not meet the criteria for class II indications at the time of ICD implantation.42 This group either had negative EPS, or EPS was not performed. These findings argue for a better stratification strategy among BrS patients in the future. A multiparametric approach has been attempted aiming at better risk stratification.43–45 An escalating accumulation of multiple high-risk factors (e.g. family history of sudden death, positive EPS, syncope and type 1 ECG pattern) predicts a progressively increased risk of future SCD or ventricular arrhythmic events.43,44 A score model recently proposed by Sieira et al. reported a high predictive performance of 0.82; however, further validation is required.45 This model includes spontaneous type 1 ECG, early family history of SCD, EPS inducibility, syncope, sinus node dysfunction and SCD, and gives a higher score for symptoms and EPS inducibility (Figure 3).

Medications Quinidine – a class I anti-arrhythmic medication and an Ito current inhibitor – is an established medication used to prevent and terminate ventricular arrhythmia, electrical storm and frequent electric ICD shocks in BrS patients.46,47 Anguera et al. conducted a multicentre study in Spain and found that 29 of 820 BrS patients (3.5%) with ICD were treated with quinidine for electrical storm or frequent ICD shocks.47

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Clinical Arrhythmias Table 1: Electrophysiology Studies in Predicting Cardiac Events Study

EPS (n)

Spontaneous Symptom (+) EPS (+)

EPS Protocol

Type 1 ECG

Follow-up Event No. (%) HR (Months)

Takagi et al. 200738

146 (188 total) 143/188 (76%)

83/188 (57%)

114/188 (78%) 2 sites, 3 extrastimuli

PRELUDE Registry

308

171 (56%)

65 (21%)

126 (41%)

2 sites, 2 cycle lengths, 34.0 3 extrastimuli (median)

14 (4.5%)

n.s.

FINGER Brugada Syndrome Registry37

638

297 (47%)

233 (36%)

262 (41%)

2 sites, 2 cycle lengths, 31.9 3 extrastimuli (median)

23 (3.6%)

n.s.

Sierra et al. 201529

403

101 (25%)

121 (33%)

71 (18%)

1 site, 3 cycle lengths, 3 extrastimuli

57.3 (median)

25 (6.2%)

8.3

Sierra et al. 201735

215

0 (0%)

17 (8%)

1 site, 3 cycle lengths, 3 extrastimuli

52.8 (median)

5 (2.3%)

3.5

Sroubek et al. 201636,*

1312

696 (47%)

429 (33%)

253 (19%) 1–2 sites, 2–3 cycle 38.3 ≤2 extrastimuli lengths, 1–3 extrastimuli (median)

65 (5.0%)

3.3 (≤2 extrastimuli)

37.0 (mean) 13/166 (7.8%)

n.s.

*Sroubek et al. is a pooled analysis of eight studies including data from PRELUDE and FINGER registries. EPS = electrophysiology study.

Figure 3: A Risk Score Model for Predicting Future Arrhythmia Events, Including Sudden Cardiac Death and ICD Shocks, in Brugada Syndrome A

B Points

Spontaneous type 1 1 Early familial SCD 1 Inducible EPS

Syncope

SND

SCD

Survival time probability

Risk factor

1.0

0.8

0.6

Patients at risk

>5 points

0.4

0.2

0.0 .0 0 points 1 point 2 points 3 points 4 points >5 points

0 points 1 point 2 points 3 points 4 points

191 41 78 26 35 30

2.5 136 30 55 15 27 20

5.0 Time (years) 91 24 25 14 18 16

7.5

10.0

64 17 13 10 13 14

43 11 6 4 12 9

A: Risk factors that are included in the score model with assigned points. SCD refers to presentation as aborted sudden cardiac death. B: Kaplan–Meier curve showing the risk stratification by risk scores. EPS: electrophysiology study; SCD = sudden cardiac death; SND = sinus node dysfunction. Source: Sieira et al. 2017.45 Reproduced with permission from Oxford University Press.

During a follow-up of 60 ± 41 months, 19 patients (66%) remained free of ICD shocks. Quinidine treatment decreased the total shocks from 203 to 41, with the median number of shocks per patient decreased from 6 (interquartile range [IQR] 4–9) to 0 (IQR 0–2.5).40 Others have explored quinidine as a potential therapy for long-term SCD prevention, especially among asymptomatic patients with arrhythmia inducibility.48–50 Belhassen et al. studied 96 BrS patients, in which 66 patients (10 patients with previous aborted SCD, 20 with syncope and 40 asymptomatic) were induced with VF using an aggressive stimulation protocol (two sites and up to three extrastimuli).49 Quinidine was able to prevent VF induction in 52 of the 58 (89.6%) patients tested. During a median follow-up of 113 months, the overall annual arrhythmic events were 1%. However, the caveats of this study included an aggressive stimulation protocol and low long-term medication adherence (60%), due to side-effects.49 Low tolerance and medication adherence caused by the sideeffects of quinidine have been a concern. It has been shown

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that the risk of arrhythmic events in quinidine recipients was associated with medication interruption.40,49 Side-effects are reported to be as high as 36–38% of patients administered a daily dose of quinidine bisulfate (QBS) 1,500 mg or hydroquinidine (HQC) 900 mg.39,49 Medication discontinuation was reported at 14–30% due to medication intolerance.41,49 Diarrhoea is the most common adverse effect (9–18%), and other side-effects include thrombocytopenia (6.6–13.6%), and less commonly allergic reactions (<5%), oesophagitis (<5%), side node dysfunction (<5%) and lupus-like reactions (<5%).39,49 QTc prolongation was often observed (the change by percentage was reported from <10% to 15.8%); however, torsades de pointes was not reported.47–50 A lower dosage (daily HQC dose 600 mg) appears to be better tolerated.50,51 Further lower dosages (QBS or HQC ≤600 mg) have been reported to reduce side-effects while maintaining efficacy;52 however, concerns exist regarding the reduced suppression of VF inducibility and possible compromised anti-arrhythmic effects at doses lower than 600 mg.51 Despite great efficacy in treating BrS, quinidine is currently an endangered species due to the shrinking pharmaceutical market for quinidine in the era of newer anti-arrhythmic medications for common cardiac arrhythmias. AstraZeneca was the main quinidine manufacturer, but stopped production in 2006. According to a survey of physicians in 131 countries, limited access to quinidine was reported in 76% of countries (including Thailand and the Philippines, where BrS has a high prevalence).53 Even in the US, where quinidine is still produced, it is not readily available in many healthcare facilities. The use of isoproterenol infusion is a class IIb recommendation for electrical storm in BrS patients.26 Other oral medications suggested as long-term alternatives to quinidine have been explored. Cilostazol, bepridil and denopamine, alone or combined, have been reported to prevent VF storm in BrS patients in clinical cases after initial stabilisation with isoproterenol. 54–56 Cilostazol, an inhibitor of phosphodiesterase III, increases inward the calcium current and suppresses the Ito current by increasing heart rate. Case reports have demonstrated its efficacy in suppressing recurrent VF and VT.57,58 However, its failure to suppress VF storm in BrS patients has also been reported.59,60 Bepridil is a multichannel blocker that inhibits L- and T-type calcium channels, as well as all potassium channels. Aizawa et al. reported the efficacy of bepridil efficacy in suppressing recurrent VF in five BrS patients (a total of 19 shocks were given

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Brugada Syndrome in a year before bepridil and two shocks while on bepridil).56 The combination of bepridil and cilostazol has been proposed for its possible synthetic effects in VF prevention and the attenuation of cilostazol-induced palpitations.55 This regimen was shown to effectively suppress recurrent VF and ICD shocks in five BrS patients (13 ICD shocks in total in an accumulated period of 55 months before medication, and 0 shocks in an accumulated 272 months while on medication).55 Despite the promising results, the numbers of patients in these studies are low, with relatively short follow-up periods. Direct comparison with quinidine has also not been studied. Future studies are needed to further address these issues.

Figure 4: Epicardial Voltage Map of the Right Ventricle Showing a Low-voltage Zone (<1.5 mV) at Baseline and After Administration of Procainamide and Milrinone A

Baseline

Radiofrequency Ablation Radiofrequency ablation (RFA) has arisen as a promising therapeutic option for BrS in the past decade. Studies have demonstrated that in addition to abnormally low voltage, prolonged duration and fractionated electrograms, histological/molecular changes including inflammation, fibrosis and low expression of Cx43 have also been found at the anterior RVOT epicardium.18–20 These findings have established the foundation of ablating the substrate as a feasible treatment for BrS. The current consensus recommendation considers RFA as a reasonable therapy for BrS patients with arrhythmic storms or repeated appropriate ICD shocks (Class IIb).26 With the progress made in recent years, there is hope that RFA might even offer a ‘cure’ for selected patients.61

Procainamide

Milrinone

EPI RVOT

Baseline

EPI RVOT

Procainamide

RFA Approaches: Endocardial versus Epicardial Despite early attempts for ablation beginning with endocardial approaches (endocardial ablation of arrhythmogenic premature ventricular contraction (PVC) and endocardial mapping with ablation of late-activation zone),62,63 later studies have shown that most of the electrophysiological substrate locates at the RVOT epicardium,19,64–66 and thus epicardial ablation has become a more accepted approach due to its improved efficacy in eliminating arrhythmogenic substrates. A recent meta-analysis including 11 case series and 11 case reports (total number of patients: 233) has provided a systemic overview on the evidence of RFA in BrS.67 A comparison was made between the following ablation strategies: epicardial mapping with substrate ablation (n=180), endocardial-only mapping with ablation (n=17), VF-triggering PVC ablation (n=5) and mixed approaches (n=30). Elimination of type 1 Brugada ECG pattern was achieved in 98.3% of the epicardial approach groups versus 34.8% in the endocardial approach.67 The success rates in preventing VT/VF were 96.7%, 70.6% and 80.0% in epicardial, endocardial and triggering PVC ablation strategies, respectively.67 Since the landmark study in 2011 by Nademanee et al. – the first report of successful epicardial ablation in nine patients with BrS and frequent VF episodes – recent years have seen advances in substrate mapping and ablation, as well as end point tests of successful ablation (Table 2).19

Substrate Mapping and the Use of Sodium Channel Blockers Endocardial and epicardial electroanatomic mapping of RV is widely performed in order to identify the substrate in BrS patients.19,36,64–66,68,69 Notably, in patients undergoing both epicardial and endocardial mapping, no endocardial substrate was identified in 93% of cases.67 Areas with abnormal electrograms (low voltage, fractionation, prolonged duration or late potentials) are marked as substrate for ablation. The definition of abnormal electrograms has been slightly different in various studies: the cutoff of low voltage ranges between

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A: Baseline epicardial unipolar voltage map of a patient with Brugada syndrome. Areas of low voltage can be depicted at the base and lateral wall of the RV. B: Voltage map of the same patient after the administration of procainamide (a sodium channel blocker) produces accentuation of the same area of inflammation. C: Reversal of the same area of inflammation to a low-voltage zone can be appreciated after an infusion of milrinone (a phosphodiesterase inhibitor). D: Baseline epicardial voltage map of the same patient with BrS and surface ECG shows the characteristic type 1 pattern on ECG. E: Administration of procainamide produces late potentials and a more prominent ST segment on surface ECG. EPI RVOT = right ventricular outflow tract epicardium.

1.0 mV and 1.5 mV, fractionation is defined as less than two versus three components, and prolonged duration is defined as >80 ms versus 200 ms (80 ms in most of the studies) (Table 2). Notably, assessment of a low-voltage area could vary depending on tissue contact, pericardial fat and pericardial fluid during flushing.61 Avoiding the sole use of low-voltage criteria is recommended to increase the accuracy of substrate mapping.61 Sodium channel blockers have been used to increase the sensitivity of substrate identification (Figures 4 and 5). In 2015 Brugada et al. reported the successful identification and epicardial ablation of substrate with the additional use of flecainide, which increased the abnormal electrogram area from 17.6 cm2 to 27.3 cm2.66 The increased sensitivity of substrate mapping with a sodium channel blocker was echoed in other ensuing studies.19,64 A report including 135 BrS patients (with spontaneous or induced VT/VF) further demonstrated the efficacy of the epicardial mapping and substrate-based ablation approach in preventing future VT/VF.64 In this study, Pappone et al. showed that the areas of substrate were larger in symptomatic BrS patients, in contrast to asymptomatic patients at diagnosis (4.6 cm2 versus 8.0 cm2 in patients with induced VT/VF versus patients with aborted SCD).64 Ajmaline infusion expanded the substrate area (the median area increased from 4.6 cm2 to 15.7 cm2 in patients with induced VT/VF, and from 8.0 cm2 to 20.0 cm2 in patients with SCD at presentation), corresponding with an increase in type 1 ST elevation on ECG.

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Clinical Arrhythmias Table 2: Clinical Studies on Epicardial Radiofrequency Ablation in Brugada Syndrome Study

Substrate Mapping

Substrate Location

and Identification

and Area

RFA Techniques Immediate Outcome

Follow-up VA (Months) Recurrence

Nademanee et al. 201168

Low voltage: <1 mV Fractionation (≥2 deflections) Prolonged duration (>80 ms) Late potentials (>100 ms)

Anterior RVOT Area N/A

30–50 W T up to 45°C 24.8 min

Negative EPS: 7/9 (78%) 20 ± 6 ECG normalisation: 8/9 (89%)

1/9 (11%)

Zhang et al. 201665

2 patients ± procainamide Low voltage: ≤1 mV Fractionation and prolonged duration (unspecified)

Anterior RVOT Area 16.0 cm2, increased with procainamide

Up to 50 W T up to 45°C

ECG normalisation: 9/11 (82%) 25 ± 11 Negative EPS: 8/9 (89%)

3/11 (27.3%)

Chung et al. 201769

± Warm water instillation Low voltage: <1.5 mV Fractionation >3 deflections Prolonged duration >80 ms Late potentials

RVOT and anterior RV; 10.3 cm2 at baseline and 14.5 cm2 after warm water

20–35W ≥120s each RFA Total 27.5 min

Substrate elimination in 18 ± 9 repeat mapping: 11/11 (100%) ECG normalisation: 5/11 (45%) Negative EPS: 11/11 (100%)

1/11 (9%)

Brugada et al. 201566

± Flecainide (2 mg/kg × 10 min) RVOT, anterior RV; 17.6 cm2 at baseline and 28.5 cm2 Low voltage: <1.5 mV (main) Fractionation: >3 deflections after flecainide Prolonged duration >80 ms Late potentials

40 W limit 45°C 30–60s each RFA Total 23.8 min

Substrate elimination with 5 (3.8–5.3) 0/14 (0%) flecainide in repeat mapping: 14/14 (100%) Negative EPS: 14/14 (100%) ECG normalisation with flecainide: 14/14 (100%)

Nademanee et al. 201719

± Ajmaline (50–80 mg × 5 min) or procainamide (750–1000 mg × 20–30 min) Low voltage: ≤1 mV Fractionation: >2 deflections Prolonged duration >80 ms or late potentials

RVOT, extending to RV body 20–45W (15/28) and inferior wall (7/28) after sodium channel blockers; 10.3 cm2 at baseline and 19.5 cm2 after ajmaline; procainamide increased area to a lesser extent

± Ajmaline (1 mg/kg × 5 min) Low voltage: <1.5 mV Fractionation: >2 deflections Prolonged duration >200 ms (main)

RVOT, extending to RV free wall after ajmaline; 4.6–8.0 cm2 at baseline and 15.7–20 cm2 after ajmaline

Pappone et al. 135 201764

35–45 W; N/A

ECG normalisation at N/A baseline: 28/28 (100%); however, 5/28 (18%) had type 1 ECG pattern after ajmaline and higher lead placement

3/28 (10.7%)

ECG normalisation with 10 (8–12) ajmaline: 135/135 (100%) Elimination of substrate in remapping with ajmaline: 135/135 (100%) Negative EPS: 135/135 (100%)

2/135 (1.5%)

EPS = electrophysiology study; N/A = not applicable; RFA = radiofrequency ablation; RV: right ventricle; RVOT = right ventricular outflow tract; VA = ventricular arrhythmia.

More recently, Pappone et al. demonstrated that after ajmaline administration, patients with no prior arrhythmia inducibility developed inducibility without any significant difference in substrate characteristics.70 Moreover, substrate size was found to be the only predictor of inducibility (OR 4.51, 95% CI [2.51–8.09], p<0.001), with a size of 4 cm2 more commonly observed in patients with inducible arrhythmias (area under the curve 0.98, p<0.001). Substrate ablation was associated with ECG normalisation and not arrhythmia re-inducibility.70 These observed correlations further suggest that improving the sensitivity of substrate identification is the key to improving ablation efficacy. Similar to diagnosing the drug-induced type 1 BrS ECG pattern, the sodium channel blockers ajmaline (1 mg/kg × 5 min), flecainide (2 mg/kg × 10 min) and procainamide (750–1,000 mg for 20–30 min) have been utilised in different studies (Table 2). Procainamide appears to increase the substrate to a lesser extent than ajmaline.19 There is no direct comparison between ajmaline and flecainide. However, in diagnosing the drug-induced type 1 ECG pattern, a higher sensitivity of ajmaline (1 mg/kg × 5 min) over flecainide (2 mg/kg × 5 min) was reported.71

Attenuation of Brugada Syndrome Phenotype by General Anaesthesia An observation of the effect of general anaesthesia on BrS phenotype during RFA in BrS patients was recently reported. 65

AER_Romero_FINAL.indd 24

General anaesthesia was induced by propofol bolus and maintained by sevofluorane. After the induction of anaesthesia, ST elevation (0.32 ± 0.01 mV versus 0.19 ± 0.02 mV, p<0.001) and J-wave amplitude (0.47 ± 0.02 mV versus 0.31 ± 0.03 mV, p<0.001) significantly reduced. The ECG pattern was reversed to a nondiagnostic pattern in 28 out of 36 (77.8%) patients (Figure 6A). However, the arrhythmogenic substrate area during anaesthesia was still significantly enlarged after administration of ajmaline (3.6 ± 0.5 cm 2 versus 20.3 ± 0.8 cm 2). 65 This study has demonstrated a significant clinical implication in assessing the substrate area during RFA under anaesthesia.

Efficacy of the Radiofrequency Ablation Procedure Technical advances in ablating catheters might have improved the efficacy of substrate elimination.19 A contact force of at least 5 g is recommended to effectively ablate lesions with a radiofrequency power of 20–45 W.19 The electrogram voltage amplitude drastically decreases during RFA. The reduction of voltage to <0.5 mV (dense scar tissue), with the disappearance of the mid and late components of fractionated potentials, indicates the elimination of the arrhythmogenic substrate (Figure 5).19,64 In studies conducted thus far, various tests have been utilised as evidence of successful ablation, including normalisation of type 1 ECG

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Brugada Syndrome Figure 5: ECG and Epicardial Potential Duration Map at Baseline, After Ajmaline Infusion and Post-ablation

Baseline I II III aVR aVL aVF V1 II V2 II V1 III V2 III V1 IV V2 IV Ajmaline challenge I II III aVR aVL aVF V1 II V2 II V1 III V2 III V1 IV V2 IV Post ablation I II III aVR aVL aVF V1 II V2 II V1 III V2 III V1 IV V2 IV Red regions represent areas with an electrogram potential duration â&#x2030;¤110 ms, purple regions represent areas with an electrogram potential duration â&#x2030;Ľ210 ms and the green/blue regions represent a borderline area with an electrogram potential duration between 110 ms and 200 ms. Prolonged fragmentation and delayed electrograms disappeared after ablation (red asterisks). Source: Pappone et al. 2017.64 Reproduced with permission from Wolters Kluwer Health

pattern (Figure 6B), abolishment of VT/VF inducibility and elimination of substrate in remapping (Figure 5). Persistent or recurrent J-ST elevation has been shown to be associated with recurrence of VT/ VF after RFA.67 In a 2017 report by Nademanee et al., the authors recommended eliminating all substrate areas with abnormal lowvoltage and fractionated electrograms, confirmed by repeat substrate

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mapping, rather than using VT/VF inducibility or ECG normalisation as the end points for epicardial ablation.19

Ongoing Clinical Trials Despite various studies reporting on the success of epicardial ablation with low recurrence of VT/VF, the sample sizes in most of these studies

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Clinical Arrhythmias Figure 6: General Anaesthesia Attenuates Brugada ECG Pattern A

AWAKE

AJMALINE

I II III aVR aVL aVF V1 II V2 II

are small. Additionally, the lack of control groups, different protocols employed (including substrate mapping and different sodium channel blockers used) and varying follow-up durations in each study make it difficult to draw clear conclusions regarding the efficacy of RFA for treating BrS. A multicenter study (Bangladesh Risk of Acute Vascular Events [BRAVE] study, ClinicalTrials.gov identifier NCT02704416) has commenced and is currently in the recruiting phase to test the efficacy of epicardial ablation in BrS patients to prevent VT/VF episodes. An estimated 184 patients will be randomised to two arms: continued ICD therapy (control arm) or epicardial ablation plus continued ICD (intervention arm). This study is expected to be completed in 2021.

V1 III

Conclusion

V2 III V1 IV V2 IV B

Spontaneous Type I ECG pattern

ACUTE ABLATION RESULTS After ablation

Ajmaline 1 mg/kg after ablation

I II III aVR aVL aVF V1 II V2 II V1 III V2 III V1 IV V2 IV Baseline 12-lead ECG I II III aVR aVL aVF V1 V2 V3 V4 V5 V6

13-MONTH FOLLOW-UP AFTER ABLATION Baseline high right precordial leads I II III aVR aVL aVF V1 II V2 II V1 III V2 III V1 IV V2 IV

Ajmaline 1 mg/kg

A: General anaesthesia attenuates Brugada ECG pattern. The spontaneous type 1 ECG pattern while awake (left) was attenuated after general anaesthesia (middle); it recurred after ajmaline challenge (right). Source: Ciconte et al. 2018.72 Reproduced with permission from Elsevier. B: ECG patterns before, immediately after ablation and at 13 months’ follow-up. Top left: spontaneous type 1 pattern before ablation. Top middle and right: disappearance of type 1 pattern after ablation, without and with ajmaline challenge. Bottom, disappearance of type 1 ECG pattern persisted 13 months after ablation, without and with ajmaline challenge. Rectangles highlight the ECG patterns in high V1–V2 leads. GA: general anaesthesia. Source: Pappone et al. 2017.64 Reproduced with permission from Wolters Kluwer Health

rugada P, Brugada J. Right bundle branch block, persistent B ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome. A multicenter report. J Am Coll Cardiol 1992;20:1391–6. PMID: 1309182. 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. https://doi.org/10.1161/01.CIR.0000152479.54298.51; PMID: 15655131. Antzelevitch C. Brugada syndrome. Pacing Clin Electrophysiol. 2006;29:1130–59. https://doi.org/10.1111/j.15408159.2006.00507.x; PMID: 17038146. Papadakis M, Papatheodorou E, Mellor G, et al. The diagnostic yield of Brugada syndrome after sudden death with normal autopsy. J Am Coll Cardiol 2018;71:1204–14. https://doi. org/10.1016/j.jacc.2018.01.031; PMID: 29544603. Chen Q, Kirsch GE, Zhang D, et al. Genetic basis and molecular mechanism for idiopathic ventricular fibrillation. Nature 1998;392:293–6. https://doi.org/10.1038/32675; PMID: 9521325. Kapplinger JD, Tester DJ, Alders M, et al. An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing. Heart Rhythm 2010;7:33–46. https://doi. org/10.1016/j.hrthm.2009.09.069; PMID: 20129283. Le Scouarnec S, Karakachoff M, Gourraud JB, et al. Testing the burden of rare variation in arrhythmia-susceptibility genes provides new insights into molecular diagnosis for Brugada syndrome. Hum Mol Genet 2015;24:2757–63. https://doi. org/10.1093/hmg/ddv036; PMID: 25650408. Risgaard B, Jabbari R, Refsgaard L, et al. High prevalence of genetic variants previously associated with Brugada syndrome in new exome data. Clin Genet 2013;84:489–95. https://doi.org/10.1111/cge.12126; PMID: 23414114. Bezzina CR, Barc J, Mizusawa Y, et al. Common variants

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10.

11.

12.

13.

14.

15.

16.

17.

This review summarises progress in the understanding and management of BrS in recent years. Not only has new knowledge been acquired in the genetics and molecular mechanisms of BrS, but recent years have also seen progress made in risk stratification as well as the development of promising new therapies, including epicardial ablation for BrS. Future studies are needed to further clarify the pathogenesis of this complex disease and to guide clinical practice, including genetic testing, risk stratification and selection of therapies.

Clinical Perspective • The complexity of Brugada syndrome (BrS) continues to evolve, and therefore understanding the mechanisms of this disease is imperative to provide better alternatives for treatment. • Early detection and risk stratification are areas of major importance in the treatment of BrS. • Radiofrequency ablation of RVOT substrate has arisen as a promising treatment modality for BrS, although larger scale and long-term follow-up studies are required to further determine its merit.

at SCN5A-SCN10A and HEY2 are associated with Brugada syndrome, a rare disease with high risk of sudden cardiac death. Nat Genet 2013;45:1044–9. https://doi.org/10.1038/ ng.2712; PMID: 23872634. Hu D, Barajas-Martinez H, Pfeiffer R, et al. Mutations in SCN10A are responsible for a large fraction of cases of Brugada syndrome. J Am Coll Cardiol 2014;64:66–79. https://doi. org/10.1016/j.jacc.2014.04.032; PMID: 24998131. Behr ER, Savio-Galimberti E, Barc J, et al. Role of common and rare variants in SCN10A: results from the Brugada syndrome QRS locus gene discovery collaborative study. Cardiovasc Res 2015;106:520–9. https://doi.org/10.1093/cvr/cvv042; PMID: 25691538. Ghouse J, Have CT, Skov MW, et al. Numerous Brugada syndrome-associated genetic variants have no effect on J-point elevation, syncope susceptibility, malignant cardiac arrhythmia, and all-cause mortality. Genet Med 2017;19:521–8. https://doi.org/10.1038/gim.2016.151; PMID: 27711072. Antzelevitch C. The Brugada syndrome: ionic basis and arrhythmia mechanisms. J Cardiovasc Electrophysiol 2001;12:268– 72. https://doi.org/10.1046/j.1540-8167.2001.00268.x; PMID: 11232628. Meregalli PG, Wilde AA, Tan HL. Pathophysiological mechanisms of Brugada syndrome: depolarization disorder, repolarization disorder, or more? Cardiovasc Res 2005;67:367– 78. https://doi.org/10.1016/j.cardiores.2005.03.005; PMID: 15913579. Elizari MV, Levi R, Acunzo RS, et al. Abnormal expression of cardiac neural crest cells in heart development: a different hypothesis for the etiopathogenesis of Brugada syndrome. Heart Rhythm 2007;4:359–65. https://doi.org/10.1016/j. hrthm.2006.10.026; PMID: 17341404. Catalano O, Antonaci S, Moro G, et al. Magnetic resonance investigations in Brugada syndrome reveal unexpectedly high rate of structural abnormalities. Eur Heart J 2009;30:2241–8. https://doi.org/10.1093/eurheartj/ehp252; PMID: 19561025. Bastiaenen R, Cox AT, Castelletti S, et al. Late gadolinium

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enhancement in Brugada syndrome: A marker for subtle underlying cardiomyopathy? Heart Rhythm 2017;14:583–9. https://doi.org/10.1016/j.hrthm.2016.12.004; PMID: 27919765. Nademanee K, Raju H, de Noronha SV, et al. Fibrosis, Connexin-43, and conduction abnormalities in the Brugada syndrome. J Am Coll Cardiol 2015;66:1976–86. https://doi. org/10.1016/j.jacc.2015.08.862; PMID: 26516000. Nademanee K, Hocini M, Haissaguerre M. Epicardial substrate ablation for Brugada syndrome. Heart Rhythm 2017;14:457–61. https://doi.org/10.1016/j.jacc.2015.08.862; PMID: 26516000. Pieroni M, Notarstefano P, Oliva A, et al. Electroanatomic and pathologic right ventricular outflow tract abnormalities in patients with Brugada syndrome. J Am Coll Cardiol 2018;72:2747–57. https://doi.org/10.1016/j.jacc. 2018.09.037; PMID: 30497561. Corrado D, Zorzi A, Cerrone M, et al. Relationship between arrhythmogenic right ventricular cardiomyopathy and Brugada syndrome: new insights from molecular biology and clinical implications. Circ Arrhythm Electrophysiol 2016;9:e003631. https://doi.org/10.1161/CIRCEP.115.003631; PMID: 26987567. Moncayo-Arlandi J, Brugada R. Unmasking the molecular link between arrhythmogenic cardiomyopathy and Brugada syndrome. Nat Rev Cardiol 2017;14:744–56. https://doi. org/10.1038/nrcardio.2017.103; PMID: 28703223. Cerrone M, Lin X, Zhang M, et al. Missense mutations in plakophilin-2 cause sodium current deficit and associate with a Brugada syndrome phenotype. Circulation 2014;129:1092– 103. https://doi.org/10.1161/CIRCULATIONAHA.113.003077; PMID: 24352520. Jansen JA, Noorman M, Musa H, et al. Reduced heterogeneous expression of Cx43 results in decreased Nav1.5 expression and reduced sodium current that accounts for arrhythmia vulnerability in conditional Cx43 knockout mice. Heart Rhythm 2012;9:600–7. https://doi.org/10.1016/ j.hrthm.2011.11.025; PMID: 22100711. Casado-Arroyo R, Berne P, Rao JY, et al. Long-term trends in newly diagnosed Brugada syndrome: implications for risk

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Clinical Arrhythmias

Obesity and Atrial Fibrillation: Epidemiology, Pathophysiology and Novel Therapeutic Opportunities Vishal Vyas 1,2,3 and Pier Lambiase 3,4 1. Barts and The London School of Medicine and Dentistry, London, UK; 2. Queen Mary University of London, London, UK; 3. Barts Heart Centre, St Bartholomew’s Hospital, London, UK; 4. Institute of Cardiovascular Science, University College London, London, UK

Abstract Obesity is already a major global public health issue, implicated in a vast array of conditions affecting multiple body systems. It is now also firmly established as an independent risk factor in the incidence and progression of AF. The rapidly rising morbidity, mortality and healthcare costs associated with AF despite implementation of the three pillars of AF management – anticoagulation, rate control and rhythm control – suggest other strategies need to be considered. Compelling data has unveiled novel insights into adipose tissue biology and its effect on arrhythmogenesis while secondary prevention strategies targeting obesity as part of a comprehensive risk factor management programme have been demonstrated to be highly effective. Here, the authors review the epidemiological basis of the obesity–AF relationship, consider its underlying pathophysiology and discuss new therapeutic opportunities on the horizon.

Keywords Atrial fibrillation, obesity, obesity paradox, adiposity, epicardial fat, risk factor management Disclosure: VV’s research is funded jointly by Barts Charity and Abbott Vascular. PL is supported by National Institute for Health Research Biomedical Research Centre at University College London Hospitals NHS Foundation Trust and Barts Biomedical Research Centre. Received: 10 December 2018 Accepted: 28 January 2019 Citation: Arrhythmia & Electrophysiology Review 2019;8(1):28–36. DOI: https://doi.org/10.15420/aer.2018.76.2 Correspondence: Pier Lambiase, UCL Institute of Cardiovascular Science, Gower Street, London, WC1E 6BT, UK. E: p.lambiase@ucl.ac.uk Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Worldwide obesity has reached pandemic proportions with more than 1.9 billion adults classed as overweight in 2016, of which 650 million were obese.1 Since it is a major modifiable risk factor for so many cardiovascular diseases, it is no surprise there has been an exponential increase in cases of AF coinciding with the rise in obesity. While there were an estimated 8.8 million cases of AF in 2010 in Europe alone, by 2060, this is estimated to rise to 17.9 million.2 Moreover, obesity is now the second biggest attributable risk factor for AF after hypertension. Together with overweight, it accounted for 17.9% of all AF cases in the Atherosclerosis Risk in Communities (ARIC) study.3 While AF risk appears to follow a linear pattern with increase in BMI, the pathophysiological basis of the obesity–AF relationship is complex and multifactorial.4 Indeed, various epidemiological studies have demonstrated an apparent paradox with regard to outcomes in AF patients; overweight and mildly obese patients with AF appear to have an overall better prognosis in terms of all-cause mortality compared with lean patients with AF.5 This is consistent with other cardiovascular diseases.

targets and the importance of a holistic approach to dealing with this burgeoning public health issue.

In this review, we will begin with a detailed discussion of the epidemiological links between obesity and AF highlighting the benefits and relative limitations of using BMI and other anthropometric markers in assessing adiposity (obesity is typically defined as BMI >30 kg/m2). We will outline general mechanisms contributing to AF and place obesity in this context, focusing on the pathophysiological mechanisms that underpin the obesity–AF relationship with emphasis on recent insights derived from studies on adipose tissue biology. Finally, we discuss novel therapeutic

Notably, BMI has even been associated with progression of AF from paroxysmal to persistent in a two large community cohort studies.13,14 The mean age of patients in the Olmsted County study by Tsang et al. was 71, suggesting that this relationship may not necessarily be applicable to a younger cohort of patients.13 However, a subsequent retrospective Danish registry study of 271,203 women who had given birth found that while the overall AF incidence remained low in this young population, obesity remained a significant independent predictor for AF.15 Indeed, the generalisability of the obesity-induced

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Epidemiology of the Obesity–AF Relationship Early associations between AF and obesity were observed in patients undergoing cardiac surgery, with high BMI being reported in numerous studies as a major risk factor for post-operative AF.6–8 Various studies including the Framingham Heart Study and a meta-analysis has indicated that a rise in BMI parallels a marked increase in AF risk (Table 1).9,10 The Women’s Health Study found that for every 1 kg/m2 increase in BMI, there was a 4.7% increase in risk of developing AF.4 In a cohort of 47,589 patients prospectively followed up for a mean of 5.7 years in the Danish Diet, Cancer and Health Study, BMI independently correlated with increased AF risk regardless of gender.11 In a recently published cohort of 67,238 patients derived from a database of healthcare claims in the US, obesity was associated with new onset AF independent of age, diabetes, hypertension and gender.12

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Obesity and Atrial Fibrillation Table 1: Population Studies Showing an Association of Obesity with AF Study

Country

Cohort Details

Participant Characteristics

AF Outcomes

• Atherosclerosis Risk in Communities Study • Prospective cohort • Mean follow-up 17.1 years

• 14,598 participants • 55% female • Mean age 54.2 years

17.9% AF attributed to overweight and obesity

Tedrow et al. 20104

• Women’s Health Study • Prospective cohort • Mean follow-up 12.9 years

• 34,309 participants • 100% female • Mean age 55 years

4.7% increase in AF per 1 kg/m2 increase in BMI

Wang et al. 20049

• F ramingham Heart and Offspring Studies • Prospective cohort • Mean follow-up 13.7 years

• 5,282 participants • 55% female • Mean age 57 years

4% increase in AF per 1 kg/m2 increase in BMI

Frost et al. 200511

Denmark

• Danish Diet, Cancer, and Health Study • Prospective cohort • Mean follow-up 5.7 years

• 47,589 participants • 53% female • Mean age 56 years

Hazard ratio of 1.08 for men and 1.06 for women for AF/flutter per 1 kg/m2 increase in BMI

Foy et al. 201812

• Insurance database • Prospective cohort • Follow-up 8 years

• 67,278 participants • 76.9% female • Mean age 43.8 years

Odds ratio of 1.4 for AF in obese participants compared with non-obese

Tsang et al. 200813

• O lmsted County patients with paroxysmal AF • Prospective cohort • Median follow-up 5.1 years

• 3,248 participants • 46% female • Mean age 71 years

BMI predicted progression of paroxysmal to permanent AF with hazard ratio of 1.04

Sandhu et al. 201414

• Women’s Health Study • Prospective cohort • Median follow-up 16.4 years

• 34,309 participants • 100% female • Age ≥45 years

BMI associated with non-paroxysmal compared with paroxysmal AF with hazard ratio of 1.07

Karasoy et al. 201315

Denmark

• Registry of young women giving birth • Retrospective registry • Median follow-up 4.6 years

• 271,203 participants • 100% female • Mean age 30.6 years

Hazard ratio for AF 1.07 in obese women compared with normal weight

• Tertiary medical centre database • Prospective cohort • Mean follow-up 6.4 years

• 18,290 participants • 27% female • Mean age 49 years

Hazard ratio for AF of 2.04 for obese compared with normal weight

• K orean National Health Insurance database • Retrospective cohort • Mean follow-up 7.5 years

• 389,321 participants • 47.9% female • Mean age 45.6 years

Hazard ratio of 1.3 for AF in obese compared with non-obese

Huxley et al. 2011

Berkovitch et al. 201616 Israel

Lee et al. 201717

South Korea

AF risk remains true across geographical and racial boundaries. Berkovitch et al. demonstrated in a large Israeli cohort of 18,290 men and women that overweight and obesity were associated with a higher AF risk and that weight reduction corresponded to a reduced risk of developing AF.16 They reported a 7% reduction in AF incidence for every 1 kg/m2 drop in BMI. Much of the obesity–AF risk is often attributed to other coexisting cardiovascular risk factors given obesity is associated with conditions such as diabetes and hypertension. A Korean study attempted to account for this by reviewing a cohort of so-called metabolically healthy obese (MHO) patients; those with a high BMI but who were free of other morbidity.17 They retrospectively reviewed nearly 400,000 patients and found the MHO cohort also had an increased risk of AF development; on multivariate analysis they had a hazard ratio of 1.3 compared with their healthy non-obese counterparts. This would suggest that the obesity–AF relationship appears to stand beyond conventional risk factors.

The Obesity Paradox and AF While there is a consistently and extensively reported relationship between increasing BMI and AF risk, progression and recurrence, a counter-intuitive opposite effect is observed regarding mortality. Known as the obesity paradox, overweight (BMI 25–30 kg/m2) and mildly obese (BMI 30–35 kg/m2) people appear to have lower all-cause mortality in long-term follow-up studies.18–20 Indeed, this phenomenon stands true for many cardiovascular diseases.5 A meta-analysis

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pooling nine studies involving 49,364 participants found that underweight (BMI <18.5 kg/m2) Asian patients with AF were at increased risk of embolic events, such as stroke and systemic embolism, as well as cardiovascular and all-cause death.21 Additionally, they found that in all AF patients, overweight and obesity were not associated with these outcomes. In order to dissect the potential reasons for this paradox, it is important to consider the characteristics of the patients included in these studies. The authors allude to various confounding factors that could account for this phenomenon. First, a greater proportion of patients with AF in cohort studies tend to be overweight or obese (78% in the Pandey study) while those patients who have normal BMI tend to be significantly older (in the Sandhu et al. cohort, obese patients were significantly younger).18,19 Age is particularly relevant given it is a major predictor of all-cause mortality in AF.22 Second, there appears to be a greater use of rhythm control strategies and anticoagulation in patients with high BMI, potentially to account for a greater proportion of persistent AF in groups with a higher BMI.18 Third, patients with high BMI tend to have higher blood pressures facilitating greater use of appropriate cardiac medications.23 Fourth, patients with an apparently normal BMI may have other medical conditions which lead to a relatively catabolic or pro-inflammatory state and that increased BMI provides a metabolic reserve in this case. Fifth, cardiorespiratory fitness is being increasingly recognised as a major factor in reducing AF.

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Clinical Arrhythmias Figure 1: Factors Contributing to the Obesity Paradox

Greater metabolic reserve

Cardiorespiratory fitness

Higher blood pressure leading to increased medication use

Catabolic/ pro-inflammatory state

Limitations of anthropometric markers such as BMI in assessing adiposity

Rhythm control strategies

Age

Unreported confounders

Reasons for obesity paradox in AF

Selection bias

Qureshi et al. demonstrated in a large multi-racial cohort of 64,561 adults that for every one metabolic equivalent achieved during treadmill testing, there was a 7% lower risk of incident AF even when accounting for potential confounders.24 In the CARDIO-FIT study, Sanders et al. showed in 308 patients with AF that for every two metabolic equivalents gained following their risk factor management and tailored exercise programme, there was a twofold improvement in arrhythmia-free survival.25 This was accompanied by reduced AF burden and an improvement in symptoms. More recently, Malmo et al. found that after a 12-week interval training programme for patients with paroxysmal AF, AF burden, as measured by implantable loop recorders, reduced by 50% compared with controls.26 Additionally, the authors observed a trend towards fewer cardioversions and hospital admissions alongside significant symptomatic improvements.

and overweight groups (stratified by BMI).29 However, in each group, a higher waist-to-hip ratio reflecting central adiposity was associated with excess mortality risk.

The BMI Effect

Obesity sits alongside a number of conventional cardiovascular risk factors that often accompany it and increase AF risk, such as diabetes, hypertension, metabolic syndrome and ischaemic heart disease. These factors will promote structural atrial remodeling, fibrosis, wave break, micro reentry and AF, even in the absence of obesity. Importantly, some of the mechanistic pathways that lead to AF in these conditions are shared with obesityâ&#x20AC;&#x201C;AF pathophysiology. For instance, hypertension induces haemodynamic changes such as increases in left ventricular filling pressures, stiffness and diastolic dysfunction that are also seen in obese states.31 Moreover, activation of the renin-angiotensinaldosterone system typically observed in hypertensive patients, is similarly seen in obesity.32 Adipocytes have been documented to directly produce aldosterone, and aldosterone antagonists have been noted to be particularly effective in patients with heart failure with reduced ejection fraction with associated abdominal obesity.33â&#x20AC;&#x201C;35 In the case of diabetes, persistent hyperglycaemia is associated with the development of advanced glycation end-products which can infiltrate

There are relative pros and cons of using BMI as a measure of adiposity. BMI is the most widely used marker of obesity with obvious advantages in terms of ease of obtaining height and weight data on patients. However, it fails to capture body fat distribution or take into account body composition.27,28 For instance, athletes with a high muscle mass and a higher weight may fall into an overweight category despite having a relatively low body fat composition. On the other hand, central abdominal obesity is associated with deleterious outcomes.29 Various other anthropometric markers, such as waist circumference and waist-to-hip ratio, may better indicate the distribution of adiposity and better reflect risk. Indeed, lean body mass was recently reported in a Danish registry cohort as the predominant anthropometric risk factor for AF with other markers not showing an association with AF when adjusted for lean body mass.30 In a cohort of 130,473 UK Biobank participants without any smoking-related disease or weight loss, no significant difference in mortality was seen between normal

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Taken together, there are numerous potential causes that could account for this apparent obesity paradox seen with AF and other cardiovascular conditions (Figure 1). Furthermore, additional unaccounted confounding factors and selection bias, such as a genetic predisposition to AF, also need to be considered. Certainly, given the improvements observed in AF outcomes with risk factor management and weight loss, the apparent obesity paradox should not deter from an aggressive risk factor optimisation strategy to manage AF.

The Pathophysiological Context of the Obesityâ&#x20AC;&#x201C;AF Relationship

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Obesity and Atrial Fibrillation the myocardium provoking fibrosis and hypertrophy, in turn distorting the architecture of the heart to make it more conducive to AF genesis.36,37 While this can be independent of obesity, the fibrotic mediators, such as the transforming growth factor beta (TGF-beta) superfamily, are common to both pathways.36 Similarly, diastolic dysfunction is common in the diabetic heart and is similar to that seen in obesity. Factors such as sleep apnoea/obesity hypoventilation syndrome (often known together as sleep-related breathing disorders) are emergent players to consider. In a study looking at patients being evaluated for bariatric surgery, sleep-related breathing disorders were present in 88% of patients.38 Moreover, the Sleep Heart Health Study demonstrated that patients with sleep-related breathing disorders were at fourfold increased risk of AF and threefold increased risk of non-sustained ventricular tachycardia following adjustment for several confounders.39 We will discuss the mechanistic basis for this in the following section.

Obesity-Related Haemodynamic Changes Obesity is associated with a host of haemodynamic changes that alter cardiac structure and physiology to make it more conducive to AF development and maintenance. Adiposity is associated with an increase in total blood volume with this typically resulting in increased cardiac output. With little change in heart rate, the rise in cardiac output is predominantly due to an increase in stroke volume. Unfortunately, a sustained rise in cardiac output is associated with left ventricular enlargement and eccentric or concentric hypertrophy.40 With raised left ventricular filling pressures, diastolic dysfunction occurs and over time with persistently raised filling pressures and left ventricular hypertrophy, systolic impairment may also occur.41 In addition to this, increased BMI is associated with left atrial enlargement with raised left atrial pressures and volumes.42 A consequent increase in pulmonary capillary pressures result. With obesity commonly associated with sleep-related breathing disorders, the cycle of repeated hypoxia, acidosis and arousal from sleep can alter autonomic tone, increasing the risk of abnormal cardiac impulse formation, as well as increasing pulmonary arterial pressures which in turn can lead to right ventricular hypertrophy and failure.39 Left unchecked, biventricular hypertrophy and impairment can result with associated distortion in left atrial architecture and haemodynamics providing the ideal substrate for AF genesis and persistence.

Epicardial Fat, Adipose Tissue Biology and AF Given adipose tissue distribution appears to be a key factor in determining cardiovascular risk, it is no surprise that the role of distinct adipose tissue depots is of intense interest.43 With more sophisticated cross-sectional imaging modalities such as CT and MRI being increasingly used for cardiac imaging, the visceral fat layer directly overlying the myocardium – epicardial adipose tissue (EAT) – can be directly imaged. Of note, pericardial fat is often referred to interchangeably with EAT in the literature but strictly speaking paracardial fat refers to the layer of fat external to the parietal pericardium and pericardial fat is the combination of both EAT and paracardial fat.44 EAT covers 80% of the heart’s surface and up to 20% of the heart’s weight, predominantly overlying the coronaries, atrioventricular and interventricular grooves but also spanning the atria and ventricles.45,46 There are no fascial boundaries between EAT and the myocardium and they share the same blood supply, the coronary vessels, facilitating direct paracrine and vasocrine effects on the heart.47 EAT’s physiological roles include thermoregulation, a source of energy and

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mechano-protection.47,48 A seminal post-mortem study assessing adiposity of the heart in 1933 showed that 98% of obese patients had excessive epicardial fat.49 Cross-sectional imaging data has indicated EAT volume correlates with increased AF risk with left atrial EAT volume a particular predictor of AF.50–52 Worse outcomes following AF ablation and also post-operative AF in the cardiac surgical setting have been reported.51,53 A meta-analysis confirming this association between EAT and AF has shown an overall odds ratio of 2.61 per each standard deviation increase in EAT volume with an even higher odds ratio for persistent AF.54

Role of Inflammation EAT is a highly active visceral tissue producing a host of different proand anti-inflammatory adipocytokines, metabolic and growth factors that can directly diffuse into the myocardium.45,48 Various lines of evidence suggest local inflammation is a key mediator in AF. In a study looking at the immune cell profile of patients undergoing valve surgery with either no history of AF or those with persistent AF, the number of CD45+ cells (a pan-leukocyte marker) was significantly higher in the atrial myocardium of AF patients.55 This was corroborated in a study by Smorodinova et al. demonstrating that not only were there higher CD45+ cell populations in the AF cohort but specifically CD3+ T lymphocytes and CD68+ cells (likely corresponding to dendritic cells) were significantly higher in the AF cohort.56 In coronary artery bypass surgery patients, where AF is a common post-operative complication, high levels of pro-inflammatory cytokines including tumour necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and IL-6 were observed in the EAT compared with subcutaneous adipose tissue samples.57 AF patients undergoing valve surgery were found to have higher levels of right atrial nuclear factor-kappa beta (NF-kappa beta), which is a key regulator of the immune response. Additionally, TNFalpha and IL-6 levels were higher and increased fibrosis and severe lympho-monocyte infiltration were seen.58 Clearly, local inflammation mediated by a locally driven immune cell and cytokine response appears to play a key role in AF pathophysiology and is likely to underpin the EAT-AF relationship.

Fibrosis and Lipotoxicity Alongside inflammation, fibrosis is recognised as a central factor in the development of an arrhythmogenic substrate.41 Pro-inflammatory cytokines and growth factors such as activin A and matrix metalloproteinases are likely to mediate a fibrotic effect on the atrial myocardium via paracrine pathways.59,60 In a study by Venteclef et al, only the EAT secretome – and not the subcutaneous secretome – applied to an atrial preparation induced myocardial fibrosis with the myofibroblasts able to produce extracellular matrix components.59 This fibrotic effect was attributed to activin A which reproduced the significant fibrotic effect when applied to the atrial preparation with upregulation of pro-fibrotic genes. The fibrotic effect was negated by application of an activin-A antibody.59 Activin-A is a member of the TGF-beta superfamily and induced expression of TGF-beta1 and beta2 in the same study.59 TGF-beta1 has been found to cause selective atrial fibrosis and increase vulnerability to AF when overexpressed in a transgenic mouse model.60 Fibrosis plays a major role in creating the electrical heterogeneity, regions of local conduction block, changes in atrial refractoriness and the formation of reentrant circuits that ultimately form the substrate for AF.61,62 While inflammation and fibrosis play central roles in the obesity–AF cascade, direct fatty infiltration of the myocardium in obesity is also

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Clinical Arrhythmias likely to play a role in inducing deleterious structural and electrical changes in the atria.63 Mahajan et al. used an ovine model of obesity with sheep fed a high-fat diet for a period of 72 weeks.63 Extensive imaging and electrophysiological analysis showed that the sheep displayed a higher AF burden with enlarged atria and EAT fatty infiltration of the posterior left atrial wall. This was accompanied by significant atrial fibrosis, reductions in conduction velocity in both atrial chambers and reduced posterior left atrial endocardial voltages. These insights into adiposity and AF must be put into context of the study. It used a laboratory animal model of obesity with sheep fed a high calorie and high fat diet that may not necessarily reflect the model of obesity seen worldwide, which is caused by Western diet and sedentary lifestyle. The authors acknowledge that it is not possible to draw a causal link between fatty infiltration and AF from this study.63

Direct Electrophysiological Effects of the Secretome In addition to the inflammatory and fibrotic mediators that may underpin the obesity–AF relationship, visceral fat and its secretome has been reported to have direct electrophysiological effects in left atrial (LA) cardiomyocyte co-culture experiments in rabbits.64 Lin et al. demonstrated that epicardial, abdominal and retrosternal adipocytes all prolong the LA action potential, while epicardial adipocytes also significantly altered the resting membrane potential.64 The late sodium current, L-type calcium channel current and transient outward current were all increased in the co-cultured cells while delayed rectifier potassium currents were smaller.64 The authors also noted greater isoprenaline-induced delay after depolarisations in the co-cultured cells.64 Taken together, these changes in action potential would all promote arrhythmogenicity in left atrial cardiomyocytes and illustrate the extensive direct modulatory effects of visceral fat.

Autonomic Nervous System in Obesity Autonomic dysfunction secondary to obesity with concomitant sleep apnoea has been shown to trigger AF in animal models.65 Moreover, EAT contains the ganglionated plexi that are thought to be key mediators of autonomic modulation of the heart.66 In a canine model by Po et al., parasympathomimetics were injected into EAT resulting in bradycardia followed by premature depolarisations and subsequent spontaneous AF.67 The site of firing was thought to arise from both the pulmonary vein and non-pulmonary vein sites. Further evidence of the role of ganglionated plexi in AF comes from ablation of the plexi as part of AF ablation procedures, which tends to diminish AF inducibility.68 A recent study looked at a cohort of paroxysmal AF patients undergoing coronary artery bypass surgery where botulinum toxin targeting the ganglionated plexi was injected into the EAT at the time of operation. The investigators found that there was a significant reduction (7% versus 30%) in the percentage of patients having postoperative AF in the botulinum toxin group at 30 days with a sustained difference seen at 1-year follow-up.69,70 The mechanism for this observed effect is likely to involve targeting the deleterious role of the autonomic nervous system on AF inducibility. Botulinum toxin inhibits the exocytic release of acetylcholine from pre-synaptic vesicles affecting parasympathetic cholinergic neurotransmission.71 When injected into the epicardial fat pads which play host to ganglionated plexi, which harbours predominantly parasympathetic neurons, it is likely to cause temporary suppression of cholinergic firing. AF vulnerability is linked to the duration of the atrial effective refractory period (ERP) and the dispersion of the ERP.72 Vagal activation shortens the atrial ERP and increases dispersion. A canine study has demonstrated increased ERP

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dispersion and increased AF vulnerability after toxin was injected into the epicardial fat pads.72 With regard to the longer-term suppression of AF reported in the study, the study authors refer to autonomic hyperactivity and AF forming a cycle with autonomic activity triggering AF and then AF further enhancing autonomic activity.73 The authors allude to ‘breaking this cycle’ thus preventing the atrial remodelling associated with prolonged periods of AF and reducing the vulnerability to episodes of AF in the longer term.70 The obesity–AF relationship is complex with multiple insults, such as inflammation, fibrosis, lipotoxicity and autonomic dysregulation, combined with haemodynamic and mechanical changes forming the substrate and trigger for AF. With accompanying obesity-related comorbidities such as diabetes, hypertension, sleep-related breathing disorders and ischaemic heart disease included in this picture, an optimal milieu for AF maintenance is created. Figure 2 summarises these mechanisms.

Management of AF in Obese Patients Drug Therapy The effect of obesity on AF risk extends to altering aspects of management in AF patients. One of the pillars of AF management is anticoagulation to minimise thromboembolic complications associated with the condition. In a recent study reviewing warfarin dosing in patients stratified by BMI, participants with a high BMI, particularly more than 40 kg/m2 had significantly higher warfarin requirements.74 A higher weekly dose of warfarin may have implications for time to discharge if the drug is commenced in hospital or in maintaining time in therapeutic range. It would seem that the use of direct oral anticoagulants (DOACs) including dabigatran, apixaban, rivaroxaban and edoxaban for thromboembolism prophylaxis would address this issue. However, there is a paucity of large-scale clinical trial data or pharmacokinetic analyses in patients of high BMI with most of the data gleaned from subgroup analyses.75 Guidance from the International Society on Thrombosis and Haemostasis suggests avoidance of DOACs in morbidly obese patients (BMI >40 kg/ m2) or with a weight of >120 kg, due to limited clinical data.76 Yet this approach would exclude a large number of patients who may benefit from DOACs. Indeed, in a study of healthy volunteers with a weight of more than 120 kg who were taking rivaroxaban, the differences in factor Xa inhibition were 10% lower compared with those of normal weight.77 Kaplan et al. recently evaluated obese patients including those with a BMI >40 kg/m2 undergoing direct current cardioversion (DCCV) for AF or atrial flutter on DOACs and warfarin and found there was a very low incidence of stroke with none seen in the BMI >40 kg/ m2 cohort at 30 days.78 While the patient cohort group consisted of only 761 patients, this study would suggest DOACs appear to be safe in a cohort who have a relatively elevated risk for stroke in the first month post-DCCV.

AF Procedures A second pillar of AF management is rhythm control, with one of the most commonly performed procedures for patients in AF being DCCV. This facilitates prompt evaluation of symptomatology and, in the longer term, the assessment of changes in cardiac dimensions and function when in sinus rhythm. In turn, this should guide ongoing management. Patients with a higher body weight have been found to have a lower success rate with cardioversion.79 This is likely to be due to a lower energy being delivered to the heart in patients with a higher body

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Obesity and Atrial Fibrillation Figure 2: Schematic Representing the Mechanistic Relationship Between Obesity and AF Obesity

Cardiovascular risk factors Hypertension Diabetes Hyperlipidaemia Sleep-related breathing disorders

Fibrosis Pro-fibrotic molecules, e.g. TGF-β and MMPs

Autonomic changes

EAT Secretome Ganglionated plexi

Inflammation Adipocytokines Endocrine and paracrine effects

Haemodynamic changes

Ventricular remodelling

Left atrial remodelling Distortion in architecture Fatty infiltration Electrical heterogeneity Conduction changes

Ischaemic heart disease

AF EAT = epicardial adipose tissue; MMPs = matrix metalloproteinases; TGF- = transforming growth factor-beta.

weight with higher energies in a subsequent study being associated with a greater likelihood of successful cardioversion in obese patients.80 Higher energies would achieve increased local atrial current densities to depolarise both atria simultaneously and re-establish sinus rhythm. A recent randomised study sought to identify additional strategies alongside higher energy delivery that would enhance the success rate of the procedure.80 The authors found that the use of paddles (rather than adhesive patches), manual pressure applied by two operators with a gloved hand when patches are used, as well as escalation of energies up to 360 J, would enhance the likelihood of successful cardioversion in obese patients. Catheter ablation is a principal rhythm control tool with various studies demonstrating that a higher BMI corresponds to a higher AF recurrence risk.81–84 While complication rates generally do not differ in the studies, greater radiation exposure was noted in one study.83 Winkle et al. noted that minor complications were significantly higher in the morbidly obese group (BMI >40 kg/m2), although no differences in major complications were observed.81 The authors allude to the role of weight loss strategies to optimise the success of AF ablation.

Novel Therapeutic Opportunities Epicardial Adipose Tissue Biology Having extensively reviewed the critical local role of EAT in mediating the obesity–AF relationship, it is no surprise that it is an emerging therapeutic target. Arresting the inflammatory cascade in EAT by targeting specific adipocytokines using antibody approaches would help to reduce this major component of AF genesis and maintenance. Similarly, antibodies to pro-fibrotic agents such as TGF-beta, ideally targeted to the adipose tissue for instance with nanoparticle technology, would help to improve selectivity of delivery and minimise off-target effects, improving safety.85

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Agents that reduce EAT volume have also been investigated. In a cohort of patients with diabetes, Iacobellis et al. demonstrated a near 40% reduction in EAT (as measured by echocardiography) in the group given liraglutide, a glucagon-like peptide 1 (GLP-1) agonist in addition to metformin.86 There was no double-blinding or reporting of cardiovascular outcomes but liraglutide and GLP-1 analogues could be a new area of therapeutic investigation. Indeed, GLP-1 receptors are present in adipose tissue and appear to regulate adipogenesis providing some mechanistic explanation of the phenomenon observed.87 The sodium-glucose co-transporter 2 inhibitor dapaglifozin has been shown to produce loss in body weight and concomitant reduction in EAT volumes as well as reduction in systemic TNF-alpha levels.88 Moreover, dapiglifozin-treated EAT explants demonstrated lower levels of chemokines compared with untreated explants.89 Further work to assess AF outcomes in patients with diabetes treated with these agents would help guide the use of these medications in reducing AF risk among this group.

Role of Imaging EAT has been shown to be an independent risk factor in AF incidence and progression across a range of different settings. Cross-sectional imaging approaches such as CT and MRI may help to form novel algorithms to predict AF risk and progression. This would be particularly relevant to AF ablation. Standards and guidelines with regards to cutoff EAT volumes to predict AF risk would need to be well-validated in large cohorts for them to have widespread clinical utility. One study looking at 283 patients with AF looked at echocardiographyderived EAT thicknesses and suggested using cut-off EAT thicknesses values of 6 mm for paroxysmal AF and 6.9 mm for persistent AF.90 While echocardiography is widely available and inexpensive, there are significant limitations with regards to reproducibility and lack of volumetric data. Moreover, quantification of EAT sub-depots, for instance around the left atrium, is not possible. Antonopoulos et al.

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Clinical Arrhythmias used adipose tissue CT attenuation to create the fat attenuation index, a new metric to study adipose tissue.91 The fat attenuation index reflects the degree of adipocyte differentiation and lipid accumulation in fat depots.91 The metric correlates well with coronary inflammation, reliably separating stable and unstable lesions in acute coronary syndromes.91 In the case of AF, a similar technique may help to identify EAT that is particularly inflamed and hence more likely to be pathogenic.

Primary prevention of AF in the obese at-risk cohort would be the next step in helping to control the obesity–AF epidemic. For instance, a combination of imaging to calculated threshold volumes of visceral fat (such as EAT) to guide risk stratification and using drugs such as GLP-1 analogues and sodium-glucose co-transporter 2 inhibitors in people with diabetes and obesity.

Conclusion Risk Factor Management Sanders et al. have extensively contributed to the evidence base for a comprehensive risk factor management approach to AF.92–6 This approach is akin to the secondary prevention approach used for patients with ischaemic heart disease. There have been trials that look at the role of weight loss alongside risk factor optimization, such as good diabetic control, achieving hypertension targets, lipidlowering strategies, smoking cessation and alcohol reduction, as well as improving cardio-respiratory fitness.25,92–6 This has produced significant benefits in reducing the burden of AF. Moreover, reverse cardiac remodelling and even a regression from persistent to paroxysmal or no AF has been demonstrated.92,95 Notably, a dose-dependent relationship between weight loss and freedom from AF was observed.93 The value of a physician-led service was highlighted, given 84% patients who achieved >10% weight loss were in the physician-led clinic.93 The costeffectiveness of such intense risk factor management was evaluated by the same group who found that with less medication needed, fewer hospitalisations, emergency attendances and procedures, the cost-saving benefit amounted to US$12,094. This corresponded to an increase of 0.193 quality-adjusted life years.96 Dietary intervention and bariatric surgery are other avenues to facilitate weight loss. Data remains largely speculative with regard to dietary approaches to reducing AF risk while bariatric surgery can achieve significant sustained weight loss and concomitant large reductions in AF risk.97 In the Swedish Obese Subjects cohort study following-up 2,000 patients undergoing bariatric surgery, a 29% reduction in AF risk compared with controls was observed at follow-up of 19 years.98 Differences in AF rates were only seen between the groups after 5 years, highlighting the importance of sustained weight loss and the temporal delay in altering the AF substrate.

orld Health Organization. Obesity and Overweight W Factsheet. Available at: http://www.who.int/news-room/factsheets/detail/obesity-and-overweight. (Accessed 1 December 2018). Krijthe BP, Kunst A, Benjamin EJ, et al. Projections on the number of individuals with atrial fibrillation in the European Union, from 2000 to 2060. Eur Heart J 2013;34:2746–51. https://doi.org/10.1093/eurheartj/eht280; PMID: 23900699. Huxley RR, Lopez FL, Folsom AR, et al. Absolute and attributable risks of atrial fibrillation in relation to optimal and borderline risk factors: the atherosclerosis risk in communities (ARIC) study. Circulation 2011;123:1501–8. https://doi.org/10.1161/CIRCULATIONAHA.110.009035; PMID: 21444879. Tedrow UB, Conen D, Ridker PM, et al. The long- and shortterm impact of elevated body mass index on the risk of new atrial fibrillation the WHS (women’s health study). J Am Coll Cardiol 2010;55:2319–27. https://doi.org/10.1016/j. jacc.2010.02.029; PMID: 20488302. Elagizi A, Kachur S, Lavie CJ, et al. An overview and update of obesity and the obesity paradox in cardiovascular diseases. Prog Cardiovasc Dis 2018;61:142–50. https://doi.org/10.1016/j. pcad.2018.07.003; PMID: 29981771. Sumeray M, Steiner M, Sutton P, et al. Age and obesity as risk factors in perioperative atrial fibrillation. Lancet 1988;2:448. https://doi.org/10.1016/S0140-6736(88)90433-3; PMID: 2900371. Zacharias A, Schwann TA, Riordan CJ, et al. Obesity and risk of new-onset atrial fibrillation after cardiac surgery. Circulation 2005;112:3247–55. https://doi.org/10.1161/ CIRCULATIONAHA.105.553743; PMID: 16286585. Echahidi N, Mohty D, Pibarot P, et al. Obesity and

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The seemingly inexorable rise of AF cases worldwide is paralleled by the obesity epidemic. Their associated morbidity and mortality combined with huge financial costs mark out the obesity–AF relationship as one of global health importance. The epidemiological associations suggest that obesity increases the risk of AF incidence, progression and recurrence. The numerous pathophysiological mechanisms highlight the complexity of the relationship but also illustrate the potential for new therapeutic opportunities such as targeting the inflammatory-fibrotic cascade. Moreover, a comprehensive risk factor management approach appears to be a realistic, cost-effective and efficacious solution to addressing this problem. Long-term studies will confirm whether such strategies yield improvements in hard outcomes such as mortality.

Clinical Perspective • Obesity is a key driver in the exponential rise of AF cases worldwide. • High BMI is a major predictor of AF incidence and progression. • Epicardial adipose tissue (EAT) is the visceral fat layer directly surrounding the myocardium and it plays a critical role in obesity–AF pathophysiology. EAT’s secretome of inflammatory mediators and pro-fibrotic molecules contribute to the substrate of AF, and EAT harbours the ganglionated plexi that can trigger AF. • Cross-sectional imaging of visceral fat together with antibodybased therapeutic agents targeting the inflammatory-fibrotic cascade may prove to be novel tools in AF management. • A comprehensive risk factor management programme is both a clinically and cost-effective strategy to manage AF.

metabolic syndrome are independent risk factors for atrial fibrillation after coronary artery bypass graft surgery. Circulation 2007;116:213–9. https://doi.org/10.1161/ CIRCULATIONAHA.106.681304; PMID: 17846306. Wang TJ, Parise H, Levy D, et al. Obesity and the risk of newonset atrial fibrillation. JAMA 2004;292:2471–7. https://doi. org/10.1001/jama.292.20.2471; PMID: 15562125. Wong CX ST, Sun MT, Mahajan R, et al. Obesity and the risk of incident, post-operative, and post-ablation atrial fibrillation: a meta-analysis of 626,603 individuals in 51 studies. JACC Clin Electrophysiol 2015;1:139–52. https://doi.org/10.1016/j. jacep.2015.04.004; PMID: 29759357. Frost L, Hune LJ, Vestergard P. Overweight and obesity as risk factors for atrial fibrillation or flutter: the Danish diet, cancer, and health study. Am J Med 2005;118:489–95. https://doi. org/10.1016/j.amjmed.2005.01.031; PMID: 15866251. Foy AH, Mandrola J, Liu G, et al. Relation of obesity to new-onset atrial fibrillation and atrial flutter in adults. Am J Cardiol 2018;121:1072–75. https://doi.org/10.1016/j. amjcard.2018.01.019; PMID: 29501206. Tsang TS, Barnes ME, Miyasaka Y, et al. Obesity as a risk factor for the progression of paroxysmal to permanent atrial fibrillation: a longitudinal cohort study of 21 years. Eur Heart J 2008;29:2227–33. https://doi.org/10.1093/eurheartj/ehn324; PMID: 18611964. Sandhu RK, Conen D, Tedrow UB, et al. Predisposing factors associated with development of persistent compared with paroxysmal atrial fibrillation. J Am Heart Assoc 2014;3:e000916. https://doi.org/10.1161/JAHA.114.000916; PMID: 24786144. Karasoy D, Bo Jensen T, Hansen ML, et al. Obesity is a risk factor for atrial fibrillation among fertile young women: a nationwide cohort study. Europace 2013;15:781–6. https://doi.

org/10.1093/europace/eus422; PMID: 23284141. 16. B erkovitch A, Kivity S, Klempfner R, et al. Body mass index and the risk of new-onset atrial fibrillation in middle-aged adults. Am Heart J 2016;173:41–8. https://doi.org/10.1016/j. ahj.2015.11.016; PMID: 26920595. 17. Lee H, Choi EK, Lee SH, et al. Atrial fibrillation risk in metabolically healthy obesity: a nationwide population-based study. Int J Cardiol 2017;240:221–7. https://doi.org/10.1016/j. ijcard.2017.03.103; PMID: 28385358. 18. Pandey A, Gersh BJ, McGuire DK, et al. Association of body mass index with care and outcomes in patients with atrial fibrillation: results from the ORBIT-AF registry. JACC Clin Electrophysiol 2016;2:355–63. https://doi.org/10.1016/j. jacep.2015.12.001; PMID: 29766895. 19. Sandhu RK, Ezekowitz J, Andersson U, et al. The ‘obesity paradox’ in atrial fibrillation: observations from the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial. Eur Heart J 2016;37:2869–78. https://doi.org/10.1093/eurheartj/ehw124; PMID: 27071819. 20. Wang J, Yang YM, Zhu J, et al. Overweight is associated with improved survival and outcomes in patients with atrial fibrillation. Clin Res Cardiol 2014;103:533–42. https://doi. org/10.1007/s00392-014-0681-7; PMID: 24535378. 21. Zhu W, Wan R, Liu F, et al. Relation of body mass index with adverse outcomes among patients with atrial fibrillation: a meta-analysis and systematic review. J Am Heart Assoc 2016;5:e004006. https://doi.org/10.1161/JAHA.116.004006; PMID: 27613773. 22. Miyasaka Y, Barnes ME, Gersh BJ, et al. Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence. Circulation 2006;114:119–25. https://doi.

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Obesity and Atrial Fibrillation

org.10.1161/CIRCULATIONAHA.105.595140; PMID: 16818816. 23. G elber RP, Gaziano JM, Manson JE, et al. A prospective study of body mass index and the risk of developing hypertension in men. Am J Hypertens 2007;20:370–7. https://doi.org/10.1016/j. amjhyper.2006.10.011; PMID: 17386342. 24. Qureshi WT, Alirhayim Z, Blaha MJ, et al. Cardiorespiratory fitness and risk of incident atrial fibrillation: results from the Henry ford exercise testing (FIT) project. Circulation 2015;131:1827–34. https://doi.org/10.1161/ CIRCULATIONAHA.114.014833; PMID: 25904645. 25. Pathak RK, Elliott A, Middeldorp ME, et al. Impact of CARDIOrespiratory FITness on arrhythmia recurrence in obese individuals with atrial fibrillation: the CARDIO-FIT study. J Am Coll Cardiol 2015;66:985–96. https://doi.org/10.1016/j. jacc.2015.06.488; PMID: 26113406. 26. Malmo V, Nes BM, Amundsen BH, et al. Aerobic interval training reduces the burden of atrial fibrillation in the short term: a randomized trial. Circulation 2016;133:466–73. https://doi.org/10.1161/CIRCULATIONAHA.115.018220; PMID: 26733609. 27. Nazare JA, Smith J, Borel AL, et al. Usefulness of measuring both body mass index and waist circumference for the estimation of visceral adiposity and related cardiometabolic risk profile (from the INSPIRE ME IAA study). Am J Cardiol 2015;115:307–15. https://doi.org/10.1016/j.amjcard.2014.10.039; PMID: 25499404. 28. De Schutter A, Lavie CJ, Kachur S, et al. Body composition and mortality in a large cohort with preserved ejection fraction: untangling the obesity paradox. Mayo Clin Proc 2014;89:1072–9. https://doi.org/10.1016/j.mayocp.2014.04.025; PMID: 25039037. 29. Bowman K, Atkins JL, Delgado J, et al. Central adiposity and the overweight risk paradox in aging: follow-up of 130,473 UK Biobank participants. Am J Clin. Nutr. 2017;106:130–5. https:// doi.org/10.3945/ajcn.116.147157; PMID: 28566307. 30. Fenger-Gron M, Overvad K, Tjoneeland A, et al. Lean body mass is the predominant anthropometric risk factor for atrial fibrillation. J Am Coll Cardiol 2017;69:2488–97. https://doi. org/10.1016/j.jacc.2017.03.558; PMID: 28521886. 31. Verdecchia P, Angeli F, Reboldi G. Hypertension and atrial fibrillation: doubts and certainties from basic and clinical studies. Circ Res 2018;122:352–68. https://doi.org/10.1161/ CIRCRESAHA.117.311402; PMID: 29348255. 32. Sarzani R, Salvi F, Dessi-Fulgheri P, et al. Renin-angiotensin system, natriuretic peptides, obesity, metabolic syndrome, and hypertension: an integrated view in humans. J Hypertens 2008;26:831–43. https://doi.org/10.1097/HJH.0b013e3282f624a0; PMID: 18398321. 33. Nguyen Dinh Cat A, Briones AM, Callera GE, et al. Adipocytederived factors regulate vascular smooth muscle cells through mineralocorticoid and glucocorticoid receptors. Hypertension 2011;58:479–88. https://doi.org/10.1161/ HYPERTENSIONAHA.110.168872; PMID: 21788604. 34. Briones AM, Nguyen Din Cat A, Callera GE. Adipocytes produce aldosterone through calcineurin-dependent signalling pathways. Implications in diabetes mellitusassociated obesity and vascular dysfunction. Hypertension 2012;59:1069–78. https://doi.org/10.1161/ HYPERTENSIONAHA.111.190223; PMID: 22493070. 35. Olivier A, Pitt B, Girerd N et al. Effect of eplerenone in patients with heart failure and reduced ejection fraction: potential effect modification by abdominal obesity, Insight from the EMPHASIS-HF trial. Eur J Heart Fail 2017;19:1186–97. https://doi. org/10.1002/ejhf.792; PMID: 28303624. 36. Boudina S, Abel ED. Diabetic cardiomyopathy, causes and effects. Rev Endocr Metab Disord 2010;11:31–9. https://doi. org/10.1007/s11154-010-9131-7; PMID: 20180026. 37. De Sensi F, De Potter TM, Cresti A, et al. Atrial fibrillation in patients with diabetes: molecular mechanisms and therapeutic perspectives. Cardiovasc Diagn Ther 2015;5:364–73. PMID: 26543823. 38. Frey WC, Pilcher J. Obstructive sleep-related breathing disorders in patients evaluated for bariatric surgery. Obes Surg 2003;13:676–83. https://doi. org/10.1381/096089203322509228; PMID: 14627460. 39. Mehra R, Benjamin EJ, Shahar E, et al. Sleep Heart Health Study. Association of nocturnal arrhythmias with sleepdisordered breathing: the Sleep Heart Health Study. Am J Respir Crit Care Med 2006;173:910–6. https://doi.org/10.1164/ rccm.200509-1442OC; PMID: 16424443. 40. Alpert MA, Lavie CJ, Agrawal, et al. Obesity and heart failure: epidemiology, pathophysiology, clinical manifestations and management. Transl Res 2014;164:345–56. https://doi. org/10.1016/j.trsl.2014.04.010; PMID: 24814682. 41. Lavie CJ, Pandey A, Lau DH, et al. Obesity and atrial fibrillation prevalence, pathogenesis, and prognosis. J Am Coll Cardiol 2017;70:2022–35. https://doi.org/10.1016/j.jacc.2017.09.002; PMID: 29025560. 42. Kumar PV, Mundi A, Caldito G, et al. Higher body mass index is an independent predictor of left atrial enlargement. Int J Clin Med 2011;2:556–60. https://doi.org/10.4236/ijcm.2011.25091. 43. Fox CS, Massaro JM, Hoffman U, et al. Abdominal visceral and subcutaneous adipose tissue compartments association with metabolic risk factors in the Framingham heart study. Circulation 2007;116:39–48. https://doi.org/10.1161/ CIRCULATIONAHA.106.675355; PMID: 17576866. 44. Wong CX, Ganesan AN, Selvanayagam JB. Epicardial fat and atrial fibrillation: current evidence, potential mechanisms, clinical implications, and future directions. Eur Heart J 2017;38:1294–1302. https://doi.org.10.1093/eurheartj/ehw045;

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PMID: 26935271. 45. S acks HS, Fain JN. Human epicardial adipose tissue: a review. Am Heart J 2007;153: 907–17. https://doi.org/10.1016/j. ahj.2007.03.019; PMID: 17540190. 46. Muhib S, Fujino T, Sato N, et al. Epicardial adipose tissue is associated with prevalent atrial fibrillation in patients with hypertrophic cardiomyopathy. Int Heart J 2013;54:297–303 https://doi.org/10.1536/ihj.54.297; PMID: 24097220. 47. Sidossis L, Kajimura S. Brown and beige fat in humans: thermogenic adipocytes that control energy and glucose homeostasis. J Clin Invest 2015;125:478–86. https://doi. org/10.1172/JCI78362; PMID: 25642708. 48. Iacobellis G. Local and systemic effects of the multifaceted epicardial adipose tissue depot. Nat Rev Endocrinol 2015;11:363– 71. https://doi.org/10.1038/nrendo.2015.58; PMID: 25850659. 49. Smith HL, Willius FA. Adiposity of the heart. Arch Intern Med 1933;52:911–31. https://doi.org/10.1001/ archinte.1933.00160060085007. 50. Al Chekakie MO, Welles CC, Metoyer R, et al. Epicardial fat is independently associated with human atrial fibrillation. J Am Coll Cardiol 2010;56:784–8. https://doi.org/10.1016/j. jacc.2010.03.071; PMID: 20797492. 51. Tsao H-M, Hu W-C, Wu M-H, et al. Quantitative analysis of quantity and distribution of epicardial adipose tissue surrounding the left atrium in patients with atrial fibrillation and effect of recurrence after ablation. Am J Cardiol 2011;107:1498–1503. https://doi.org/10.1016/j. amjcard.2011.01.027; PMID: 21414593. 52. Nakamori S, Nezafat M, Nho LH, et al. Left atrial epicardial fat volume is associated with atrial fibrillation: a prospective cardiovascular magnetic resonance 3D Dixon study. J Am Heart Assoc 2018;7:e008232. https://doi.org/10.1161/ JAHA.117.008232; PMID: 29572324. 53. Opolski MP, Staruch AD, Kusmierczyk M, et al. Computed tomography angiography for prediction of atrial fibrillation after coronary artery bypass grafting: proof of concept. J Cardiol 2015;65:285–92. https://doi.org/10.1016/j. jjcc.2014.12.006; PMID: 25578786. 54. Wong CX, Sun MT, Odutayo A, et al. Associations of general adiposity and epicardial fat with atrial fibrillation. Circ Arrhythm Electrophysiol 2016;9:1–15. https://doi.org/10.1161/ CIRCEP.116.004378; PMID: 27923804. 55. Chen MC, Chang JP, Liu WH, et al. Increased inflammatory cell infiltration in the atrial myocardium of patients with atrial fibrillation. Am J Cardiol 2008;102:861–5. https://doi. org/10.1016/j.amjcard.2008.05.038; PMID: 18805111. 56. Smorodinova N, Blaha M, Melenovsky V, et al. Analysis of immune cell populations in atrial myocardium of patients with atrial fibrillation or sinus rhythm. PLoS One 2017;12:e01726911. https://doi.org/10.1371/journal.pone.0172691; PMID: 28225836. 57. Mazurek T, Zhang L, Zalewski A, et al. Human epicardial adipose tissue is a source of inflammatory mediators. Circulation 2003;108:2460–6. https://doi.org/10.1161/01. CIR.0000099542.57313.C5; PMID: 14581396. 58. Qu YC, Du YM, Wu SL, et al. Activated nuclear factor-kappaB and increased tumor necrosis factor-alpha in atrial tissue of atrial fibrillation. Scand Cardiovasc J 2009;43:292–7. https://doi. org/10.1080/14017430802651803; PMID: 19169931. 59. Venteclef N, Guglielmi V, Balse E, et al. Human epicardial adipose tissue induces fibrosis of the atrial myocardium through the secretion of adipo-fibrokines. Eur Heart J 2013:1–12. https://doi.10.1093/eurheartj/eht099; PMID: 23525094. 60. Verheule S, Sato T, Everett TT, et al. Increased vulnerability to atrial fibrillation in transgenic mice with selective atrial fibrosis caused by overexpression of TGF-β1. Circ Res 2004;94:1458–65. https://doi.org/10.1161/01. RES.0000129579.59664.9d; PMID: 15117823. 61. Hatem SN, Redheuil A, Gandjbakhch E. Cardiac adipose tissue and atrial fibrillation: the perils of adiposity. Cardiovasc Res 2016;109:502–9. https://doi.org/10.1093/cvr/cvw001; PMID: 26790475. 62. Verheule S, Tuyls E, Gharaviri A, et al. Loss of continuity in the thin epicardial layer because of endomysial fibrosis increases the complexity of atrial fibrillatory conduction. Circ Arrhythm Electrophysiol 2013;6:202–11. https://doi.org/10.1161/ CIRCEP.112.975144; PMID: 23390124. 63. Mahajan R, Lau DH, Brooks AG, et al. Electrophysiological, electroanatomical and structural remodeling of the atria as a consequence of sustained obesity. J Am Coll Cardiol 2015;66:1–11. https://doi.org/10.1016/j.jacc.2015.04.058; PMID: 26139051. 64. Lin Y-K, Chen Y-C, Chen J-H, et al. Adipocytes modulate the electrophysiology of atrial myocytes: implications in obesity-induced atrial fibrillation. Basic Res Cardiol 2012;107:293. https://doi.org.10.1007/s00395-012-0293-1; PMID: 22886089. 65. Iwasaki YK, Shi Y, Benito B, et al. Determinants of atrial fibrillation in an animal model of obesity and acute obstructive sleep apnea. Heart Rhythm 2012;9:1409–16. https:// doi.org/10.1016/j.hrthm.2012.03.024; PMID: 22440155. 66. Balcioglu AS, Cıçek D, Akinci S, et al. Arrhythmogenic evidence for epicardial adipose tissue: heart rate variability and turbulence are influenced by epicardial fat thickness. Pacing Clin Electrophysiol 2015;38:99e106. https://doi.org.10.1111/ pace.12512; PMID: 25224491. 67. Po SS, Scherlag BJ, Yamanashi WS, et al. Experimental model for paroxysmal atrial fibrillation arising at the pulmonary

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Montecucco C, Shiavo G, Tugnoli V, et al. Botulinum neurotoxins: mechanism of action and therapeutic applications. Mol Med Today 1996;2:418–24. https://doi. org/10.1016/1357-4310(96)84845-3; PMID: 8897436. Oh S, Choi E-K, Zhang Y, et al. Botulinum toxin injection in epicardial autonomic ganglia temporarily suppresses vagally mediated atrial fibrillation. Circ Arrhyth Electrophysiol 2011;4:560–5. https://doi.org/10.1161/CIRCEP.111.961854; PMID: 21659633. Yu L, Scherlag BJ, Sha Y, et al. Interactions between atrial electrical remodelling and autonomic remodelling: How to break the vicious cycle. Heart Rhythm 2012;9:804–9. https://doi. org/10.1016/j.hrthm.2011.12.023; PMID: 22214613. Tellor KB, Nguyen SN, Bultas AC, et al. Evaluation of the impact of body mass index on warfarin requirements in hospitalized patients. 2018;12:207–16. https://doi. org.10.1177/1753944718781295; PMID: 29914293. Buckley LF, Rybak E, Aldemerdash A, et al. Direct oral anticoagulants in patients with atrial fibrillation and renal impairment, extremes in weight, or advanced age. Clin Cardiol 2017;40:46–52. https://doi.org/10.1002/clc.22591; PMID: 27716948. Martin K, Beyer-Westendorf J, Davidson BL, et al. Use of the direct oral anticoagulants in obese patients: guidance from the SSC of the ISTH. J Thromb Haemost 2016;14:1308–13. https://doi.org/10.1111/jth.13323; PMID: 27299806. Kubitza D, Becka M, Zuehldorf M, et al. Body weight has limited influence on the safety, tolerability, pharmacokinetics, or pharmacodynamics of rivaroxaban (BAY 59-7939) in healthy subjects. J Clin Pharmacol 2007;47:218–26. https://doi. org/10.1177/0091270006296058; PMID: 17244773. Kaplan RM, Diaz CL, Strzelczyk T, et al. Outcomes with novel oral anticoagulants in obese patients who underwent electrical cardioversion for atrial arrhythmias. Am J Cardiol 2018;122:1175–8. https://doi.org/10.1016/j. amjcard.2018.06.022; PMID: 30072132. Levy S, Lauribe P, Dolla E, et al. A randomized comparison of external and internal cardioversion of chronic atrial fibrillation. Circulation 1992;86:1415-20. https://doi. org/10.1161/01.CIR.86.5.1415; PMID: 1423954. Voskoboinik A, Moskovitch J, Plunkett G, et al. Cardioversion of atrial fibrillation in obese patients: Results from the Cardioversion-BMI randomized controlled trial. J Cardiovasc Electrophysiol 2019;30:155–61. https://doi.org.10.1111/ jce.13786; PMID: 30375104. Winkle RA, Mead RH, Engel G, et al. Impact of obesity on atrial fibrillation ablation: patient characteristics, long-term outcomes, and complications. Heart Rhythm 2017;14:819–27. https://doi.org/10.1016/j.hrthm.2017.02.023; PMID: 28232261. Sivasambu B, Balouch MA, Zghaib T, et al. Increased rates of atrial fibrillation recurrence following pulmonary vein isolation in overweight and obese patients. J Cardiovasc Electrophysiol 2018;29:239–45. https://doi.org/10.1111/jce.13388; PMID: 29131442. Glover BM, Hong KL, Dagres N, et al. Impact of body mass index on the outcome of catheter ablation of atrial fibrillation. Heart 2019;105:244–50. https://doi.org/10.1136/ heartjnl-2018-313490; PMID: 30279268. De Maat GE, Mulder B, Berretty WL, et al. Obesity is associated with impaired longterm success of pulmonary vein isolation: a plea for risk factor management before ablation. Open Heart 2018;5:e000771. https://doi.org/10.1136/ openhrt-2017-000771; PMID: 29862033. Xue Y, Xu X, Zhang X, et al. Preventing diet-induced obesity in mice by adipose tissue transformation and angiogenesis using targeted nanoparticles. Proc Natl Acad Sci USA 2016;113:5552–7. https://doi.org/10.1073/pnas.1603840113; PMID: 27140638. Iacobellis G, Mohseni M, Bianco SD, et al. Liraglutide causes large and rapid epicardial fat reduction. Obesity 2017;25:311–6. https://doi.org/10.1002/oby.21718; PMID: 28124506. Yang J, Ren J, Song J, et al. Glucagon-like peptide 1 regulates adipogenesis in 3T3-L1 preadipocytes. 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2013;310:2050–60. https://doi.org/10.1001/jama.2013.280521; PMID: 24240932. 93. Pathak RK, Middeldorp ME, Meredith M, et al. Long term effect of goal directed weight management in an atrial fibrillation cohort: a long-term follow-up study (LEGACY Study). J Am Coll Cardiol 2015;65:2159–69. https://doi. org/10.1016/j.jacc.2015.03.002; PMID: 25792361. 94. Pathak RK, Middeldorp ME, Lau D, et al. Aggressive risk factor reduction study for atrial fibrillation and implications for the outcome of ablation: The ARREST-AF Cohort Study. J Am Coll Cardiol 2014;64:2222–31. https://doi.org/10.1016/j. jacc.2014.09.028; PMID: 25456757. 95. Middeldorp ME, Pathak RK, Meredith M, et al. PREVEntion and regressive Effect of weight-loss and risk factor modification on Atrial Fibrillation: the REVERSE-AF study. Europace

2018;20:1929–35. https://doi.org/10.1093/europace/euy117; PMID: 29912366. 96. Pathak RK, Evans M, Middeldorp ME, et al. Cost-effectiveness and clinical effectiveness of the risk factor management clinic in atrial fibrillation: the CENT study. JACC: Clin Electrophysiol 2017;3:436–47. https://doi.org/10.1016/j.jacep.2016.12.015; PMID: 29759599. 97. Nalliah CJ, Sanders P, Kalman, JM. The impact of diet and lifestyle on atrial fibrillation. Curr Card Rep 2018;20: 137. https://doi.org/10.1007/s11886-018-1082-8; PMID: 30315401. 98. Jamaly S, Carlsson L, Peltonen M, et al. Bariatric surgery and the risk of new-onset atrial fibrillation in Swedish obese subjects. J Am Coll Cardiol 2016;68:2497–504. https://doi. org/10.1016/j.jacc.2016.09.940; PMID: 27931605.

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Clinical Arrhythmias

Atrial Fibrosis: Translational Considerations for the Management of AF Patients Stylianos Tzeis 1 , Dimitrios Asvestas 1 and Panos Vardas 2 1. Cardiology Department, Mitera General Hospital, Hygeia Group, Athens, Greece; 2. Heart Sector, Hygeia Group Hospitals, Athens, Greece

Abstract Fibrosis plays a fundamental role in the initiation and maintenance of AF, mainly due to enhanced automaticity and anisotropy-related re-entry. The identification and quantification of atrial fibrosis is achieved either preprocedurally by late gadolinium enhancement MRI or intraprocedurally using electroanatomic voltage mapping. The presence and extent of left atrial fibrosis among AF patients may influence relevant decision making regarding the need for anticoagulation, the adoption of rate versus rhythm control and mainly the type of ablation strategy that will be followed during interventional treatment. Several types of individualised substrate modifications targeting atrial fibrotic areas have been proposed, although their impact on patient outcome needs to be further investigated in adequately powered prospective randomised controlled clinical trials.

Keywords Ablation, AF, atrial fibrosis, substrate modification Disclosure: The authors have no conflicts of interest to declare. Received: 14 December 2018 Accepted: 6 February 2019 Citation: Arrhythmia & Electrophysiology Review 2019;8(1):37–41. DOI: https://doi.org/10.15420/aer.2018.79.3 Correspondence: Stylianos Tzeis, 6, Eryhthrou Stavrou, Maroussi, Athens, PC 15123, Greece. E: stzeis@otenet.gr Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

AF is the most common cardiac arrhythmia with a complex and multifactorial pathophysiological background. In their seminal publication, Haissaguerre et al. shed light on the role of rapidly firing pulmonary vein sources in the initiation of AF paroxysms.1 Apart from the role of pulmonary vein-triggering foci, underlying electrical and structural remodelling also contributes to the onset and perpetuation of AF, especially in advanced stages of its natural course. The term ‘electrical remodelling’ mainly reflects the modification of the electrophysiological characteristics of atrial myocytes, while the hallmark of ‘structural remodelling’ is the underlying atrial fibrosis. Interestingly, these two components of atrial remodelling exhibit a substantial mechanistic interplay. The fundamental role of fibrosis in the pathogenesis of AF has attracted intense research interest with evident clinical implications for pertinent management strategies. Fibrosis is characterised by the proliferation of fibroblasts, which subsequently differentiate into myofibroblasts secreting extracellular matrix proteins (collagen). The disorganised myocardial architecture and cellular content promotes arrhythmogenesis in multiple ways.2 Fibroblasts and myofibroblasts may couple electrically to neighbouring cardiomyocytes, modifying their electrical properties and promoting automaticity and ectopic firing.3 In addition, the expanded extracellular matrix disrupts normal electrical cellular coupling, thus enhancing microstructural discontinuities and intensifying directionally dependent variation of conduction velocity. The latter augmentation of tissue anisotropy increases the susceptibility to unidirectional block and re-entry, and contributes to triggering and maintenance of AF. 4,5 Experimental data further supported the key role of atrial fibrosis,

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demonstrating that regions of fibrosis or scar may anchor fibrillatory rotors,6 while re-entrant drivers in persistent AF are confined to specific regions that constitute boundary zones between fibrotic and non-fibrotic tissue.7

Preprocedural Identification of Atrial Fibrotic Areas A method that has been used in limited centres for the identification, localisation and quantification of atrial fibrosis is late gadolinium enhancement (LGE) MRI. The contrast agent accumulates in the extracellular space owing to altered washout kinetics compared with normal tissue, resulting in a higher signal intensity in fibrotic areas due to abundant extracellular space.8 Specific MRI protocols have been introduced and clinically tested for imaging of atrial fibrosis.9,10 The identified fibrotic areas are colour coded on the surface of the left atrial shell, allowing the quantification and subsequent staging of left atrial fibrosis based on the ratio of the volume of the fibrotic left atrial wall (delayed enhancement) to the total left atrial wall volume.9,11 The value of MRI for non-invasive assessment of underlying atrial fibrosis is also supported by data showing that histological findings of collagen content in surgical biopsy specimens correlate with respective tissue characterisation by LGE-MRI.10 Several studies have also shown a high level of agreement between regions of scar identified by LGE-MRI and low-voltage areas identified by electroanatomic voltage mapping.12–14 However, contradictory results have also been reported. In cohorts of patients subjected to AF ablation, the highest LGE coverage is located at the left pulmonary vein antral, left lateral and left posterior wall,15 while low-voltage zones are preferentially distributed in the anterior

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Clinical Arrhythmias wall, septum and posterior wall.16 Interestingly, the reported correlation between different techniques used for fibrosis delineation is influenced by the previous history of catheter ablation, since ablated atrial tissue is more easily identifiable by MRI, contrary to the non-iatrogenic diffuse interstitial atrial fibrosis.17 Despite recent progress in the reproducibility of left atrial fibrosis assessment,18 inherent caveats mainly stem from the reduced thickness of the atrial wall compared with the spatial resolution of the MRI. Additional limitations that may impair image quality and accuracy in LGE quantification include subjectivity in the definition of left atrial borders during segmentation, irregular rhythm and respiration pattern, increased body mass index and other types of technical faults. Another tool that has been proposed for the assessment of underlying fibrosis is surface ECG. The more extensive the underlying atrial fibrosis, the slower the conduction within the left atrium, resulting in a prolonged duration of the sinus P wave. Jadidi et al. have reported a correlation between the extent of left atrial low-voltage substrate, which is indicative of underlying fibrosis, and the duration of amplified sinus P wave.19 They also proposed that a cut-off value of 150 msec identifies patients with fibrotic substrate who are also at increased risk of arrhythmia recurrence following catheter ablation of AF and offers high sensitivity and specificity. Thus, this widely available, non-invasive, low-cost tool could be used in everyday practice for the preprocedural assessment of underlying atrial fibrosis content, as well as improve the success rate of invasive arrhythmia management.

Impact on Patient Management The evaluation of atrial fibrosis as the main indicator of underlying structural remodelling may affect decision making at several stages of the management plan of AF patients. The respective AF treatment domains that are influenced by the presence of underlying atrial fibrosis are assessment of stroke risk and need for anticoagulation; decision for rhythm control strategy; and modification of adopted strategy during catheter ablation.

Assessment of Stroke Risk and Need for Anticoagulation Atrial fibrosis is associated with a worsened prognosis among AF patients. Patients with more severe left atrial LGE are more likely to have a history of stroke and to present with left atrial appendage thrombus or spontaneous echocardiographic contrast in transoesophageal echocardiography.20,21 In an observational study, King et al. demonstrated that left atrial LGE severity, as a marker of fibrotic structural remodelling, is associated with increased risk of major adverse cardiovascular and cerebrovascular events, particularly stroke or transient ischaemic attack.22 Similarly, MĂźller et al. showed that a left atrial low-voltage area that was evaluated by intraprocedural mapping during AF catheter ablation (bipolar voltage <0.5 mV) was associated with history of stroke and silent cerebral ischaemia.23 These findings support a potential role of atrial fibrosis in the stratification of ischaemic stroke risk among AF patients. The adopted risk-stratification schemes (CHA2DS2-VASc score) mainly aim to identify patients with a truly low risk score who do not require antithrombotic therapy. Therefore, the presence of atrial fibrosis, especially if severe, may influence decision making in favour of anticoagulation prescription in patients without clinical risk factors who would not otherwise be considered as suitable candidates for anticoagulation protection.24

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In the case presented in Figure 1, a young woman with homozygous thalassaemia and paroxysmal AF was prescribed anticoagulant treatment despite the absence of any clinical ischaemic risk factors, and solely based on the extensive atrial fibrosis identified during voltage mapping. However, despite similar anecdotal cases, adequately powered prospective studies are needed to validate the role of atrial fibrosis for guidance of antithrombotic treatment in AF patients.

Decision for Rhythm Control Strategy The assessment of atrial fibrosis may aid in the selection of patients anticipated to gain benefit from rhythm control management.25 Accumulating data support the notion that the higher the burden of atrial fibrosis, the more complex the underlying mechanism of AF, and thus the more challenging is sinus rhythm maintenance. Jadidi et al. demonstrated that the mean AF cycle length is inversely related to the extent of LGE on CMR.26 Cochet et al. found that left atrial fibrosis, as assessed by LGE, is the only independent predictor of the number of re-entrant regions and the complexity of underlying re-entrant activity in the left atrium among persistent AF patients subjected to high-resolution electrocardiographic imaging.27 These findings are consistent with evidence derived from experimental studies.28,29 Furthermore, in the clinical context, the amount of preablation atrial fibrosis, as estimated by LGE-MRI, is independently associated with the likelihood of arrhythmia recurrence.9,27 The left atrial wall structural remodelling stage (Utah stage) is the strongest predictor of ablation outcome in multivariate analyses.10 Therefore, especially in the case of persistent and long-term persistent AF, a large volume of atrial fibrosis evidenced by LGE-MRI may serve as a gatekeeper to rule out patients from undergoing one or more demanding ablations in the challenging pursuit of sinus rhythm maintenance.

Impact on Ablation Strategy A wide circumferential electrical isolation of pulmonary veins remains the cornerstone of AF ablation.30 However, despite the need for an adjunctive ablation strategy in addition to pulmonary vein isolation to improve the low rates of sinus rhythm maintenance in patients with persistent and long-standing-persistent AF, randomised clinical trials have failed to show an additional benefit from linear lesions and ablation of complex fractionated electrograms.31 Atrial fibrosis is an attractive target for ablation among patients with AF, as it has been proposed to participate in the complex interplay of diverse pathophysiological mechanisms.32 Despite an existing contradiction on potential spatial correlation between re-entrant activity and underlying atrial fibrosis in AF,27,33 several computational, experimental and human studies have supported the role of atrial fibrosis in anchoring re-entry during AF.34,35 The evident link between fibrotic substrate and re-entrant drivers perpetuating AF has rendered these late gadolinium enhanced areas as potential ablation targets, lending support to the development of an adjunctive ablation strategy to be implemented in addition to pulmonary vein isolation. The first step in the incorporation of atrial fibrosis as an ablation target during invasive management of AF is the accurate identification of atrial fibrotic areas during voltage mapping. Several studies have shown a spatial correlation between low-voltage areas detected by intraprocedural voltage mapping and fibrotic areas identified by delayed enhancement cardiac MRI.36 The evolution of 3D electroanatomic mapping tools and high-density voltage mapping improved the

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Atrial Fibrosis Figure 1: 3D Electroanatomical Mapping During Scheduled Catheter Ablation in a Woman with Thalassaemia and AF

Electroanatomical mapping was performed during scheduled catheter ablation for this woman with thalassaemia major (beta thalassaemia homozygous state) and early persistent AF. She had no clinical thromboembolic risk factors and a CHA2DS2-VASc score of 1 due to her gender. The voltage map was performed in sinus rhythm and demonstrated extensive fibrosis using strict voltage criteria for identification of â&#x20AC;&#x2DC;scarâ&#x20AC;&#x2122; (â&#x2030;¤0.2 mV). Viable tissue was identified only in 17.6% of the left atrial surface. Based on these procedural findings, no ablation lesions were deployed, a rate-control strategy was adopted, and anticoagulant therapy was recommended in contradiction to the current guidelines.

identification of pathological tissue.37 However, voltage mapping during AF tends to overestimate the extent of underlying atrial fibrosis due to significant differences in electrogram voltage amplitude between sinus rhythm and AF at the same sites among persistent AF patients.38 The optimal cut-off value for accurate demarcation of left atrial scar displays regional variation, and a bipolar voltage of 0.27 mV best identified atrial scar compared with delayed enhancement cardiac MRI.39 The optimal ablation method of atrial fibrotic areas in the context of AF ablation has not been clarified. Several ablation strategies targeting atrial fibrotic areas have been proposed in the context of persistent AF ablation.

amplitude of the recorded bipolar electrograms with diverse criteria (less than 0.1 mV, or more than 50% compared with baseline).43,44 The homogenisation lesions within the fibrotic area are complemented by deployment of linear lesions to eliminate conductions channels that increase the likelihood of iatrogenic re-entrant arrhythmias. Yamaguchi et al. reported that implementation of the homogenisation strategy in addition to pulmonary vein isolation in patients with persistent AF and underlying atrial fibrosis significantly increases the likelihood of sinus rhythm maintenance compared with pulmonary vein isolation alone.44

Selective Ablation of Atrial Low-voltage Sites

Homogenisation of the Low-voltage Area

A caveat of targeting all atrial fibrotic areas during substrate modification in persistent AF is the lack of specificity in identifying underlying driver re-entrant circuits or rotors.27 In other words, the majority of pathophysiological culprit re-entrant regions are located within atrial fibrotic areas. However, several fibrotic areas do not home re-entrant circuits, and thus their ablation would not be expected to have an impact on AF organisation or termination.27 Therefore, it seems intriguing to select the low-voltage areas to be targeted during ablation based on the presence of certain electrogram criteria suggestive of a critical role in arrhythmia perpetuation. In this concept, the combined implementation of selection criteria based on both indices of electrical remodelling (specific activation patterns) and structural remodelling (low-voltage areas suggestive of fibrosis) aim to increase the specificity of localising target sites for ablation.

Another ablation approach for the management of underlying atrial fibrosis is the homogenisation of low-voltage areas. This method aims to eliminate all detectable electrograms within the borders of the low-voltage area. In contradiction to the clear procedural endpoint of the BIFA strategy, the homogenisation method aims to reduce the

Several groups have proposed similar strategies of selective ablation of low-voltage atrial regions. Jadidi et al. identified low-voltage areas of interest for subsequent ablation based on specific regional activation patterns including repetitive presence of prolonged fractionation

Box Isolation of the Fibrotic Area The isolated fibrotic areas should also be connected to neighbouring anchoring lines, such as the circumferential pulmonary vein isolation lines or other empirical lines, including the roof line, mitral isthmus line or anterior line.40,41 The deployed connection lesions aim to prevent micro or macro re-entrant arrhythmias through iatrogenically formed conduction channels around the isolated fibrotic areas. This strategy of individualised substrate modification has been reported to improve the ablation success rate when applied in addition to pulmonary vein isolation during ablation of paroxysmal and non-paroxysmal AF (Figure 2).42

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Clinical Arrhythmias Figure 2: Patient with Persistent AF Subjected to Redo Ablation

A: After isolation of the reconnected right inferior pulmonary vein with spot lesions, detailed voltage mapping in sinus rhythm demonstrated patchy fibrosis mainly located at the posterior wall. B: In the context of an individualised invasive management, a posterior box lesion was performed. The figure shows the ablation catheter deploying the roof line with the circular catheter situated at the posterior wall. C: After completion of the posterior box, the elimination of electrical activity on the circular catheter validates the electrical isolation of the posterior wall. D: Final voltage map showing an absence of electrical activity at the posterior wall.

(>70% of AF cycle length), repetitive rotational activity or discrete rapid activity.45 The same group demonstrated that the ablation of those sites in addition to pulmonary vein isolation was associated with significantly reduced recurrence of atrial tachyarrhythmias compared with pulmonary vein isolation only.45 Furthermore, targeted ablation of specific electrograms in low-voltage areas in addition to wide antral circumferential ablation in patients with persistent AF has been reported to improve patient outcome.46

Other Ablation Strategies Targeting Low-Voltage Areas A personalised substrate-modification method targeting left atrial low-voltage areas combining several of the elements described in the aforementioned strategies has been reported. Rolf et al. targeted low-voltage areas for substrate modification by homogenisation of the respective area, or deployment of strategic linear lesions either to encircle and electrically isolate large low-voltage areas or to connect these areas with non-conducting structures.47 The combined application of this individualised substrate modification with pulmonary vein isolation significantly increased AF-free survival compared with pulmonary vein isolation alone.

typical stepwise ablation approach, without, however, implementing any additional substrate ablation in addition to pulmonary vein isolation in more than 50% of patients. These findings further support the concept of an individualised substrate-modification approach tailored to the specific left atrial tissue characteristics of each patient, avoiding potential unnecessary ablation and enhancing procedural safety.

Conclusion The role of atrial fibrosis in the maintenance of persistent AF is well established. Despite our progress in accurately identifying the presence, location and extent of atrial fibrosis, there are gaps in understanding the optimal way of targeting those fibrotic areas of interest during catheter ablation. Diverse existing ablation strategies aiming to modify the arrhythmogenic substrate and to improve the outcome of patients with persistent AF subjected to catheter ablation need to be tested in adequately powered prospective, multicentre studies. These findings are expected to pave the way towards more effective invasive management of AF.

Clinical Perspective In the same context, the multicentre, randomised Electrophysiological Substrate Ablation in the Left Atrium During Sinus Rhythm (STABLESR) trial evaluated the safety and efficacy of a substrate-modification strategy targeting the fibrotic areas in patients with non-paroxysmal AF, with a procedural aim of total tissue homogenisation in low-voltage zones (0.1â&#x20AC;&#x201C;0.4 mV), complex electrogram elimination in the transitional zones and de-channelling if considered necessary.48 This strategy resulted in similar rates of arrhythmia-free survival compared with the

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â&#x20AC;˘ Left atrial fibrosis is independently associated with history of stroke and is a risk factor for future thromboembolic events. Evaluation of atrial fibrosis might improve thromboembolic risk stratification. â&#x20AC;˘ Substrate-modification strategies targeting low-voltage areas in the left atrium may improve the long-term outcome of AF ablation.

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Atrial Fibrosis 1.

10.

11.

12.

13.

14.

15.

16.

17.

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18. C ochet H, Mouries A, Nivet H, et al. Age, atrial fibrillation, and structural heart disease are the main determinants of left atrial fibrosis detected by delayed-enhanced magnetic resonance imaging in a general cardiology population. J Cardiovasc Electrophysiol 2015;26:484–92. https://doi. org/10.1111/jce.12651; PMID: 25727248. 19. Jadidi A, Müller-Edenborn B, Chen J, et al. The duration of the amplified sinus-P-wave identifies presence of left atrial low voltage substrate and predicts outcome after pulmonary vein isolation in patients with persistent atrial fibrillation. JACC Clin Electrophysiol 2018;4:531–43. https://doi.org/10.1016/j. jacep.2017.12.001; PMID: 30067494. 20. Daccarett M, Badger TJ, Akoum N, et al. Association of left atrial fibrosis detected by delayed-enhancement magnetic resonance imaging and the risk of stroke in patients with atrial fibrillation. J Am Coll Cardiol 2011;57:831–8. https://doi. org/10.1016/j.jacc.2010.09.049; PMID: 21310320. 21. Akoum N, Fernandez G, Wilson B, et al. Association of atrial fibrosis quantified using LGE-MRI with atrial appendage thrombus and spontaneous contrast on transesophageal echocardiography in patients with atrial fibrillation. J Cardiovasc Electr 2013;24:1104–9. https://doi.org/10.1111/jce.12199; PMID: 23844972. 22. King JB, Azadani PN, Suksaranjit P, et al. Left atrial fibrosis and risk of cerebrovascular and cardiovascular events in patients with atrial fibrillation. J Am Coll Cardiol 2017;70:1311–21. https://doi.org/10.1016/j.jacc.2017.07.758; PMID: 28882227. 23. Müller P, Makimoto H, Dietrich JW, et al. Association of left atrial low-voltage area and thromboembolic risk in patients with atrial fibrillation. Europace 2018;20(FI_3):f359–65. https://doi.org/10.1093/europace/eux172; PMID: 29016757. 24. Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Europace 2016;18:1609–78. https://doi.org/10.1016/j.rec.2016.11.033; PMID: 28038729. 25. Akoum N, Daccarett M, McGann C, et al. Atrial fibrosis helps select the appropriate patient and strategy in catheter ablation of atrial fibrillation: a DE-MRI guided approach. J Cardiovasc Electrophysiol 2011;22:16–22. https://doi. org/10.1111/j.1540-8167.2010.01876.x; PMID: 20807271. 26. Jadidi AS, Cochet H, Shah AJ, et al. Inverse relationship between fractionated electrograms and atrial fibrosis in persistent atrial fibrillation: combined magnetic resonance imaging and high-density mapping. J Am Coll Cardiol 2013;62:802–12. https://doi.org/10.1016/j.jacc.2013.03.081; PMID: 23727084. 27. Cochet H, Dubois R, Yamashita S, et al. Relationship between fibrosis detected on late gadolinium-enhanced CMR and re-entrant activity assessed with ECGI in human persistent atrial fibrillation. JACC Clin Electrophysiol 2018;4:17–29. https://doi.org/10.1016/j.jacep.2017.07.019; PMID: 29479568. 28. Zlochiver S, Muñoz V, Vikstrom KL, et al. Electrotonic myofibroblast-to-myocyte coupling increases propensity to reentrant arrhythmias in two-dimensional cardiac monolayers. Biophys J 2008;95:4469–80. https://doi. org/10.1529/biophysj.108.136473; PMID: 18658226. 29. Tanaka K, Zlochiver S, Vikstrom KL, et al. Spatial distribution of fibrosis governs fibrillation wave dynamics in the posterior left atrium during heart failure. Circ Res 2007;101:839–47. 10.1161/CIRCRESAHA.107.153858; PMID: 17704207. 30. Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ ECAS/APHRS/ SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation: Executive summary. Europace 2018;20:157–208. https://doi.org/10.1093/ europace/eux275; PMID: 29016841. 31. Verma A, Jiang CY, Betts TR, et al. Approaches to catheter ablation for persistent atrial fibrillation. N Engl J Med 2015;372:1812–22. https://doi.org/10.1056/NEJMoa1408288; PMID: 25946280. 32. Hansen BJ, Zhao J, Fedorov VV. Fibrosis and atrial fibrillation: computerized and optical mapping: a view into the human atria at submillimeter resolution. JACC Clin Electrophysiol 2017;3:531–46. https://doi.org/10.1016/j.jacep.2017.05.002; PMID: 29159313. 33. Chrispin J, Gucuk Ipek E, Zahid S, et al. Lack of regional association between atrial late gadolinium enhancement

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on cardiac magnetic resonance and atrial fibrillation rotors. Heart Rhythm 2016;13:654–60. https://doi.org/10.1016/j. hrthm.2015.11.011; PMID: 26569460. Gonzales MJ, Vincent KP, Rappel WJ, et al. Structural contributions to fibrillatory rotors in a patient-derived computational model of the atria. Europace 2014;16(Suppl 4):iv3–10. https://doi.org/10.1093/europace/euu251; PMID: 25362167. Hansen BJ, Zhao J, Csepe TA, et al. Atrial fibrillation driven by micro-anatomic intramural re-entry revealed by simultaneous sub-epicardial and sub-endocardial optical mapping in explanted human hearts. Eur Heart J 2015;36:2390–401. https://doi.org/10.1093/eurheartj/ehv233; PMID: 26059724. Oakes RS, Badger TJ, Kholmovski EG, et al. Detection and quantification of left atrial structural remodeling with delayedenhancement magnetic resonance imaging in patients with atrial fibrillation. Circulation 2009;119:1758–67. https://doi. org/10.1161/CIRCULATIONAHA.108.811877; PMID: 19307477. Asvestas D, Vlachos K, Bazoukis G. Left atrial voltage mapping using a new impedance-based algorithm in patients with paroxysmal atrial fibrillation. Pacing Clin Electrophysiol 2018;41:1447–53. https://doi.org/10.1111/pace.13501; PMID: 30225845. Masuda M, Fujita M, Iida O, et al. Comparison of left atrial voltage between sinus rhythm and atrial fibrillation in association with electrogram waveform. Pacing Clin Electrophysiol 2017;40:559–67. https://doi.org/10.1111/pace.13051; PMID: 28211132. Kapa S, Desjardins B, Callans DJ, et al. Contact electroanatomic mapping derived voltage criteria for characterizing left atrial scar in patients undergoing ablation for atrial fibrillation. J Cardiovasc Electrophysiol 2014;25:1044–52. https://doi.org/10.1111/jce.12452; PMID: 24832482. Kottkamp H, Bender R, Berg J. Catheter ablation of atrial fibrillation: how to modify the substrate? J Am Coll Cardiol 2015;65:196–206. https://doi.org/10.1016/j.jacc.2014.10.034; PMID: 25593061. Tzeis S, Luik A, Jilek C, et al. The modified anterior line: an alternative linear lesion in perimitral flutter. J Cardiovasc Electrophysiol 2010;21:665–70. https://doi.org/10.1111/j.15408167.2009.01681.x; PMID: 20050958. Kottkamp H, Berg J, Bender R, et al. Box isolation of fibrotic areas (BIFA): a patient-tailored substrate modification approach for ablation of atrial fibrillation. J Cardiovasc Electrophysiol 2016;27:22–30. https://doi.org/10.1111/jce.12870; PMID: 26511713. Yang G, Yang B, Wei Y, et al. Catheter ablation of nonparoxysmal atrial fibrillation using electrophysiologically guided substrate modification during sinus rhythm after pulmonary vein isolation. Circ Arrhythm Electrophysiol 2016;9:e003382. https://doi.org/10.1161/CIRCEP.115.003382; PMID: 26857907. Yamaguchi T, Tsuchiya T, Nakahara S, et al. Efficacy of left atrial voltage-based catheter ablation of persistent atrial fibrillation. J Cardiovasc Electrophysiol 2016;27:1055–63. https://doi.org/10.1111/jce.13019; PMID: 27235000. Jadidi AS, Lehrmann H, Keyl C, et al. Ablation of persistent atrial fibrillation targeting low-voltage areas with selective activation characteristics. Circ Arrhythm Electrophysiol 2016;9:pii:e002962. https://doi.org/10.1161/ CIRCEP.115.002962; PMID: 26966286. Efremidis M, Vlachos K, Letsas KP, et al. Targeted ablation of specific electrogram patterns in low-voltage areas after pulmonary vein antral isolation in persistent atrial fibrillation: termination to an organized rhythm reduces atrial fibrillation recurrence. J Cardiovasc Electrophysiol 2019;30:47–57. https://doi. org/10.1111/jce.13763; PMID: 30288830. Rolf S, Kircher S, Arya A, et al. Tailored atrial substrate modification based on low-voltage areas in catheter ablation of atrial fibrillation. Circ Arrhythm Electrophysiol 2014;7:825–33. https://doi.org/10.1161/CIRCEP.113.001251; PMID: 25151631. Yang B, Jiang C, Lin Y, et al. STABLE-SR (Electrophysiological Substrate Ablation in the Left Atrium During Sinus Rhythm) for the treatment of nonparoxysmal atrial fibrillation: a prospective, multicenter randomized clinical trial. Circ Arrhythm Electrophysiol 2017;10. https://doi.org/10.1161/ CIRCEP.117.005405; PMID: 29141843.

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Clinical Arrhythmias

The Atrial Phenotype of the Inherited Primary Arrhythmia Syndromes Giulio Conte, 1,2 Ulrich Schotten 3 and Angelo Auricchio 1,2 1. Division of Cardiology, Cardiocentro Ticino, Lugano, Switzerland; 2. Centre for Computational Medicine in Cardiology, Faculty of Informatics, Università della Svizzera Italiana, Lugano, Switzerland; 3. Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht, the Netherlands

Abstract Over the past two decades, our understanding of inherited primary arrhythmia syndromes has been enriched by studies that have aimed to define the clinical characteristics and the genetic, cellular and molecular features predisposing patients to an enhanced risk of ventricular arrhythmias. In contrast, very little is known about the causative role of inherited cardiac channelopathies on atrial conduction abnormalities possibly leading to different atrial tachyarrhythmias. The diagnostic and therapeutic management of patients with an inherited cardiac channelopathy presenting with atrial arrhythmias remains highly challenging and is in urgent need of improvement. This review will assess the current knowledge on atrial electrical abnormalities affecting patients with different forms of inherited primary arrhythmia syndromes, including long and short QT syndromes, early repolarisation syndrome, catecholaminergic polymorphic ventricular tachycardia and Brugada syndrome.

Keywords Inherited primary arrhythmia syndromes, channelopathies, Brugada syndrome, atrial arrhythmias, atrial fibrillation, genotype, phenotype, electrocardiography, long QT syndrome, short QT syndrome, early repolarisation syndrome, catecholaminergic polymorphic ventricular tachycardia Disclosure: The authors have no conflicts of interest to declare. Received: 21 December 2018 Accepted: 30 January 2019 Citation: Arrhythmia & Electrophysiology Review 2019;8(1):42–6. DOI: https://doi.org/10.15420/aer.2019.4.2 Correspondence: Giulio Conte, Electrophysiology Unit, Division of Cardiology, Fondazione Cardiocentro Ticino, Lugano, Switzerland. E: Giulio.Conte@cardiocentro.org Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

The Risk of Atrial Arrhythmias in Inherited Primary Arrhythmia Syndromes The inherited primary arrhythmia syndromes (IPAS) are a heterogeneous group of diseases caused by mutations in genes encoding for cardiac ion channels. People affected by one of these inherited diseases have no overt structural cardiac abnormalities but are at higher risk of sudden cardiac death due to the occurrence of life-threatening ventricular arrhythmias.1 Cardiac channelopathies include Brugada syndrome (BrS), short and long QT syndromes (SQTS and LQTS), early repolarisation syndrome (ERS) and catecholaminergic polymorphic ventricular tachycardia (CPVT).1 The vast majority of IPAS present with a specific ECG phenotype, characterised by an abnormal ventricular depolarisation and/or repolarisation phase, such as the coved-type ST-segment elevation in the right precordial leads, infero-lateral early repolarisation (ER), long QT and short QT intervals.1,2 These abnormalities reflect altered imbalance in ionic currents of cardiac myocytes, that may lead to development of ventricular arrhythmias such as monomorphic, polymorphic ventricular tachycardia (VT) or VF. Since the diagnostic ECG ventricular pattern of many IPAS is dynamic and often concealed, it is particularly difficult to estimate the prevalence of these diseases in the general population. However, most studies indicate that BrS is probably the most common with a prevalence ranging from 1:2,000 in Europe to 1:1,000 in Asian and south-east Pacific countries, followed by LQTS which has an estimated prevalence

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of four in 10,000 worldwide.1 BrS may present overlapping ECG and clinical features with ERS and an ER pattern in the infero-lateral leads with a J-point elevation ≥0.2 mV has been observed in up to 6% of community-based middle-aged subjects without BrS.3 SQTS and CPVT are the two rarest cardiac channelopathies with a prevalence of 2.7 in 100,000 and 1 in 10,000, respectively, worldwide.1 Both atrial and ventricular cardiomyocytes may express proteins encoded by the same mutated gene, which makes atrial arrhythmias common in patients with inherited primary arrhythmia syndromes.4 Paroxysmal AF is by far the most common atrial arrhythmia observed in these patients, and is occasionally the first and only manifestation of an inherited cardiac ion channel dysfunction.2,5 While the prevalence of paroxysmal AF in the young (aged <50 years) is 0.1%, prevalence of AF is significantly higher among people with IPAS, ranging from 2% for patients with genetically proven LQTS to 30% for subjects with SQTS (Table 1).6–8 In recent years, scientific evidence has been provided on the genetic basis of AF in the general population. Many monogenic mutations or rare variants have been identified.14 However, although useful in understanding the pathophysiology of AF, these mutations or rare variants have limited value in explaining the heritability of AF, accounting only for sporadic or familial cases of AF. Genomewide association studies for AF have identified 97 loci that are

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Inherited Primary Arrhythmia Syndromes significantly associated with an increased risk of AF that might be potential signals for the causative genes.14 It is still unknown the specific role of genetic variants in enhancing the risk of atrial arrhythmias in IPAS.

Table 1: Prevalence of Atrial Arrhythmias in Inherited Primary Arrhythmia Syndromes

Long QT Syndrome

Long QT syndrome

4 in 10,000

Eleven LQTS susceptibility genes have been described so far. However, mutations in three genes (KCNQ1-mediated LQT1, KCNH2-mediated LQT2, and SCN5A-mediated LQT3) account for 75% of clinically definite LQTS. It has been shown that a patient with LQTS has a 17-fold higher risk of experiencing AF before the age of 50 compared with populationbased individuals (RR 17.5, CI 2.2â&#x20AC;&#x201C;139.6).7 Of patients with genetically proven LQTS and AF, 63% present with a loss-of-function mutation in KCNQ1.7

Short QT syndrome

2.7 in 100,000

30%

Brugada syndrome

1 in 2,000

20%

Early repolarisation syndrome

Unknown

15%

Catecholaminergic polymorphic ventricular tachycardia

1 in 10,000

Unknown

Prevalence

Atrial Arrhythmias Rate

Kirchhoff et al. reported that patients with LQTS have altered atrial electrophysiology due to the prolongation of the atrial action potential and the atrial effective refractory period (Figure 1). These alterations, possibly determined by a dysfunction of KCNQ1-encoded IKs, lead to an enhanced susceptibility for an atrial form of torsades de pointes, having a longer cycle length, but resembling AF on the surface ECG (Table 2).9 Similarly, Satoh and Zipes reported the effects of caesium chloride, a potassium channel blocker, in determining polymorphic atrial tachyarrhythmias by producing early after-depolarisations in canines. Based on these observations, it might be speculated that patients with LQTS present a similar arrhytmogenic platform for the development of both ventricular and atrial tachyarrhythmias.10

Short QT Syndrome Three gain-of-function gene mutations encoding for cardiac potassium channels have been associated with SQTS: KCNH2 (SQT1), KCNQ1 (SQT2) and KCNJ2 (SQT3). AF is common in patients with SQTS and in half of all cases it is the first clinical manifestation of the syndrome.8 The potential physio-pathological mechanism responsible in SQTS for both atrial and ventricular arrhythmias is shortening of the refractory period due to a gain of function of potassium channels.11

Early Repolarisation Syndrome and Catecholaminergic Polymorphic Ventricular Tachycardia No specific information is available on atrial arrhythmias in patients with ERS and CPVT. Junttila et al. reported that paroxysmal AF occurs in 15% of middle-aged subjects with an infero-lateral ER pattern.12 A gain-of-function in gene encoding in the cardiac potassium channel (Kir6.1) is associated with both increased AF susceptibility and ER, indicating a role for the ion channel function in both ventricular and atrial repolarisation.13 Ventricular pathophysiological mechanisms leading to ERS are still controversial and no specific studies have been carried out to assess the atrial electrophysiological abnormalities in these patients. Atrial tachyarrhythmias seem to be rare in patients with CPVT. Exercise-induced supraventricular arrhythmias have been only sporadically reported in patients with CPVT and no further specific data have been reported.1,4 More than half of CPVT cases are caused by autosomal-dominant missense mutations in the ryanodine receptor (RyR2), which is the major calcium (Ca 2+) release channel on the sarcoplasmic reticulum (SR) required for excitationcontraction coupling in cardiac muscle.15 In mouse models of CPVT, it has been shown that RyR2-mediated diastolic SR Ca 2+ leak in atrial

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Figure 1: Effects of Different Cardiac Channelopathies on Atrial Electrophysiology

Duration of action potential

Brugada syndrome Long QT syndrome

Short QT syndrome

Atrial effective refractory period

Long QT syndrome

Short QT syndrome

Intra-atrial conduction

Brugada syndrome

Sinus node function Brugada syndrome Catecholaminergic polymorphic ventricular tachycardia

myocytes is associated with AF.16 Moreover, most experimental studies agree that RyR2 phosphorylation by protein kinase A and Ca 2+ calmodulin-dependent protein kinase II can potentiate SR Ca 2+ leak, which is associated with ectopic activity and susceptibility to arrhythmias in CPVT.17

Atrial Arrhythmias in Brugada Syndrome The ECG hallmark of BrS is the presence of a coved-type ST-segment elevation of >2 mm (Brugada type 1 ECG) in at least one right precordial lead (V1 and V2), placed in a standard or superior position.2 The Brugada type 1 ECG can be concealed, becoming apparent only under certain conditions such as fever or enhanced vagal tone. Most prominent ECG changes usually appear just before the onset of ventricular arrhythmias. The Brugada type 1 ECG is required for the diagnosis of BrS and, in the case of a non-diagnostic baseline ECG, can be unmasked by the IV administration of sodium channel blockers, such as ajmaline or flecainide.2 The ECG phenotypic expression of BrS is determined by the presence of an outward shift of the balance in repolarising currents

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Clinical Arrhythmias Table 2: Atrial Arrhythmia Features in Long and Short QT Syndromes and Brugada Syndrome Long QT Syndrome

Short QT Syndrome

Brugada Syndrome

ECG hallmark

QTc >440/460 ms

QTc <320 ms

Coved type ST-segment elevation (Type 1 ECG)

Ventricular arrhythmia

Polymorphic ventricular tachycardia

Ventricular fibrillation

Polymorphic ventricular tachycardia/ ventricular fibrillation

Atrial arrhythmia

Polymorphic atrial tachycardia

Atrial fibrillation

Prevalence of AF

LQT1: 2.4% LQT2: 0% LQT3: 1.7%

30%

20%

Mean age at AF diagnosis (years)

Known susceptibility genes

11 genes (most commonly KCNQ1, KCNH2, SCN5A)

3 genes (KCNH2, KCNQ1, KCNJ2)

19 genes (SCN5A, KNCJ8, CACNA1C, CACNA2D1, CACNB2b, ABCC9, SCN10A, GpD1L, SCN1B, KCNE3, SCN3B, KCND3, RANGFR, SLMAP, SCN2B, PKP2, FGF12, HEY2, SEMA3A)

Response to drugs

Ameliorative response: mexiletine Ameliorative response: quinidine; Proarrhythmic effects: amiodarone, sotalol propafenone

at the level of the right ventricular outflow tract (RVOT), caused by a decrease in sodium or calcium channel currents or an increase in outward potassium currents, which creates a notch in the action potential of the epicardium resulting in a transmural voltage gradient.18 Although the pathophysiological origin of the syndrome is still under debate, there is general consensus that the presence of functional abnormalities in the epicardial RVOT leads to the ventricular phenotypic manifestation of the disease. Nademanee et al. observed that abnormal fractionated late potentials can be found in the RVOT epicardium of people with BrS and can be eliminated by catheter ablation.19 These findings were later confirmed by Pappone et al., who reported that epicardial mapping and ablation of BrS can be safely performed and its efficacy can be confirmed by post-ablation remapping and flecainide testing, and results in the elimination of abnormal substrate and simultaneous disappearance of the typical BrS ECG pattern and no further inducibility of VT/VF.20 Pharmacological therapy with quinidine together with ICD implantation can be used as an alternative to catheter ablation in high-risk patients.21 The efficacy of quinidine is based on its blocking effects on Ito currents (transient outward potassium currents) and can be tested by the absence of VT/VF inducibility during programmed ventricular stimulation.21 Moreover, it has been recently reported in a series of 20 BrS patients undergoing RVOT endomyocardial biopsy that pathologic findings with myocardial inflammation were present in 75% of cases, which prompts the question of whether a combination of electrical and structural abnormalities can explain the arrhythmogenic substrate of BrS.22 Among people with IPAS, BrS is the most genetically heterogeneous disease and has a considerable allelic heterogeneity: mutations in different genes can, in fact, lead to the same clinical manifestation and different mutations in each gene can eventually cause the disease. In addition, different gene mutations and variants can coexist and affect one or more subunits of the potassium, calcium and sodium channel structures.23 BrS has been associated with mutations in 19 different genes. Genetic abnormalities are found in up to 30% of genotyped patients with BrS.24

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Ameliorative response: quinidine Proarrhythmic effects: flecainide, propafenone

Paroxysmal AF is the most common supraventricular arrhythmia in patients with BrS, occurring in about 20% of cases.2,25 Paroxysmal AF represents a relevant clinical issue in BrS for several reasons. Patients with BrS who develop paroxysmal AF have a more severe phenotype and advanced disease process with higher incidence of syncopal episodes, spontaneous or induced sustained ventricular arrhythmias and spontaneous Brugada type 1 ECG.26,27 The incidence of AF is higher in patients with an ICD and up to 20% of these patients can experience inappropriate shocks because of AF with rapid ventricular response.28 Appropriate screening and the choice of the most appropriate type of device (single, dual-chamber or subcutaneous), together with careful programming, is necessary to correctly detect episodes of fast AF and reduce the rate of inappropriate shocks, which are significantly affecting the quality of life of these generally young patients. Moreover, patients with BrS who develop AF have a more frequent positive genetic test, but SCN5A mutation has been associated with prolonged atrial conduction time and AF induction at EPS, but not disease severity.29 The pharmacological treatment of paroxysmal AF in BrS is limited by being unable to use conventional AADs with sodium channel blocking properties, which might be pro-arrhythmic, exposing patients to the development of life-threatening arrhythmias. Indeed, according to the brugadadrugs.org website, flecainide, ajmaline, procainamide, pilsicainide, propafenone are drugs that should be strongly avoided because they have been associated with an enhanced risk of ventricular arrhythmias. Amiodarone, propanolol, verapamil and vernakalant should be preferentially avoided, while there is no mention on the use of sotalol, quinidine or other beta-blockers. However, the latter are underused and not well tolerated by these young patients due to their side-effects. Although pulmonary vein (PV) isolation is currently the most widespread ablation strategy to treat patients with paroxysmal AF, the choice of the best invasive treatment in patients with BrS remains controversial. Indeed, in the general population, pathophysiological mechanisms leading to AF include adverse remodelling of the atrial electro-anatomical substrate and/or abnormal triggered activity.30

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Inherited Primary Arrhythmia Syndromes Pulmonary vein ectopic activity has been established to be the main trigger of paroxysmal AF in patients without structural heart disease.31 Conversely, the pathophysiological mechanisms of AF in patients with BrS are still unknown and the role of PV triggering remains uncertain.32 Moreover, long-term results of AF ablation in patients with BrS are relatively poor when compared with similarly aged with lone AF.33 In fact, at a mean follow-up time of 22 months, nearly 65% of BrS patients were free from AF recurrences after having PV isolation. The arrhythmogenic substrate of BrS might not be restricted to the ventricular level. Similar atrial changes could be the substrate for reentrant atrial tachyarrhythmias but have not been extensively studied. The presence of a prominent transient outward current in atria and the observation that episodes of AF are triggered by closely coupled atrial extrasystoles points to the possibility that a substrate similar to that responsible for ventricular arrhythmogenesis may also be responsible for the development of AF in patients with BrS.34 As for ventricular arrhythmias, the onset of AF in these patients is often preceded by fluctuations in autonomic tone and most AF episodes occur at night.29 Vagal stimulation might reduce atrial conduction velocities and shorten the effective refractory period facilitating the induction of AF.29,30 Apart from AF, BrS can coexist with other forms of atrial arrhythmias, including atrioventricular nodal reentrant tachycardia (AVNRT). Indeed, a concealed BrS ECG is present in 27% of patients presenting with AVNRT.35 In these cases, genetic variants known or suspected to cause loss of function of sodium channel current may provide a mechanistic link between AVNRT and BrS and predispose to the expression of both phenotypes.35

Assessment of Atrial Electrical Activity in Patients with Brugada Syndrome The baseline ECG of people who are prone to AF is easily obtainable and non-invasive and might reflect subclinical structural atrial abnormalities resulting from adverse remodelling of the atrial electroanatomical substrate.36,37 The P-wave on surface ECG represents atrial depolarisation and its duration may be a reliable non-invasive measurement of atrial conduction time. Previous studies have indicated that abnormal P-wave axis and long P-wave duration are strongly associated with an increased risk of AF.38,39 Moreover, P-wave indices which include a summary measure of duration, area and amplitude have been proposed to quantify the atrial electrical properties derived from the ECG, but they have shown only limited value in predicting AF occurrence.40 The baseline ECG of patients with BrS reflects atrial electrical abnormalities resulting from the presence of an atrial channelopathy independently from the presence of previous episodes of AF. Patients with BrS have a longer P-wave duration compared with healthy controls.41,42 This anomaly might be due to the prolonged atrial action potential and increased intra-atrial conduction time reported by Kusano et al.25 These researchers did not find any significant difference in electrophysiological parameters, such as intra-atrial conduction time, duration of local atrial electrograms and atrial effective refractory period between BrS patients with type 1 and those with type 2 or type 3 determined by ECG. This shows the potential existence of a miscorrelation between the atrial and ventricular ECG phenotype, due to a different location or density of the imbalanced ion channels between atria and RVOT.

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Figure 2: Left Atrial High-Density Mapping of a Patient with Brugada Syndrome Undergoing AF Ablation Low voltage area with abnormal electrograms

Recently, the existence of a concealed abnormal atrial phenotype has been documented in BrS without history of AF. 43 Indeed, BrS patients without history of AF present with marked atrial electrical abnormalities which are even more pronounced when compared with those displayed by patients with paroxysmal AF. Moreover, the abnormal P-wave parameters can be detected even in the absence of an overt ventricular ECG phenotype, symptoms or SCN5A gene mutation, indicating the existence of a constant abnormal atrial phenotype and the presence of an atrial-ventricular phenotypic mismatch. The normal action potential in atria differs from that of the ventricle with respect to ion channel currents that contribute to resting membrane potential, phase 1 and phase 3 of the action potential. 44 Experimental and clinical evidence suggests that there is heterogeneity of sodium currents among atrial and epicardial ventricular myocytes.44,45 Indeed, sodium current density is much greater in atrial versus ventricular cells and time constants for activation and inactivation are more rapid in atrial myocytes. These structural and pharmacological differences between atrial and ventricular sodium channels might be exaggerated in patients with an inherited sodium channel dysfunction and might explain the presence of a constantly abnormal atrial phenotype in people with BrS. High-density atrial endocardial mapping might be a useful tool to assess the presence of atrial electrical abnormalities in patients with BrS and documented atrial arrhythmias (Figure 2).

Conclusion and Future Perspectives Available scientific data highlights the evidence that the arrhythmogenic substrate of an inherited ion channel dysfunction is not restricted to the ventricular level and similar abnormalities affect the atrial electrophysiological properties creating the substrate for the occurrence of reentrant atrial tachyarrhythmias. However, specific data on the involvement of the pathogenic process at the level of the atria are lacking and the relationship between the atrial and ventricular phenotype has not been deeply investigated in IPAS. A modelling approach to understanding inherited primary electrical disorders at the atrial level and detailed information about threedimensional distribution of atrial action potentials in people with cardiac channelopathies is of paramount importance. A full insight into atrial involvement in inherited primary arrhythmia syndromes provided by high-resolution ECG and mapping systems, and cardiac simulations might enrich our understanding of the pathophysiological

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Clinical Arrhythmias mechanisms underlying the development of atrial arrhythmias in these patients. In the last decade, particular attention has been focused on the development of atrial-selective drugs for the prevention of AF with the goal of avoiding ventricular pro-arrhythmic effects.45,46 While atrial-selective sodium channel blockers with preferential atrial activity, such as ranolazine, might be useful in the management of AF in the general population, different effects of these drugs might be revealed in patients with a cardiac channelopathy. Indeed, the use of atrial selective sodium channel blockers may be pro-arrhythmic in BrS patients and may, eventually, lead to the development of AF. In-depth characterisation of pathogenesis of atrial arrhythmias in IPAS might have significant clinical implications in the diagnostic and therapeutic management of a much larger group of individuals at risk of AF and, in general, in a very large group of patients affected by lone atrial fibrillation or other cardiac causes.

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Clinical Perspective • The arrhythmogenic substrate of an inherited ion channel dysfunction is not restricted to the ventricular level and similar abnormalities affect the atrial electrophysiological properties creating the substrate for the occurrence of atrial tachyarrhythmias. • Patients with Brugada syndrome present with a concealed abnormal atrial phenotype that can be detected even in the absence of an overt ventricular phenotype. • In-depth characterisation of pathogenesis of atrial arrhythmias in patients with cardiac channelopathies have significant clinical implications in the diagnostic and therapeutic management and lead to a better understanding of the pathophysiological mechanisms and to a more appropriate individualised treatment.

16. S han J, Xie W, Betzenhauser M, et al. Calcium leak through ryanodine receptors leads to atrial fibrillation in 3 mouse models of catecholaminergic polymorphic ventricular tachycardia. Circ Res 2012;111:708–17. https://doi.org/10.1161/ CIRCRESAHA.112.273342; PMID: 22828895. 17. Dobrev D, Wehrens XH. Role of RyR2 phosphorylation in heart failure and arrhythmias: controversies around ryanodine receptor phosphorylation in cardiac disease. Circ Res 2014;114:1311–9; https://doi.org/10.1161/ CIRCRESAHA.114.300568; PMID: 24723656. 18. Yan GX, Antzelevitch C. Cellular basis for the Brugada syndrome and other mechanisms of arrhythmogenesis associated with ST-segment elevation. Circulation 1999;100:1660–6. https://doi.org/10.1161/01.CIR.100.15.1660; PMID: 10517739. 19. Nademanee K, Hocini M, Haïssaguerre M. Epicardial substrate ablation for Brugada syndrome. Heart Rhythm 2017;14:457–61. https://doi.org/10.1016/j.hrthm.2016.12.001; PMID: 27979714. 20. Pappone C, Brugada J, Vicedomini G, et al. Electrical substrate elimination in 135 consecutive patients with Brugada syndrome. Circ Arrhythm Electrophysiol 2017;10:e005053. https:// doi.org/10.1161/CIRCEP.117.005053; PMID: 28500178. 21. Belhassen B, Glick A, Viskin S. Efficacy of quinidine in high-risk patients with Brugada syndrome. Circulation 2004;110:1731–7. https://doi.org/10.1161/01.CIR.0000143159.30585.90; PMID: 15381640. 22. Pieroni M, Notarstefano P, Oliva A, et al. Electroanatomic and pathologic right ventricular outflow tract abnormalities in patients with Brugada syndrome. J Am Coll Cardiol 2018;72:2747–57. https://doi.org/10.1016/j.jacc.2018.09.037; PMID: 30497561. 23. Bezzina CR, Lahrouchi N, Priori SG. Genetics of sudden cardiac death. Circ Res 2015; 116:1919–36. https://doi. org/10.1161/CIRCRESAHA.116.304030; PMID: 26044248. 24. Giustetto C, Cerrato N, Gribaudo E, et al. Atrial fibrillation in a large population with Brugada electrocardiographic pattern: prevalence, management, and correlation with prognosis. Heart Rhythm 2014;11:259–65. https://doi.org/10.1016/j. hrthm.2013.10.043; PMID: 24513919. 25. Kusano KF, Taniyama M, Nakamura K, et al. Atrial fibrillation in patients with Brugada syndrome relationships of gene mutation, electrophysiology, and clinical backgrounds. J Am Coll Cardiol 2008;51:1169–75. https://doi.org/10.1016/j. jacc.2007.10.060; PMID: 18355654. 26. Bigi MA, Aslani A, Shahrzad S. Clinical predictors of atrial fibrillation in Brugada syndrome. Europace 2007;9:947–50. https://doi.org/10.1093/europace/eum110; PMID: 17540664. 27. Bordachar P, Reuter S, Garrigue S, et al. Incidence, clinical implications and prognosis of atrial arrhythmias in Brugada syndrome. Eur Heart J 2004;25:879–84. https://doi. org/10.1016/j.ehj.2004.01.004; PMID: 15140537. 28. Conte G, Sieira J, Ciconte G, et al. Implantable cardioverterdefibrillator therapy in Brugada syndrome: a 20-year singlecentre experience. J Am Coll Cardiol 2015;65:879–88. https://doi. org/10.1016/j.jacc.2014.12.031; PMID: 25744005. 29. Morita H, Kusano-Fukushima K, Nagase S, et al. Atrial fibrillation and atrial vulnerability in patients with Brugada syndrome. J Am Coll Cardiol 2002;40:1437–44. https://doi. org/10.1016/S0735-1097(02)02167-8; PMID: 12392834. 30. Calkins H, Kuck KH, Cappato R, et al. 2012 HRS/EHRA/ ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design. Heart Rhythm 2012;9:632–96.e21. https://doi.org/10.1016/j. hrthm.2011.12.016; PMID: 22386883. 31. Haïssaguerre M, Jaïs P, Shah DC, et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the

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pulmonary veins. N Engl J Med 1998;339:659–66. https://doi. org/10.1056/NEJM199809033391003; PMID: 9725923. Francis J, Antzelevitch C. Atrial fibrillation and Brugada syndrome. J Am Coll Cardiol 2008;51:1149–53. https://doi. org/10.1016/j.jacc.2007.10.062; PMID: 18355651. Conte G, Chierchia GB, Wauters K, et al. Pulmonary vein isolation in patients with Brugada syndrome and atrial fibrillation: a 2-year follow-up. Europace 2014;16:528–32. https://doi.org/10.1093/europace/eut309; PMID: 24108229. Iwasaki YK, Nishida K, Kato T, Nattel S. Atrial fibrillation pathophysiology: implications for management. Circulation 2011;124:2264–74. https://doi.org/10.1161/ CIRCULATIONAHA.111.019893; PMID: 22083148. Hasdemir C, Payzin S, Kocabas U, et al. High prevalence of concealed Brugada syndrome in patients with atrioventricular nodal reentrant tachycardia. Heart Rhythm 2015;12:1584–94. https://doi.org/10.1016/j.hrthm.2015.03.015; PMID: 25998140. German DM, Kabir MM, Dewland TA, et al. Atrial fibrillation predictors: importance of the electrocardiogram. Ann Noninvasive Electrocardiol 2016;21:20–29. https://doi.org/10.1111/ anec.12321; PMID: 26523405. Rangel MO, O’Neal WT, Soliman EZ. Usefulness of the electrocardiographic P-wave axis as a predictor of atrial bibrillation. Am J Cardiol 2016;117:100–4. https://doi. org/10.1016/j.amjcard.2015.10.013; PMID: 26552511. Soliman EZ, Prineas RJ, Case LD, et al. Ethnic distribution of ECG predictors of atrial fibrillation and its impact on understanding the ethnic distribution of ischemic stroke in the Atherosclerosis Risk in Communities (ARIC) study. Stroke 2009;40:1204–11. https://doi.org/10.1161/ STROKEAHA.108.534735; PMID: 19213946. Magnani JW, Williamson MA, Ellinor PT, et al. P wave indices: current status and future directions in epidemiology, clinical, and research applications. Circ Arrhythm Electrophysiol 2009;2:72–9. https://doi.org/10.1161/CIRCEP.108.806828; PMID:19808445. Yamada T, Watanabe I, Okumura Y, et al. Atrial electrophysiological abnormality in patients with Brugada syndrome assessed by P-wave signal-averaged ECG and programmed atrial stimulation. Circ J 2006;70:1574–9. https:// doi.org/10.1253/circj.70.1574; PMID: 17127802. Furukawa Y, Yamada T, Okuyama Y, et al. Increased intraatrial conduction abnormality assessed by P-wave signal-averaged electrocardiogram in patients with Brugada syndrome. Pacing Clin Electrophysiol 2011;34:1138–46. https://doi.org/10.1111/ j.1540-8159.2011.03122.x; PMID: 21605130. Smits JP, Koopmann TT, Wilders R, et al. A mutation in the human cardiac sodium channel (E161K) contributes to sick sinus syndrome, conduction disease and Brugada syndrome in two families. J Mol Cell Cardiol 2005;38:969–81. https://doi. org/10.1016/j.yjmcc.2005.02.024; PMID: 15910881. Conte G, Caputo ML, Volders PGA, et al. Concealed abnormal atrial phenotype in patients with Brugada syndrome and no history of atrial fibrillation. Int J Cardiol 2018;253:66–70. https:// doi.org/10.1016/j.ijcard.2017.09.214; PMID: 29306474. Li GR, Lau CP, Shrier A. Heterogeneity of sodium current in atrial vs epicardial ventricular myocytes of adult guinea pig hearts. J Mol Cell Cardiol 2002;34:1185–94. https://doi. org/10.1006/jmcc.2002.2053; PMID: 12392892. Burashnikov A, Di Diego JM, Zygmunt AC, et al. Atriumselective sodium channel block as a strategy for suppression of atrial fibrillation: differences in sodium channel inactivation between atria and ventricles and the role of ranolazine. Circulation 2007;116:1449–57. https://doi.org/10.1161/ CIRCULATIONAHA.107.704890; PMID: 17785620. Burashnikov A, Antzelevitch C. Atrial-selective sodium channel blockers: do they exist? J Cardiovasc Pharmacol 2008;52:121–8. https://doi.org/10.1097/ FJC.0b013e31817618eb; PMid:18670368.

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Electrophysiology and Ablation

The Evolving Role of Catheter Ablation in Patients With Heart Failure and AF Sandeep Prabhu, Wei H Lim and Richard J Schilling Department of Cardiac Electrophysiology, St Bartholomew’s Hospital, London, UK

Abstract AF and heart failure are emerging epidemics worldwide. Several recent trials have provided a growing evidence base for the benefits of catheter ablation in this patient group, which are yet to be universally adopted in clinical practice guidelines. This paper provides a summary of recent developments in this field and provides pragmatic advice to the treating physician regarding the appropriate role of catheter ablation in the overall management of patients with comorbid AF and heart failure.

Keywords AF, heart failure, catheter ablation, medical rate control, sinus rhythm, left ventricular ejection fraction, catheter ablation Disclosure: The authors have no conflicts of interest to declare. Received: 29 November 2018 Accepted: 27 January 2019 Citation: Arrhythmia & Electrophysiology Review 2019;8(1):47–53. DOI: https://doi.org/10.15420/aer.2019.9.2 Correspondence: Richard J Schilling, St Bartholomew’s Hospital, Department of Cardiac Electrophysiology, W Smithfield, London EC1A 7BE, UK. E: Richard.Schilling@bartshealth.nhs.uk Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Heart failure (HF) and AF are two conditions that are increasing in prevalence worldwide.1,2 They frequently co-exist and in recent years, the clinical and physiological intersection between arrhythmia and HF has become an area of renewed interest, particularly as interventional treatments for rhythm disorders have advanced and moved into the mainstream of cardiac management. In particular, AF, the most frequently encountered cardiac arrhythmia, is now no longer considered as a passive bystander in the setting of HF, but rather an active determinant of clinical outcome,and in some circumstances, the critical driver of the HF itself. 3–5 In this modern context, it is important to re-evaluate the role of existing medical and interventional strategies in the management of patients with co-morbid AF and HF.

Older Studies and Their Limitations The management of AF in HF has been coloured by two early large randomised trials which demonstrated no mortality benefit of pharmacological rhythm control over rate control. In what is still the largest randomised study ever conducted in AF, the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial evaluated overall mortality in 4,060 patients with varying AF burdens, 26% of whom had HF.6 Patients were randomised to a strategy of pharmacological rhythm control (n=2,033) or rate control (n=2,027). No difference was seen between the groups at 5 years, and there was a trend towards a worsened outcome in the rhythm control group (p=0.08). Less well-known is a detailed sub-analysis of the data showing that the presence of sinus rhythm (SR) was associated with a significantly reduced mortality (HR 0.54; p<0.0001) that was largely offset by the increased mortality associated with anti-arrhythmic medical therapy

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to achieve SR, predominately (63%) amiodarone (HR 1.41; p=0.0005).7 Additionally, HF symptoms were also significantly improved with rhythm control.8 Roy et al. randomised 1,376 patients with HF (left ventricular ejection fraction [LVEF] 27 ± 6%) to rhythm (n=682) or rate control (n=684), and also showed no difference in mortality (p=0.59).9 There are two crucial limitations of this study, which largely reflect the limitations of rhythm control management at the time. Firstly, amiodarone, known to be associated with increased mortality, was the rhythm control agent used in the majority (84%) of patients. Ablation was used in only 3.2% of patients. Secondly, it is important to note the study compared treatment strategies (rhythm control to rate control) and so was inherently limited by the poor efficacy of medical rhythm control strategies to maintain durable SR. At 5 years follow-up, only 42% of patients in the rhythm control arm were free from AF. This limited the study’s ability to assess the effect of durable SR upon outcome. Despite these limitations, these studies continue to influence the current clinical guidelines for management of AF, including in those with concurrent HF.

Catheter Ablation for AF in Heart Failure The recent advent of catheter ablation as a mainstream treatment for AF has allowed the restoration of SR with improved efficacy and without the toxicities of long-term anti-arrhythmic therapy. Consequently, a consistent body of evidence has been developed demonstrating the benefits of catheter ablation in patients with systolic HF compared to standard medical therapy. This has recently been expertly reviewed by Mukherjee et al.10 Table 1 summarises the existing randomised data comparing catheter ablation to medical therapy (either rhythm or rate control). Consistent improvements in ejection fraction, functional

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Electrophysiology and Ablation Table 1: Randomised Studies Comparing Catheter Ablation to Medical Treatment in Heart Failure Study

Average LVEF

Treatment Arms

Cardiac

Clinical Outcomes

Improvements McDonald et al. 200435

18%

CA versus MRC

↑ LVEF

Not assessed

Jones et al. 2008

24%

CA versus MRC

↑ VO2 max ↑ QOL ↓ BNP

Not assessed

Khan et al. 200826

28%

CA versus CRT + atrioventricular node ablation

↑ LVEF ↑ 6MWT distance ↑ QOL

Not assessed

Hunter et al. 201446

33%

CA versus MRC

↑ VO2 max ↑ QOL ↓ Serum BNP

Not assessed

Di Biase et al. 201611

203

30%

CA versus amiodarone

↑ LVEF ↑ 6MWT dist. ↑ QOL

↓ Overall mortality ↓ Unplanned hospitalisation

Prabhu et al. 20175

33%

CA versus MRC

↑ ↓ ↓ ↓ ↓

Marrouche et al. 20184

363

32%

CA versus standard medical therapy

↑ LVEF

LVEF LVESV NYHA class Serum BNP Diffuse fibrosis

Not assessed

↓ Primary endpoint (Overall mortality + HF admissions) ↓ Overall mortality ↓ CV mortality ↓ HF admissions

BNP = brain natriuretic peptide; CA = catheter ablation; HF = heart failure; LVEF = left ventricular ejection fraction; LVESV = left ventricular end systolic volume; MRC = medical rate control; NYHA = New York Heart Association; QOL = quality of life; 6MWT = 6-minute walk test.

capacity (both objective and subjectively assessed), biomarkers and objective quality of life measures have been demonstrated. The Ablation vs. Amiodarone for Treatment of Atrial Fibrillation in Patients with Congestive Heart Failure and an Implanted ICD/CRTD (AATAC-AF) study specifically compared the efficacy of a strategy of rhythm control with catheter ablation to rhythm control with amiodarone in patients with HF, by randomising 203 patients to either strategy.11 The ablation arm demonstrated unequivocal superiority in terms of maintaining SR (70% versus 34% at 24 months; p<0.001), in addition to reduced mortality (8% versus 18%; p=0.037) and unplanned hospitalisations (RR 0.55; 95% CI [0.39– 0.76]). The Catheter Ablation versus Standard Conventional Therapy in Patients with Left Ventricular Dysfunction and Atrial Fibrillation (CASTLE-AF) study compared catheter ablation to standard medical therapy in patients with HF and was specifically powered to evaluate the hard-clinical endpoints of mortality and HF hospitalisation.4 In addition to significantly fewer patients randomised to catheter ablation meeting the primary endpoint (28.5% versus 44.6%; HR 0.62; p=0.007), individual secondary endpoints including overall mortality (HR 0.53; p=0.01) cardiovascular death (HR 0.49; p=0.009) and unplanned HF admissions (HR 0.56; p=0.004), all reached significance in favour of catheter ablation.4 Several recent meta-analyses have consistently shown improvements in ejection fraction, quality of life, functional capacity, hospitalisation and mortality.12–14 Recently, the much-anticipated results of the Catheter Ablation Versus Anti-arrhythmic Drug Therapy for AF (CABANA) trial were presented at the 2018 HRS Late Breaking Clinical Trials Session. That trial randomised 2,204 patients with AF to either catheter ablation (n=1,108) or standard medical therapy (n=1,092). Although the

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primary endpoint (composite of all-cause mortality, disabling stroke, serious bleeding or cardiac arrest) was negative for the overall study (p=0.30), those patients undergoing catheter ablation with symptomatic HF (NYHA II+), had a significant 49% reduction in the primary endpoint.

The Interaction of AF and Heart Failure AF and HF share several pathophysiological mechanisms, each of which promote the progression of the other. AF drives HF by three primary mechanisms: • tachycardia;15 • ventricular irregularity;16 and • the loss of atrial contractile function.17 Irrespective of its aetiology, HF creates a physiological environment which facilitates the development and progression of AF through adverse atrial remodelling.18–19 This occurs through: • raised filling pressures;20 • abnormal calcium handling;21 and • the activation of neural-hormonal pathways which promote atrial stretch and fibrosis.22 For this reason, AF and HF frequently co-exist with reported rates as high as 35% in some studies.23 Disentangling the “chicken and egg” relationship between the two can be challenging for the treating physician, particularly as the symptoms of both conditions are often non-specific (such as exertional dyspnoea and fatigue) with palpitations often absent. In patients with dilated cardiomyopathy, the presence of AF at the time of initial presentation with HF has been reported as high as 68%.5 Nonetheless, attempting to ascertain the contributory

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Catheter Ablation in Patients with Heart Failure and AF significance of the AF to the HF is crucial as the elimination of AF in some patients, may have a dramatic impact upon cardiac function.

AF-mediated Heart Failure

Treated

Untreated Tachycardia Loss of atrial contractile function Ventricular irregularity

Loss of atrial contractile function Ventricular irregularity

Limitations of Medical Rate Control Importantly, the benefits of restoring SR for improving ventricular function seen in the CAMERA-MRI study were demonstrated even in well-managed rate-controlled AF. Average ventricular rates were within guideline criteria before randomisation and further improved in the MRC arm during the study period. While the concept of tachycardiamediated cardiomyopathy has been well-described, the ability for irregular ventricular activity and/or the loss of atrial contractile function to mediate reduced systolic function in the absence of rapid rates is relatively novel. Hsu et al. first described significant improvements in LVEF post catheter ablation even in patients adequately rate-controlled at baseline.25 Furthermore, in a small randomised study comparing the restoration of SR with catheter ablation to the ultimate rate control of pacing and AV node ablation, Khan et al., demonstrated a greater improvement in LVEF in those in SR.26 Figure 1 illustrates a likely hypothesis for this. SR is the only treatment strategy that completely treats all three drivers of HF, thus explaining its benefit over pacing and atrioventricular node (AVN) ablation which are still unable to restore atrial contractile function.26 As demonstrated in the CAMERA-MRI study, even maximal MRC is unable to match the average ventricular rates achieved by the restoration of SR. As such, MRC effectively only partially treats the tachycardia component, with no impact on the other mechanisms. At 6 months, mean heart rate was significantly lower in the catheter ablation group (all of whom were in SR, compared to the MRC group, all of whom were in AF (67 ± 9.1 versus 86 ± 14 BPM; p<0.0001). Similar findings were seen for resting and post exercise heart rates.5 Additionally, in a sub-study of CAMERA-MRI, the restoration of SR also resulted in a regression of adverse ventricular remodelling (ventricular diffuse fibrosis) compared to MRC, suggesting an additional benefit of SR in the context of HF.27

Loss of atrial contractile function Ventricular irregularity

Sinus rhythm

Tachycardia

AVN ablation

Tachycardia

Rate control

Tachycardia

No treatment

The ability of AF to cause systolic dysfunction has been somewhat underappreciated,particularly where the cause of HF is uncertain (often classed as idiopathic).24 The recently reported Catheter Ablation Versus Medical Rate Control in AF and Systolic Dysfunction (CAMERAMRI) study evaluated 66 patients with persistent AF and LVEF ≤45%, who were randomised to either catheter ablation or continuing ongoing medical rate control (MRC).5 All patients were on established anti-failure medical therapy and had optimal MRC at baseline. Patients underwent cardiac MRI at baseline and 6 months post randomisation. At 6 months, the catheter ablation group had substantially improved LVEF compared to the MRC arm (18.3 % improvement versus 4.4%; p<0.0001). Furthermore, 71% patients undergoing catheter ablation with no evidence of scarring (or late gadolinium enhancement) on baseline MRI imaging, had normalised LV function by 6 months, suggesting this imaging feature may identify those patients with a true underlying AF mediated cardiomyopathy.

Figure 1: Comparison of AF Treatment Strategies in Addressing the Drivers of Heart Failure

Medical rate control offers partial treatment only of tachycardia, with no effect upon ventricular irregularity or restoring atrial contractile function. Atrioventricular node ablation completely addresses ventricular irregularity and tachycardia, but with no impact upon atrial contractile function given AF remains untreated. Sinus rhythm is the only treatment strategy which completely addresses all three drivers of HF. AVN = atrioventricular node.

worsen the ventricular function in these patients. The current literature offers minimal guidance in this area. Hsu et al. published the outcomes for 58 patients undergoing catheter ablation, compared to 58 patients without HF. They found no impact of underlying structural heart disease upon outcome.25 Similarly, the CASTLE-AF study included 46% of patients with ischaemic cardiomyopathy and found no difference in the primary outcome, even when stratified by HF type (p=0.56).4 In the CAMERA-MRI study, those patients with non-ischaemic cardiomyopathy with evidence of scarring using late gadolinium enhancement on cardiac MRI, still had a significant improvement in LVEF following catheter ablation, although the magnitude of such improvement was proportional to the extent of scarring present at baseline.5 In contrast, recent multicentre series and a meta-analyses of catheter ablation in HF, suggested that the presence of structural heart disease and fibrosis predicted a worse long-term outcome with respect to LVEF improvement, freedom from AF and mortality.12,28,29 Until more prospective studies are completed, which specifically compare clinical outcomes of patients with known structural heart disease including extensive fibrosis, the extent to which this feature should influence treatment decisions is unclear. Nonetheless, given the results of the CAMERA-MRI study, the presence of minimal fibrosis should likely not deter from an ablation strategy.

Other Types of Heart Failure

What Constitutes Success in Catheter Ablation for HF?

What of those patients with known underlying causes of HF, such as ischaemic cardiomyopathy? Ostensibly in such patients, the degree of ventricular impairment would be determined largely by the underlying structural heart disease, e.g. the extent of myocardial infarct, rather than the impact of AF, although the associated presence of AF may

The vast majority of AF encountered in the setting of HF is persistent, particularly in the circumstance where AF is the primary driver of the left ventricular dysfunction. Yet persistent AF outcomes post catheter ablation are consistently reported as inferior to those of paroxysmal AF. Such pessimism about outcome may deter physicians from tackling

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Electrophysiology and Ablation these challenging cases. There are two important factors to consider here. Firstly, although the gold standard definition of AF recurrence is defined as any AF or AT >30 seconds for clinical trial outcomes,30 this definition of success likely has little utility in the setting of patients with predominately long-standing persistent AF. The Substrate and Trigger Ablation for Reduction of AF Trial (STAR-AF II), is the largest clinical trial of patients with persistent AF.31 It followed up 589 patients for 18 months with weekly transtelephonic rhythm monitoring, in addition to regular Holter monitoring. Procedural success improved from 44%–75%, simply by altering the cut-off for defining recurrence from >30 seconds to >24 hours of AF.32 Importantly, even 24 hours of AF over 18 months of follow-up still equates to an AF burden of 0.002%. More recently, the utility of the traditional cut-off of >30 seconds has been questioned by Steinberg et al. who evaluated the 12-month outcomes for 615 patients with dual chamber cardiac implantable electronic devices with at least one episode of AF >30 seconds detected at baseline.33 They found that AF between 30 seconds and 2 minutes was a poor predictor of clinically meaningful AF with 36% of patients experiencing no further episodes of AF >2 minutes over the study period. Importantly, recent trials of catheter ablation in HF have measured AF burden in addition to the conventional definition of recurrence.4–5,11 A post hoc analysis of the CASTLE-AF study, in which all participants had a dual chamber ICD or cardiac resynchronisation therapy (CRT) device implanted, demonstrated that recurrence (determined by AF >30 seconds) had no statistical relationship with the primary endpoint.34 In contrast, an AF burden of 6% or less, predicted a 2.5–3.3-fold freedom from the primary endpoint, compared to those with AF burden >6%. In that study, although the average AF burden in the catheter ablation arm at final follow-up was 27%, the median AF burden was 0%, suggesting the majority of patients in the catheter ablation arm had actually no clinically significant AF, and the reported average may have been driven by a smaller number of patients with very high AF burdens.

higher occurrence of the primary endpoint (mortality or unplanned HF-related admission) compared to those with LVEF ≥25%.4 These findings suggest that patients with more severe HF may not benefit from catheter ablation. Finally, given the nature of the intervention, blinding of study participants to treatment allocation was not possible. However, in many studies, the endpoint adjudicators were blinded to treatment allocation.

Ongoing Trials of Catheter Ablation in Heart Failure There are three recent large randomised controlled trials evaluating catheter ablation in patients with HF. The AF Management in Congestive Heart Failure With Ablation (AMICA; NCT00652522) study was completed in 2017 and compared LVEF at 12 months following ablation or MRC or atrioventricular (AV) node ablation in patients with persistent AF, LVEF <35% and NYHA class II/III. The Rhythm Control – Catheter Ablation With or Without Antiarrhythmic Drug Control of Maintaining Sinus Rhythm Versus Rate Control With Medical Therapy and/or Atrio-ventricular Junction Ablation and Pacemaker Treatment for AF (RAFT-AF; NCT01420393) study is evaluating mortality or unplanned HF-related hospitalisation in patients with paroxysmal or persistent AF, LVEF <45% and NYHA II/III heart failure randomised to catheter ablation or rate control (pharmacological or AVN ablation). The Ablation of AF in Heart Failure Patients (CONTRA-AF; NCT03062241), study is evaluating mortality or unplanned HF-related hospitalisation in patients with paroxysmal or persistent AF, LVEF <35% and dual chamber ICDs, or CRT-D in situ in patients randomised to balloon cryoablation for AF or medical therapy. The publication of these studies in due course will greatly improve our understanding of the role of catheter ablation in HF.

Risks, Complications and Cost-effectiveness of Catheter Ablation

Thus, AF burden reduction, rather than freedom from recurrence, is probably a far more useful treatment aim, and reported high rates of recurrence should not deter from the use of catheter ablation as an anti-heart failure treatment in patients with persistent AF and HF. However, the exact magnitude of burden reduction required to derive clinical benefit is likely yet to be fully elucidated.

Despite the presence of systolic dysfunction, several prospective and retrospective analyses have shown generally low complication rates in patients with concurrent AF and HF,4–5 or at least rates comparable to patients without HF.36 Although not overtly apparent in large published data sets, perceivably patients with more severe HF phenotypes may have higher rates of thrombo-embolic complications.35,37

Limitations of Clinical Trials

Particular attention should be paid to pre-procedural, intraprocedural and post-procedural anti-coagulation with uninterrupted anti-coagulation strategies with either vitamin K antagonists or direct-acting oral anti-coagulants (DOACs) being the preferred option, to further minimise the risk of thrombo-embolism.38–40 As with all AF ablation procedures, detailed discussion of the recognised risks of AF ablation (including stroke, cardiac tamponade, atrio-oesophogeal fistula, groin complications and adjacent nerve injury), should be central to informed consent.

It is worth noting that despite consistency of findings in recent clinical trials, there are important limitations that should be noted. With the exception of CASTLE-AF and AATAC-AF, most studies have had modest patient numbers. The findings are really only applicable to candidates with stable, well-compensated HF who were otherwise suitable for catheter ablation. This may have resulted in selection bias towards less severe HF phenotypes. The randomised study of catheter ablation and MRC by Macdonald et al., which included generally sicker patients than other studies (average LVEF 16%; 91% NYHA III, average of 19 previous hospitalisations and longer average AF durations of 4–5 years), showed poor success rates (50% restoration to SR) and did not show a significant improvement in LVEF on cardiac MRI (CMR).35 Additionally, a secondary analysis of patients in the CASTLE-AF study highlighted that those with LVEF <25% had a significantly

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Cost-effectiveness analyses of AF ablation are generally lacking. However, the weight of data suggests that the cost:benefit ratio favours ablation in younger, highly symptomatic patients with poor response to anti-arrhythmic medications, and frequent hospitalisations.40 This most ardently applies to patients with concurrent HF who frequently fail medical therapy and frequently require hospitalisation in the setting

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Catheter Ablation in Patients with Heart Failure and AF Figure 2: A Proposed Treatment Algorithm for the Management of Patients With AF and Heart Failure Concurrent AF and HF

Establish on: 1. Anticoagulation 2. Medical anti-failure and 3. Rate control therapy 4. MDT, HF and AF management

Attempt cardioversion

Long-term AF management

Underlying structural cause of HF

Otherwise unexplained HF

Clear or likely history of AF-mediated HF

Contra-indication to catheter ablation

Cardiac MRI

No or minimal scarring present

Patient preference for ablation

Maintaining SR without amiodarone

Extensive scarring or underlying cause of HF evident on cardiac MRI

Failure of rhythm control or amiodarone required*

Ongoing medical rhythm control

Electrical cardioversion +/- short-term amiodarone followed by reassessment of symptoms and LVEF in SR

Improvement in LVEF

Unable to cardiovert†

Improvement in symptoms

No improvement of LVEF or symptoms

Failure of medical rhythm control

Maintaining SR without amiodarone

Catheter ablation strategy (+/- short-term amiodarone) Patient preference for ablation

Failure of rhythm control or amiodarone required* Failed ablation strategy‡

Ongoing medical rhythm control

Ongoing medical rate control

Persisting tachycardia

CRT implantation + AVN ablation * Although catheter ablation may be preferable to indefinite amiodarone therapy, ongoing amiodarone therapy with close regular monitoring for toxicity, for selected patients who elect to do so, is not unreasonable. † In the absence of contraindications to catheter ablation. ‡ Ablation strategy may involve one or more repeat procedures as clinically indicated. AVN = atrioventricular node; CMR = cardiac MRI; HF = heart failure; LVEF = left ventricular ejection fraction; MDT = multidisciplinary team; MRC = medical rate control; SR = sinus rhythm.

of AF-mediated acute on chronic exacerbations of HF. Nonetheless, a specific cost-effectiveness of analysis of ablation in AF and HF patients is yet to be formally undertaken.

Limitations of Current Clinical Guidelines Current guidelines are yet to be updated to reflect the emerging role of catheter ablation in the setting of HF. The European Society of Cardiology and the American College of Cardiology/American Heart Association guidelines have no specific recommendations for the role of catheter ablation in HF.41,42 In contrast, the National Institute for Health and Care Excellence guideline on the management of AF suggests rhythm control should be the firstline treatment for patients in whom HF is “thought to be primarily caused by the AF”, 43 leaving open an initial ablation strategy management option. Recent trial data have heralded a call for guidelines to be updated in the near future.24,44

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A New Treatment Algorithm for Catheter Ablation in Heart Failure Given that the results of contemporary clinical trials are yet to be reflected in practice management guidelines, we attempt to provide some pragmatic guidance to manage patients presenting with co-morbid AF and HF, with a focus on the role of catheter ablation (Figure 2). Priorities for patients presenting with co-morbid AF and HF are the commencement of anti-coagulation, medical anti-failure pharmacological therapy, suppression of overt tachycardia and the establishment of a multidiscliplinary HF team, ideally including a HF cardiology specialist and HF nurse. Acute management of AF with electrical cardioversion is preferable at this stage. With regards to long-term management of AF, patients can divided into two main groups.

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Electrophysiology and Ablation Firstly, patients with a clear clinical history of AF-mediated cardiomyopathy may present with co-diagnosis of AF and HF, may have documented normal LV function while in SR, and not have underlying structural heart disease. Patients not wanting to take antiarrhythmic drug (AAD) therapy, those who fail first-line AAD therapy or who can only maintain SR with amiodarone, should be offered catheter ablation. Secondly, in patients with a known cause of HF, the contribution of AF to the LV dysfunction and/or symptoms should be clarified with the restoration of SR with the assistance of short-term amiodarone. Those patients demonstrating a significant improvement in LVEF and/or symptoms should be considered for catheter ablation as an alternative to long-term amiodarone therapy. In those patients where the cause of HF is unclear, cardiac MRI is a useful tool for further stratification. Based on the findings of the CAMERA-MRI study, patients with no or minimal scarring should be considered to have an underlying AF-mediated cardiomyopathy and managed as per patients in the first group. Those patients with extensive scarring, or where CMR identifies an underlying cause of HF, e.g. cardiac sarcoid, should be managed as those in the second group. Patients deriving no benefit in symptoms or LVEF improvement from SR, or who eventually fail a strategy of catheter ablation, should have ongoing MRC, with the option of CRT implantation and AVN ablation available to those with persistent tachycardia. Catheter ablation should be performed by experienced operators in high volume centres with specialised expertise in complex ablation and the management of advanced cardiomyopathy. It also should be noted that there are no current data regarding the safety and efficacy of cryoablation as an ablation strategy in patients with HF, and the vast majority of clinical trials in AF and HF have utilised RF-based catheter ablation. Similarly, as with persistent AF, the optimal ablation strategy beyond PVI is unknown.

avarese G, Lund LH. Global public health burden of heart S failure. Card Fail Rev 2017;3:7–11. https://doi.org/10.15420/ cfr.2016:25:2; PMID: 28785469. 2. Chugh SS, Roth GA, Gillum RF, Mensah GA. Global burden of atrial fibrillation in developed and developing nations. Glob Heart 2014;9:113–9. https://doi.org/10.1016/j. gheart.2014.01.004; PMID: 25432121. 3. Miyasaka Y, Barnes ME, Gersh, BJ, et al. Incidence and mortality risk of congestive heart failure in atrial fibrillation patients: a community-based study over two decades. Eur Heart J 2006;27:936–41. https://doi.org/10.1093/eurheartj/ ehi694; PMID:16399778. 4. Marrouche NF, Brachmann J, Andresen D, et al. Catheter ablation for atrial fibrillation with heart failure. N Engl J Med 2018;378:417– 27. https://doi.org/10.1056/NEJMoa1707855; PMID: 29385358. 5. Prabhu S, Taylor AJ, Costello BT, et al. Catheter ablation versus medical rate control in atrial fibrillation and systolic dysfunction: the CAMERA-MRI study. J Am Coll Cardiol 2017;70:1949–61. https:// doi.org/10.1016/j.jacc.2017.08.041; PMID: 28855115. 6. Wyse DG, Waldo AL, DiMarco JP, et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002;347:1825–33. https://doi.org/10.1056/ NEJMoa021328; PMID: 12466506. 7. Corley SD, Epstein AE, DiMarco JP, et al. Relationships between sinus rhythm, treatment, and survival in the atrial fibrillation follow-up investigation of Rhythm Management (AFFIRM) study. Circulation 2004;109:1509–13. https://doi. org/10.1161/01.CIR.0000121736.16643.11; PMID: 15007003. 8. Guglin M, Chen R, Curtis AB, et al. Sinus rhythm is associated with fewer heart failure symptoms: insights from the AFFIRM trial. Heart Rhythm 2010;7:596–601. https://doi.org/10.1016/j. hrthm.2010.01.003; PMID: 20159046. 9. Qin D, Leef G, Alam MB, et al. Mortality risk of long-term amiodarone therapy for atrial fibrillation patients without structural heart disease. Cardiol J 2015;22:622–9. https://doi. org/10.5603/CJ.a2015.0055; PMID: 26412606. 10. Mukherjee RK, Williams SE, Niederer SA, O’Neill MD. Atrial

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Conclusion There is now a considerable body of evidence suggesting that the maintenance of SR while avoiding long-term AADs such as amiodarone, in patients with AF and HF leads to improved clinical outcomes with respect to LV function, symptoms, hospitalisation and mortality. Catheter ablation provides this and should be considered as an important part of HF management in these patients. The traditional measures of success following catheter ablation, namely AF recurrence, likely have little relevance to long-term clinical outcome in these patients and catheter ablation should not be withheld as a treatment option for this reason alone. Instead, catheter ablation should be viewed as a tool to control AF burden and consequently improve HF and clinical outcomes. Additionally, cardiac MRI may be utilised as an important stratification tool in identifying patients with a likely AF-mediated cardiomyopathy and therefore likely to derive the most benefit from rhythm control with catheter ablation.

Clinical Perspective • An increasing body of evidence suggests that catheter ablation for AF is effective, feasible and safe with improvements in symptoms, ventricular function, reduced heart failure-related hospitalisation and mortality. • Although yet to be formally reflected in clinical guidelines, catheter ablation for AF in patients with AF should be strongly considered in patients with heart failure, particularly those unable or unwilling to take anti-arrhythmic drug therapy, such as amiodarone. • In patients with AF and an otherwise unexplained cardiomyopathy, cardiac MRI can be a useful stratification tool. The absence of scarring is suggestive of an underlying AF-mediated cardiomyopathy, even in the setting of adequate rate control, and these patients will gain the most benefit from catheter ablation.

fibrillation ablation in patients with heart failure: one size does not fit all. Arrhythm Electrophysiol Rev 2018;7:84–90. https:// doi.org/10.15420/aer.2018.11.3; PMID: 29967679. Di Biase L, Mohanty P, Mohanty S, et al. Ablation versus amiodarone for treatment of persistent atrial fibrillation in patients with congestive heart failure and an implanted device: results from the AATAC multicenter randomized trial. Circulation 2016;133:1637–44. https://doi.org/10.1161/ CIRCULATIONAHA.115.019406; PMID: 27029350. Anselmino M, Matta M, D’Ascenzo F, et al. Catheter ablation of atrial fibrillation in patients with left ventricular systolic dysfunction: a systematic review and meta-analysis. Circ Arrhythm Electrophysiol 2014,7:1011–8. https://doi.org/10.1161/ CIRCEP.114.001938; PMID: 25262686. Smer A, Salih M, Darrat YH, et al. Meta-analysis of randomized controlled trials on atrial fibrillation ablation in patients with heart failure with reduced ejection fraction. Clin Cardiol 2018;41:1430–8. https://doi.org/10.1002/clc.23068; PMID: 30178507. Ma Y, Bai F, Qin F, et al. Catheter ablation for treatment of patients with atrial fibrillation and heart failure: a meta-analysis of randomized controlled trials. BMC Cardiovasc Disord 2018;18:165. https://doi.org/10.1186/s12872-018-0904-3; PMID: 30103676. Peters KG, Kienzle MG. Severe cardiomyopathy due to chronic rapidly conducted atrial fibrillation: complete recovery after restoration of sinus rhythm. Am J Med 1988;85:242–4. https:// doi.org/10.1016/S0002-9343(88)80352-8; PMID: 3400701. Clark DM, Plumb VJ, Epstein AE, Kay GN. Hemodynamic effects of an irregular sequence of ventricular cycle lengths during atrial fibrillation. J Am Coll Cardiol 1997;30:1039–45. https://doi. org/10.1016/S0735-1097(97)00254-4; PMID: 9316536. Benchimol A, Duenas A, Liggett MS, Dimond EG. Contribution of atrial systole to the cardiac function at a fixed and at a variable ventricular rate. Am J Cardiol 1965;16:11–21. https:// doi.org/10.1016/0002-9149(65)90003-2; PMID: 14314196. Prabhu S, Voskoboinik A, McLellan AJ, et al. Biatrial electrical and structural atrial changes in heart failure: electroanatomic

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mapping in persistent atrial fibrillation in humans. JACC Clin Electrophysiol 2018;4:87–96. https://doi.org/10.1016/j. jacep.2017.08.012; PMID: 29600790. Sanders P, Morton JB, Davidson NC, et al. Electrical remodeling of the atria in congestive heart failure: electrophysiological and electroanatomic mapping in humans. Circulation 2003;108:1461–8. https://doi.org/10.1161/01. CIR.0000090688.49283.67; PMID: 12952837. John B, Stiles MK, Kuklik P, et al. Reverse remodeling of the atria after treatment of chronic stretch in humans: implications for the atrial fibrillation substrate. J Am Coll Cardiol 2010;55:1217–26. https://doi.org/10.1016/j.jacc.2009.10.046; PMID: 20298929. Ling LH, Khammy O, Byrne M, et al. Irregular rhythm adversely influences calcium handling in ventricular myocardium: implications for the interaction between heart failure and atrial fibrillation. Circ Heart Fail 2012;5:786–93. https://doi. org/10.1161/CIRCHEARTFAILURE.112.968321; PMID: 23014130. Tsai CT, Lai LP, Kuo KT, et al. Angiotensin II activates signal transducer and activators of transcription 3 via Rac1 in atrial myocytes and fibroblasts: implication for the therapeutic effect of statin in atrial structural remodeling. Circulation 2008;117:344–55. https://doi.org/10.1161/ CIRCULATIONAHA.107.695346; PMID: 18172037. Ziaei F, Zaman M, Rasoul D, et al. The prevalence of atrial fibrillation amongst heart failure patients increases with age. Int J Cardiol 2016;214:410–1. https://doi.org/10.1016/j. ijcard.2016.03.198; PMID: 27088400. Prabhu S, Kistler PM. Atrial fibrillation, an under-appreciated reversible cause of cardiomyopathy: implications for clinical practice from the CAMERA-MRI study. Heart Lung Circ 2018;27:652–5. https://doi.org/10.1016/S1443-9506(18)301525; PMID: 29706180. Hsu LF, Jaïs P, Sanders P, et al. Catheter ablation for atrial fibrillation in congestive heart failure. N Engl J Medicine 2004;351:2373–83. https://doi.org/10.1056/NEJMoa041018; PMID: 15575053. Khan MN, Jais P, Cummings J, et al. Pulmonary-vein isolation

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Catheter Ablation in Patients with Heart Failure and AF

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for atrial fibrillation in patients with heart failure. N Engl J Med 2008;359:1778–85. https://doi.org/10.1056/NEJMoa0708234; PMID: 18946063. Prabhu S, Costello BT, Taylor AJ, et al. Regression of diffuse ventricular fibrosis following restoration of sinus rhythm with catheter ablation in patients with atrial fibrillation and systolic dysfunction: a substudy of the CAMERA MRI Trial. JACC Clin Electrophysiol 2018;4:999–1007. https://doi.org/10.1016/j. jacep.2018.04.013; PMID: 30139501. Prabhu S, Ling LH, Ullah W, et al. The impact of known heart disease on long-term outcomes of catheter ablation in patients with atrial fibrillation and left ventricular systolic dysfunction: a multicenter international study. J Cardiovas Electrophysiol 2016;27:281–9. https://doi.org/10.1111/jce.12899; PMID: 26707369. Addison D, Farhad H, Shah RV, et al. Effect of late gadolinium enhancement on the recovery of left ventricular systolic function after pulmonary vein isolation. J Am Heart Assoc 2016;5:e003570. https://doi.org/10.1161/JAHA.116.003570; PMID: 27671316. Calkins H, Kuck KH, Cappato R, et al. 2012 HRS/EHRA/ ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design. Europace 2012;14:528–606. https://doi.org/10.1093/europace/ eus027; PMID: 22389422. Verma A, Jiang CY, Betts TR, et al. Approaches to catheter ablation for persistent atrial fibrillation. New Engl J Med 2015;372:1812–22. https://doi.org/10.1056/NEJMoa1408288; PMID: 25946280. Conti S, Jiang CY, Betts TR, et al. Effect of different cutpoints for defining success post-catheter ablation for persistent atrial fibrillation: a substudy of the STAR AF II trial. JACC

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Clin Electrophysiol 2017;3:522–3. https://doi.org/10.1016/j. jacep.2016.12.006; PMID: 29759610. 33. S teinberg JS, O’Connell H, Li S, Ziegler PD. Thirty-second gold standard definition of atrial fibrillation and its relationship with subsequent arrhythmia patterns. Circ Arrhythm Electrophysiol 2018;11:e006274. https://doi.org/10.1161/CIRCEP.118.006274; PMID: 30002065. 34. Brachmann J, Marrouche N. Atrial fibrillation burden and impact on mortality and hospitalization – the CASTLE-AF trial. Abstract presented at: Heart Rhythm Society Scientific Sessions; May 11, 2018; Boston, MA, US 35. MacDonald MR, Connelly DT, Hawkins NM, et al. Radiofrequency ablation for persistent atrial fibrillation in patients with advanced heart failure and severe left ventricular systolic dysfunction: a randomised controlled trial. Heart 2011;97:740–7. https://doi.org/10.1136/hrt.2010.207340; PMID: 21051458. 36. Ullah W, Ling LH, Prabhu S, et al. Catheter ablation of atrial fibrillation in patients with heart failure: impact of maintaining sinus rhythm on heart failure status and long-term rates of stroke and death. Europace 2016;18:679–86. https://doi.org/10.1093/europace/euv440; PMID: 26843584. 37. Hughes M, Lip GY. Stroke and thromboembolism in atrial fibrillation: a systematic review of stroke risk factors, risk stratification schema and cost effectiveness data. Thromb Haemost 2008;99:295–304. https://doi.org/10.1160/TH07-080508; PMID: 18278178. 38. Nagao T, Suzuki H, Matsunaga S, et al. Impact of periprocedural anticoagulation therapy on the incidence of silent stroke after atrial fibrillation ablation in patients receiving direct oral anticoagulants: uninterrupted vs. interrupted by one dose strategy. Europace 2018. https://doi. org/10.1093/europace/euy224; PMID: 30376051. 39. Calkins H, Willems S, Gerstenfeld EP, et al. Uninterrupted

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dabigatran versus warfarin for ablation in atrial fibrillation. N Engl J Med 2017;376:1627–36. https://doi.org/10.1056/ NEJMoa1701005; PMID: 28317415. Chang AY, Kaiser D, Ullal A, et al. Evaluating the costeffectiveness of catheter ablation of atrial fibrillation. Arrhythm Electrophysiol Rev 2014;3:177–83. https://doi.org/10.15420/ aer.2014.3.3.177; PMID: 26835088. Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 2016;37:2893–962. https:// doi.org/10.1093/eurheartj/ehw210; PMID: 27567408. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/ HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/ American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014;64:e1–76. https://doi.org/10.1016/j.jacc.2014.03.022; PMID: 24685669. Atrial fibrillation: management. 2014. Available at: https:// www.nice.org.uk/guidance/cg180 (accessed 25 February 2019) Baher A, Marrouche NF. Treatment of atrial fibrillation in patients with co-existing heart failure and reduced ejection fraction: time to revisit the management guidelines? Arrhythm Electrophysiol Rev 2018;7:91–4. https://doi.org/10.15420/ aer.2018.17.2; PMID: 29967680. Jones DG, Haldar SK, Hussain W, et al. A randomized trial to assess catheter ablation versus rate control in the management of persistent atrial fibrillation in heart failure. J Am Coll Cardiol 2013;61:1894–903. https://doi.org/10.1016/j. jacc.2013.01.069; PMID: 23500267. Hunter RJ, Berriman TJ, Diab I, et al. A randomized controlled trial of catheter ablation versus medical treatment of atrial fibrillation in heart failure (the CAMTAF Trial). Circ Arrhythm Electrophysiol 2014;7:31–8. https://doi.org/10.1161/ CIRCEP.113.000806; PMID: 24382410.

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Electrophysiology and Ablation

Ventricular Tachycardia Isthmus Characteristics: Insights from High-density Mapping Ruairidh Martin, 1 Mélèze Hocini, 2 Michel Haïsaguerre, 2 Pierre Jaïs 2 and Frédéric Sacher 2 1. Freeman Hospital, Newcastle upon Tyne, UK 2. Bordeaux University Hospital, L’Institut de Rythmologie et Modélisation Cardiaque/INSERM 1045, Bordeaux, France

Abstract In the context of structural heart disease, ventricular tachycardia (VT) is related to surviving fibres in incomplete scar. New technologies which allow electroanatomic mapping at higher density and with smaller, more closely spaced electrodes have allowed new insights into the characteristics of VT circuits. VT isthmuses are complex structures, with multiple entrances, exits and dead ends of activation. The isthmus is frequently defined by regions of functional block and several VT circuits can be possible in a VT “critical zone”. In this review, we discuss these new insights and how they may improve VT ablation strategies, as well as discussing emerging technologies which may further develop our understanding.

Keywords VT, ablation, substrate mapping, catheters, arrhythmia Disclosure: RM has received a research grant from Boston Scientific and FS has received speaking honoraria. The other authors have no conflicts of interest to declare. Received: 12 December 2018 Accepted: 30 January 2019 Citation: Arrhythmia & Electrophysiology Review 2019;8(1):54–9. DOI: https://doi.org/10.15420/aer.2018.78.2 Correspondence: Ruairidh Martin, Department of Cardiology, Freeman Hospital, Freeman Road, Newcastle upon Tyne, NE7 7DN, UK. E: ruairidhmartin@nhs.net Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Ventricular tachycardia (VT) in the context of structural heart disease is related to patchy or incomplete scar; usually arising from re-entrant circuits which are dependent on surviving channels of activation through scar tissue.1–3 These protected isthmuses are critical for maintaining VT, and an improved understanding of the characteristics of VT isthmuses is important in guiding strategies for VT ablation. VT isthmuses are often unmappable in clinical practice due to non-inducibility, multiple inducible VTs which interrupt the mapping process, and haemodynamic instability during VT.4,5

Historical Data It has long been known that scar-related VT is dependent on poorlycoupled surviving fibres in scarred areas. Early catheter mapping studies identified complex signals with decremental conduction delay which were mid-diastolic during tachycardia.6 Mapping with electrode arrays during surgical ablation of post-infarction VT also identified poorly-coupled signals in areas of dense scar, further demonstrating that these signals were endocardial in origin and separated by dense scar tissue from surviving epicardial myocardium (Figure 1).7 More complex mapping of VT circuits with entrainment manoeuvres to identify concealed entrainment, post-pacing intervals and stimulusQRS times as well as electrogram (EGM) characteristics, identified the existence of more complex elements of the VT circuit. This included inner and outer loops, a common isthmus and bystander loops or dead ends of activation (Figure 2).8 These techniques are, however, relatively time-consuming because gathering information at each individual point requires entrainment (without terminating the tachycardia) and

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measurement of intervals. This limits the maximal spatial resolution of the technique and does not allow determination of the anatomical characterisation of the key parts of the VT circuit. Early electroanatomic mapping systems were used to identify VT circuits with a greater degree of spatial accuracy. This allowed identification of the key characteristics of VT circuits, with identification of typical isthmus orientation and position in post-infarct VTs.1,3 The limited number of recorded points and relatively large sensing bipole used when mapping with an ablation catheter limited the ability of these studies to define the characteristics of VT isthmuses more clearly. Consequently, understanding of the isthmus was limited to site and general orientation, rather than an understanding of more complex details, such as position within the scar, morphology, conduction velocities, and the role of functional and complete block.

High-density Mapping Electroanatomic mapping systems and multipolar mapping systems have been developed which allow collection of greater numbers of EGM from smaller, more closely spaced electrodes (Table 1).9 One of the primary limitations of the techniques described above is that the EGMs were often recorded with a large electrode surface area, particularly in the case of a 3.5 mm ablation catheter tip and relatively large bipolar spacing. Human mapping studies performed with multipolar catheters have clearly demonstrated the effect of increasing bipole distance on the relative sizes of near- and far-field EGMs with clear implications for the ability of human observers and machine algorithms to differentiate the two (Figure 3).10,11 This work has been developed further using the

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Ventricular Tachycardia Isthmus Advisor™ HD Grid mapping catheter (Abbott) in sheep, demonstrating that near-field signals from poorly coupled abnormal fibres are largely unaffected by bipole spacing (as long as the fibre lies between the two poles) but that far-field signals are significantly lessened by reducing the bipole spacing, thereby improving near-field detection.12

Figure 1: Endocardial Scar Substrate After MI A

Marking sutures

Ventricular tachycardia (CL 300 ms)

NSR pre-section (CL 20 ms)

NSR post-resection (CL 750 ms)

Aneurysmotomy

2 3 V5R RV LV

1 mV

The other significant improvement of modern mapping systems lies in the number of EGMs that can be collected, stored and analysed by multipolar recording catheters and improved software. The increase from tens of EGMs in the initial studies to tens of thousands with modern systems has resulted in several major improvements. The resolution of the maps generated has significantly improved. The time taken to generate a map has reduced as multipolar catheters record from areas of myocardium, rather than single points, allowing rapid collection of points over a large area.14,15 By collecting multiple

2 3 4 5

Electrode array

Endocardium

7 8 9 10 11 12 13 14 15 16 17 18 19 20 Time

200 ms

A: Recordings were made with a multielectrode array before and after resection of endocardial scar. B: VT recordings identify mid-diastolic signals in dense scar (arrows point to signals.). In sinus rhythm, there are corresponding LAVA signals late after the local farfield electrogram (arrows). After resection of the endocardial scar, the LAVAs are no longer present and VT is non-inducible. CL = cycle length; LAVA = local abnormal ventricular activity NSR = normal sinus rhythm; VT = ventricular tachycardia. Source: Miller et al.7 Reproduced with permission from Wolters Kluwer Health.

Figure 2: Components of the Ventricular Tachycardia Circuit Identified by Pacing and Entrainment Manoeuvres Outer loop 25 22

Common pathway 10

CP entrance

3 E

QRS onset

30 C

EGMs at each location, outlier signals arising from ectopy, noise or catheter instability can be excluded, improving the quality of the signals recorded. While these improvements do not allow mapping on the 100 µm scale, to identify activation patterns in individual surviving bundles, they do allow a greater appreciation of VT circuit activation than has been possible before. Several recent studies using small-electrode multipolar mapping catheters and high-density electroanatomic mapping systems have recently been performed in animals and humans, which have improved our understanding of the properties of VT circuits.

Electrode

A second major limitation of these studies is that the resolution of the mapping techniques is not fine enough to determine the properties of the VT isthmus in detail. A microelectrode study (on a scale of 100 µm) of excised infarcted human papillary muscles identified complex activation patterns in a thin layer of surviving endocardial fibres overlying a densely infarcted zone. Slow conduction in these fibres was the result of activation at near normal speeds on a microscopic level following a zig-zag course through poorly coupled fibres, resulting in overall slowing of conduction.13 Close bipolar spacing is also helpful in this regard, in that the position of the EGM is more accurately determined as signals are recorded from a smaller volume.

CP exit

6 H Inner loop

ECG The key components of the VT circuit are identified: the common pathway, outer loop, inner loop through scar tissue, and dead-end activation (C, E, H). Pacing manoeuvres allow identification of these sites in principle, but use in routine mapping of VTs is limited by the stability of the VT and the time taken to pace at multiple sites. CP = common pathway; VT = ventricular tachycardia. Source: Stevenson et al. 1993.8 Reproduced with permission from Wolters Kluwer Health.

Isthmus Architecture Mapping studies in pigs and humans have confirmed the presence of complex isthmus architecture, as suggested by computer modelling and pacing and entrainment mapping in the era before electroanatomic mapping. A canine left anterior descending (LAD) infarct model mapped with a 192-electrode array identified an isthmus defined by two parallel lines of conduction block.16 This general structure of the common isthmus has been subsequently confirmed in a porcine infarct model, but with multiple entrance and exit sites in 11% of VTs.17 Data from human VT studies confirms this general principle.18 A multicentre study of high-density VT maps found that isthmuses were defined by lines of block, but that multiple entrances and exits were common. Further, in humans, dead ends of activation were also common and regions of activation within dense scar, consistent with inner-loop activation, were also observed.18 This increase in complexity in human studies over animal models is perhaps to be expected. The average time from MI to VT mapping in human studies is far longer, 10–20 years, than the few months possible in an animal model. 18,19 The delay in local abnormal ventricular activity (LAVA) and degree of fractionation of EGMs

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are known to be associated with time from infarction, suggesting a prolonged period of remodelling, which results in increasing architectural complexity with time.20 This complex architecture has important implications in clinical practice. Both animal and human mapping studies have demonstrated that the same region of poorly-coupled fibres can sustain multiple VTs. Activation passes through the critical VT-supporting area in different directions during different tachycardias, with entrance zones becoming exit zones and vice versa.17,18 Successful ablation in this context requires complete elimination of all potential VT channels. This tendency for several VTs to be possible in an individual patient partly explains why ablation of clinical VTs alone is a less successful strategy than a substrate-based approach, which addresses all potential circuits.21

Conduction Velocity in the Ventricular Tachycardia Circuit It has long been known that slow conduction, as evidenced by fractionated EGMs, is necessary for VT to be sustained. It also known that conduction velocities in scar tissue are non-uniform and that

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Electrophysiology and Ablation Table 1: Comparison of Commonly Used High-density Electroanatomical Mapping Systems and Catheters System EnSite Precision (Abbott Vascular)

CARTO 3 (Biosense Webster)

Rhythmia (Boston Scientific)

Localisation

Typical Number of

Technology

Points/Map

Magnetic and impedance

Thousands

Magnetic and impedance

Thousands

Thousands to tens of thousands

Mapping Catheter

Electrodes

Electrode Spacing

HD Grid

16 × 1 mm ring electrodes

3-3-3 mm on four spines 3 mm apart in planar formation

Livewire Duo-Decapolar

20 × 1 mm ring electrodes

2-2-2 or 2-5-2 mm on a single catheter

PentaRay

20 × 1 mm ring electrodes

2-5-2 or 4-4-4 mm on five radiating spines

Lasso

10 or 20 × 1 mm ring electrodes 4.5, 6 or 8 mm on a circular spine

DecaNav

10 × 1 mm ring electrodes

2-8-2 mm on a single catheter

Orion

64 × 0.4 mm2 patch electrodes

2.5 mm on eight spines of a collapsible mini basket

Figure 3: The Impact of Electrode Characteristics on Electrogram Recordings A: 2-6-2mm mapping catheter

B: 3.5mm ablation catheter

heterogenous anisotropy results from surviving bundles of myocytes, separated by fibrous tissue and arranged in a mesh-like pattern.22 Previous studies, both surgical and catheter-based, have lacked the resolution to establish whether there is a particular pattern to conduction slowing in the VT circuit. Data from high-density mapping in both animals and humans has identified clear slowing of conduction at VT entrance and exit zones, but relative preservation of conduction velocities in the mid-isthmus (Figure 4).17,18 The absolute values for conduction velocity were higher in a porcine model than in humans, but the velocities recorded in human high-density mapping studies match those seen in surgical mapping studies and the discrepancy likely reflects inter-species difference in myocardial conduction velocity.23

A: Electrograms recorded with a dedicated mapping catheter. Clearly separated near-field and far-field components are visible. B: Electrograms recorded at the same site (0.6 mm separation) with a 3.5 mm ablation catheter. The near-field component is almost completely obscured by the much larger far-field component. C: A 3D mapping system demonstrating the relative positions of the electrograms recorded. Electrode orientation is similar with each catheter. FF = far-field; NF = near-field. Source: Berte et al.10 Reproduced with permission from John Wiley and Sons.

Figure 4: Wavefront Velocity in the Ventricular Tachycardia Circuit B

550

0.1

0 Velocity (m/s)

Conduction velocity (m/s)

0 Activation time (ms)

1.00

0.75

0.03 1.7e-06 0.0036

The Role of Functional Block and Slow Conduction

0.50

0.25

0.00 Entrance Isthmus Region

Exit

A: timing data has been extracted from the Rhythmia mapping system and reanalysed using custom scripts in MATLAB software (MathWorks). Activation time is represented by colour and identifies a single loop re-entrant ventricular tachycardia (VT) in the border of a large anteroseptal scar region. Activation proceeds through the VT isthmus before breaking out into the outer loop (white dashed line). To the right of the image, activation proceeds in a re-entrant loop (white arrow) but to the left, activation is stopped by a line of block (white circle). Conduction velocity is indicated by the grayscale overlay and clearly shows zones of very slow conduction or block defining the lateral margins of the isthmus. There is another line of block outside the isthmus which results in a single loop, rather than dual loop, VT circuit. There are regions of slow conduction in the entrance and exit of the isthmus. Other regions of slow conduction are present elsewhere in the ventricle, but do not play a direct role in the VT circuit. B: median conduction velocity in entrance, isthmus and exit zones, and median (apparent) conduction velocity in zones of complete block and functional block which define the isthmus. P-values for comparisons are shown. Source: Martin et al.18 Reproduced with permission from Wolters Kluwer Health.

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The deceleration of activation wavefronts at entrance and exit zones may be due to one, or more likely a combination, of several factors. Activation in healthy myocardium and in the mid-isthmus is largely linear and orthogonal to fibre orientation. At entrance and exit zones, however, the wavefront curves around the lateral borders of the isthmus, are often perpendicular to fibre orientation. This abrupt change in activation vector as well as increased axial resistivity and myocardial thickness gradient, are likely to contribute to slowing. Further, there is greater slowing of activation in entrance zones due to collision of opposing wavefronts in double-loop circuits.24

As well as slow conduction playing an important role in the entrance and exit zones of the protected part of the VT circuit, regions of slow conduction and/or functional block also seem to be important in defining the VT isthmus. Early animal studies in a canine infarct model identified regions of functional block that were present during tachycardia. High-density mapping in animal and human studies has confirmed this finding. Lines of complete block with well-defined double potentials are observed. However, many VT circuits are also bordered, at least in part, by regions of very slow activation, evidenced by long fractionated EGMs (Figure 5).17,18 Conduction in these lateral borders is sufficiently slow to protect the central isthmus. Substrate mapping studies in an animal model identified critical sites in zones of maximal wavefront deceleration in sinus rhythm. These sites were located in regions of dense scar (<0.55 mV) and served as

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Ventricular Tachycardia Isthmus Figure 5: Slow Conduction in the Borders of a Ventricular Tachycardia Isthmus

Figure 7: Comparison of Activation and Pace Mapping of the Ventricular Tachycardia Exit A

Median voltage of local mid-isthmus signal

Median voltage

0.4

0.3 0.2 0.1 0.0

Sinus/paced Rhythm

An activation map of ventricular tachycardia 18 years after MI. The isthmus is defined by a combination of lines of complete block (black dots) particularly in regions of very low voltage and slow conduction or functional block (gray dots). Activation proceeds from a single entrance to an apical exit (white dashed lines). There is also activation of a very large area of dead-end activation (white circle) with mid-diastolic activation, partially delimited by the mitral annulus. Source: Martin et al.18 Reproduced with permission from Wolters Kluwer Health.

Figure 6: A Critical Zone Anchoring Multiple Ventricular Tachycardias

I II III aVR aVL aVF V1 V2 V3 V4 V5 V6 Mapping RVA

A: An example of a monomorphic VT mapped using both activation and entrainment techniques. The length of the isthmus determined by activation mapping was measured from the proximal curvature (entrance) to the distal curvature (exit) and is highlighted in a red dashed ellipse. Dimensions of the isthmus were also measured using standard entrainment criteria and included sites with concealed QRS on all 12 electrogram (EGM) leads and PPITCL â&#x2030;¤30 ms (gray dashed rectangle). Although the two methods similarly identified the proximal curvature (entrance) and the width of the common channel, entrainment mapping overestimated the length of the isthmus, particularly at the exit site. The pseudo-exit is the zone considered part of the circuit using entrainment mapping but not part of the circuit by activation mapping (black dots). C: An example of entrainment from a pseudoexit site (electrode, shown in B). The bipolar EGM at the pacing site occurs just before the QRS complex (EGM to QRS of 36 ms; 9% of the TCL). Entrainment from this site resulted in concealed QRS fusion, as the stimulated pacing site assumes a similar wave front vector to the VT (solid arrow). However, in contrast to a true exit site, pacing from a pseudo-exit site resulted in a longer PPI with PPI-TCL of 25 ms. This is because the pacing site is beyond the distal curvature (white arrows) and propagation of its wave front in the figure-eight configuration (black arrows) assume a curvature shape that encounters a partially refractory tissue, both result in slower conduction and prolonged postpacing interval. PCL = paced cycle length; PPI: postpacing interval; RVA = right ventricular apex; TCL: tachycardia cycle length. Source: Anter et al. 2016.17 Reproduced with permission from Wolters Kluwer Health.

with a cycle length and activation wavefront orientations which differ to the clinical VTs may not identify regions of functional block that are critical to the VT isthmus.26,27 Furthermore, not all LAVA and late potentials lie in critical parts of the VT circuit. Complete substrate elimination, while currently the strategy with the best supporting evidence, may not be entirely necessary for the elimination of all VTs.

A: Many years after MI, there is an area of scar extending from the endocardium. There is a fine mesh of surviving fibres on the endocardial surface. B: In ventricular tachycardia (VT), there is slow conduction, collision and functional block to create a protected isthmus channel (red lines). C: Current high-resolution technologies do not capture the complex zig-zag activation in the scar but can identify the path of activation through the critical isthmus. D: A second VT in the same scar is characterised by collision and functional block at different sites, resulting in a different pattern of activation and breakout site. E: Mapped with a high-resolution electroanatomical system, VT2 appears to have a different isthmus, which overlaps with that mapped in VT1.

anchors of multiple VTs of different configurations and cycle lengths. Multiple VTs are common in clinical practice.25

Implications for Substrate Mapping The increasing evidence for the role of functional block in VT circuits provides an explanation for the observation of more than one VT breaking out from the same region of scar. A region of slow conduction which acts as a lateral border for one VT may act as the entrance or exit zone for another (Figure 6). The role of functional block results in major limitation of current substrate-mapping approaches, which often rely on a single map generated in either sinus or a paced rhythm.21 Mapping in a rhythm

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It has been suggested that there may be VT critical zones which serve as the focal point for wavefront slowing and curvature, which can lead to re-entry in multiple different morphologies, leading to multiple VTs.25 Identification of these critical zones in clinical practice may improve the results of substrate mapping by identifying specific areas of LAVA. Strategies to demarcate such zones are needed, but approaches which use pacing from multiple sites and/or different cycle lengths have been shown to improve detection of poorly coupled fibres and are likely to be useful.27 Evidence to support ablation of a targeted subset of LAVA with dynamic poor coupling comes from studies using close-coupled extra-stimuli to identify dynamic increases in EGM duration and latency. Although small, these studies have demonstrated a high rate of non-inducibility and low rate of VT recurrence with a targeted approach.28,29

Implications for Pace Mapping and Entrainment Mapping One of the most interesting observations from high resolution studies is the poor correlation of activation mapping and entrainment

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Electrophysiology and Ablation mapping, particularly in exit zones, at this resolution. Entrainment from sites well beyond the breakout curvature of the activation map still allow concealed entrainment with post-pacing intervals that are consistent with pacing from within the circuit (Figure 7).17 This may be because conduction velocities are relatively slow at the lateral edges of the breakout zone and so activation through this zone contributes very little to the overall morphology of the surface QRS complex. Ablation at these distal sites may fail to terminate tachycardia, however, as activation is still able to break out laterally to healthy myocardium. This phenomenon, although not formally studied, may also have implications for pace mapping. Some studies of pace mapping suggest that the preferred strategy would be to ablate at the entrance site of the identified VT isthmus, which perhaps alleviates this problem.30 Conversely, entrainment and high-density mapping may complement each other. Entrainment remains useful in atrial macroreentry with high-density mapping, and high-density maps may allow a more focused entrainment strategy.31,32

Future Directions The limitations of current technologies for mapping VT have been reviewed elsewhere, but recent developments in high-resolution mapping are unlikely to be the final improvements in the field.33 The lower limit for electrode size and spacing, beyond which even smaller, more closely-spaced electrodes are no longer helpful, has not been reached. Anatomical studies suggest that the surviving fibres which support tachycardia are about 100 µm in diameter. It is likely that further miniaturisation of recording electrodes to this scale – and perhaps even beyond – will yield more nuanced data on characteristics of VT activation. Any improvement in mapping resolution, however must be matched by localisation accuracy to be clinically useful, as even very large numbers of poorly-located points will not provide an accurate assessment of the isthmus architecture. The corresponding development of software systems to collect and annotate tens, and possibly hundreds of thousands of EGMs will also continue. Already the number of EGMs collected by current systems defies useful real-time manual analysis in clinical care. Algorithms

e Chillou C, Lacroix D, Klug D, et al. Isthmus characteristics d of reentrant ventricular tachycardia after myocardial infarction. Circulation 2002;105:726–31. https://doi.org/10.1161/ hc0602.103675; PMID: 11839629. Ciaccio EJ, Ashikaga H, Kaba RA, et al. Model of reentrant ventricular tachycardia based on infarct border zone geometry predicts reentrant circuit features as determined by activation mapping. Heart Rhythm 2007;4:1034–45. https://doi. org/10.1016/j.hrthm.2007.04.015; PMID: 17675078. Soejima K, Stevenson WG, Sapp JL, et al. Endocardial and epicardial radiofrequency ablation of ventricular tachycardia associated with dilated cardiomyopathy: the importance of low-voltage scars. J Am Coll Cardiol 2004;43:1834–42. https:// doi.org/10.1016/j.jacc.2004.01.029; PMID: 15145109. Santangeli P, Frankel DS, Tung R, et al. Early mortality after catheter ablation of ventricular tachycardia in patients with structural heart disease. J Am Coll Cardiol 2017;69:2105–15. https://doi.org/10.1016/j.jacc.2017.02.044; PMID: 28449770. Tung R, Vaseghi M, Frankel DS, et al. Freedom from recurrent ventricular tachycardia after catheter ablation is associated with improved survival in patients with structural heart disease: an International VT Ablation Center Collaborative Group study. Heart Rhythm 2015;12:1997–2007. https://doi. org/10.1016/j.hrthm.2015.05.036; PMID: 26031376. Josephson ME, Horowitz LN, Farshidi A. Continuous local electrical activity. A mechanism of recurrent ventricular tachycardia. Circulation 1978;57:659–65. https://doi. org/10.1161/01.CIR.57.4.659; PMID: 630672. Miller JM, Tyson GS, Hargrove WC, et al. Effect of subendocardial resection on sinus rhythm endocardial electrogram abnormalities. Circulation 1995;91:2385–91. https://doi.org/10.1161/01.CIR.91.9.2385; PMID: 7729025. Stevenson WG, Khan H, Sager P, et al. Identification of reentry circuit sites during catheter mapping and radiofrequency ablation of ventricular tachycardia late after myocardial

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to display activation throughout the tachycardia cycle length, such as ripple mapping in CARTO (Biosense Webster) or LumiPoint in Rhythmia (Boston Scientific), have been developed and are entering clinical practice.34–37 More sophisticated algorithms to analyse signal characteristics, improving distinction of near-field and far-field signals, and improving annotation of local timing, are in development and will greatly aid the clinician in understanding the VT circuit. Another signalprocessing algorithm which shows promise is omnipolar mapping, in which simultaneous analysis of multiple bipolar EGMs allows estimation of wavefront speed and direction from a single beat, assisting in rapid mapping of unstable tachycardias and minimising direction-dependent effects on voltage measurement.

Summary High-density mapping technologies have improved our understanding of the characteristics of VT isthmuses. These are complex structures with multiple entrances and exits which are defined by a mixture of complete and functional block. These characteristics allow multiple VTs to arise from the same area of substrate. This has clear implications for substrate mapping and ablation strategies, and improved techniques to identify VT critical zones for targeted ablation may improve VT ablation outcomes.38,39

Clinical Perspective • Ventricular tachycardia (VT) circuits are complex with multiple entrances, exits and dead ends. Tortuous isthmuses are common. • Local electrogram voltage in the VT isthmus is low, consistent with previous definitions of dense scar. • Regions of slow conduction play an important role in defining VT isthmuses. These functional elements may make identification of isthmuses in sinus or paced rhythm difficult. • Several VT circuits may be supported by a single VT critical zone, where a combination of anatomical and functional block supports re-entry.

infarction. Circulation 1993;88:1647–70. https://doi. org/10.1161/01.CIR.88.4.1647; PMID: 8403311. Koutalas E, Rolf S, Dinov B, et al. Contemporary mapping techniques of complex cardiac arrhythmias – identifying and modifying the arrhythmogenic substrate. Arrhythm Electrophysiol Rev 2015;4:19–27. https://doi.org/10.15420/aer.2015.4.1.19; PMID: 26835095. Berte B, Relan J, Sacher F, et al. Impact of electrode type on mapping of scar-related VT. J Cardiovasc Electrophysiol 2015;26:1213–23. https://doi.org/10.1111/jce.12761. PMID: 26198475. Tschabrunn CM, Roujol S, Dorman NC, et al. High-resolution mapping of ventricular scar: comparison between single and multielectrode catheters. Circ Arrhythm Electrophysiol 2016;9:pii: e003841. https://doi.org/10.1161/CIRCEP.115.003841. PMID: 27307518. Takigawa M, Relan J, Martin R, et al. Detailed analysis of the relation between bipolar electrode spacing and far- and nearfield electrograms. JACC Clin Electrophysiol 2019;5:66. https://doi. org/10.1016/j.jacep.2018.08.022; PMID: 30678788. de Bakker JM, van Capelle FJ, Janse MJ, et al. Slow conduction in the infarcted human heart. ‘Zigzag’ course of activation. Circulation 1993;88:915–26. https://doi.org/10.1161/01. CIR.88.3.915; PMID: 8353918. Hooks DA, Yamashita S, Capellino S, et al. Ultra-rapid epicardial activation mapping during ventricular tachycardia using continuous sampling from a high-density basket (Orion™) catheter. J Cardiovasc Electrophysiol 2015;26:1153–4. https://doi.org/10.1111/jce.12685; PMID: 25867547. Takigawa M, Frontera A, Thompson N, et al. The electrical circuit of a hemodynamically unstable and recurrent ventricular tachycardia diagnosed in 35 s with the Rhythmia mapping system. J Arrhythm 2017;33:505–7. https://doi. org/10.1016/j.joa.2017.06.002. PMID: 29021859. Dillon SM, Allessie MA, Ursell PC, Wit AL. Influences of

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anisotropic tissue structure on reentrant circuits in the epicardial border zone of subacute canine infarcts. Circ Res 1988;63:182–206. https://doi.org/10.1161/01.RES.63.1.182; PMID: 3383375. Anter ETC, Buxton AE, Josephson ME. High-resolution mapping of postinfarction reentrant ventricular tachycardia: electrophysiological characterization of the circuit. Circulation 2016;134: 314–27. https://doi.org/10.1161/ CIRCULATIONAHA.116.021955; PMID: 27440005. Martin R, Maury P, Bisceglia C, et al. Characteristics of scar-related ventricular tachycardia circuits using ultrahigh-density mapping. Circ Arrhythm Electrophysiol 2018; 11:e006569. https://doi.org/10.1161/CIRCEP.118.006569; PMID: 30354406. Sacher F, Tedrow UB, Field ME, et al. Ventricular tachycardia ablation: evolution of patients and procedures over 8 years. Circ Arrhythm Electrophysiol 2008;1:153–61. https://doi. org/10.1161/CIRCEP.108.769471; PMID: 19808409. Bogun F, Krishnan S, Siddiqui M, et al. Electrogram characteristics in postinfarction ventricular tachycardia: effect of infarct age. J Am Coll Cardiol 2005;46:667–74. https://doi. org/10.1016/j.jacc.2005.01.064; PMID: 16098433. Di Biase L, Burkhardt JD, Lakkireddy D, et al. Ablation of stable VTs versus substrate ablation in ischemic cardiomyopathy: the VISTA randomized multicenter trial. J Am Coll Cardiol 2015;66:2872–82. https://doi.org/10.1016/j.jacc.2015.10.026; PMID: 26718674. de Bakker JM, van Capelle FJ, Janse MJ, et al. Reentry as a cause of ventricular tachycardia in patients with chronic ischemic heart disease: electrophysiologic and anatomic correlation. Circulation 1988;77:589–606. https://doi. org/10.1161/01.CIR.77.3.589; PMID: 3342490. Kléber AG, Janse MJ, Wilms-Schopmann FJ, et al. Changes in conduction velocity during acute ischemia in ventricular myocardium of the isolated porcine heart. Circulation

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1986;73:189–98. https://doi.org/10.1161/01.CIR.73.1.189; PMID: 3940667. 24. F ast VG, Kléber AG. Role of wavefront curvature in propagation of cardiac impulse. Cardiovasc Res 1997;33: 258–71. https://doi.org/10.1016/S0008-6363(96)00216-7; PMID: 9074688. 25. Anter E, Kleber AG, Rottmann M, et al. Infarct-related ventricular tachycardia: redefining the electrophysiological substrate of the isthmus during sinus rhythm. JACC Clin Electrophysiol 2018;4:1033–48. https://doi.org/10.1016/ j.jacep.2018.04.007; PMID: 30139485. 26. Martin C, Martin R, Wong T, et al. Effect of activation wavefront on electrogram characteristics during ventricular tachycardia ablation. EP Europace 2017;19(Suppl 1):i16. https:// doi.org/10.1093/europace/eux283.046. 27. Tung R, Josephson ME, Bradfield JS, Shivkumar K. Directional influences of ventricular activation on myocardial scar characterization: voltage mapping with multiple wavefronts during ventricular tachycardia ablation. Circ Arrhythm Electrophysiol 2016;9:e004155. https://doi.org/10.1161/ CIRCEP.116.004155; PMID: 27516464. 28. Shariat MH, Gupta D, Gul EE, et al. Ventricular substrate identification using close-coupled paced electrogram feature analysis. Europace 2018. https://doi. org/10.1093/europace/euy265; PMID: 30481301; epub ahead of press.

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29. d e Riva M, Naruse Y, Ebert M, et al. Targeting the hidden substrate unmasked by right ventricular extrastimulation improves ventricular tachycardia ablation outcome after myocardial infarction. JACC Clin Electrophysiol 2018;4:316–27. https://doi.org/10.1016/j.jacep.2018.01.013; PMID: 30089556. 30. 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. https://doi.org/10.1016/j.hrthm.2013.10.042; PMID: 24513915. 31. Pathik B, Lee G, Nalliah C, et al. Entrainment and high-density three-dimensional mapping in right atrial macroreentry provide critical complementary information: Entrainment may unmask ‘visual reentry’ as passive. Heart Rhythm 2017;14:1541–9. https://doi.org/10.1016/j.hrthm.2017.06.021; PMID: 28625927. 32. Kumar S, Tedrow UB, Stevenson WG. Entrainment mapping. Card Electrophysiol Clin 2017;9:55–69. https://doi.org/10.1016/ j.ccep.2016.10.004; PMID: 28167086. 33. Graham AJ, Orini M, Lambiase PD. Limitations and challenges in mapping ventricular tachycardia: new technologies and future directions. Arrhythm Electrophysiol Rev 2017;6:118–24. https://doi.org/10.15420/aer.2017.20.1. PMID: 29018519. 34. Jamil-Copley S, Vergara P, Carbucicchio C, et al. Application

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of ripple mapping to visualize slow conduction channels within the infarct-related left ventricular scar. Circ Arrhythm Electrophysiol 2015;8:76–86. https://doi.org/10.1161/ CIRCEP.114.001827; PMID: 25527678. Luther V, Linton NW, Jamil-Copley S, et al. A prospective study of ripple mapping the post-infarct ventricular scar to guide substrate ablation for ventricular tachycardia. Circ Arrhythm Electrophysiol 2016;9:e004072. https://doi. org/10.1161/CIRCEP.116.004072; PMID: 27307519. Katritsis G, Luther V, Kanagaratnam P, Linton NW. Arrhythmia mechanisms revealed by ripple mapping. Arrhythm Electrophysiol Rev 2018;7:261–4. https://doi.org/10.15420/aer.2018.44.3; PMID: 30588314. Martin CA, Takigawa M, Martin R, et al. Use of novel electrogram ‘Lumipoint’ algorithms to detect critical isthmus and abnormal potentials for ablation in ventricular tachycardia. EP Europace 2018;20(Suppl 4):iv22–3. https://doi. org/10.1093/europace/euy202.004. Magtibay K, Massé S, Asta J, et al. Physiological assessment of ventricular myocardial voltage using omnipolar electrograms. J Am Heart Assoc 2017;6:e006447. https://doi.org/10.1161/ JAHA.117.006447; PMID: 28862942. Massé S, Magtibay K, Jackson N, et al. Resolving myocardial activation with novel omnipolar electrograms. Circ Arrhythm Electrophysiol 2016;9:e004107. https://doi.org/10.1161/ CIRCEP.116.004107; PMID: 27406608.

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Electrophysiology and Ablation

Complications of Cryoballoon Pulmonary Vein Isolation Shinsuke Miyazaki and Hiroshi Tada Department of Cardiovascular Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan

Abstract Since the cryoballoon (CB) was introduced into clinical practice, more than 400,000 patients have undergone a pulmonary vein (PV) isolation with a CB throughout the world. Although the efficacy of the first-generation CB was limited, the recently introduced secondgeneration CB has achieved a greater uniformity in cooling, which has facilitated a shorter time to PV isolation, shorter procedural times, higher rates of freedom from atrial fibrillation and low rates of PV reconnections. Currently, a single short freeze strategy with a single 28 mm balloon has become the standard technique based on the balance of procedural efficacy and safety. However, enhanced cooling characteristics may also result in a greater potential for collateral damage to non-cardiac structures. Knowledge about the potential complications is essential when performing the procedure. In this article, we describe the important complications that should be noted during a CB procedure, and how to minimise the risk of complications based on our experience.

Keywords Cryoballoon, pulmonary vein isolation, complications, catheter ablation, atrial fibrillation Disclosure: Shinsuke Miyazaki has received speaker’s honoraria from Medtronic and is a member of Medtronic’s advisory board. Hiroshi Tada has no conflicts of interest to declare. Acknowledgement: The authors acknowledge John Martin’s assistance in the preparation of this manuscript. Received: 6 December 2018 Accepted: 28 January 2019 Citation: Arrhythmia & Electrophysiology Review 2019;8(1):60–4. DOI: https://doi.org.10.15420/aer.2018.72.2 Correspondence: Shinsuke Miyazaki, Department of Cardiovascular Medicine, Faculty of Medical Sciences, University of Fukui, 23–3 Matsuokashimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui 910-1193, Japan. E: mshinsuke@k3.dion.ne.jp Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Pulmonary vein isolation (PVI) has become an accepted therapeutic strategy for AF. 1 The cryoballoon (CB) ablation system has been introduced into clinical practice as a tool for a single-shot anatomical based-PVI, and a comparable efficacy of the CB ablation to radiofrequency (RF) ablation has been demonstrated in a prospective randomised study. 2–4 The recently introduced second-generation CB (Arctic Front Advance, Medtronic) has become the standard tool owing to the greater cooling effect and higher efficacy when compared with the firstgeneration CB.5,6 However, this also raises concern of collateral damage to non-cardiac structures. Several recent studies have shown that the enhanced cooling effect successfully reduced the freezing interval to 180 seconds (single freeze) or time-to-isolation of the guided-strategy, and eliminated the bonus freeze without a reduction in long-term efficacy.7–10 This article focuses on the representative complications in second-generation CB ablation procedures.

freezing being immediately terminated with a double-stop technique, active deflation, when the CMAP significantly decreases.12–15 We looked at the incidence and characteristics of PNI in 550 AF patients who underwent PVI using one 28 mm second-generation CB and a single 3-minute freeze strategy under CMAP monitoring.16 A total of 34 (6.2%) patients experienced PNI during the right superior pulmonary vein (RSPV; n=30) and inferior PV ablation (n=4). However, no patients experienced left PNI. Applications were interrupted using double-stop techniques after median 136-second (25–75th percentile: 104–158) applications, and a PVI was already achieved in all but one case. Persistent AF, larger RSPV ostia, and deeper balloon positions on fluoroscopy were associated with higher incidences of PNI. The incidence of PNI during the procedure, and 1 day and 1 month afterwards was 6.2%, 2.4%, and 1.6%, respectively. All PNI was asymptomatic and reversible during the follow-up period. The CMAP amplitude during the emergent deflation predicted the delay in the PNI recovery, and all incidents of PNI recovered by the next day in patients with a remaining CMAP amplitude of >0.2 mV.

Phrenic Nerve Injury CB ablation is associated with a significant risk of phrenic nerve injury (PNI) due to the limited balloon size, and right PNI is the most common complication in the CB ablation procedure.3–6,11 The reported incidence of PNI varies owing to different definitions (of PNI), balloon generations (first or second), balloon size, freezing regimen and protective manoeuvres. Currently, continuous monitoring of the diaphragmatic compound motor action potentials (CMAPs) has become an accepted technique in clinical practice, which involves

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These data suggest that early recognition of CMAP amplitude reductions and immediate active deflations appear to be essential for early recovery from PNI. The key to minimising the risk of PNI is to ensure the balloon position is as antral as possible, and for this purpose, a proximal-seal technique (Figure 1) is recommended to avoid any deep CB positioning.6 If no leak is visible on venography, withdraw the CB slightly and allow a leak around the PV–balloon interface to better define the PV ostium and ensure a proximal ablation. Then, reapply only the minimal amount

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Complications of Cryoballoon Ablation of pressure needed to regain the occlusion before the ablation. Since the CB size becomes slightly larger when the freezing starts, a small leakage is generally sealed by the CB applications. However, it should be noted that PNI could occur even when the balloon position is proximal, presumably because the phrenic nerve course varies among patients. Therefore, careful CMAP monitoring is mandatory during applications regardless of the RSPV size. Obtaining a stable position of the pacing catheter is important given that catheter dislodgement also results in a decrease in the CMAP amplitude. Pacing should be continued during the initial thawing time because PNI could occur during that period.16 Since this complication is usually asymptomatic, a chest X-ray is recommended before the procedure and on the next day. PNI is almost always asymptomatic and reversible during the follow-up period if the procedure was carefully performed, thus PNI is the most common, but is not a serious complication in the CB ablation procedure.

PV Stenosis PV stenosis has been a well-recognised complication of AF ablation regardless of the use of the energy sources.1,17 Moreover, there are data showing a progression of stenosis during the 3 months after RF ablation.17 The reported incidence of PV stenosis could differ due to different ablation techniques, definitions of PV stenosis, and intensity of the screening for this complication. Generally, it is believed that cryoablation has a lower risk of PV stenosis due to tissue shrinkage when compared with RF ablation because of the preservation of the basic underlying tissue architecture with preserved endocardial contours and minimal cartilage formation after the ablation.18 Since PV stenosis has not been evaluated with adequate modalities in the vast majority of centres, the reported data is limited. A few have revealed that first-generation CB ablation could result in PV stenosis and that a longer application time and use of a 23 mm CB increased the risk of this complication.3 Severe PV stenosis has also been reported after the introduction of the second-generation CB.19,20 We investigated 276 patients who underwent CB PVI using one 28 mm balloon with a single 3-minute freeze strategy.21 If the balloon temperatures reached −60°C or PNI was suspected, freezing was terminated. Enhanced cardiac CT was obtained before and >3 months after the procedure. Follow-up CT obtained at a median of 5.0 months post-procedure revealed no PVs with moderate (50–75%) or severe (>75%) stenosis. Asymptomatic mild stenosis (25–50%) was documented in 16/1,101 (1.4%) PVs, but did not progress during the follow-up period. These results are presumably because the applications were terminated when the balloon temperature reached −60°C and the maximal application duration was 180 seconds. Also, the proximal seal technique was applied to avoid the balloon being vigorously wedged inside the PVs. The use of a 23 mm CB should to avoided because almost all PVs could be isolated by 28 mm CB and a small balloon could become wedged inside the vein.22 Based on the present study data, PV stenosis might not be an issue with the current second-generation CB ablation strategy if the procedure is carefully performed, and routine evaluation of PV stenosis seems not to be necessary.

Cardiac Tamponade Cardiac tamponade is the most common potentially life-threatening complication associated with AF ablation. In a dedicated worldwide

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Figure 1: Proximal Seal Technique A

Instead of initiating ablation after the initial venogram despite contrast retention (A), the CB is gently pulled back to reveal the real PV ostium by noting contrast leak (B). Then, the CB is slightly pushed to obtain a complete occlusion at the real PV ostium (C). CB = cryoballoon; LSPV = left superior PVl; PV = pulmonary vein.

survey, cardiac tamponade was reported to be the most frequent cause of peri-procedural death, accounting for 25% of the deaths, of which 3% occurred later than 30 days post-procedure.1,23,24 We analysed the incidence and characteristics of cardiac tamponade in 5,222 AF ablation procedures in 3,483 patients.25 Cardiac tamponade occurred in 51 procedures/patients, and the incidence was 0.98% per procedure and 1.46% per patient. While there was no significant predictor of this complication, the use of a CB was associated with a lower incidence. The results are in accordance with a randomised prospective study and retrospective registry showing a lower risk of tamponade in CB ablation compared with RF ablation.4,26 The RF ablation requires multiple catheters including mapping catheters and an ablation catheter for the PVI, and the complexity could explain the higher incidence of tamponade. RF ablation of tissue resulted in a reduction in the forces required to perforate the atrial wall; however, treatment with cryoablation did not significantly alter the forces required to induce a perforation, which may explain the lower incidence of tamponade.27 Although the incidence is low in CB ablation procedures, careful manipulation of the CB with a guidewire (Achieve catheter, Medtronic) and careful manoeuvring of the FlexCath sheath (Medtronic) to avoid scratching the atrium are essential to avoid this complication.

Oesophageal Injury and Atrio-oesophageal Fistulae Atrio-oesophageal fistulae are a rare complication of PVI using not only RF but also CB.1 This is a direct result of the proximity of the oesophagus and the posterior wall of the LA.28,29 In RF ablation, strategies such as modifying energy delivery at the posterior LA close to the oesophagus can minimise the risk. However, in the CB ablation, the posterior LA lesion size cannot specifically be controlled. In the CB ablation, a total of 11 cases of atrio-oesophageal fistulae were reported from more than 120,000 cases worldwide, which is considerably lower than that in RF ablation.30 The balloon inflation time was significantly longer in the patients with atrio-oesophageal fistulae than in those without, and all cases of atrio-oesophageal fistulae occurred in relation to the left PVs. Since the occurrence of oesophageal fistulae is rare, studies evaluating the impact of oesophageal protection measures have considered the occurrence of endoscopy-detected oesophageal lesions (EDOLs) as the yardstick of the comparison. Despite some limitations of monitoring the luminal oesophageal temperature (LOT), it is suggested as one method of possibly minimising the risk of EDOLs based on the data that EDOLs were more frequently observed in patients with a lower oesophageal temperature during CB ablation.31–33 However, the use of an oesophageal probe for LOT

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Electrophysiology and Ablation Figure 2: In Type-A, the Oesophagus is Located Between the Right and Left Inferior Pulmonary Vein Ostia Type A

Type B

RIPV E

LIPV Ao

RIPV

LIPV E

Vagal nerve networks may be widely impaired by CB applications applied at the RIPV (red curve) and LIPV (blue curve) ostia, respectively. In type-B, the oesophagus is located close to the LIPV ostium, but apart from the RIPV ostium. The vagal nerve networks may be partly impaired by CB applications applied at the LIPV (blue curve) ostia, but not all are impaired. On the contrary, the oesophagus gets wedged between the balloon anteriorly and thoracic spinal column or aorta posteriorly, increasing the likelihood of exposure to oesophageal injury. Ao: aorta; CB = cryoballoon; E = oesophagus; LA = left atrium; LIPV = left inferior pulmonary vein; RIPV = right inferior pulmonary vein.

monitoring to avoid oesophageal injury during AF ablation remains unproven in the current guidelines.1 We investigated 104 patients with paroxysmal AF undergoing second-generation cryoballoon ablation with a single 3-minute freeze strategy followed by endoscopy. 34 Temperature probes were used in the first 40 patients, but not in the other 64 patients. The incidence of ODELs was significantly higher to monitor LOT in the former rather than the latter group (8/40 versus 1/64; p<0.0001). The use of oesophageal probes was the sole predictor of EDOLs. These data suggest that oesophageal temperature probes themselves may contribute to the thermal injury of the oesophagus. Ahmed et al. reported a 17% incidence of EDOLs after first-generation CB ablation with the use of oesophageal probes, while Guiot et al. reported a 0% incidence without the use of oesophageal probes.35,36 Our results were in accordance with these data. We speculate that, during cryoablation of the left inferior pulmonary vein (LIPV), the oesophagus gets wedged between the balloon anteriorly and thoracic spinal column or aorta posteriorly, increasing the likelihood of exposure to injury (Figure 2).34 We recommend that: • Freezing at the LIPV should be short. • Proton-pump inhibiters should be prescribed for 1 month after the procedure to facilitate the healing of oesophageal injury. • Deep sedation should be avoided. It has been reported that the use of general anaesthesia increases the risk of oesophageal damage in RF ablation presumably due to reduced motility and reduced deglutination of the oesophagus.37 In the current short-freezing strategy, regardless of the oesophageal temperature monitoring, the risk of oesophageal fistulae seems to be extremely low with CB ablation.

Gastric Hypomotility The vagal nerve fibres innervating the pyloric sphincter and stomach travel in the left vagal trunk along the anterior aspect of the oesophagus

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close to the posterior LA and PVs.28 It is well known that injury to the vagal nerve can result in gastric hypomotility characterised by delayed gastric emptying in the absence of an obstructing structural lesion in the stomach manifested as abdominal bloating.38 The incidence is likely underestimated because most asymptomatic patients have not been systemically screened. As mentioned above, we investigated the incidence of silent gastric hypomotility in 104 patients with paroxysmal AF undergoing secondgeneration cryoballoon with a single 3-minute freeze strategy followed by endoscopy.33,34 Temperature probes were used in the first 40 patients to monitor the oesophageal temperature, but not in the other 64 patients. The presence of food in the stomach after overnight fasting without obstruction was defined as gastroparesis. The incidence of silent gastric hypomotility was similar between the groups (7/40 versus 11/64; p=0.967), and it was resolved in all patients on repeat endoscopy performed 1–3 months later. The oesophageal temperature was similar in patients with and without silent gastric hypomotility. In multivariate analyses, a shorter distance between the oesophagus and the right inferior PV ostium was the sole predictor of gastric hypomotility. The study clarified that second-generation CB ablation carried a significant risk of silent gastric hypomotility, and the anatomical location of the oesophagus – rather than oesophageal temperature – helped to identify high-risk populations for gastric hypomotility. It is likely that gastric hypomotility frequently occurs immediately after CB ablation but only a few patients become symptomatic. Another study showed that 3% (n=3) of patients exhibited symptomatic gastric hypomotility despite cryoapplication being terminated when the LOT reached 25°C.39 The symptoms (abdominal bloating and repeated vomiting) manifested 2–5 days post-procedure, after the stomach had time to be filled with food, and abdominal imaging demonstrated marked gastric dilatation with retained food. After fasting for 4–5 days and treatment with panthenol, metoclopramide, and erythromycin, the symptoms were gone and imaging findings showed a complete recovery 7–11 days post-procedure.40 We defined a type-A oesophageal location when the oesophagus was located between the inferior PVs (apart from the LIPV and relatively close to the RIPV) at the inferior PV level, and type-B oesophageal location when the oesophagus was surrounded by the descending aorta, spine, and LIPV (close to the LIPV and apart from the RIPV; Figure 2). The incidence was significantly higher in patients with a type-A rather than a type-B oesophageal location (11.1% versus 1.2%; p=0.083), which was in accordance with the reported incidence of asymptomatic gastric hypomotility (33.3% versus 10.7%).34 The higher incidence of gastric hypomotility with CBs compared with RF ablation may be explained by the differences in the lesion configuration or greater transmural penetration by the CB ablation. We assume that the complex network of nerves located at the anterior aspect of the oesophagus may be widely damaged during ablation of the LIPV and the RIPV in patients whose oesophagus is located between these veins (type-A), increasing the risk of gastric hypomotility (Figure 2). It does not make sense to use LOT monitoring to anticipate this complication. We recommend that: • The freezing time should be short for the lower PVs, especially in the high-risk population evaluated on pre-procedural imaging. • Excessive drinking and eating should be avoided post-procedure given the high incidence of asymptomatic gastric hypomotility.

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Complications of Cryoballoon Ablation Stroke Since the incidence of a stroke is low, protective manoeuvres have been considered for silent strokes that were detected on diffusion-weighted MRI on the day after the procedure.41 Possible embolic materials are thrombi, gas bubbles and particulate debris produced during an LA ablation, and silent strokes have been produced experimentally by injecting small-size solid particles or gaseous microbubbles into the brain in animal models.42–44 In RF ablation, the most important step toward reducing symptomatic stroke and transient ischaemic attack rates is to implement uninterrupted anticoagulation into the management of patients undergoing ablation.1 According to guidelines, all AF ablation procedures should be performed under uninterrupted warfarin or dabigatran (class 1, level A).1 However, cryoablation is generally regarded as tissue-friendly and is associated with a significantly lower incidence of thrombus formation compared with RF ablation.18 We investigated the factors associated with the incidence of silent strokes during second-generation CB ablation.45,46 We gave 256 AF patients a brain MRI 1 day after the PVI using second-generation cryoballoons with a single 28 mm balloon and a short-freeze strategy. Silent strokes were detected in 26.5% (n=68) of the patients, and none of the patients reported any neurological symptoms. Reinsertion of a once withdrawn cryoballoon and additional LA mapping with a multielectrode catheter significantly increased the incidence of silent strokes. Transient coronary air embolisms were significantly associated with the incidence of silent strokes. On the contrary, an uninterrupted anticoagulation regimen, cryoballoon air removal with extracorporeal balloon inflations,

alkins H, Kuck KH, Cappato R, et al. 2012 HRS/EHRA/ C 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: a report of the Heart Rhythm Society (HRS) Task Force on Catheter and Surgical Ablation of Atrial Fibrillation. Heart Rhythm 2012;9:632–96. https://doi.org/10.1016/j. hrthm.2011.12.016; PMID: 22386883. Kojodjojo P, O’Neill MD, Lim PB, et al. Pulmonary venous isolation by antral ablation with a large cryoballoon for treatment of paroxysmal and persistent atrial fibrillation: medium-term outcomes and non-randomised comparison with pulmonary venous isolation by radiofrequency ablation. Heart 2010;96:1379–84. https://doi.org/10.1136/ hrt.2009.192419; PMID: 20801856. Packer DL, Kowal RC, Wheelan KR, et al. Cryoballoon ablation of pulmonary veins for paroxysmal atrial fibrillation: first results of the North American Arctic Front (STOP AF) pivotal trial. J Am Coll Cardiol 2013;61:1713–23. https://doi. org/10.1016/j.jacc.2012.11.064; PMID: 23500312. Kuck KH, Brugada J, Fürnkranz A, et al. Cryoballoon or radiofrequency ablation for paroxysmal atrial fibrillation. N Engl J Med 2016;374:2235–45. https://doi.org/10.1056/ NEJMoa1602014; PMID: 27042964. Martins RP, Hamon D, Césari O, et al. Safety and efficacy of a second-generation cryoballoon in the ablation of paroxysmal atrial fibrillation. Heart Rhythm 2014;11:386–93. https://doi. org/10.1016/j.hrthm.2014.01.002; PMID: 24389575. Su W, Kowal R, Kowalski M, et al. Best practice guide for cryoballoon ablation in atrial fibrillation: the compilation experience of more than 3,000 procedures. Heart Rhythm 2015;12:1658–66. https://doi.org/10.1016/j.hrthm.2015.03.021; PMID: 25778428. Ciconte G, de Asmundis C, Sieira J, et al. Single 3-minute freeze for second-generation cryoballoon ablation: oneyear follow-up after pulmonary vein isolation. Heart Rhythm 2015;12:673–80. https://doi.org/10.1016/j.hrthm.2014.12.026; PMID: 25542427. Miyazaki S, Hachiya H, Nakamura H, et al. Pulmonary vein isolation using a second-generation cryoballoon in patients with paroxysmal atrial fibrillation: one-year outcome using a single big-balloon 3-minute freeze technique. J Cardiovasc Electrophysiol 2016;27:1375–80. https://doi.org/10.1111/ jce.13078; PMID: 27534931. Chun KR, Stich M, Fürnkranz A, et al. Individualized cryoballoon energy pulmonary vein isolation guided by real-time pulmonary vein recordings, the randomized ICE-T trial. Heart Rhythm 2017;14:495–500. https://doi.org/10.1016/j.

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strength of the MRI magnet, internal electrical cardioversion, and touch-up ablation were not associated with the incidence of silent strokes. These results suggest that air embolisms are the main mechanism of silent strokes, and the injected air volume might determine the type of lesion. These findings underscore the importance of careful de-airing management during procedures using large bore transseptal sheaths in the LA. As well as the strict anticoagulation protocol according to the guidelines1, we recommend: • Careful sheath management; • Submerged loading of the catheter into the introducer before sheath insertion to minimise the ingression of air; • Slow catheter insertion and withdrawal from the sheath because air can be introduced into the transseptal sheath with suction when catheters are removed. • Reinsertion of a used CB and exchanging catheters with complex geometries via the FlexCath sheath, should be avoided.

Clinical Perspective • Cryoballoon ablation is associated with several procedural complications and that knowledge is essential for physicians who are involved in the procedure. • Balloon positioning and freeze dosing are the key to minimise the risk of complication while maintaining the procedure’s efficacy.

hrthm.2016.12.014; PMID: 27956248. 10. A ryana A, Kenigsberg DN, Kowalski M, et al. Verification of a novel atrial fibrillation cryoablation dosing algorithm guided by time-to-pulmonary vein isolation: Results from the Cryo-DOSING Study (Cryoballoon-ablation DOSING Based on the Assessment of Time-to-Effect and Pulmonary Vein Isolation Guidance). Heart Rhythm 2017;14:1319–25. https://doi. org/10.1016/j.hrthm.2017.06.020; PMID: 28625929. 11. Metzner A, Rausch P, Lemes C, et al. The incidence of phrenic nerve injury during pulmonary vein isolation using the second-generation 28 mm cryoballoon. J Cardiovasc Electrophysiol 2014;25:466–70. https://doi.org/10.1111/ jce.12358; PMID: 24400647. 12. Franceschi F, Dubuc M, Guerra PG, Khairy P. Phrenic nerve monitoring with diaphragmatic electromyography during cryoballoon ablation for atrial fibrillation: the first human application. Heart Rhythm 2011;8:1068–71. https://doi. org/10.1016/j.hrthm.2011.01.047; PMID: 21315843. 13. Kowalski M, Ellenbogen KA, Koneru JN. Prevention of phrenic nerve injury during interventional electrophysiologic procedures. Heart Rhythm 2014;11:1839–44. https://doi. org/10.1016/j.hrthm.2014.06.019; PMID: 24952147. 14. Ghosh J, Sepahpour A, Chan KH, et al. Immediate balloon deflation for prevention of persistent phrenic nerve palsy during pulmonary vein isolation by balloon cryoablation. Heart Rhythm 2013;10:646–52. https://doi.org/10.1016/j. hrthm.2013.01.011; PMID: 23333737. 15. Kulkarni N, Su W, Wu R. How to prevent, detect and manage complications caused by cryoballoon ablation of atrial fibrillation. Arrhythm Electrophysiol Rev 2018;7:18–23. https://doi. org/10.15420/aer.2017.32.1; PMId: 29636968. 16. Miyazaki S, Kajiyama T, Watanabe T, et al. Characteristics of phrenic nerve injury during pulmonary vein isolation using a 28-mm second-generation cryoballoon and short freeze strategy. J Am Heart Assoc 2018;7:pii:e008249. https://doi. org/10.1161/JAHA.117.008249; PMID: 29574457. 17. Holmes DR, Monahan KH, Packer D. Pulmonary vein stenosis complicating ablation for atrial fibrillation: clinical spectrum and interventional considerations. JACC Cardiovasc Interv 2009:267–76. https://doi.org/10.1016/j.jcin.2008.12.014; PMID: 19463436. 18. Khairy P, Chauvet P, Lehmann J, et al. Lower incidence of thrombus formation with cryoenergy versus radiofrequency catheter ablation. Circulation 2003;107:2045–50. https://doi. org/10.1161/01.CIR.0000058706.82623.A1; PMID: 12668527. 19. Watanabe K, Nitta J, Sato A, et al. Hemoptysis after five months of cryoballoon ablation: what is the relationship? HeartRhythm Case Rep 2017;3:357–9. https://doi.org/10.1016/j. hrcr.2017.05.010; PMID: 28748144. 20. Narui R, Tokuda M, Matsushima M, et al. Incidence and

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factors associated with the occurrence of pulmonary vein narrowing after cryoballoon ablation. Circ Arrhythm Electrophysiol 2017;10:e004588. https://doi.org/10.1161/CIRCEP.116.004588; PMID: 28630168. Miyazaki S, Kajiyama T, Hada M, et al. Does second-generation cryoballoon ablation using the current single short freeze strategy produce pulmonary vein stenosis? Int J Cardiol 2018;272:175–8. https://doi.org/10.1016/j.ijcard.2018.08.004; PMID: 30093139. Chen S, Schmidt B, Bordignon S, et al. Practical techniques in cryoballoon ablation: how to isolate inferior pulmonary veins. Arrhythm Electrophysiol Rev 2018;7:11–7. https://doi. org/10.15420/aer.2018;1;2; PMID: 29686870. Cappato R, Calkins H, Chen SA, 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. https://doi.org/10.1161/CIRCEP.109.859116; PMID: 19995881. Cappato R, Calkins H, Chen SA, et al. Delayed cardiac tamponade after radiofrequency catheter ablation of atrial fibrillation: a worldwide report. J Am Coll Cardiol 2011;58:2696–7. https://doi.org/10.1016/j.jacc.2011.09.028; PMID: 22152959. Hamaya R, Miyazaki S, Taniguchi H, et al. Management of cardiac tamponade in catheter ablation of atrial fibrillation: single-centre 15 year experience on 5222 procedures. Europace 2018;20:1776–82. https://doi.org/10.1093/europace/eux307; PMID: 29161368. Schmidt M, Dorwarth U, Andresen D, et al. German ablation registry: Cryoballoon vs. radiofrequency ablation in paroxysmal atrial fibrillation – one-year outcome data. Heart Rhythm 2016;13:836–44. https://doi.org/10.1016/j.hrthm.2015.12.007; PMID: 26681608. Quallich SG, Van Heel M, Iaizzo PA. Optimal contact forces to minimize cardiac perforations before, during, and/or after radiofrequency or cryothermal ablations. Heart Rhythm 2015;12:291–6. https://doi.org/10.1016/j.hrthm.2014.11.028; PMID: 25461502. Sánchez-Quintana D, Cabrera JA, Climent V, et al. Anatomic relations between the esophagus and left atrium and relevance for ablation of atrial fibrillation. Circulation 2005;112:1400–5. https://doi.org/10.1161/ CIRCULATIONAHA.105.551291; PMID: 16129790. Romero J, Avendano R, Grushko M, et al. Oesophageal injury during af ablation: techniques for prevention. Arrhythm Electrophysiol Rev 2018;7:24–31. https://doi.org/10.15420/ aer.2017.46.2; PMID: 29636969. John RM, Kapur S, Ellenbogen KA, Koneru JN. Atrioesophageal fistula formation with cryoballoon ablation is most commonly related to the left inferior pulmonary vein. Heart Rhythm 2017;14:184–9. https://doi.org/10.1016/j.hrthm.2016.10.018;

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Electrophysiology and Ablation PMID: 27769853. 31. M etzner A, Burchard A, Wohlmuth P, et al. Increased incidence of esophageal thermal lesions using the secondgeneration 28-mm cryoballoon. Circ Arrhythm Electrophysiol 2013;6:769–75. https://doi.org/10.1161/CIRCEP.113.000228; PMID: 23748208. 32. Fürnkranz A, Bordignon S, Böhmig M, et al. Reduced incidence of esophageal lesions by luminal esophageal temperature-guided second-generation cryoballoon ablation. Heart Rhythm 2015;12:268–74. https://doi.org/10.1016/j. hrthm.2014.10.033; PMID: 25446159. 33. Miyazaki S, Nakamura H, Taniguchi H, et al. Esophagus related complications during second-generation cryoballoon ablation insight from simultaneous esophageal temperature monitoring from two esophageal probes. J Cardiovasc Electrophysiol 2016;27:1038–44. https://doi.org/10.1111/ jce.13015; PMID: 27221011. 34. Miyazaki S, Nakamura H, Taniguchi H, et al. Gastric hypomotility after second-generation cryoballoon ablationunrecognized silent nerve injury after cryoballoon ablation. Heart Rhythm 2017;14:670–7. https://doi.org/10.1016/j. hrthm.2017.01.028; PMID: 28434448. 35. Ahmed H, Neuzil P, d’Avila A, et al. The esophageal effects of cryoenergy during cryoablation for atrial fibrillation. Heart Rhythm 2009;6:962–9. https://doi.org/10.1016/j. hrthm.2009.03.051; PMID: 19560085. 36. Guiot A, Savouré A, Godin B, Anselme F. Collateral nervous

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damages after cryoballoon pulmonary vein isolation. J Cardiovasc Electrophysiol 2012;23:346–51. https://doi. org/10.1111/j.1540-8167.2011.02219.x; PMID: 22081875. Di Biase L, Saenz LC, Burkhardt DJ, et al. Esophageal capsule endoscopy after radiofrequency catheter ablation for atrial fibrillation: documented higher risk of luminal esophageal damage with general anesthesia as compared with conscious sedation. Circ Arrhythm Electrophysiol 2009;2:108–12. https://doi. org/10.1161/CIRCEP.108.815266; PMID: 19808454. Shah D, Dumonceau JM, Burri H, et al. Acute pyloric spasm and gastric hypomotility: an extracardiac adverse effect of percutaneous radiofrequency ablation for atrial fibrillation. J Am Coll Cardiol 2005;46:327–30. https://doi.org/10.1016/j. jacc.2005.04.030; PMID: 16022963. Hasegawa K, Miyazaki S, Hisazaki K, et al. Gastric hypomotility after luminal esophageal temperature guided secondgeneration cryoballoon pulmonary vein isolation. Circ Arrhythm Electrophysiol 2018;11:e006691. https://doi.org/10.1161/ CIRCEP.118.006691; PMID: 30354316. Kuwahara T, Takahashi A, Takahashi Y, et al. Clinical characteristics and management of periesophageal vagal nerve injury complicating left atrial ablation of atrial fibrillation: lessons from eleven cases. J Cardiovasc Electrophysiol 2013; 24:847–51. https://doi.org/10.1111/jce.12130; PMID: 23551640. Deneke T, Jais P, Scaglione M, et al. Silent cerebral events/ lesions related to atrial fibrillation ablation: a clinical review. J Cardiovasc Electrophysiol 2015;26:455–63. https://doi.

org/10.1111/jce.12608; PMID: 25556518. 42. H aines DE, Stewart MT, Dahlberg S, et al. Microembolism and catheter ablation I: a comparison of irrigated radiofrequency and multielectrode-phased radiofrequency catheter ablation of pulmonary vein ostia. Circ Arrhythm Electrophysiol 2013;6:16–22. https://doi.org/10.1161/CIRCEP.111.973453; PMID: 23392585. 43. Takami M, Lehmann HI, Parker KD, et al. Effect of left atrial ablation process and strategy on microemboli formation during irrigated radiofrequency catheter ablation in an in vivo model. Circ Arrhythm Electrophysiol 2016;9:e003226. https://doi. org/10.1161/CIRCEP.115.003226; PMID: 26763224. 44. Haines DE, Stewart MT, Barka ND, et al. Microembolism and catheter ablation II: effects of cerebral microemboli injection in a canine model. Circ Arrhythm Electrophysiol 2013;6:23–30. https://doi.org/10.1161/CIRCEP.112.973461; PMID: 23275248. 45. Miyazaki S, Watanabe T, Kajiyama T, et al. Thromboembolic risks of the procedural process in second-generation cryoballoon ablation procedures: analysis from realtime transcranial doppler monitoring. Circ Arrhythm Electrophysiol 2017;10:pii:e005612. https://doi.org/10.1161/ CIRCEP.117.005612; PMID: 29247032. 46. Miyazaki S, Kajiyama T, Yamao K, et al. Silent cerebral events/ lesions after second-generation cryoballoon ablation: How can we reduce the risk of silent strokes? Heart Rhythm 2018;1:41–8. https://doi.org.10.1016/j.hrthm.2018.07.011; PMID: 30017816.

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Electrophysiology and Ablation

Papillary Muscle Ventricular Tachycardia or Ectopy: Diagnostics, Catheter Ablation and the Role of Intracardiac Echocardiography Josef Kautzner and Petr Peichl Department of Cardiology, Institute for Clinical and Experimental Medicine (IKEM), Prague, Czech Republic

Abstract Ventricular arrhythmias originating from the papillary muscle of the left or right ventricle are specific clinical entities. They are usually focal in origin and can be identified by a characteristic ECG pattern. Intracardiac echocardiography appears to be the most suitable imaging method for assessment of the exact location of the focus at papillary muscles in association with activation mapping. We recently confirmed that ectopic foci were located within the distal, mid, or proximal (basal) third of the papillary muscle in 67%, 19%, and 14% of patients, respectively. Radiofrequency ablation has the potential to cure these specific arrhythmias. However, the procedure is usually challenging for catheter instability, despite navigation with intracardiac echocardiography. Cryoablation, which ensures catheter tip stability, could be a viable alternative in cases of the failure of radiofrequency catheter ablation.

Keywords Papillary muscle, ventricular tachycardia, ventricular premature contractions, catheter ablation, intracardiac echocardiography Disclosure: JK has received speaker honoraria from Boehringer Ingelheim, Biosense Webster, Biotronik, Boston Scientific, Medtronic, Merck Sharp & Dohme, Pfizer, and St Jude Medical; and has served as a consultant for Bayer, Boehringer Ingelheim, Biosense Webster, Boston Scientific, Medtronic, Liva Nova and St Jude Medical. PP has received speaker honoraria from St Jude Medical (Abbott), and has served as a consultant for Biotronik and Boston Scientific. This study was supported by the research grants of the Ministry of Health of the Czech Republic: Conceptual development of research organization – IKEM, IN 00023001. Received: 14 December 2018 Accepted: 12 February 2019 Citation: Arrhythmia & Electrophysiology Review 2019;8(1):65–9. DOI: https://doi.org/10.15420/aer.2018.80.2 Correspondence: Josef Kautzner, Institut klinické a experimentální medicíny, Vídeňská 1958/9 140 21 Praha, Czech Republic. E: josef.kautzner@ikem.cz Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

The origin of idiopathic ventricular tachycardia (VT) or symptomatic premature ventricular contractions (PVCs) from papillary muscle (PM) was first described in 2008 as a distinct clinical syndrome by a group from Birmingham, Alabama, US.1 Out of 290 patients ablated for idiopathic VT or symptomatic PVCs, seven patients were recognised who had the ablation site at the base of the posteromedial PM. The ECG pattern was characteristic, showing a right bundle branch block and superior axis deviation. The main mechanism of these arrhythmias was identified as a non-reentrant mechanism (automaticity or triggered activity). Activation mapping revealed the source of focal activity at the base of the posterior PM. All patients were free of PVCs or VT at 9 months follow-up. One cannot dismiss the question why such an entity was not described earlier. One explanation could be that it is difficult to exactly locate the focus without direct visualisation with echocardiography and/ or intracardiac echocardiography. The other reason could be that this arrhythmia was often misdiagnosed with fascicular VTs or with arrhythmias from the mitral annulus region. It is no surprise that the same group published another series of six cases of focal arrhythmias originating from the base or midportion of the anterior PM in the left ventricle (LV) 1 year later.2 Again, ECG showed typical morphology of a right bundle branch block with inferior axis deviation. Successful ablation required a cool tip or 8 mm tip catheter. Finally, in 2010, ventricular arrhythmias from the PM in the right ventricle (RV) were described by Crawford et al. in eight of 169 patients with idiopathic

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RV arrhythmias.3 The majority originated in the septal PM (n=8), while anterior and posterior were a less frequent source of focus (n=4 and n=3, respectively). Focal sources of arrhythmias at the PMs were also described in patients after myocardial infarction. Interestingly, these patients presented with heterogeneous late gadolinium enhancement within the region of the PMs,4,5 and such PM substrate may even participate in reentrant VTs. Even more recently, PMs were recognised to also be a source of focally triggered VF.6–8 In one report, the moderator band was identified as a source of focal trigger for VF.8 The other series described two patients with VF originating from the left posteromedial PM. However, four patients had VF from the RV, specifically from the posterolateral PM.7

Anatomical Considerations In the LV, the PMs are part of the mitral valve apparatus. The anterolateral PM originates from the anterolateral LV wall, and provides chordae to the anterolateral half of the anterior and posterior mitral leaflets. The posteromedial PM originates from the inferoseptal LV wall, and provides chordae to the posteromedial half of both leaflets. Imaging studies revealed that both PMs vary significantly in size and shape. Online use of intracardiac echocardiography (ICE) revealed that PMs can have two heads.9

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Electrophysiology and Ablation Figure 1: Left Ventricular Papillary Muscles as Visualised by Intracardiac Echocardiography and Corresponding Typical ECG Morphology of Ectopy

Figure 2: Morphology of the Anterior Right Ventricular Papillary Muscle as Shown by Intracardiac Echocardiography I

I II III aVR

II III aVR aVL

aVL aVF V1 V2 V3 V4 V5 V6

I II III aVR aVL aVF V1 V2 V3 V4

aVF V1 V2 V3 V4 V5 V6 Note that the moderator band is connected to the base of the papillary muscle. The right panel shows ECG morphology of the ectopic beat that was successfully ablated on the tip of the anterior right ventricular papillary muscle.

origin in the PMs can be suspected from the morphology of the QRS and from the location of the transition zone. Differentiation between anterolateral and posteromedial PM can be made using the axis in the frontal plane. Focus in posteromedial PM has a superior axis, which is similar to left posterior fascicular and or perimitral arrhythmias. Arrhythmias from the anterolateral PM have an inferior axis similar to arrhythmias from the left anterior fascicle and the anterior part of the mitral annulus (Figure 1).

V5 V6 (A) Posteromedial papillary muscle and (B) anterolateral papillary muscle.

Our recent multicentre experience in 34 patients with idiopathic VT/ PVC from PM included the detailed description of the anatomy of PMs using ICE.10 The anterolateral PM was shorter (23 ± 4 mm) than the posteromedial PM (28 ± 7 mm). In about one-third of patients, the PM was formed by two distinctly separate heads. Two-head PM can be considered as a normal anatomical variant (Figure 1). In the RV, the PMs are even more complex in arrangement.11 The moderator band is a prominent muscular trabeculation that crosses from the septum to the free wall of the RV and provides support to the anterior PM of the TV (Figure 2). It contains the right bundle branch of the conduction system and its terminal arborisation. The posterior PM provides chordae to the posterior and septal leaflets. The conus PM provides chordae to the septal leaflet of the valve. From a histological point of view, the PMs contain ventricular myocytes and a rich subendocardial network of Purkinje fibers covered by a layer of endothelium. The ventricular myocardium and the Purkinje network are connected only at localised regions near the PM base, explaining why separate Purkinje potentials can be recorded here.

Differential Diagnosis ECG Since idiopathic LV arrhythmias arising from the PMs, left fascicles, and mitral annulus, and ventricular arrhythmias arising from the septal PM or RV outflow tract may have similar ECG morphologies, differential diagnosis based on ECG is very important. Arrhythmias originating from the LV have right bundle branch morphology in lead V1. The

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Several studies suggested characteristics that can distinguish among the aforementioned arrhythmias.12,13 Narrower QRS (<130 ms) and rR’ pattern in V1 are characteristic of fascicular arrhythmias, as they use by definition the conduction system.12–14 In contrast, broad QRS and the absence of rR’ are features typically observed in PM arrhythmias. The recent algorithm based on this value suggests high sensitivity and specificity (approximately 90%). Arrhythmias from the mitral annulus are characterised by positive concordance in chest leads, as compared with PM arrhythmias with the transition zone between V3 and V4. This reflects the location of the base of the PM approximately in the middle of the long axis of the ventricle. Other studies demonstrated that an R/S ratio <1 in lead V6 in the LV anterolateral region and QRS duration >160 ms in the posteroseptal region were the only reliable predictors for differentiating PM VTs from fascicular arrhythmias.13 Another sign to differentiate between PM and fascicular arrhythmia is Q waves in limb leads. Their presence in leads I, aVL or II, III and aVF suggests a fascicular origin.14 Ventricular arrhythmias from the RV PM are much less frequent than arrhythmias from the LV. In general, such arrhythmias have a left bundle branch block morphology and an rS or QS pattern in lead V1 (Figure 2). Among them, the focus in the septal PM may resemble the source in the RV outflow tract on ECG, especially when the focus is on the conus PM.11 Then, the QRS is positive from lead I to III. Some additional characteristics may favour an origin from the parahisian area,15 including prominent R waves in leads I and aVL, and a lower R wave amplitude in lead III than lead II. Other right-sided PM arrhythmias have a wider QRS complex with a notched appearance in the precordial leads. Posterior or anterior RV papillary muscles usually have a superior axis with a late R wave transition (>V4) as

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Papillary Muscle Ventricular Tachycardia or Ectopy compared with septal PM arrhythmias, which often have an inferior axis and an earlier R wave transition. 3,16 Finally, the discrepancy between leads II and III was proposed as a simple sign, suggesting an exit from a mid-cavitary structure.17 Discrepancy means a predominantly positive QRS complex in lead II with a negative QRS complex in lead III (positive/negative discordance, equivalent to a frontal axis of −30° to +30°) or the opposite finding (negative/positive discordance, equivalent to a frontal axis of +150° to +210°). The first scenario (i.e. positive/negative discordance) suggests the source from the LV septum or RV (either parahisian or moderator band/right septal PM), while the latter (i.e. negative/positive discordance) suggests the LV free wall (anterolateral PM). While negative/positive discordance is very specific for anterolateral PM, its sensitivity is low (most anterolateral PM foci have an inferior axis).

Figure 3: Site of Successful Ablation at the Ectopic Focus at the Tip of the Lateral Head of the Anterolateral Papillary Muscle I II III aVR aVL aVF V1 V2 V3 V4 V5 V6 27ms Abl d

Abl p

The right panel shows the corresponding electrogram at the site.

Patients with arrhythmias from PM tend to be older compared with patients with fascicular or perimitral arrhythmias.12 They more often have coronary artery disease and some degree of LV dysfunction. They are frequently treated with beta-blockers, while calcium channel blockers are often used for fascicular arrhythmias.

in the QRS during an electrophysiology study, and were able to abolish PVCs with a single wide ablation at the base of the PM.13 This supports the hypothesis that variation of QRS is caused by multiple exits from a single intrapapillary focus. Furthermore, this finding can also be explained by the presence of other endocavitary structures that can connect the PMs, such as the chordae tendineae and false tendons.

Imaging Techniques

Management

Echocardiography is a part of the diagnostic workup for every patient. In selected cases, cardiac magnetic resonance is used. Most idiopathic PM arrhythmias have normal findings both on echocardiography and cardiac magnetic resonance. However, late gadolinium may be detected in the PM in some idiopathic patients, corresponding with localised areas of low voltage.14 This finding is more frequent in patients with ischaemic heart disease.4 ICE may also reveal hyperdensities in PMs; however, no rigorous study has been performed to set criteria for the presence of a scar in PM.

Patients with focal VT and or PVC originating from PMs generally have a good prognosis. Treatment is indicated mainly in symptomatic cases or when frequent ventricular ectopy (generally defined as >10–20% of all beats in a 24-hour recording) results in arrhythmia-mediated cardiomyopathy. The rare exemption is the scenario when PM houses the focal trigger for VF.7,8 Another situation is when PM is involved in reentrant arrhythmias in patients after myocardial infarction.4,5 In such cases, an ICD is generally recommended.

Clinical Parameters

Catheter Ablation ICE appears to be the most suitable for assessment of the exact location of the focus at PMs. Its role was already emphasised in 2010 by a group from the Mayo Clinic.18 In another study, 7% of 122 patients presented with ectopy from left-sided PMs as confirmed by ICE.14 Intraprocedural imaging also helped in differential diagnosis between PM-related arrhythmia and fascicular tachycardia. Our experience confirms this notion, as without online imaging it is difficult or even impossible to describe the exact location of the focus.

Electrophysiological Study Regarding the mechanisms of arrhythmias from PM, the vast majority are focal in origin and thus, non-reentrant. This mechanism is compatible with other findings, such as inducibility with isoproterenol or epinephrine infusion and burst pacing, and the finding that the first beat of tachycardia is typically similar to subsequent beats.19 In individual cases, Purkinje potentials are observed at the beginning of the QRS, suggesting the more superficial location of the focus. Some studies even suggested that the presence of Purkinje potentials at the site of origin and smaller size of the PM are associated with successful ablation of PM arrhythmias.20 Clinically, PM arrhythmias can exhibit mild spontaneous changes in QRS morphology. This can be explained by the location of the source closer to the tip of the PM and multiple exits towards the base. Indeed, Yamada et al. found spontaneous subtle changes

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Catheter ablation has emerged as the preferred treatment modality with the potential for complete cure, especially in patients without significant structural heart disease. When PVCs are frequent and/ or VT is easily inducible and tolerated, exact identification of the source by activation mapping could be relatively easy. However, to make the mapping process systematic, online imaging is preferable. In our experience, ICE is an excellent tool. It allows assessment of catheter–tissue contact and optimal alignment of the catheter with the PM axis. In addition, ICE identifies focal scars within the PM that may correspond to the site of arrhythmia origin. For proper imaging of LV PMs, the ICE catheter is deflected across the tricuspid valve into the RV and rotated clockwise to achieve a long axis view of the LV with the posteromedial PM displayed first at the bottom of the LV, and anterolateral PM to the right upon further rotation of the catheter. For RV PMs, the imaging is easier, since the ICE catheter can be placed in close vicinity of the PMs. Integrated ICE-guided imaging with electroanatomical mapping is another alternative that was demonstrated to have a higher success rate.21 Others use ICE with the magnetic sensor to enable an echo-facilitated 3D electroanatomical mapping and thus, realtime creation of precise geometries of cardiac chambers and endocavitary structures.22 Other less precise options include image integration of electroanatomical mapping with CT or cardiac magnetic resonance datasets.23

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Electrophysiology and Ablation Figure 4: Recording During Delivery of Radiofrequency Current at the Site on the Anterolateral Papillary Muscle I II III aVR aVL aVF V1

immediate defibrillation. Triggering VF during ablation at the PM was also reported by other groups.27 Regarding the set up for the ablation, we use the irrigated-tip catheter in the power-control mode starting at 30 W with an irrigation flow rate of 30 ml/minute for 30–60 seconds. We can titrate power to as high as 40 W, with the goal to achieve a decrease of 8–10 in the impedance and with a temperature limit of <40°C. The endpoint of the catheter ablation is the elimination and non-inducibility of VT or PVCs during an isoproterenol intravenous bolus and burst pacing from the RV (to a cycle length as short as 300 ms).

V2 V3 V4 V5 V6 Note the brief acceleration of ectopy and immediate disappearance during the application of the radiofrequency current (radiofrequency on marks the beginning of delivery).

As aforementioned, catheter ablation of PM arrhythmias is typically performed at the site of the earliest endocardial activation identified by activation mapping. For this purpose, a multielectrode mapping catheter could be used in an attempt to achieve faster and more precise delineation of the site of origin of arrhythmia. Sites with activation preceding approximately −25 to −30 ms the QRS complex during ectopy suggest a close proximity to the arrhythmia focus (Figure 3). In some cases, a high-frequency Purkinje potential may be present at the successful ablation site. Pace mapping could be necessary when PVCs are infrequent. However, its utility is limited due to frequent catheter instability, and also due to the fact that it identifies only the exit site and not necessarily the source. An earlier series by Yamada et al. showed that ablation at the site with excellent pace mapping frequently changed the ECG morphology, suggesting the source location to be higher or deeper along the muscle.13 A similar observation was described using an automatic pace mapping module to identify potential exits. In that study, morphological alterations were noticed in 92% of patients, requiring ablation at different exit sites.24 This suggests that the source is in the middle or apical portion of the PM, and pace mapping around the base of the PM identifies variable exits. Some groups advocated circumferential ablation around the base of the PM as a successful strategy.25 We recently confirmed that ectopic foci were located within the distal, mid, or proximal (basal) third of the PM in 67%, 19% and 14% of patients, respectively.10 A total of 86% of PM foci were acutely abolished, and very good long-term success was achieved in 65% of patients. Retrograde access into the LV was the most frequent approach (62%); however, a solely transseptal approach was selected in 29% of cases. Both approaches were utilised in 9% of cases. The location of arrhythmia focus at the tip of the PM, as determined by ICE guidance, was also described by others.26 Interestingly, acceleration of the ectopy was observed during ablation on the PM in our series in 89% of patients (Figure 4).10 In two patients (6%), accelerated ventricular rhythm triggered VF, which required

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The main challenge for catheter ablation of PM foci is the catheter tip making contact with the tissue. Depending on the individual anatomy and rotation of the heart, retrograde or transseptal access could be preferable. More recently, some groups suggested the use of cryoablation to overcome problems with catheter instability. Comparing the efficacy of 8 mm cryoablation catheter versus 4 mm irrigated tip catheter showed 100% success in eliminating focus on the PM for cryoablation (12 patients), as compared with 78% for radiofrequency ablation (nine patients).28 In addition, no recurrences were observed in patients after cryoablation, while there was a 44% recurrence rate after radiofrequency ablation. The group at the University of Pennsylvania published their recent experience with cryoablation after a failure of radiofrequency ablation.29 They reported success in >90% of cases. In contrast, cryoablation has some disadvantages, such as less manoeuvrability, reduced lesion depth, and the inability to accurately track the catheter tip in the electroanatomical map. They reported on the use of a 6 mm Freezor Xtra catheter (Medtronic), which is able to fit through an Agilis or SL0 sheath.29 An 8 mm cryocatheter is considered less useful, as it is more difficult to manipulate, requires a larger diameter of the sheath, and may have limited reach due to its shorter length (90 cm).

Complications In our experience, procedure-related complications are infrequent. When a retrograde aortic approach is used, damage to the aortic valve is a possibility. A few case reports have described worsening mitral regurgitation following ablation, and mechanisms may include PM dysfunction or catheter entrapment in the MV apparatus.30,31 VF induction may occur during radiofrequency application at the moderator band or PMs, requiring external defibrillation, and a new right bundle branch block may develop postprocedure in 40% of patients with moderator band ventricular arrhythmias.

Conclusion The PMs are a recognised site of origin of ventricular arrhythmias both in patients without and with structural heart disease. The mechanism is predominantly focal and certain ECG features could be characteristic. Catheter ablation of focal sources is highly effective, but challenging. The reason is tremendous variability of the anatomy of PMs and instability of the ablation catheter on the moving structure. The use of ICE is fundamental to allow real-time visualisation of PMs, and ensure proper positioning of the catheter and tip-tissue contact. Cryoablation could be considered as an option to increase catheter stability and improve outcomes, especially in cases of failed radiofrequency ablation.

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Papillary Muscle Ventricular Tachycardia or Ectopy

Clinical Perspective • Ventricular arrhythmias originating from the papillary muscles of the left or right ventricle are mostly focal in origin and have a characteristic ECG pattern. • Ectopic foci are predominantly located within the apical part of the muscles. • Intracardiac echocardiography provides a unique tool to confirm the exact location of the focus identified by activation mapping. • Although radiofrequency ablation has great potential to cure these specific arrhythmias, cryoablation may be a better alternative for some challenging cases, mainly due to better catheter tip stability.

oppalapudi H, Yamada T, McElderry HT, et al. Ventricular D tachycardia originating from the posterior papillary muscle in the left ventricle: a distinct clinical syndrome. Circ Arrhythm Electrophysiol 2008;1:23–9. https://doi.org/10.1161/ CIRCEP.107.742940; PMID: 19808390. 2. Yamada T, McElderry HT, Okada T, et al. Idiopathic focal ventricular arrhythmias originating from the anterior papillary muscle in the left ventricle. J Cardiovasc Electrophysiol 2009;20:866–72. https://doi.org/10.1111/j.15408167.2009.01448.x; PMID: 19298560. 3. Crawford T, Mueller G, Good E, et al. Ventricular arrhythmias originating from papillary muscles in the right ventricle. Heart Rhythm 2010;7:725–30. https://doi.org/10.1016/ j.hrthm.2010.01.040; PMID: 20206325. 4. Bogun F, Desjardins B, Crawford T, et al. Post-infarction ventricular arrhythmias originating in papillary muscles. J Am Coll Cardiol 2008;51:1794–802. https://doi.org/10.1016/ j.jacc.2008.01.046; PMID: 18452787. 5. Yamada T, Tabereaux PB, Doppalapudi H, et al. Successful catheter ablation of a ventricular tachycardia storm originating from the left ventricular posterior papillary muscle involved with a remote myocardial infarction. J Interv Card Electrophysiol 2009;24:143–5. https://doi.org/10.1007/s10840008-9327-x; PMID: 19015967. 6. Van Herendael H, Zado ES, Haqqani H, et al. Catheter ablation of ventricular fibrillation: importance of left ventricular outflow tract and papillary muscle triggers. Heart Rhythm 2014;11:566–73. https://doi.org/10.1016/j.hrthm.2013.12.030; PMID: 24398086. 7. Santoro F, Di Biase L, Hranitzky P, et al. Ventricular fibrillation triggered by PVCs from papillary muscles: clinical features and ablation. J Cardiovasc Electrophysiol 2014;25:1158–64. https://doi.org/10.1111/jce.12478; PMID: 24946987. 8. Sadek MM, Benhayon D, Sureddi R, et al. Idiopathic ventricular arrhythmias originating from the moderator band: electrocardiographic characteristics and treatment by catheter ablation. Heart Rhythm 2015;12:67–75. https://doi. org/10.1016/j.hrthm.2014.08.029; PMID: 25240695. 9. Ker J. Bigeminy and the bifid papillary muscle. Cardiovasc Ultrasound 2010;8:13. https://doi.org/10.1186/1476-7120-8-13; PMID: 20409312. 10. Peichl P, Baran J, Wichterle D, et al. The tip of the muscle is a dominant location of ventricular ectopy originating from papillary muscles in the left ventricle. J Cardiovasc Electrophysiol 2018;29:64–70. https://doi.org/10.1111/jce.13338; PMID: 28884872. 11. Hai, SHJJ, DeSimone, CV, Vaidya VR, Asirvatham, SJ. Endocavitary structures in the outflow tract: anatomy and electrophysiology of the conus papillary muscles. J Cardiovasc Electrophysiol 2014;25:94–8. https://doi.org/10.1111/jce.12291; PMID: 24102678. 12. Al’Aref SJ, Ip JE, Markowitz SM, et al. Differentiation

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of papillary muscle from fascicular and mitral annular ventricular arrhythmias in patients with and without structural heart disease. Circ Arrhythm Electrophysiol 2015;8:616–24. https:// doi.org/10.1161/CIRCEP.114.002619; PMID: 25925230. Yamada T, Doppalapudi H, McElderry HT, et al. Electrocardiographic and electrophysiological characteristics in idiopathic ventricular arrhythmias originating from the papillary muscles in the left ventricle: relevance for catheter ablation. Circ Arrhythm Electrophysiol 2010;3:324–31. https://doi. org/10.1161/CIRCEP.109.922310; PMID: 20558848. Good E, Desjardins B, Jongnarangsin K, et al. Ventricular arrhythmias originating from a papillary muscle in patients without prior infarction: A comparison with fascicular arrhythmias. Heart Rhythm 2008;5:1530–7. https://doi. org/10.1016/j.hrthm.2008.08.032; PMID: 18984528. Lian-Pin W, Yue-Chun L, Jing-Lin Z, et al. Catheter ablation of idiopathic premature ventricular contractions and ventricular tachycardias originating from right ventricular septum. PLoS ONE 2013; 8:e67038. https://doi.org/10.1371/journal. pone.0067038; PMID: 23825610. Santoro F, DI Biase L, Hranitzky P, et al. Ventricular tachycardia originating from the septal papillary muscle of the right ventricle: electrocardiographic and electrophysiological characteristics. J Cardiovasc Electrophysiol 2015;26:145–50. https://doi.org/10.1111/jce.12551; PMID: 25229319. Enriquez A, Pathak RK, Santangeli P, et al. Inferior lead discordance in ventricular arrhythmias: A specific marker for certain arrhythmia locations. J Cardiovasc Electrophysiol 2017;28:1179–86. https://doi.org/10.1111/jce.13287; PMID: 28677887. Abouezzeddine O, Suleiman M, Buescher T, et al. Relevance of endocavitary structures in ablation procedures for ventricular tachycardia. J Cardiovasc Electrophysiol 2010;21:245–54. https:// doi.org/10.1111/j.1540-8167.2009.01621.x; PMID: 19817930. Madhavan M, Asirvatham SJ. The fourth dimension: endocavitary ventricular tachycardia. Circ Arrhythm Electrophysiol 2010;3:302–4. https://doi.org/10.1161/CIRCEP.110.958280; PMID: 20716720. Yokokawa M, Good E, Desjardins B, et al. Predictors of successful catheter ablation of ventricular arrhythmias arising from the papillary muscles. Heart Rhythm 2010;7:1654–9. https://doi.org/10.1016/j.hrthm.2010.07.013; PMID: 20637311. Yamada T, McElderry HT, Doppalapudi H, Kay GN. Realtime integration of intracardiac echocardiography and electroanatomic mapping in PVCs arising from the LV anterior papillary muscle. Pacing Clin Electrophysiol 2009;32:1240–3. https://doi.org/10.1111/j.1540-8159.2009.02472.x; PMID: 19719506. Proietti R, Rivera S, Dussault C, et al. Intracardiac echofacilitated 3D electroanatomical mapping of ventricular arrhythmias from the papillary muscles: assessing the ‘fourth dimension’ during ablation. Europace 2017;19:21–8. https://

doi.10.1093/europace/euw099; PMID: 27485578. 23. N akahara S, Toratani N, Takayanagi K. Catheter ablation of ventricular tachycardia originating from the left posterior papillary muscle guided by the shadow of a multipolar catheter. Indian Pacing Electrophysiol J 2012;12:186–9. https://doi.org/10.1016/S0972-6292(16)30525-3; PMID: 22912539. 24. Chang YT, Lin YJ, Chung FP, et al. Ablation of ventricular arrhythmia originating at the papillary muscle using an automatic pacemapping module. Heart Rhythm 2016;13:1431–40. https://doi.org/10.1016/j.hrthm.2016.03.017; PMID: 27324561. 25. Wo HT, Liao FC, Chang PC, et al. Circumferential ablation at the base of the left ventricular papillary muscles: A highly effective approach for ventricular arrhythmias originating from the papillary muscles. Internat J Cardiol 2016;220:876–82. https://doi.org/10.1016/j.ijcard.2016.06.151; PMID: 27400187. 26. Kawakami H, Noda T, Miyamoto K, et al. Successful catheter ablation of idiopathic ventricular tachycardia originating from the top of the left ventricular posterior papillary muscle near the chordae tendineae: Usefulness of intracardiac three-dimensional echocardiography. HeartRhythm Case Rep 2015;1:110–3. https://doi.org/10.1016/j.hrcr.2014.12.011; PMID: 28491524. 27. Yamabe H, Miyazaki T, Takashio S, et al. Radiofrequency energy induced ventricular fibrillation in a case of idiopathic premature ventricular contraction originating from the left ventricular papillary muscle. Intern Med 2010;49:1863–6. https://doi.org/10.2169/internalmedicine.49.3618; PMID: 20823646. 28. Rivera S, Ricapito Mde L, Tomas L, et al. Results of cryoenergy and radiofrequency-based catheter ablation for treating ventricular arrhythmias arising from the papillary muscles of the left ventricle, guided by intracardiac echocardiography and image integration. Circ Arrhythm Electrophysiol 2016;9:e003874. https://doi.org/10.1161/CIRCEP.115.003874; PMID: 27069089. 29. Gordon JP, Liang JJ, Pathak RK, et al. Percutaneous cryoablation for papillary muscle ventricular arrhythmias after failed radiofrequency catheter ablation. J Cardiovasc Electrophysiol 2018;29:1654–63. https://doi.org/10.1111/ jce.13716; PMID: 30106213. 30. Mochizuki A, Nagahara D, Takahashi H, et al. Worsening of mitral valve regurgitation after radiofrequency catheter ablation of ventricular arrhythmia originating from a left ventricular papillary muscle. Heart Rhythm Case Rep 2017;3:215–8. https://doi.org/10.1016/j.hrcr.2017.01.003; PMID: 28491805. 31. Desimone CV, Hu T, Ebrille E, et al. Catheter ablation related mitral valve injury: the importance of early recognition and rescue mitral valve repair. J Cardiovasc Electrophysiol 2014;25:971–5. https://doi.org/10.1111/jce.12439; PMID: 24758402.

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Drugs and Devices

Introducing Vernakalant into Clinical Practice Angela JM Hall and Andrew RJ Mitchell Department of Cardiology, Jersey General Hospital, Jersey, Channel Islands

Abstract Vernakalant is an antiarrhythmic drug licensed for the pharmacological cardioversion of recent onset AF. Randomised clinical trials, backed up by real-world experience, have confirmed its efficacy at restoring sinus rhythm. Vernakalant can be administered simply with a short time to action, facilitating early discharge from hospital in selected patients in place of electrical cardioversion. The authors explore the data behind vernakalant and discuss how it can be introduced into clinical practice.

Keywords AF, vernakalant, cardioversion, antiarrhythmic drugs Disclosure: The authors have no conflicts of interest to declare. Received: 29 November 2018 Accepted: 24 January 2019 Citation: Arrhythmia & Electrophysiology Review 2019;8(1):70–4. DOI: https://doi.org/10.15420/aer.2018.71.2 Correspondence: Angela Hall, Department of Cardiology, Jersey General Hospital, Gloucester Street, St Helier, Jersey JE1 3QS, Channel Islands. E: an.hall@health.gov.je Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

AF is the most common clinical arrhythmia, affecting at least 1–2% of the population.1,2 Its prevalence increases with age, with 5% of people aged over 65 years developing AF, climbing to 8% in those aged over 75 years.3 AF is associated with increased morbidity and mortality and has significant public health implications.4 Patients presenting with new onset AF to emergency departments can be managed in a number of different ways, depending on the clinical scenario. In general, either a rate control or rhythm control strategy is chosen. When an early rate control strategy is selected, the options are either electrical cardioversion under sedation or to use a pharmacological agent to facilitate chemical cardioversion. The European Society of Cardiology 2016 guidelines recommend the use of flecainide, amiodarone, propafenone, ibutilide or vernakalant for pharmacological cardioversion, with the choice of agent guided by the presence of any underlying heart disease (Figure 1).5

of about 3 hours and up to 8 hours in poor metabolisers.9 Peak plasma concentrations are evident at the end of the 10-minute infusion but fall rapidly at the end of infusion. Vernakalant is contraindicated when:

Vernakalant is an atrial-selective compound that rapidly blocks potassium and sodium ion channels in all phases of the atrial action potential.6 Potassium currents that are expressed specifically in the atria and involved in atrial repolarisation are blocked before the secondary effect of sodium channels inhibition. Vernakalant is unique among antiarrhythmic drugs because its affinity for the activated sodium channel becomes greater as heart rate increases.7 The pharmacological profile of vernakalant addresses many problems of other antifibrillatory drugs by selectively targeting ion channels that are expressed primarily in atrial cardiomyocytes. Blocking the rapidly activating potassium current accounts for only mild QT prolongation and this rapidly returns to baseline after cessation of the infusion.8

Vernakalant is not recommended in patients with:

• systolic blood pressure is <100 mmHg; • severe aortic stenosis or heart failure (New York Heart Association [NYHA] Class III and IV) is present; • an acute coronary syndrome has occurred within the previous 30 days; or • there is QT prolongation >440 msec. Vernakalant should also be avoided when intravenous Class I and III antiarrhythmic drugs have been administered within the previous 4 hours. Prior to its administration, patients should be adequately hydrated with a normal potassium level.

• • • • •

left ventricular ejection fraction <35%; hypertrophic obstructive cardiomyopathy; restrictive cardiomyopathy or constrictive pericarditis; advanced hepatic impairment; or clinically meaningful valvular stenosis.

Safety Profile

There is insufficient data relating to the administration of vernakalant if Class I or III intravenous antiarrhythmic drugs have been given between 4 and 24 hours prior to use. Furthermore, vernakalant should be used with caution in patients with NYHA Class I and II heart failure due to the increased risk of hypotension and non-sustained ventricular arrhythmias.

The pharmacokinetic profile of vernakalant demonstrates rapid distribution with a short half-life, so therefore it is less likely to cause drug– drug interactions.7 Vernakalant is metabolised by the liver with a half-life

The Atrial arrhythmia Conversion Trial (ACT V; NCT00989001) Phase IIIb study of vernakalant in patients with recent onset symptomatic AF

Access at: www.AERjournal.com

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Vernakalant in Clinical Practice Figure 1: Rhythm Control Management of Recent Onset AF Recent onset AF Yes

Haemodynamic instability? Elective

Patient choice

Pharmacological cardioversion Urgent

Electrical cardioversion (class IB)

Severe HFrEF, significant aortic stenosis

Coronary artery disease, moderate HFrEF or HFmrEF/HFpEF, abnormal LVH

IV amiodarone (class IA)

IV vernakalant (class IIbB) IV amiodarone (class IA)

No relevant structural heart disease

IV flecainide (class IA) IV ibutilide (class IIaB)* IV propafenone (class IA) IV vernakalant (class IA)

Pill in the pocket: Flecainide (class IIaB) Propafenone (class IIaB)

* Ibutilide should not be used in patients with long QT interval. HFmrEF = heart failure with mid-range ejection fraction; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; LVH = left ventricular hypertrophy. Source: Kirchoff et al.5 Reproduced with permission from Oxford University Press.

was stopped 2010 after a single serious case of cardiogenic shock following infusion of vernakalant, although it was not certain that the drug was involved. This was unpublished, and the ACT V study was discontinued. As a result, the European Medicines Agency updated the listed contraindications.10 In a pooled analysis of safety data, 773 patients who received vernakalant and 335 who had placebo in the ACT I–IV, Conversion of Rapid AF Trial (CRAFT) and Phase II/III Tolerance and Efficacy Study of RSD1235 in Patients With Atrial Flutter (Scene 2) studies, demonstrated vernakalant to be well tolerated without clinically relevant adverse events compared with placebo or amiodarone.7,11 Serious adverse events related to medication administration was reported in 2.1% of people receiving vernakalant, compared to 0.3% of those receiving placebo.11 Hypotension as a serious event was reported in 1.2% versus 0.3% in the placebo group and when this occurred in the first 2 hours it was most common in patients with heart failure.11 Bradycardia was slightly more common in the vernakalant group, but rarely led to discontinuation of the drug. There was no significant effect on the ventricular rate during AF while receiving vernakalant and neither was there no excess in ventricular arrhythmias compared to placebo. Non-sustained ventricular arrhythmias were, however, more prevalent in the presence of heart failure and hence the cautionary use in this group (7.3% versus 1.6% in placebo at 2 hours).11 The most commonly reported side-effects are shown in Table 1. In the above pooled safety data, taste disturbance, sneezing, paraesthesia and nausea were most commonly reported; these are believed to be secondary to the effects on sodium channels in the central nervous system.11

AF continues after a 15-minute observation time, the infusion can be repeated at a slightly lower dose. Vernakalant should be given in a suitable environment, that is, one with emergency and defibrillation equipment available. Ideally, an echocardiogram should be performed prior to administration, or information from a recent scan available, to ensure that there are no structural contraindications for the use of vernakalant. An electrocardiogram in AF and another after cardioversion has taken place is also advisable. One vial of vernakalant is sufficient for both infusions if needed, and if the infusion is well tolerated and can be given peripherally. A condensed version of the protocol for administration is shown in Figure 2.

Clinical Trials The efficacy of vernakalant was researched in a single dose finding trial, three randomised placebo-controlled phase III trials, one randomised active-controlled trial with amiodarone, and a phase IV open-label study (Table 2).12–18 The ACT I and III trials showed vernakalant was significantly more effective than the placebo in converting AF of short duration (>3 hours to ≥7 days; 51.7% versus 4%; p<0.001; and 51.2% versus 3.6%; p<0.0001).14,15 When compared to amiodarone, vernakalant was more effective in achieving cardioversion of short duration AF (3–48 hours) within 90 minutes of drug infusion.12 The median time to conversion was 11 and 8 minutes, respectively, in the ACT I and III studies and rates of conversion was highest when the AF was of a duration ≤48 hours (62.1% versus 4.9%; p<0.001). The ACT IV study complemented this data and demonstrated restoration of sinus rhythm with vernakalant in 50.9% within 14 minutes.16

Administration Vernakalant is administered intravenously as a weight-calculated dose and infused over 10 minutes. The patient requires continuous cardiac monitoring throughout with close observation of vital signs. If

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The ACT II study focused on post-cardiac surgery patients – coronary artery bypass or valvular surgery – who developed AF for between 24 hours and 7 days.13 Sinus rhythm was achieved in 47% versus

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Drugs and Devices Table 1: Side-effects Reported With Vernakalant Very common

Common

Uncommon

• Dysgeusia • Sneezing

• • • • • • • •

• • • • • • • • • • • • •

Dizziness Headache Paraesthesia Bradycardia Hypotension Cough Nausea and vomiting Pruritus

Vasovagal syncope Eye irritation Visual impairment Sinus arrest Complete heart block LBBB/RBBB Ventricular tachycardia Ventricular ectopics Prolonged QT Flushing Dyspnoea Diarrhoea Infusion site irritation

LBBB = left bundle branch block; RBBB = right bundle branch block.

Figure 2: Protocol for IV Administration of Vernakalant

• Dilute to a concentrate of 4 mg/ml (with 0.9% sodium chloride or 5% glucose) • Dose calculated according to weight:* ≤100 kg: 25 ml of vernakalant 20 mg/ml in 100 ml of diluent ≥100 kg: 30 ml of vernakalant 20 mg/ml in 120 ml of diluent • Recommended initial infusion: 3 mg/kg over 10 min

Sinus rhythm Continue infusion until complete, then stop

Sinus rhythm After the second infusion, if the patient converts to sinus rhythm, then stop

AF or flutter

*Doses apply to weight 40–113 kg. For patients ≥113 kg, the maximum initial dose is 339 mg (84.7 ml of 4 mg/ml solution) over 10 minutes. The second infusion must not exceed 226 mg (56.5 ml) over 10 minutes.

14% in the placebo group within 90 minutes (p<0.001) with a median conversion time of 12 minutes. The Vernakalant vs Amiodarone in Recent Onset AF (AVRO) comparison trial between amiodarone and vernakalant, including patients with AF duration of 3–48 hours, resulted in 51.7% versus 5.2% conversion within 90 minutes, with the highest conversion rates in the vernakalant group (p<0.0001).12 Two further non-randomised studies compared vernakalant to flecainide (oral, 300 mg single dose) or propafenone (600 mg) in shorter duration AF of <48 hours.19,20 Cardioversion in the vernakalant groups were higher with 86–93% in sinus rhythm at 2 hours compared to 78% in the flecainide and propafenone groups at 8 hours. Cardioversion was also considerably quicker with vernakalant (9–10 minutes versus 163–166 minutes). Hospital stay was shorter in the vernakalant group.

Post-marketing Studies Post-marketing studies have identified high cardioversion success rates. A real-world study included patients of AF onset ≤48 hours demonstrated 84.5% conversion to sinus rhythm with mean time to

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conversion 9 minutes and total hospital stay averaging 165 minutes.21 The retrospective Malmö registry evaluated the median conversion time to be 11 minutes and 76% of patients converted to sinus rhythm when the AF duration was <10 hours compared to 66% when the AF was >10 hours.22 A retrospective single-centre, single-arm study, reported 86% successful cardioversions with vernakalant and a median time of 8 minutes.23 Post-marketing comparison trials have shown promising results when comparing vernakalant to other antiarrhythmic drugs. A nonrandomised retrospective study compared vernakalant to flecainide, with 100 participants in each group and an endpoint of conversion to sinus rhythm within 120 minutes.24 Cardioversion success was 67% in the vernakalant group versus 46% in the flecainide group. Patients in the vernakalant group were older with higher CHA2DS2-VASc scores, yet there was no difference in complication rates. A previous small, sequential study that also comparedoral flecainide to vernakalant demonstrated time to conversion of 163 minutes with flecainide versus 10 minutes with vernakalant.19 Vernakalant was compared to ibutilide in a recent trial, demonstrating similar conversion rates (52.78% versus 52.38% respectively), but more rapid average conversion time (11.8±4.3 minutes versus 33.9±20.25 minutes; p<0.0001).25 A greater number of patients in the vernakalant group were ready for discharge at 2 hours, compared to the ibutilide group (38.89% versus 11.9%, respectively).25 This further demonstrates the benefits of rapid conversion, including negating the need for electrical cardioversion, reduction in length of hospital stay, not needing concomitant treatments or longer-term antiarrhythmics, and a reduced risk of AF relapse. An earlier study also compared vernakalant and ibutilide, with similar reults.26 Conversion time to sinus rhythm was shorter in the vernakalant group (median 10 minutes versus 26 minutes, p=0.01), and the conversion success within 90 minutes was significantly higher in the vernakalant group (69% versus 43%, logrank p=0.002). 26 More patients converted prior to administration of the second infusion in the vernakalant group and fewer patients in the vernakalant group needed electrical cardioversion (13 versus 26 patients in the ibutilide group). Vernakalant was compared to electrical cardioversion in a retrospective study by Heikkola et al.27 The vernakalant group (n=197) had lower numbers to successful conversion (66.5%) than the electrical cardioversion group (n=199; 94%). However, the vernakalant group were discharged sooner, with lower rates of AF recurrence at 1-year follow-up (36% versus 63%).27 A contemporary real-world study in Belgium evaluated 97 patients in the emergency department during 2017 and 2018 and concluded that 85.4% of patients avoided hospitalisation (95% CI [76.1–94.8]). The majority of treated patients (84.1%) did not need electrical cardioversion.28

Licence The EU approved vernakalant in 2010 for the cardioversion of AF of less than 7 days in duration, or for post-operative AF less than 3 days in duration. Vernakalant has been marketed in some, but not all European countries. Other countries, notably in Asia, have also approved the drug.10

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Vernakalant in Clinical Practice Table 2: The Efficacy of Vernakalant for Conversion of AF to Sinus Rhythm Study

Design

AF Duration

Time to Conversion (Median)

Conversion to Sinus Rhythm Versus Placebo or Control

ACT I17

Double-blind, placebo controlled

336

3 hours to 45 days

11 min

51.7% versus 4%

ACT II13

Double-blind, placebo controlled

160

3–72 hours

12 min

47% versus 14%

ACT III

Double-blind, placebo controlled

265

3 hours to 45 days

8 min

51.2% vs 3.6%

ACT IV16

Open label

167

3 hours to 45 days

14 min

50.9%

AVRO12

Double-blind, active controlled

232

3–48 hours

11 min

51.7% versus 5.2%

CRAFT

Randomised controlled trial, double blind

3–72 hours

14 min

61% versus 5% (within 30 min)

Randomised controlled trial, double blind

3 hours to 45 days (atrial flutter)

SCENE 218

Cost Vernakalant is more expensive than other antiarrhythmic medicines, e.g. amiodarone and flecainide.25 A costing analysis was undertaken by Vogiatzis et al. in their trial comparing vernakalant with ibutilide.25 The ibutilide group were less likely to leave hospital at 2 hours and therefore incurred higher costs in terms of subsequent management and hospitalisation. While vernakalant is five to six times more expensive than ibutilide, the overall treatment costs were lower in the vernakalant group due to fewer adverse effects and shorter hospital stays. This is supported by the studies mentioned above, where more rapid discharge occurs due to successful early cardioversion with vernakalant, and it can be further supported by local audit data.

Local Use and Audit In the British Isles, vernakalant was introduced in the Channel Island of Jersey in 2016, following approval from the local drugs and therapeutics committee. This involved production of robust protocols and policy. Review of the evidence and real-world data was necessary in order to inform our colleagues in relation to medicines governance and the practical aspects of implementation. Education and communication were central to this and has enabled a safe and effective process. An on-going audit demonstrates an 87% success rate in the conversion from recent onset AF to sinus rhythm. There have been no serious untoward events, although a small number of patients have experienced sneezing as a side-effect. Vernakalant has mostly been used in the emergency department, although two patients were treated in the high dependency unit and later discharged home. Of the 87% who reverted to sinus rhythm, all were discharged home at 2 hours. The remaining patients were either discharged home in rate-controlled AF, with one patient admitted for overnight observation due to a slightly

o AS, Hylek EM, Philips KA, et al. Prevalence of diagnosed G atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study. JAMA 2001;285:2370–5. https://doi.org/10.1001/JAMA.285.18.2370; PMID: 11343485. Lip GY, Tse HF, Lane DA. Atrial fibrillation. Lancet 2012;379: 648–61. https://doi.org/10.1016/S0140-6736(11)61514-6; PMID: 22166900. Naccarelli GV, Varker H, Lin J, Schulman KL. Increasing prevalence of atrial fibrillation and flutter in the United States. Am J Cardiol 2009;104:1534–9. https://doi.org/10.1016/ j.amjcard.2009.07.022; PMID: 19932788. Krijthe BP, Kunst A, Benjamin EJ, et al. Projections on the number of individuals with atrial fibrillation in the European Union, from 2000 to 2060. Eur Heart J 2013;34:2746–51. https:// doi.org/10.1093/eurheartj/eht280; PMID: 23900699. Kirchoff P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 2016;37:2893–962. https:// doi.org/10.1093/eurheartj/ehw210; PMID: 27567408. Fedida D, Orth PM, Chen JY, et al. The mechanism of atrial

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10.

11.

3% versus 0%

elevated heart rate in AF. All patients were seen at 4 weeks in the local arrhythmia clinic and at follow-up, 87% of patients remained in sinus rhythm with no AF recurrence. Protocols and algorithms produced for the implementation of vernakalant have been shared with 10 centres in the UK, whom are making their own applications to obtain this novel antiarrhythmic.

Conclusion Vernakalant offers a novel approach to pharmacological cardioversion. Ease of administration and success rates for the conversion of recent onset AF encourage utilisation, particularly in the emergency department and acute care settings. The safety profile is reassuring as long as patients are selected appropriately. Post-marketing studies continue to be conducted with systematic reviews and meta-analysis published, demonstrating continued efficacy and overall effectiveness.

Clinical Perspective • AF is increasing in prevalence and is a frequent cause of hospital attendance. • Vernakalant is an antiarrhythmic drug licensed for pharmacological cardioversion of recent onset AF. • Vernakalant is administered via an IV infusion in a monitored, clinical environment and is safe and effective in the cardioversion of recent onset AF. • Clinical trials and real-world data support international guidelines recommending vernakalant as a treatment of choice in selected patients with AF. • When rhythm control is required, vernakalant offers a novel approach to facilitating rapid pharmacological conversion to sinus rhythm.

antiarrhythmic action of RSD1235. J Cardiovasc Electrophysiol 2005;16:1227–38. https://doi.org/10.1111/j.1540-8167. 2005.50028.x; PMID: 16302909. Savelieva I, Graydon R, Camm, AJ. Pharmacological cardioversion of atrial fibrillation with vernakalant: evidence in support of the ESC Guidelines. Europace 2014;16:162–73. https://doi.org/10.1093/europace/eut274; PMID: 24108230. Dorian P, Pinter A, Mangat I, et al. The effect of vernakalant (RSD1235), an investigational antiarrhythmic agent, on atrial electrophysiology in humans. J Cardiovasc Pharmacol 2007;50:35– 40. https://doi.org/10.1097/FJC.0b013e3180547553; PMID: 17666913. Mao Z, Wheeler JJ, Clohs L, et al. Pharmacokinetics of novel atrial selective antiarrhythmic agent vernakalant hydrochloride injection (RSD1235): influence of CYP2D6 expression and other factors. J Clin Pharmacol 2009;49:17–29. https://doi.org/10.1177/0091270008325148; PMID: 18927241. Camm AJ. The vernakalant story: how did it come to approval in Europe and what is the delay in the U.S.A? Curr Cardiol Rev 2014;10:309–14. https://doi.org/10.2174/157340 3X10666140513103709; PMID: 24821654. European Medicines Agency. Assessment Report for Brinavess.

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International Nonproprietary Name: Vernakalant. London: European Medicines Agency; 2011. Available at: https://www.ema. europa.eu/docs/en_GB/document_library/EPAR_-_Public_ assessment_report/human/001215/WC500097150.pdf (accessed 18 February 2019). Camm AJ, Capucci A, Hohnloser SH, et al. A randomized active-controlled study comparing the efficacy and safety of vernakalant to amiodarone in recent-onset atrial fibrillation. J Am Coll Cardiol 2011;57:313–21. https://doi.org/10.1016/ j.jacc.2010.07.046; PMID: 21232669. Kowey P, Dorian P, Mitchell L, et al. Vernakalant hydrochloride for the rapid conversion of atrial fibrillation after cardiac surgery: a randomized, double-blind, placebo-controlled trial. Circ Arrhythm Electrophysiol 2009;2:652–9. https://doi. org/10.1161/CIRCEP.109.870204; PMID: 19948506. Pratt CM, Roy D, Torp-Pedersen C, et al. Usefulness of vernakalant hydrochloride injection for rapid conversion of atrial fibrillation. Am J Cardiol 2010;106:1277–83. https://doi. org/10.1016/j.amjcard.2010.06.054; PMID: 21029824. Roy D, Rowe BH, Stiell IG, et al. A randomised controlled trial of RSD1235, a novel antiarrhythmic agent, in the treatment of recent onset atrial fibrillation. J Am Coll Cardiol 2004;44:2355–61.

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Drugs and Devices https://doi.org/10.1016/j.jacc.2004.09.021; PMID: 15607398. 16. S tiell IG, Roos JS, Kavanagh KM, et al. A multicenter, openlabel study of vernakalant for the conversion of atrial fibrillation to sinus rhythm. Am Heart J 2010;159:1095–101. https://doi.org/10.1016/j.ahj.2010.02.035; PMID: 20569725. 17. Roy D, Pratt CM, Torp-Pederson C, et al. Vernakalant hydrochloride for rapid conversion of atrial fibrillation: a phase 3, randomized, placebo-controlled trial. Circulation 2008;117:1518–25. https://doi.org/10.1161/ CIRCULATIONAHA.107.723866; PMID: 18332267. 18. Camm AJ, Toft E, Torp-Pederson C, et al. Efficacy and safety of vernakalant in patients with atrial flutter: a randomized, double-blind, placebo-controlled trial. Europace 2012;14:804–9. https://doi.org/10.1093/europace/eur416; PMID:22291438. 19. Conde D, Costabel JP, Caro M, et al. Flecainide versus vernakalant for conversion of recent-onset atrial fibrillation. Int J Cardiol 2013;168:2423–5. https://doi.org/10.1016/ j.ijcard.2013.02.006; PMID: 23518212. 20. Conde D, Costabel J, Aragon M, et al. Propafenone versus vernakalant for conversion of recent-onset atrial fibrillation.

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21.

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Cardiovasc Ther 2013;31:377–80. https://doi.org/10.1111/17555922.12036; PMID: 23683253. Costabel J, Lambardi F, Aragon M, et al. Predictors of conversion of recent-onset atrial fibrillation treated with vernakalant. Pacing Clin Electrophysiol 2015;38:196–200. https:// doi.org/10.1111/pace.12548; PMID: 25469647. Juul-Möller S. Vernakalant in recently developed atrial fibrillation: how to translate pharmacological trials into clinical practice. European Journal of Cardiovascular Medicine 2013;2:226–33. Cosin-Sales J, Loscos A, Peiro A, et al. Real-world data on the efficacy of vernakalant for pharmacological cardioversion in patients with recent-onset atrial fibrillation. Rev Esp de Cardiol 2016;69:619–20. https://doi.org/10.1016/j.rec.2016.02.020; PMID: 27131972. Pohjantahti-Maaroos H, Hyppola H, Lekkala M, et al. Intravenous vernakalant in comparison with intravenous flecainide in the cardioversion of recent-onset atrial fibrillation. Eur Heart J Acute Cardiovasc Care 2017;1:204887261772855. https://doi. org/10.1177/2048872617728558; PMID: 28849946.

25. V ogiatzis I, Papavasiliou E, Dapcevitch I, et al. Vernakalant versus ibutilide for immediate conversion of recent-onset atrial fibrillation. Hippokratia 2017:21:67–73. PMID: 30455558. 26. Simon A, Niederdoeckl J, Skyllouriotis E, et al. Vernakalant is superior to ibutilide for achieving sinus rhythm in patients with recent-onset atrial fibrillation: a randomised controlled trial at the emergency department. Europace 2017:19:233–40. https://doi.org/10.1093/europace/euw052; PMID: 28175295. 27. Heikkola, A, Pohjantahti H, Sinisalo E, et al. Comparison of intravenous vernakalant and electrical cardioversion in recent-onset atrial fibrillation: effect on time to restore sinus rhythm and length of hospital stay. Eur Heart J 2017;38(Suppl 1):ehx504.P3632. https://doi.org/10.1093/eurheartj/ehx504. P3632. 28. Correvio Pharma Corp. Correvio announces EU survey data demonstrating Brinavess successfully avoided hospitalization in 85% of patients. Vancouver: Correvio, 2018. Available at: https://correvio.com/wp-content/uploads/2018/08/2018-0816-CORV-Brinavess-in-Belgium-Final-Clean-1.pdf (accessed 8 February 2019).

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The British Heart Rhythm Society is proud to partner AER in its effort to inform, educate and support clinicians with an interest in heart rhythm management.

We would encourage readers to become members. Membership is only £60 a year (£40 for nurse or trainee members). By joining the BHRS you are both supporting and being a member of the British heart rhythm community. You also have the following benefits:

Access to BHRS members areas on the website. This contains:

• Educational material like our monthly ECG and electrograms cases • Business cases, job descriptions and standard operating procedures – why do the work yourself when another member has already done it for you? • Slide presentations

Representation at the top level of UK and European health care.

The BHRS has advises the UK government on health care issues, training and policy related to heart rhythm care. We have a seat on the European Heart Rhythm Association national society working groups and the British Cardiovascular Society • Cardiac physiologist influence and representation at the Academy of Healthcare Science (AHCS), National School of Healthcare Science (NSHCS) and Improving Quality in Physiological Services (IQIPS) professional boards • Gaining and maintaining BHRS certification in Devices, Electrophysiology and Nursing/Clinical certification • Discounted rates for Heart Rhythm Congress (Membership fee is taken off the registration fee to attend) • A chance to influence BHRS by voting in council elections, and standing for office (council minutes are published openly on our website) • Access and support from a multidisciplinary council with the ability to raise concerns and voice opinion regardless of profession. We also regularly offer advice to our members who have professional concerns or challenges

To become a member go to our website http://www.bhrs.com/how-to-join

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